Articoli di riviste sul tema "MIRAGES-2"

This article discusses the image of Kaunas as a city of love, which is noticeable in different narratives: novels The Novel of Kaunas (1973) by Alfonsas Bieliauskas and Tūla (1993) by Jurgis Kunčinas, the social advertisement “Wherever I Am: Kaunas Is My Hometown” by Monika Vilčinskienė (2008) and the representative Kaunas video “Kaunas Is Sharing Love” by the Studio of Kaunas Cinema (2013). The concept of “narrative as a socially symbolic act” (Fredric Jameson) and the concept of “chronotope” (Mikhail Bakhtin) help to analyse emerging images of the city. The investigation reveals that all the narratives represent: 1) love for Kaunas, 2) a city where people are (happily or unhappily) in love, 3) personified city, which is in love. This shows the mark of love which is significant in the whole narrative of Kaunas. However, different modes of art production propose different mirages of this city. The chronotope of unhappy love is noticeable in the novels representing soviet Kaunas, while the chronotope of idyllic city is very bright in non-literary narratives representing current Kaunas.

Self-gravitational structure formation theory for astrophysics and cosmology is revised using nonlinear fluid mechanics. Gibson’s 1996–2000 theory balances fluid mechanical forces with gravitational forces and density diffusion with gravitational diffusion at critical viscous, turbulent, magnetic, and diffusion length scales termed Schwarz scales. Condensation and fragmentation occur for scales exceeding the largest Schwarz scale rather than LJ, the length scale introduced by Jeans in his 1902 inviscid-linear-acoustic theory. The largest Schwarz scale is often larger or smaller than LJ. From the new theory, the inner-halo 1021 m dark-matter of galaxies comprises ∼105fossil-LJ-scale clumps of 1012 Earth-mass fossil-LSV-scale planets called primordial fog particles (PFPs) condensed soon after the cooling transition from plasma to neutral gas, 300,000 years after the Big Bang, with PFPs tidally disrupted from their clumps forming the interstellar medium. PFPs explain Schild’s 1996 “rogue planets…likely to be the missing mass” of a quasar lens-galaxy, inferred from twinkling frequencies of the quasar mirages, giving 30 million planets per star. The non-baryonic dark matter is super-diffusive and fragments at large LSD scales to form massive outer-galaxy-halos. In the beginning of structure formation 30,000 years after the Big Bang, with photon viscosity values ν of 5×1026 m2 s−1, the viscous Schwarz scale matched the horizon scale LSV≈LH<LJ, giving 1046 kg proto-superclusters and finally 1042 kg proto-galaxies. Non-baryonic fluid diffusivities D∼1028 m2 s−1 from galaxy-outer-halo LSD scales 1022 m measured in a dense galaxy cluster by Tyson, J. A., and Fischer, P., 1995, “Measurement of the Mass profile of Abell 1689,” Ap. J., 446, pp. L55–L58, indicate non-baryonic dark matter particles must have small mass ∼10−35 kg to avoid detection. [S0098-2202(00)01504-2]

The article is devoted to the trends in the formation of the information space of quantum technologies. As an example, the information construction of the results of an experiment to achieve quantum supremacy at Google and discussions about this in the American IT community are considered.

Abstract MIRAGE syndrome is a multisystem disorder characterized by myelodysplasia, infections, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. Mutations in the sterile alpha motif domain containing 9 (SAMD9) gene which encodes a protein involved in growth factor signal transduction are thought to cause MIRAGE syndrome. SAMD9 mutations lead to an antiproliferative effect resulting in a multisystem growth restriction disorder. Though rare, a few patients with SAMD9 mutations were reported to have hydrocephalus and/or cerebellar hypoplasia on imaging. The neuropathologic features of MIRAGE syndrome have not been previously described. Here, we describe the postmortem neuropathologic examinations of 2 patients with a clinical diagnosis of MIRAGE syndrome and confirmed SAMD9 mutations. Common features included microcephaly, hydrocephalus, white matter abnormalities, and perivascular calcifications. One of the 2 cases showed marked cerebellar hypoplasia with loss of Purkinje and granule neurons as well as multifocal polymicrogyria and severe white matter volume loss; similar findings were not observed in the second patient. These cases demonstrate the variation in neuropathologic findings in patients with MIRAGE syndrome. Interestingly, the findings are similar to those reported in ataxia-pancytopenia syndrome caused by mutations in SAMD9L, a paralogue of SAMD9.

MIRAGE syndrome is a recently described congenital condition characterized genetically by heterozygous gain-of-function missense mutations in the growth repressor sterile alpha domain containing 9 (SAMD9) located on the arm of chromosome 7 (7q21.2). The syndrome is rare and is usually diagnosed in newborns and children with myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy, hence the acronym MIRAGE. The aims of this paper are (1) to present fetal ultrasound features in a case where MIRAGE syndrome was diagnosed prenatally and (2) to review the existing literature records on prenatal manifestations of MIRAGE syndrome. In our case, the fetus had severe early fetal growth restriction (FGR) with normal Doppler studies, atypical genitalia, oligohydramnios, and hyperechogenic bowel at the routine mid-gestation anomaly scan. Amniocentesis excluded infections and numeric or structural chromosomal abnormalities while whole exome sequencing (WES) of the fetal genetic material identified the specific mutation. Targeted testing in parents was negative, suggesting the “de novo” mutation in the fetus. We could not identify other specific case reports in the literature on the prenatal diagnosis of MIRAGE syndrome. In cases reported in the literature where the diagnosis of MIRAGE syndrome was achieved postnatally, there are mentions related to the marked FGR on prenatal ultrasound. Severe early-onset FGR with no other apparent cause seems to be a central prenatal feature in these babies, and WES should be offered, especially if there are other structural abnormalities. Prenatal diagnosis of MIRAGE syndrome is possible, allowing for reproductive choices, improved counseling of parents, and better preparation of neonatal care.

This study investigates the effects of fluoride-releasing bonding composites on the development of artificially created white spot lesions ex vivo. The severity of the lesions was estimated visually using the von der Fehr Caries Index. The integrated mineral loss of the lesions (Δz) was measured using micro-radiography/microdensitometry. The results of the visual assessment indicated that teeth bonded with Reliance® exhibited more Grade 2 lesions than expected. Teeth bonded with Mirage Dual Cure®, however, showed a high prevalence of teeth with no lesions (Grade 0) and few with Grade 2. Microdensitometric analysis found 17 subsurface lesions; 14 of these were in the non-fluoridated groups (Right-On® and Heliosit®), and 3 and 1 in the fluoridated groups (Reliance® and Mirage Dual Cure®), respectively. Lesion mineral content ranged from 64·93 to 20·43 per cent for Right-On®, from 32·53 to 26·72 per cent for Heliosit®, from 19·52 to 19·58 per cent for Reliance®, and 23·58 per cent for Mirage Dual Cure®. The results of this study suggest that fluoride-releasing composites may have a caries preventive effect around orthodontic brackets.

Introduction: Signaling through JAK1 and/or JAK2 is common among tumor and non-tumor cells within peripheral and cutaneous T cell lymphomas (PTCL and CTCL). We conducted a phase II study of the JAK1/2 inhibitor, ruxolitinib, in patients (pts) with PTCL and CTCL and assessed the predictive value of genetic, immunohistochemical (IHC) and multiparametric immunofluorescence (mIF) biomarkers of JAK/STAT pathway activation for ruxolitinib response. Methods: This is an investigator-initiated multi-center phase II study for pts with relapsed or refractory (RR) PTCL or CTCL following at least 1 systemic therapy. Biopsies from each patient were subjected to next-generation sequencing for JAK1, JAK2, STAT3, STAT5 and other relevant genes along with IHC assessment for phosphorylated STAT3 (pSTAT3). Pts enrolled into biomarker-defined cohorts: 1) activating JAK and/or STAT mutations (allele frequency of 0.1 or greater); 2) no JAK/STAT mutation but ≥ 30% pSTAT3 expression among tumor cells by IHC; or 3) neither. Pts received treatment with ruxolitinib 20 mg BID until progression and were assessed for response after cycles 2, 5 and every three cycles thereafter. Tissue samples collected at baseline, on-treatment, and at progression were collected and assessed by mIF (Vectra platform, HALO analysis) using markers specific for lymphoma subtype, macrophage activation, JAK/STAT and PI3 kinase signaling. Results: The study completed enrollment with 53 pts, including 18 in cohort 1, 14 in cohort 2, and 21 in cohort 3. Cohort 3 includes 10 pts for whom JAK/STAT characterization is pending. Disease histologies per cohort are detailed in table 1. Treatment-related serious adverse events included HSV-1 stomatitis (n=1), spontaneous bacterial peritonitis (n=1), febrile neutropenia (n=3), and herpes zoster (n=1). Additional grade 3 or 4 drug-related adverse events affecting >1 pt included neutropenia (n=13), anemia (n=8), thrombocytopenia (n=5), and lymphopenia (n=3). Among the 53 pts, 4 have not yet reached first response assessment and 1 withdrew consent following only 1 week of treatment; therefore 48 are evaluable for response. Among 48 pts, there were 3 (6%) complete responses, 8 (17%) partial responses, and 6 (12.5%) with cytopenia improvement and disease stabilization lasting more than 6 months (SD>6 mo). Overall response rate (ORR) was 23% and overall clinical benefit rate (CBR) (ORR plus SD>6 mo) was 35%. Median duration of response was 7.3 months (range 1.3-26.1 months). ORRs in cohorts 1, 2 and 3 were 28%, 31%, and 12% (cohorts 1&2 vs 3, p=0.28). CBRs in cohorts 1, 2 and 3 were 44%, 46%, and 18% (cohorts 1&2 vs. 3, p=0.07) (table 2). More frequent responses were observed in the following histologies: angioimmunoblastic T cell lymphoma, peripheral T cell lymphoma with T-follicular helper phenotype, T-cell prolymphocytic leukemia, and large granular lymphocyte leukemia (table 3). Nine pre-treatment biopsies were analyzed by mIF from 4 ruxolitinib responders and 5 non-responders. The most notable finding was that responders to ruxolitinib had markedly lower pS6 expression within tumor cells of pre-treatment biopsies (mean pS6 expression 9.03 +/- 4.8 vs 48.19 +/- 6.6 for nonresponders; p=0.0027). In a patient with prolonged CR on ruxolitinib, progression biopsy was characterized by a marked increase in tumor cell pS6 staining. Additional samples are being analyzed and updated results will be reported at the meeting. Conclusion: The JAK1/JAK2 inhibitor ruxolitinib is a well-tolerated and readily available therapy for pts with relapsed/refractory PTCL and CTCL. Among patients with IHC and/or genetic evidence of JAK/STAT activation, ruxolitinib has similar efficacy to approved agents for relapsed/refractory T-cell lymphoma. The association between pS6 expression and response to ruxolitinib suggests that active PI3K/mTOR signaling confers intrinsic and acquired resistance to ruxolitinib. Disclosures Moskowitz: ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Jacobsen:Acerta: Consultancy; Novartis: Research Funding; Astra-Zeneca: Consultancy; F. Hoffmann-LaRoche: Research Funding; Merck: Consultancy, Research Funding; Takeda: Honoraria; Pharmacyclics: Research Funding. Ruan:Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie company: Research Funding; Kite: Consultancy; Juno: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding. Geyer:Amgen: Research Funding; Dava Oncology: Honoraria. Noy:Medscape: Honoraria; Janssen: Consultancy; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Straus:Elsevier (PracticeUpdate): Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria. Dogan:Roche: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Weinstock:Celgene: Research Funding. Horwitz:Aileron: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Kura: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Trillium: Research Funding; Kyowa Hakko Kirin: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Miragen: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Forty-Seven: Research Funding; Portola: Consultancy; Miragen: Consultancy; Mundipharma: Consultancy; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Innate Pharma: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Astex: Consultancy; Astex: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kura: Consultancy; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Celgene: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Aileron: Research Funding; Forty-Seven: Research Funding; Innate Pharma: Consultancy; Forty-Seven: Research Funding; Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Portola: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Trillium: Research Funding; Aileron: Research Funding; Kura: Consultancy; Miragen: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Mundipharma: Consultancy; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy; Portola: Consultancy; Forty-Seven: Research Funding; Innate Pharma: Consultancy; Affimed: Consultancy; Affimed: Consultancy. OffLabel Disclosure: Off-label use of ruxolitinib for T-cell lymphoma will be discussed

BackgroundMyelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy (MIRAGE) syndrome is a recently described congenital disorder caused by heterozygous SAMD9 mutations. The phenotypic spectrum of the syndrome remains to be elucidated.Methods and resultsWe describe two unrelated patients who showed manifestations compatible with MIRAGE syndrome, with the exception of haematological features. Leucocyte genomic DNA samples were analysed with next-generation sequencing and Sanger sequencing, revealing the patients to have two de novoSAMD9 mutations on the same allele (patient 1 p.[Gln695*; Ala722Glu] and patient 2 p.[Gln39*; Asp769Gly]). In patient 1, p.Gln695* was absent in genomic DNA extracted from hair follicles, implying that the non-sense mutation was acquired somatically. In patient 2, with the 46,XX karyotype, skewed X chromosome inactivation pattern was found in leucocyte DNA, suggesting monoclonality of cells in the haematopoietic system. In vitro expression experiments confirmed the growth-restricting capacity of the two missense mutant SAMD9 proteins that is a characteristic of MIRAGE-associated SAMD9 mutations.ConclusionsAcquisition of a somatic nonsense SAMD9 mutation in the cells of the haematopoietic system might revert the cellular growth repression caused by the germline SAMD9 mutations (ie, second-site reversion mutations). Unexpected lack of haematological features in the two patients would be explained by the reversion mutations.

Abstract While the mirage method of boundary overlap correction has been shown to be unbiased, an emphasis on the case of circular inclusion zones has led to an ambiguity in its presentation in much of the literature. We present a clarification of the method and show that its incorrect application leads to bias. We further show that depending on the method of slope correction, the potential for bias extends to variable radius plot sampling. Correct application of the mirage method has implications for when plots should be reflected, and how borderline trees should be handled on the reflected plots. FOR. SCI. 47(2):242–245.

This study was concerned with an evaluation of fluoride release from commercially available orthodontic bonding composite resins, known as Reliance® and Mirage Dual Cure®, which are claimed to release ionic floride. Forty-eight premolar teeth had brackets bonded with four different composite resins—Mirage Dual Cure®, Reliance®, Right-on® and Heliosit®. They were then immersed in a demineralizing solution. The amount of fluoride released from the composites into the solution was measured. The results indicated that Mirage Dual Curereg; released statistically significant amounts of fluoride over the first 2 days. A similar pattern was noted with Reliance® albeit releasing a lesser amount. From the third day onwards, fluoride release levelled out to concentrations similar to those of the two control materials, Right-on® and Heliosit®(i.e. 0·09 ppm). Fluoride-releasing composite resins, therefore, failed to demonstrate any potential long-term fluoride release within the ex vivo model. Even in the short term, the amount of fluoride released was very small.

Introduction: Peripheral T-cell lymphomas (PTCL) represent a heterogeneous group of aggressive non-Hodgkin lymphomas, with suboptimal outcomes with conventional chemotherapy. Autologous hematopoietic stem cell transplant (AHCT) is a therapeutic strategy for patients in first remission. However, progression-free survival (PFS) after AHCT is only 36-45% (d'Amore et al JCO 2012, Reimer et al JCO 2009), signifying an unmet therapeutic need for improving outcomes post-transplant. Maintenance therapy after AHCT may improve PFS. Romidepsin is a histone deacetylase (HDAC) inhibitor that is FDA approved for the treatment of relapsed/refractory T-cell lymphoma, and is a potential option for maintenance therapy. We present the results of the first multicenter study to evaluate the PFS of patients receiving maintenance therapy after upfront AHCT in PTCL patients. Methods: This was a phase 2, open-label, multicenter, investigator-initiated study in adult patients with PTCL (Table 1). 25 patients transplanted in first complete response or first partial response (CR1 or PR1) (Cohort 1) were evaluable for the primary endpoint of 2-year PFS. We enrolled another cohort (n=8) with high-risk histologies in CR/PR1 (n= 1), or transplanted in CR/PR2 or later (n=7) (Cohort 2). Patients underwent AHCT with carmustine, etoposide, cytarabine and melphalan (BEAM) conditioning. Maintenance romidepsin 14 mg/m2 was initiated between days 42-80 post AHCT, and administered every other week through 6 months, every 3 weeks through 1 year and every 4 weeks from 1 year through 2 years post AHCT. The Kaplan-Meier method was used to estimate PFS. Desired 2-year PFS was 70%. Results: Table 1 lists patient and disease characteristics. In Cohort 1, median follow up was 13.8 months (3.5 - 54.1 mon). Estimated 2-year PFS was 49% (30 - 80, 95% CI) (Figure 1). Median PFS was 20.0 months (12.0- NA, 95% CI). In Cohort 2, median follow up was 23.2 months (range, 9.1 - 35.7 months). Median PFS was 13.9 months (5.6 - NA, 95% CI). Estimated 2-year PFS was 47% (21 - 100, 95% CI). Angioimmunoblastic T-cell lymphoma (AITL) patients represented the largest subgroup within the study. 2-year PFS of these patients in Cohort 1 was 44% (20-96, 95% CI). In Cohort 1, 16 patients are off therapy (9 for disease progression, 2 for toxicity, 2 for patient choice and 3 completed therapy). Across cohorts, 5 patients required dose reduction. 6 patients experienced ≥ grade 3 toxicity (neutropenia=4, anemia=2, thrombocytopenia=2 and lymphopenia=2). 8 serious adverse events (SAEs) occurred in 6 patients after romidepsin treatment (epistaxis, fever, febrile neutropenia, hypotension, fatigue, myalgia, generalized muscle weakness, dyspnea, and CMV retinitis). Grade 2 toxicities included dysgeusia (5), neutropenia (3), anorexia (2), atrial fibrillation (1), hematuria (1), nausea (1), and fatigue (1). Grade 1 toxicities included dysgeusia (7), fatigue (4), nausea (4), anorexia (2), constipation (2), diarrhea (1), neutropenia (1), thrombocytopenia (1), and vomiting (1). Conclusions: Maintenance romidepsin was overall well-tolerated without significant additional grade 3-4 toxicity. At first assessment, the estimated median 2-year PFS in Cohort 1 of 49% does not indicate PFS improvement with romidepsin maintenance. Enrollment is complete and 9 patients in Cohort 1 are still on treatment. Final PFS will be updated. Disclosures Khan: ASCO/Conquer Cancer Foundation sponsored by Gilead Sciences: Research Funding; Back Bay Life Science Advisors: Honoraria. Shustov:Seattle Genetics, Inc.: Research Funding. Shadman:Sound Biologics: Consultancy; Sunesis: Research Funding; ADC Therapeutics: Consultancy; BeiGene: Research Funding; Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy; Celgene: Research Funding; TG Therapeutic: Research Funding; Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Acerta Pharma: Research Funding; Astra Zeneca: Consultancy; Atara Biotherapeutics: Consultancy; Mustang Bio: Research Funding. Cassaday:Kite/Gilead: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Other: Spouse's disclosure: employment, stock and other ownership interests; Incyte: Research Funding. Ruan:AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie company: Research Funding; Juno: Consultancy; Kite: Consultancy. Moskowitz:Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Merck: Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding. Zelenetz:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Noy:Medscape: Honoraria; Janssen: Consultancy; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Straus:Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Elsevier (PracticeUpdate): Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Kumar:Seattle Genetics: Research Funding. Sauter:Celgene: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; GSK: Consultancy. Shah:Amgen: Research Funding; Janssen: Research Funding. Matasar:Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Merck: Consultancy, Equity Ownership; Juno Therapeutics: Consultancy; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Daiichi Sankyo: Consultancy; GlaxoSmithKline: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Other: Travel, accommodation, expenses. Van Besien:Miltenyi Biotec: Research Funding. Giralt:Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy. Horwitz:Mundipharma: Consultancy; Astex: Consultancy; Trillium: Research Funding; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy; Aileron: Research Funding; Miragen: Consultancy; Celgene: Consultancy, Research Funding; Kura: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Portola: Consultancy; ADCT Therapeutics: Research Funding; Innate Pharma: Consultancy; Affimed: Consultancy; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity/Verastem: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Innate Pharma: Consultancy; Kyowa Hakko Kirin: Consultancy; Seattle Genetics: Consultancy, Research Funding; Mundipharma: Consultancy; Affimed: Consultancy; Forty-Seven: Research Funding; Portola: Consultancy; Trillium: Research Funding; Affimed: Consultancy; Miragen: Consultancy; Astex: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Miragen: Consultancy; Astex: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kura: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty-Seven: Research Funding; Portola: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Kura: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Kura: Consultancy; Innate Pharma: Consultancy; Aileron: Research Funding; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Miragen: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Trillium: Research Funding; Kyowa Hakko Kirin: Consultancy; Forty-Seven: Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; Innate Pharma: Consultancy; ADCT Therapeutics: Research Funding. OffLabel Disclosure: Romidepsin has been FDA approved for the treatment of relapsed/refractory cutaneous T-cell lymphoma and has accelerated approval for treatment of relapsed/refractory peripheral T cell lymphoma. We are studying its use as maintenance therapy after autologous stem cell transplant.

Abstract Introduction & Objectives: MRG-106 is an oligonucleotide inhibitor of miR-155, a microRNA with a strong mechanistic link to CTCL. The goals of this first-in-human study are to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of MRG-106 in patients with mycosis fungoides (MF). Methods: This Ph 1 trial employs a dose-escalation design to evaluate the administration of MRG-106 via subcutaneous (SC) injection, 2-hour intravenous (IV) infusion, or IV rapid bolus injection (≤ 900 mg/dose). An additional cohort received intralesional injections (75 mg/dose) to evaluate tolerability and efficacy with local delivery. Subjects were required to have biopsy-proven MF stage I-III with plaque and/or tumor lesions. Subjects were permitted to remain on concurrent stable CTCL therapy. Subjects received 6 doses (SC/IV) in the first 26 days of the study followed by weekly or bi-weekly doses in patients who continued beyond the first cycle. Safety was monitored by physical exams, clinical laboratory tests, and assessment of adverse events (AEs). Immunophenotyping of peripheral blood was performed to measure the impact of MRG-106 on normal immune cell subsets. The PK properties of MRG-106 were compared between different routes of administration. The effect of MRG-106 on individual skin lesions or total skin disease was assessed by the Composite Assessment of Index Lesion Severity (CAILS) score or the modified Severity Weighted Assessment Tool (mSWAT), respectively. Biopsies were collected from all subjects treated by intralesional injection and from a subset of subjects in the SC/IV cohorts to assess molecular and cellular responses to MRG-106. Baseline miR-155 expression and changes in gene expression and T cell repertoire (T cell receptor sequencing) in response to MRG-106 treatment were assessed. Results: 24 subjects (18M/6F, median age 62 yrs) have been in the study for up to 10 months (as of 7/31/2017). 4 subjects received only intralesional doses; 2 subjects were enrolled into both the intralesional and SC cohorts. 18 subjects received only SC injections or IV infusions/bolus injections of MRG-106. 22/26 subjects completed the first treatment cycle per protocol; 2 subjects are on-going. 2 subjects discontinued: one due to progressive disease found shortly after enrollment, and one due to an AE of worsening pruritus (Grade 3), judged as a dose-limiting toxicity at 900 mg SC. The drug was otherwise well-tolerated: of the other 48 drug-related AEs, all were Grade 1 or 2. The MTD has not been reached. 23/24 subjects (95%) showed improvement in either the individually treated lesion (intralesional cohort) or total skin disease (SC/IV cohorts) as measured by maximal change in CAILS or mSWAT. In the SC/IV-infusion cohorts, 17/18 subjects had an improvement in mSWAT score; 9/18 subjects (50%) reached a PR defined as ≥ 50% reduction in mSWAT score. Of the 9 subjects who received MRG-106 for &gt; 1 cycle, 78% reached a PR, suggesting that longer treatment may provide greater benefit. Improvements in mSWAT scores were observed as early as Study Day 19 (the 1st post-treatment assessment), and for all but one subject, improvements from baseline were maintained through the treatment period. Based on immunophenotyping of peripheral blood, absolute numbers and proportions of subjects' leukocyte subpopulations were not significantly altered with MRG-106 treatment, with the exception of transient increases in NK and NK T cells observed only at the highest dose. TCR sequencing of pre- and post-treatment biopsies showed that T cell clonality decreased with intralesional injection of MRG-106. miR-155 was elevated in the lesions of most subjects, drug accumulation was observed with all routes of administration, and gene expression changes were associated with inactivation of the STAT, NFκB, and PI3K/AKT pathways. Conclusions: These preliminary results suggest that MRG-106 is well-tolerated and has clinical activity as indicated by meaningful reductions in CAILS and mSWAT assessments. Exploratory analyses of lesion biopsies support the clinical activity of MRG-106 with reductions in T cell clonality and gene expression changes consistent with the known mechanism of miR-155. These encouraging data support the continued investigation of MRG-106 in MF patients and expansion of the study to include additional hematological malignancies in which miR-155 is known to be elevated and relevant. Disclosures Querfeld: Medivir: Honoraria; Actelion: Honoraria, Research Funding; MiRagen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Elorac: Research Funding; Soligenix: Research Funding; Kyowa: Research Funding; Trillium Therapeutics: Research Funding; City of Hope: Employment; Mallinckrodt: Honoraria; Mindera: Consultancy. Foss: seattle genetics: Speakers Bureau; Eisai: Honoraria; spectrum: Honoraria, Speakers Bureau; immune design: Research Funding; celgene: Honoraria. Porcu: Tetralogic: Research Funding; Celgene: Research Funding; Cell Medica: Research Funding; Galderma: Research Funding; Kura: Research Funding; Innate Pharma: Research Funding; Miragen: Research Funding; Kiowa: Research Funding. Kim: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; miRagen: Research Funding; Merck: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Soligenix: Research Funding; Portola: Consultancy, Research Funding; Neumedicine: Research Funding; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Research Funding; Horizon Pharma: Consultancy, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Tetralogic: Research Funding; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Halwani: Kyowa Hikko Kirin: Research Funding; Bristol Myers Squib: Research Funding; Seattle Genetics: Research Funding; Roche/Genentech Inc.: Research Funding; Genetech Inc.: Research Funding; Takeda: Research Funding; Pharmacyclics: Research Funding; Amgen: Research Funding; AbbVie: Research Funding; Immune Design: Research Funding; Miragen: Research Funding. Seto: miRagen Therapeutics: Employment, Equity Ownership, Patents & Royalties: Inventor on patents. Pestano: Sanofi: Equity Ownership; Cascadian Therapeutics: Equity Ownership; miRagen Therapeutics: Employment, Equity Ownership. Jackson: miRagen Therapeutics: Employment, Equity Ownership. Williams: miRagen Therapeutics: Employment, Equity Ownership. Dickinson: miRagen Therapeutics: Employment, Equity Ownership. Ruckman: miRagen Therapeutics: Employment, Equity Ownership. Gordon: Syndax: Consultancy; Taiho: Consultancy; Pre-cell: Consultancy; Bayer: Consultancy; ElevenP15: Consultancy; Clinipace: Consultancy; Ruesch Center for the Cure of Gastrointestinal Cancer: Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy; Heron Therapeutics: Consultancy; Themis: Consultancy; Caring for Colorado Foundation: Membership on an entity's Board of Directors or advisory committees; TEQ laboratories: Membership on an entity's Board of Directors or advisory committees; GLPI: Consultancy, Equity Ownership; Industrial Laboratories: Membership on an entity's Board of Directors or advisory committees; Axion: Membership on an entity's Board of Directors or advisory committees; Globavir: Consultancy; miRagen Therapeutics: Consultancy; IGM: Consultancy; Cleave Pharmaceuticals: Consultancy; Flugen: Consultancy; Inovio: Consultancy. Rubin: miRagen Therapeutics: Employment, Equity Ownership. Marshall: Colorado BioScience Association: Membership on an entity's Board of Directors or advisory committees; Atlas Venture: Consultancy; AmideBio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Fluorofinder: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; miRagen Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor on various patents.

FOULDS: Three Mantras op. 61b3; Lyra Celtica, Concerto for voice and orchestra op. 501; Apotheosis (Elegy) for violin and orchestra op. 182; Mirage op. 20. 1Susan Bickley (mezzo), 2Daniel Hope (vln), 3City of Birmingham Youth Chorus, City of Birmingham Symphony Orchestra c. Sakari Oramo. Warner Classics 2564 61525-2.

Introduction:Programmed death-1 (PD-1) inhibitors are highly active in relapsed and refractory (RR) classical Hodgkin lymphoma (cHL), however their role as part of second-line therapy (SLT) for cHL is largely unexplored. The standard approach following front-line treatment failure is SLT, aimed to achieve complete response (CR), followed by consolidation with high dose therapy and autologous stem cell transplant (HDT/ASCT). There is no one standard SLT and options include platinum-containing regimens, gemcitabine-containing regimens and more recently brentuximab vedotin (BV)-containing regimens. Due to the increasing use of BV in the front-line setting, development of SLT regimens that are both highly effective and BV-sparing are needed. In this phase II study, we aimed to establish the safety and efficacy of SLT with the PD-1 inhibitor, pembrolizumab, combined with the outpatient-administered salvage regimen, GVD (gemcitabine, vinorelbine, liposomal doxorubicin). Methods: Transplant eligible patients (pts) with RR cHL following failure of 1-line of therapy are eligible. Treatment consists of 2 to 4 cycles of pembrolizumab (200mg IV, day 1), gemcitabine (1000mg/m2 IV, days 1 and 8), vinorelbine (20mg/m2 IV, days 1 and 8) and liposomal doxorubicin (15mg/m2, days 1 and 8), given on 21-day cycles. Response is assessed by PET after 2 and 4 cycles. Pts who achieve CR by PET (Deauville ≤3) after 2 or 4 cycles proceed to HDT/ASCT. An initial safety assessment for the first 6 treated pts was completed before continuing further enrollment. We report here the results of the safety assessment and the first stage of a Simon 2-stage design. Results:To date, 18 out of a planned 39 pts enrolled; 14 completed the first 2 cycles of treatment and underwent the first response assessment. Characteristics for the 14 evaluable pts are shown in the table. In brief, median age is 36 (range 21-43), 4 (29%) have primary refractory disease and 9 (64%) relapsed within the first year of initial treatment. No dose limiting toxicities were observed during the safety assessment and no significant adverse events were observed to date. Of the 30 cycles administered, 5 (17%) cycles were delayed due to treatment related adverse events which included grade 3 rash (3%) and grade 3 liver function test abnormalities (13%). Among the 14 evaluable pts, 13 (93%) achieved CR after 2 cycles of treatment and 1 achieved partial response. To date, 3 pts are proceeding to HDT/ASCT and 11 pts completed HDT/ASCT following 2 (n=10) or 4 (n=1) cycles of treatment. Median follow-up post HDT/ASCT is 4 mos (range 0.3-8.8 mos) and all pts remain in remission to date. Conclusion:Early trial results suggest that pembrolizumab-GVD is a highly effective and well-tolerated regimen that can efficiently bridge pts with RR cHL to HDT/ASCT. Efficacy criteria for stage one of the Simon 2-stage design was met and enrollment continues to better characterize CR rate and tolerability. Disclosures Moskowitz: ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy. Shah:Amgen: Research Funding; Janssen: Research Funding. Kumar:Seattle Genetics: Research Funding. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Straus:Seattle Genetics: Consultancy, Honoraria; Elsevier (PracticeUpdate): Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees. Rodriguez-Rivera:Memorial Sloan Kettering Cancer Center: Employment. Colbourn:ABBV: Other: Stock; CELG: Other: Stock; BIIB: Other: Stock; SGEN: Other: Stock; JNJ: Other: Stock; LLY: Other: Stock; GILD: Other: Stock; MRK: Other: Stock; SNY: Other: Stock. Horwitz:Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Affimed: Consultancy; Aileron: Research Funding; Trillium: Research Funding; ADCT Therapeutics: Research Funding; Affimed: Consultancy; Astex: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Trillium: Research Funding; Astex: Consultancy; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Forty-Seven: Research Funding; Celgene: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Research Funding; Portola: Consultancy; Forty-Seven: Research Funding; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; ADCT Therapeutics: Research Funding; Astex: Consultancy; Trillium: Research Funding; Forty-Seven: Research Funding; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Affimed: Consultancy; Astex: Consultancy; Innate Pharma: Consultancy; Innate Pharma: Consultancy; Kyowa Hakko Kirin: Consultancy; Mundipharma: Consultancy; Innate Pharma: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Miragen: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; Miragen: Consultancy; Miragen: Consultancy; Portola: Consultancy; Mundipharma: Consultancy; Miragen: Consultancy; Kura: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy; Portola: Consultancy. Palomba:Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights . Noy:Prime Oncology: Honoraria; NIH: Research Funding; Janssen: Consultancy; Medscape: Honoraria; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Matasar:Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Daiichi Sankyo: Consultancy; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Merck: Consultancy, Equity Ownership; Juno Therapeutics: Consultancy; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Bayer: Other: Travel, accommodation, expenses; Janssen: Honoraria, Research Funding. Vardhana:Rheos Pharmaceuticals: Honoraria; ADC Therapeutics: Consultancy; Agios Pharmaceuticals: Honoraria. von Keudell:Bayer: Consultancy; Pharmacyclics: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy; Genentech: Consultancy; Bayer: Consultancy. Younes:Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; Syndax: Research Funding. Zelenetz:Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moskowitz:Genentech: Consultancy, Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding; ADC Therapeutics: Research Funding; Merck: Consultancy, Research Funding. OffLabel Disclosure: Pembrolizumab is not approved for second-line use for classical Hodgkin lymphoma.

Introduction: The standard therapy for early stage, unfavorable risk Hodgkin lymphoma (HL) with disease bulk is combined modality therapy, typically 4-6 cycles of ABVD followed by 30Gy involved-site radiotherapy (ISRT) (Eich JCO 2010). In this pilot study with four sequential cohorts, we studied whether consolidative radiotherapy could be reduced or eliminated in early stage, unfavorable risk HL patients treated with brentuximab vedotin (BV) and AVD chemotherapy. In the first cohort, we demonstrated that BV+AVD and 30Gy ISRT had an acceptable safety profile without significant pulmonary toxicity and promising efficacy (Kumar Blood 2016). In subsequent cohorts, we tested whether the ISRT dose could be reduced to 20Gy (cohort 2), the RT field could be reduced with consolidation volume radiation (CVRT; cohort 3), and whether radiation therapy could be eliminated (cohort 4). Methods: Patients received 4 cycles of BV 1.2 mg/kg with AVD chemotherapy every 2 weeks, followed by 30 Gy ISRT in cohort 1, 20Gy ISRT in cohort 2, 30 Gy CVRT in cohort 3, and no radiotherapy in cohort 4. CVRT targets PET-negative residual masses greater than 1.5cm on post-chemotherapy CT imaging. Eligible patients in cohorts 1-2 included untreated stage I/II, classical HL with any one of the following unfavorable risk factors: bulky disease (MSK criteria: maximal transverse or coronal diameter >7 cm on CT), elevated ESR, extranodal involvement, >2 lymph node sites, or infradiaphragmatic disease. In cohort 3-4, early stage patients with bulky disease by MSK criteria were eligible. PET/CT after 2 and 4 cycles and after ISRT were interpreted with the 5-point Deauville scale (negative=1-3). The primary endpoint of cohort 1 was to evaluate safety and tolerability of the treatment combination, with special attention to pulmonary toxicity; the primary endpoint of cohorts 2-4 was to evaluate preliminary efficacy with the rate of complete responses (CRs) at end of treatment (EOT). Results: In June 2019, the study was fully accrued with 117 patients enrolled across four cohorts. Patients had a median age of 32 (range 18-59), 98% stage II, 86% with MSK-defined disease bulk (>7cm in transverse or coronal dimension), 27% with traditionally defined bulk (>10cm in transverse dimension), 50% elevated ESR, 38% B-symptoms, 21% extranodal involvement, 56% >2 involved lymph node sites, and 3.4% infradiaphragmatic disease. 26 patients (22%) had advanced stage disease by German Hodgkin Study Group criteria: IIBX (n=16), IIBE (n=5), and IIBXE (n=6). Of the patients enrolled in cohorts 1-3 with interim PET imaging, 85% and 91% achieved a negative PET scan after 2 and 4 cycles of therapy, respectively, and 95% achieved a CR at EOT. In cohort 4, 24 of the 29 enrolled patients have completed 4 cycles of therapy. Thus far, 93% of patients achieved a negative PET-2 scan (25 of 27 patients), 77% of patients achieved a negative PET-4 scan (17 of 22 patients), and 91% achieved a CR at EOT (20 of 22 patients). The remaining two patients with equivocal PET-4 results will have repeat short-interval scans to clarify EOT response. The overall median follow-up of survivors is 29 months: 56 months for cohort 1, 38 months for cohort 2, 24 months for cohort 3, and 5 months for cohort 4. Seven events have occurred in the study thus far. In cohort 1, two patients had primary refractory disease after chemotherapy and were treated off study. In cohort 2, one patient in remission died in a motor vehicle accident and one late relapse occurred at 34 months. In cohort 3, two patients had primary refractory HL after CVRT and one relapse occurred at 9 months. Overall, the 2-year PFS is 94% (95% CI 0.90, 0.99), see Figure. Across all 4 cohorts, the BV+AVD treatment was well-tolerated; the most common toxicities were peripheral neuropathy, abdominal pain, and neutropenia that were generally mild-moderate in severity, reversible, and manageable. Conclusion: BV+AVD x 4 cycles is an active treatment program for early stage, unfavorable risk HL, including patients with bulky disease. The efficacy of BV+AVD in this setting has facilitated a safe reduction in radiation dose and field evidenced by excellent and similar outcomes across the first 3 cohorts. With substantial follow-up, 20Gy ISRT appears equivalent to 30Gy ISRT following BV+AVD. The preliminary outcomes from the final cohort with chemotherapy alone are also promising, however, follow-up is short. Updated response data will be presented at the meeting. Disclosures Kumar: Seattle Genetics: Research Funding. Casulo:Gilead: Honoraria, Other: Travel, accommodation, expenses; Roche: Other: Travel, accommodation, expenses; Celgene: Research Funding. Advani:Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Cell Medica, Ltd: Consultancy; Kura: Research Funding; Merck: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Stanford University: Employment, Equity Ownership; Seattle Genetics: Consultancy, Research Funding; Agensys: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Infinity Pharma: Research Funding; Forty-Seven: Research Funding; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Research Funding; Janssen: Research Funding; Millennium: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees. Budde:F. Hoffmann-La Roche Ltd: Consultancy. Barr:Janssen: Consultancy; Astra Zeneca: Consultancy, Research Funding; Verastem: Consultancy; Gilead: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Genentech: Consultancy. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Friedberg:Acerta: Other: Data & Safety Monitoring Committee; Bayer: Honoraria, Other: Data & Safety Monitoring Committee. Horwitz:Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Innate Pharma: Consultancy; Innate Pharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Affimed: Consultancy; Innate Pharma: Consultancy; Affimed: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Miragen: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Innate Pharma: Consultancy; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Miragen: Consultancy; Miragen: Consultancy; Portola: Consultancy; Trillium: Research Funding; Mundipharma: Consultancy; Portola: Consultancy; Astex: Consultancy; Aileron: Research Funding; Aileron: Research Funding; Celgene: Consultancy, Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; Forty-Seven: Research Funding; Forty-Seven: Research Funding; Aileron: Research Funding; Portola: Consultancy; ADCT Therapeutics: Research Funding; Affimed: Consultancy; Mundipharma: Consultancy; ADCT Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; Portola: Consultancy; Forty-Seven: Research Funding; Miragen: Consultancy; Kura: Consultancy; Kura: Consultancy; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Matasar:Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Merck: Consultancy, Equity Ownership; Juno Therapeutics: Consultancy; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Bayer: Other: Travel, accommodation, expenses; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding. Moskowitz:Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy. Noy:Prime Oncology: Honoraria; NIH: Research Funding; Medscape: Honoraria; Janssen: Consultancy; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Palomba:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Evelo: Equity Ownership; MSK (IP for Juno and Seres): Patents & Royalties; Noble Insights: Consultancy; Merck & Co Inc.: Consultancy; Seres Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Hemedicus: Speakers Bureau. Straus:Elsevier (PracticeUpdate): Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees. Younes:Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; Syndax: Research Funding. Zelenetz:Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moskowitz:ADC Therapeutics: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding.

Abstract Abstract 4759 Introduction Co-inheritance of Hb Rancho Mirage and Hb D-Punjab produces a clinically significant condition through increasing oxygen affinity that causes a compensatory erythrocytosis. We report a first case of co-inheritance of Rancho Mirage with Hb D-Punjab which differs in its clinical presentation from that described in the literature. Case presentation A 59-year-old Pakistani male was admitted to hospital because of chest tightness. The imaging studies showed no marked organomegaly or masses. Laboratory investigations revealed erythrocytosis with high hematocrit and borderline MCV and MCH. Arterial blood gas testing (ABG) showed low pO2 and JAK2 V617F mutation was not detected. Erythropoietin level was normal. Hemoglobin analysis through high performance liquid chromatography (HPLC) revealed two hemoglobin variants; Hb D-Punjab (32.5%) and the remaining Hb comprised of a fast moving variant. The variant was faster than Hb F expressing at a considerably high level. There was no detectable Hb A. (figure 1, HPLC shows both variants) At the molecular level, the β globin gene was amplified and sequenced using specific primers. DNA analysis demonstrated the presence of two mutations in Exon 3. The first one was a rare mutation in βCd 143 (CAC→GAC) causing a substitution of His→Asp that was identified as Hb-Rancho Mirage. It is speculated that the replacement of the ‘His‘ residue with that of ‘Asp’ would unequivocally alter the oxygen binding characteristics of the heme pocket. The other mutation was the common variant defined as Hb D-Punjab βCd 121 (GAA→CAA). (figure 2, DNA sequencing shows both variants). The patient had undergone regular venesection to alleviate erythrocytosis. Discussion The co-inheritance of Hb Rancho Mirage with Hb D-Punjab has never been reported previously. Both mutations exist in the β globin gene giving rise to concomitant beta chain variants. Carriers of Hb Rancho Mirage are anticipated with mild anemia. However, coexistence of both abnormal hemoglobins showed functional defects manifested as polycythemia, likely due to the disruption of the 2,3 DPG binding site which is actively involved in the allosteric equilibrium during oxygen transport. The current case depicts the first occurrence of a double heterozygosity for two beta chain variants affecting exon 3 of the β globin gene with a relatively mild to moderate phenotype. Family studies are recommended to understand further the structure and function relationship of this rare hemoglobin variant in association with a more common Hb D- Punjab. Disclosures: No relevant conflicts of interest to declare.

En 1817, le médecin anglais James Parkinson publie « An essay on the shaking palsy ». L’observation de six patients âgés de plus de 50 ans lui permet de répertorier les symptômes de cette « paralysis agitans » (paralysie agitante). Les différents symptômes avaient déjà été décrits, mais jamais réunis dans une seule et nouvelle entité nosologique. En 1868, Armand Trousseau ajoute la marche festinante à ces symptômes, et en 1872 le neurologue Jean-Martin Charcot ajoute la rigidité. Le futur créateur des Archives de neurologie baptise cette entité nosologique maladie de Parkinson. Par la suite, le processus lésionnel est décrit dans le locus niger (1919), l’effondrement du neurotransmetteur dopamine dans les années 1960, et de ses récepteurs à partir des années 1970. L’article de Bayen, et al. « Pas à pas » nous rappelle que la maladie de Parkinson comporte bien d’autres signes cliniques que les tremblements1. Ces autres signes peuvent nous aider à réaliser un diagnostic plus précoce et à avoir une prise en charge plus adaptée. Notre spécialité est une spécialité clinique : face à une toux, nous recherchons des signes pulmonaires, d’autres réalisent une tomodensitométrie, et en ce moment la couplent avec un test PCR COVID-19. Cette démarche clinique ne nous empêche pas d’être curieux et de lire, avec intérêt et sourire, les travaux publiés en 2017 par Forsythe, et al.2. D’après ces travaux, l’analyse fractale (technique d’imagerie numérique analysant la complexité) des toiles de peintres atteints de maladie de Parkinson permettrait de diagnostiquer plus précocement ces maladies. Ainsi le diagnostic chez Salvator Dali pouvait être fait à 38 ans, alors que sa main n’a tremblé qu’à 76 ans. Toujours dans « Pas à pas », Bayen, et al. prennent soin des patients atteints de maladie de Parkinson. Ils rappellent l’importance et la complexité de l’annonce du diagnostic, l’importance de l’autonomie, et l’importance des aidants. Ils évaluent la balance bénéfice-risque des différents traitements. Ils nous guident pour coordonner les soins au mieux. Dans un deuxième article, Debuyser, et al. nous présentent l’avis des patients atteints de maladie de Parkinson sur la télé-expertise3. Leurs avis s’éloignent des mirages actuels de la téléconsultation qui, faut-il le rappeler ?, ne permet pas d’ausculter les poumons. Ces patients sont prêts à l’utiliser, même si elle ne remplace pas une consultation présentielle, si elle permet de diminuer les délais de consultation d’un neurologue. Si Salvator Dali consultait en médecine générale, son médecin traitant l’observerait, à l’instar de Parkinson pour les tremblements et de Trousseau pour sa marche. Ce médecin rechercherait de la rigidité comme Charcot. Il évaluerait l’impact de ces symptômes sur le travail du maître, et sur ses loisirs, comme les échecs. Il évaluerait aussi le retentissement psychique de ces symptômes. Il annoncerait le diagnostic et l’histoire naturelle de la maladie au maître, mais en prenant en compte ce que ce patient veut savoir à ce moment donné de la maladie. Ce médecin de famille pourrait s’appuyer, avec l’accord du maître, sur l’entourage du patient et en particulier sur Gala. Après avis du maître, il coordonnerait les soins et organiserait le suivi, avec peut-être un premier avis neurologique en télé-expertise du fait des délais, en attendant mieux. Salvator Dali le remercierait probablement pour son écoute et son engagement. Et si Salvator Dali avait été dépisté à 38 ans par analyse fractale ? Son diagnostic de syndrome extrapyramidal lui aurait-il permis de peindre « Les pyramides et le sphinx de Gizeh » en 1954 ? Seule une intelligence artificielle semble capable de répondre à cette question.

Background: The acute and lymphoma subtypes Human T-lymphotropic virus 1-associated adult T-cell leukemia/lymphoma (HTLV-1 ATLL) are frequently characterized by chemo-refractoriness, a generally aggressive clinical course, and poor outcomes. Despite progress in characterizing the disease biology and the development and implementation of newer agents such as mogamulizumab, survival remains poor, especially for patients with relapsed or refractory disease. Furthermore, besides these many challenges, there is a paucity of comprehensive published data in Western (i.e. non-Japanese) patients. Methods: In a retrospective analysis, we identified 109 patients with pathologically-confirmed ATLL evaluated at our institution since 2001. 11 were excluded due to lack of clinical follow-up. Patient, disease, and treatment information was extracted for analysis. The International Prognostic Index (IPI) and Prognostic Index for PTCL-U (PIT) were calculated at time of diagnosis. Response rate was calculated based on the best response (CR/PR) during induction, with response retrospectively assessed based on available data using Lugano criteria. Median survival was calculated using Kaplan-Meier analysis and follow-up using a reverse Kaplan-Meier method, with survival and follow-up as of July 2019 Results: Ninety eight patients were included in our cohort (Table 1); 46 patients (47%) received initial treatment at another institution. The most common ATLL subtypes were lymphoma (n=43, 44%) acute (n=39, 40%), and smoldering/chronic (n=16, 16%). The median age at diagnosis was 53 years (range 30-92) and the median duration of follow-up from diagnosis was 65 months (95% CI: 41 to 178). With a median follow-up in survivors of 41.2 months, 21 patients are alive. The most common cause of death was disease (69/77 patients, 90%). The median overall survival (OS) among all patients was 13.2 months (Figure 1; range 1.3-240). For acute/lymphoma subtype disease, most patients initially received EPOCH/CHOEP (54 patients), CHOP (18 patients), or BV-CHP (3 patients); practice patterns evolved since the late 2000's to include more etoposide and BV-CHP rather than CHOP. Among 76 patients with lymphoma/acute with reviewable restaging information, 30 (40%) achieved CR. For patients with active disease following induction, a variety of subsequent therapies were used, most commonly romidepsin and pralatrexate, each utilized in 15 patients. Of 68 patients considered for transplant (55 saw a transplant physician, 13 had HLA typing sent), 23 patients ultimately underwent transplant, including 5 autologous and 18 alloSCT. Among patients referred who did not undergo transplant (N = 30), the most common reason was disease-related (24 patients, 80%) followed by patient preference (4 patients, 13%). Since 2010, only two patients underwent autoSCT at our center: one experienced primary graft failure necessitating autologous reconstitution and another lacked suitable allograft donor. Most patients, 13/18 (72%), were in CR at time of alloSCT; 11 patients underwent transplant in first remission, 7 at subsequent timepoints. Donor and graft sources included matched related (n=6), one identical twin, matched unrelated (n=2), mismatched related (n=1), mismatched unrelated (n=2), cord blood (n=4) and haploidentical (n=2). Four patients relapsed after autoSCT, 6 patients following alloSCT, and 2 treatment-related deaths occurred post alloSCT. Progression-free and OS at median follow-up of 39.2 months among alloSCT recipients was 60.6% and 64.1%, respectively (Figure 2). Conclusions: We describe the treatment patterns and outcomes for a large series of non-Japanese patients at our center with ATLL. We confirm the poor outcomes with conventional therapy seen in other studies, with only 40% of lymphoma/leukemia subtype patients achieving CR with first-line therapy, and a median OS of 13.2 months among all patients. AlloSCT offers promise as an effective option that achieved durable long-term responses in many patients, yet its applicability is limited by chemorefractory disease. Larger studies are needed to confirm our findings and to identify effective salvage therapies to attain remission and bridge patients to alloSCT. For patients ineligible for alloSCT due to age/comorbidity, lack of suitable donor, or disease refractoriness, novel therapeutic approaches are urgently needed to improve outcomes. Disclosures Moskowitz: Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Dogan:Roche: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Novartis: Consultancy. Kumar:Seattle Genetics: Research Funding. Matasar:Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Merck: Consultancy, Equity Ownership; Juno Therapeutics: Consultancy; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Daiichi Sankyo: Consultancy; GlaxoSmithKline: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Other: Travel, accommodation, expenses. Noy:Medscape: Honoraria; Janssen: Consultancy; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Perales:Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding. Straus:Elsevier (PracticeUpdate): Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria. Zelenetz:Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy; GSK: Consultancy. Horwitz:Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Celgene: Consultancy, Research Funding; Kura: Consultancy; Trillium: Research Funding; Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Portola: Consultancy; Kura: Consultancy; Infinity/Verastem: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Portola: Consultancy; Celgene: Consultancy, Research Funding; Portola: Consultancy; Astex: Consultancy; Seattle Genetics: Consultancy, Research Funding; Miragen: Consultancy; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; ADCT Therapeutics: Research Funding; Forty-Seven: Research Funding; Aileron: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy; Astex: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Forty-Seven: Research Funding; Astex: Consultancy; Mundipharma: Consultancy; Innate Pharma: Consultancy; Trillium: Research Funding; Astex: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Kyowa Hakko Kirin: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Consultancy; Innate Pharma: Consultancy; Aileron: Research Funding; Innate Pharma: Consultancy; Mundipharma: Consultancy; Trillium: Research Funding; Affimed: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADCT Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Mundipharma: Consultancy; Portola: Consultancy; Forty-Seven: Research Funding; Miragen: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Affimed: Consultancy.

Background: Treatment strategies for patients (pts) with relapsed/refractory (RR) classical Hodgkin lymphoma (cHL) continue to evolve as brentuximab vedotin (BV) and immune checkpoint inhibitors are utilized in pre-transplant salvage regimens. These new approaches are based on promising results of non-randomized trials, but it is not clear how they perform outside of clinical studies. We aimed to investigate selection patterns, toxicities, and outcomes of salvage regimens prior stem cell transplant (SCT) used currently in the United States for pts with RR cHL in the non-trial setting. Methods: We conducted a multisite, retrospective study of pts with RR cHL who were treated with a first salvage regimen (salvage 1) with intent to proceed to SCT within the past 5 years. Only pts who were treated outside of a clinical trial with salvage 1 were included. Responses were based on treating physician assessment using Revised Response Criteria for Malignant Lymphoma (Cheson et al, JCO 2014). Kaplan Meier survival curves were generated using STATA 15.0 software. Results: We identified 160 pts with diagnosis of RR cHL from 6 U.S. centers who received salvage 1 in the non-trial setting between January 2013 and January 2018. The pts' characteristics are described in Table 1. Both primary refractory pts (41%) and those with relapsed disease (59%) were included. The most common salvage 1 regimen for RR cHL was ifosfamide, carboplatin, etoposide (ICE) in 68% followed by BV monotherapy (14%) and BV+bendamustine (9%). Only 1 pt (1%) received immune checkpoint inhibitor. There were no statistically significant factors that would increase likelihood of receiving BV-containing salvage 1 including primary refractory status, age, and advanced stage. In the cohort of 59 pts who required more than one line of salvage therapy, the most common second salvage regimen (salvage 2) was BV monotherapy (42%), followed by various BV-containing combinations (22%), and ICE (19%). Only 14% of pts received 3 or more lines of salvage therapy prior to SCT. Out of 107 pts who received ICE as salvage 1, 33% were administered second salvage while out of 35 pts who received BV-containing regimen as salvage 1, 53% required salvage 2 (X2=4.7, p=0.03). Of 148 pts who ultimately underwent SCT, 52% were exposed to BV and 12% to an immune checkpoint inhibitor as part of any salvage regimen at some point prior to SCT. Response assessment to salvage 1 were available for 154 pts; 47% pts achieved complete response (CR), 30% partial response (PR), and 19% had progressive disease (PD). The responses to specific salvage 1 regimens are summarized in Table 2. For those pts undergoing salvage 2, 48% achieved CR, 19% PR and 30% had PD. Radiation was administered to 11% of pts at any point of salvage treatment prior SCT. In terms of toxicities, there were no deaths attributed to complications from any of the salvage therapies. When compared to ICE, pts undergoing BV or BV+bendamustine as salvage 1 had lower risk of neutropenic fever (0% vs 7%) and GI toxicities (10% vs 18%), but had higher risk of experiencing peripheral neuropathy (5% vs 15%). Out of 148 pts who ultimately underwent SCT, the majority had autologous (96%) and 6 (4%) pts had allogeneic SCT. The majority (73%) of patients were in CR immediately prior SCT. Four pts (3%) died due to SCT-related toxicities. BV maintenance was used in 35% of pts. Exposure to BV during salvage 1 prior SCT did not affect the likelihood of receiving BV maintenance. While there was no statistically significant difference in progression free survival (PFS) between chemotherapy only and BV-containing salvage 1, there was a trend toward improved PFS with BV-containing salvage 1 as shown in Figure 1. The 2-year PFS for chemotherapy only salvage 1 was 71% (95% CI: 60-79%) vs. 80% (95% CI: 60-91%) for BV-containing salvage treatments. Conclusion: Growing number of salvage regimens are used in RR cHL. In the current practice outside of clinical trials, 23% of RR cHL pts received BV during salvage 1. In total, 37% received more than one salvage treatment and 52% received BV as part of salvage therapy prior SCT. It is unlikely that a prospective randomized trial will be conducted to compare various salvage treatment options. However, further analysis of sub-populations who may benefit from a particular regimen or optimal treatment sequences may lead to more effective and less toxic treatment strategies for pts with RR cHL. Disclosures Svoboda: Seattle Genetics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy; Celgene: Research Funding; Kyowa: Consultancy; Kite: Consultancy. Andreadis:Genentech: Equity Ownership, Other: Spouse is Employee; Novartis: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Gilead: Consultancy; Jazz Pharmaceuticals: Consultancy; Bayer: Consultancy. Feldman:Portola Pharma: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Janssen: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Roche: Research Funding; Viracta: Research Funding; Trillium: Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Corvus: Research Funding; Roche: Research Funding; Cell Medica: Research Funding; Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Khan:Back Bay Life Science Advisors: Honoraria; ASCO/Conquer Cancer Foundation sponsored by Gilead Sciences: Research Funding. Moskowitz:ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; Merck: Research Funding; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Portell:Roche/Genentech: Research Funding; Xencor: Research Funding; TG Therapeutics: Research Funding; Acerta/AstraZeneca: Research Funding; Kite: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Bayer: Consultancy; Amgen: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; AbbVie: Research Funding; Infinity: Research Funding. Dwivedy Nasta:Merck: Consultancy, Other: data safety monitorin; 47 (Forty Seven): Research Funding; Roche: Research Funding; Rafael: Research Funding; Debiopharm: Research Funding; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria; Millenium/takeda: Research Funding. Landsburg:Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Triphase: Research Funding; Triphase: Research Funding. Barta:Mundipharma: Honoraria; Seattle Genetics: Honoraria, Research Funding; Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Mundipharma: Honoraria; Bayer: Consultancy, Research Funding; Merck: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Chong:Tessa: Consultancy; Merck: Research Funding; Novartis: Consultancy. Schuster:Acerta: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Nordic Nanovector: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Loxo Oncology: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination CAR-T and PD-1 Inhibitors, Research Funding. OffLabel Disclosure: Brentaximab vedotin containing salvage in Hodgkin lymphoma

Background/methods: Identifying relapsed or refractory (RR) classical Hodgkin lymphoma (cHL) patients (pts) eligible for lower-intensity second-line therapy (SLT) will aid in improving short-term and long-term treatment-related toxicity. We conducted a phase II study evaluating PET-adapted SLT with single-agent brentuximab vedotin (BV) followed by augICE (augmented ifosfamide, carboplatin, etoposide) for BV-naïve patients with RR cHL (Lancet Oncology 2015). In this study, patients who failed 1 line of therapy for cHL were treated with 2 or 3 cycles of BV, 1.2mg/Kg, administered weekly, 3 weeks on and 1 week off. Those who achieved PET-normalization proceeded directly to consolidation with autologous stem cell transplantation (ASCT). Those with persistent abnormalities on PET received 2 cycles of augICE prior to consideration for ASCT. At 3-year follow-up, outcomes for patients who achieved PET-normalization following BV alone or BV followed by augICE were identical. Furthermore, baseline metabolic tumor volume (bMTV) predicted outcome and improved the prognostic significance of pre-ASCT PET (Blood 2017). We now report 6-year follow-up from this study evaluating PET-adapted SLT with BV and augICE. Results: 65 pts enrolled onto this protocol, of whom 18 achieved PET-normalization (Deauville ≤ 2) after single-agent BV. These 18 pts included 8 (44%) with primary refractory disease, 7 (39%) with advanced stage disease, and 8 (44%) with extranodal disease. 17 of the 18 pts proceeded directly to ASCT and 1 pt experienced delay resulting in disease progression. That individual achieved PET-normalization following additional salvage chemotherapy (gemcitabine/vinorelbine/liposomal doxorubicin) and proceeded to ASCT. Of the other 47 pts who remained PET-positive after single-agent BV, 35 achieved PET-normalization after augICE, 9 remained PET-positive after augICE, 2 received no additional treatment before proceeding to ASCT (1 pt with Deauville 3 response to BV, 1 with Deauville 4 response), and 1 pt withdrew consent and was lost to follow-up. 64 of 65 pts proceeded to transplant and median post-ASCT follow-up is 5.98 yrs (range 4.4-7.2 yrs). 6-yr overall survival is 86%, 6-yr progression free survival (PFS) is 73%, and 6-yr time to tumor progression (TTP) is 78%. Overall, there have been 8 deaths, which were due to disease progression (n=5), progressive multifocal leukencephalopathy (PML) (n=1), treatment-related respiratory failure (n=1), and myelodysplastic syndrome (MDS) (n=1). Pts who proceeded to ASCT following single-agent BV achieved durable remission with 6-year TTP of 80%. Outcomes for the BV-only group were similar to those who required BV and augICE to become PET-negative (6-yr TTP 82%) and were more favorable than for those who remained PET-positive after BV and augICE (6-yr TTP 56%, p=0.058) (Figure 1). With 6-yr follow-up, bMTV &gt; 109.5 cm3remained prognostic for the entire group and aided in predicting which pts ultimately developed disease progression. In particular, among the pts who achieved PET-normalization with BV alone prior to ASCT, 6-yr TTP was 92% vs 40% for low and high bMTV respectively, p=0.017 (Figure 2). Similarly, for pts who achieved PET-normalization following BV and augICE, 6-yr TTP was 85% vs 33% for low and high bMTV respectively, p=0.002. Conclusions: For pts with RR cHL, long-term remission can be achieved following lower-intensity SLT with single-agent BV followed by ASCT, provided PET-normalization is achieved after single-agent BV. bMTV identifies which pts within this favorable group are likely to develop disease progression and therefore treatment strategies using bMTV to direct intensity of therapy should be explored. Disclosures Moskowitz: Erytech Pharma: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Erytech Pharma: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy. Horwitz:Seattle Genetics: Consultancy, Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; Miragen: Consultancy; Portola: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Affimed: Consultancy; Innate Pharma: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy; Trillium: Research Funding; Portola: Consultancy; Aileron: Research Funding; Mundipharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Affimed: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Forty-Seven: Research Funding; ADCT Therapeutics: Research Funding; Miragen: Consultancy; ADCT Therapeutics: Research Funding; Kyowa Hakko Kirin: Consultancy; ADCT Therapeutics: Research Funding; Astex: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin: Consultancy; Astex: Consultancy; Affimed: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Miragen: Consultancy; Kyowa Hakko Kirin: Consultancy; Miragen: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; ADCT Therapeutics: Research Funding; Mundipharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy; Celgene: Consultancy, Research Funding; Forty-Seven: Research Funding; Astex: Consultancy; Portola: Consultancy; Seattle Genetics: Consultancy, Research Funding; Kura: Consultancy; Aileron: Research Funding; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Trillium: Research Funding; Innate Pharma: Consultancy; Trillium: Research Funding; Kura: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Forty-Seven: Research Funding; Portola: Consultancy; Kura: Consultancy; Affimed: Consultancy; Kura: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding. Kumar:Seattle Genetics: Research Funding. Matasar:Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Merck: Consultancy, Equity Ownership; Juno Therapeutics: Consultancy; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Daiichi Sankyo: Consultancy; GlaxoSmithKline: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Other: Travel, accommodation, expenses. Noy:Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Janssen: Consultancy; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Palomba:Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights . Shah:Amgen: Research Funding; Janssen: Research Funding. Perales:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Kyte/Gilead: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding; NexImmune: Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy; GSK: Consultancy. Straus:Elsevier (PracticeUpdate): Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees. Younes:BMS: Research Funding; Syndax: Research Funding; Genentech: Research Funding; Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding. Zelenetz:MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moskowitz:Merck: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding; Genentech: Consultancy, Research Funding. OffLabel Disclosure: Brentuximab vedotin is not FDA approved for use in the second-line setting for Hodgkin lymphoma.

Introduction: Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) is an uncommon yet often fatal complication with an overall survival (OS) of less than 6 months. According to the clinical risk model CNS-IPI, patients with 4-6 risk factors have a 2-year rate of CNS relapse of 10%. Involvement of certain extranodal sites such as testes or breast also confers increased risk, even with low-CNS-IPI. In high-risk patients, CNS prophylaxis is usually recommended, although the optimal regimen remains unclear. In this study, we examined the efficacy of different regimens on preventing CNS relapse in high-risk patients. Methods: We reviewed all newly diagnosed patients (pts) with DLBCL at Memorial Sloan Kettering Cancer Center from 2001 to 2017 treated with frontline rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (RCHOP) or RCHOP-like regimens. Patients with primary mediastinal lymphoma, HIV-positive or known CNS disease at diagnosis were excluded. High risk for CNS (HR-CNS) relapse was defined by high-CNS IPI (4-6 risk factors) or low-CNS IPI with testicular, breast, kidney/adrenal and/or bone marrow (BM) involvement. CNS prophylaxis was administered per physician preference. Results: We identified 2002 pts treated with RCHOP or RCHOP-like regimens. Among them, 569 (28%) were classified as HR-CNS relapse and were included in the study. Median age was 68 years (range 21-91) and 290 (51%) were male. The high-risk extranodal sites were: BM, n=118 (20%); kidney/adrenal, n=106 (18%); testes, n=51 (9%) and breast, n=47 (8%). 158 pts (28%) had more than 2 extranodal sites. Cell or origin determined by Hans algorithm was non-germinal center (GCB) (non-GCB) in 40%, GCB in 39% and missing in 21%. 284 pts (50%) received CNS prophylaxis: intrathecal (IT) methotrexate (MTX) and/or IT cytarabine, n= 245 (86%); or high-dose intravenous MTX (HD-MTX), n=40 (14%). Pts's characteristics are shown in Table 1. After a median follow-up of 5.6 years, CNS relapse was observed in 36 out of 569 pts with HR-CNS relapse (5-year risk 6.4%), of whom 14 (39%) had received prophylaxis (IT, n=12; HD-MTX, n=2). The risk of CNS relapse at 5 years in pts who received IT prophylaxis was 5.6% compared with 5.2% in pts who received intravenous HD-MTX. Pts with HR-CNS relapse who did not receive prophylaxis had a 5-year risk for CNS relapse of 7.6% (p=0.34) (Figure 1). Pts with non-GCB phenotype had a higher risk of CNS relapse compared with patients with GCB subtype (5-year risk of 10% vs. 2%) (p=0.03). The median time to CNS relapse was 9 months (range 6-110 months). Pts who received prophylaxis, (either IT or HD-MTX), relapsed later than patients who did not receive prophylaxis, with a median time to relapse of 19 months (range 7-55) vs. 8 months (range 6 to 110), respectively. The risk of CNS relapse at 1 year was lower for pts who received prophylaxis (IT or HD-MTX) compared to pts who did not, 1% vs. 3.2%, risk ratio (RR) 0.30 (95% CI; 0.07,0.68). However, over time the risk of CNS relapse became similar between prophylaxis and non-prophylaxis groups, with a 5-year risk of 5.8% vs. 7.6% (RR 0.76, CI 95%; 0.37, 1.55), respectively (Figure 2). CNS relapses were confined to the CNS (n=26, 72%) or included systemic relapsed in addition to CNS (n=10, 28%). CNS sites of relapse are detailed in table 2. Overall survival (OS) in patients with CNS relapse was worse than in pts who relapsed outside the CNS, with a 2-year OS of 24% (95% CI, 12%-40%) vs. 40% (95% CI, 31%-48%), respectively (p=0.002). Conclusion: In the era of chemoimmunochemotherapy, CNS prophylaxis tended to delay relapse rather than effectively preventing it. Although we did not detect differences in the efficacy between intrathecal and intravenous HD-MTX, larger studies are needed to better compare the efficacy of these two preventive modalities. Disclosures Noy: Medscape: Honoraria; Janssen: Consultancy; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Horwitz:Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Astex: Consultancy; Innate Pharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Miragen: Consultancy; Miragen: Consultancy; Kura: Consultancy; Kura: Consultancy; Innate Pharma: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Trillium: Research Funding; Celgene: Consultancy, Research Funding; Portola: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Portola: Consultancy; Trillium: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Kura: Consultancy; Miragen: Consultancy; Affimed: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Seattle Genetics: Consultancy, Research Funding; Innate Pharma: Consultancy; Trillium: Research Funding; Forty-Seven: Research Funding; Aileron: Research Funding; Aileron: Research Funding; Astex: Consultancy; Forty-Seven: Research Funding; Miragen: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Forty-Seven: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Mundipharma: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Trillium: Research Funding; Celgene: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Kura: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Portola: Consultancy; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Forty-Seven: Research Funding; Innate Pharma: Consultancy; Kyowa Hakko Kirin: Consultancy; Portola: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADCT Therapeutics: Research Funding; Mundipharma: Consultancy; Kyowa Hakko Kirin: Consultancy. Palomba:Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights . Matasar:Juno Therapeutics: Consultancy; Merck: Consultancy, Equity Ownership; Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Other: Travel, accommodation, expenses; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Daiichi Sankyo: Consultancy; GlaxoSmithKline: Honoraria, Research Funding. Straus:Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Elsevier (PracticeUpdate): Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moskowitz:Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Erytech Pharma: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding. von Keudell:Bayer: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy; Bayer: Consultancy. Dogan:Roche: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Novartis: Consultancy. Zelenetz:DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees. Younes:BMS: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Roche: Consultancy, Honoraria, Research Funding; Xynomics: Consultancy; Syndax: Research Funding; Epizyme: Consultancy, Honoraria; HCM: Consultancy; Celgene: Consultancy, Honoraria; Takeda: Honoraria; Abbvie: Honoraria; Merck: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Biopath: Consultancy.

INTRODUCTION Despite major clinical advancements, mantle cell lymphoma (MCL) remains a therapeutic challenge with a considerable number of patients experiencing a dismal course. We sought to map the genomic landscape of MCL at diagnosis and at disease progression. We aimed to identify genomic drivers of aggressive phenotype, resistance and relapse and to characterize the genomic evolution of this disease. METHODS We evaluated the genetic landscape of 210 MCL patients, comparing patients sequenced pretreatment (pre-Tx) to those sequenced at disease progression (POD), including 23 patients with sequential samples. We used CLIA certified targeted sequencing platforms covering 151 genes recognized in lymphoma, including single nucleotide variants (SNV) and copy number alterations (CNA). We compared clinical characteristics, histologic features, IGHV mutational status and genomic profiles between pre-Tx and POD samples. We evaluated the association between genomic features and overall survival (OS) in pre-Tx cases. RESULTS Median age was 65 (range 31-92) with a male predominance (75%, n=172). Patients sequenced at POD were characterized by a higher rate of blastoid histology (31% n=20 vs. 10% n=16, p&lt;0.001) and a higher rate of high-proliferation (Ki67≥30% in 79% n=45 vs. 54% n=61, p=0.001), but rates of an 'unmutated' IGHV status were similar (68% n=23 vs. 75% n=57, p=0.6). The most prevalent genomic abnormalities (mut) seen in the entire cohort were ATM (49%, n=111); TP53 (30%, n=69); KMT2D (22%, n=51); CCND1 (16%, n=37); WHSC1 (14%, n=33); and BIRC3 (14%, n=32). Compared to pre-Tx, POD cases had higher rates of TP53mut (49% n=33 vs. 22% n=36, p&lt;0.001) and a trend towards less ATMmut (38% n=26 vs. 53% n=85, p=0.06) and CCND1mut (7% n=5 vs. 20% n=32, p=0.03). ATMmut and TP53mut were almost completely exclusive (p&lt;0.001) (figure 1). There were 110 cases with IGHV data (27% n=30 mutated and 73% n=80 unmutated). Mutated IGHV was associated with a higher rate of CCND1mut (37% n=11 vs. 8% n=6, p&lt;0.001) and NOTCH2mut (17% n=5 vs. 3% n=2, p=0.02). We evaluated pathological characteristics of the sequenced tumor biopsy. Blastoid histology (219 evaluable) observed in 16% (n=36) was associated with TP53mut (61% n=22 vs. 22% n=41, p&lt;0.0001); a lower rate of ATMmut (31% n=11 vs. 53% n=97, p=0.02); and a higher rate of SMARCA4mut (22% n=8 vs. 10% n=17, p=0.04). Similarly, a high Ki67 &gt;=30% (171 evaluable) was associated with TP53mut (38% n=63 vs. 9% n=6, p&lt;0.001) and NOTCH1mut (12% n=13 vs. 2% n=1, p=0.02); with extremely high Ki67 &gt;=60% enriched for CCND1mut (28% n=11 vs. 15% n=10 30%&gt;= Ki67 &lt; 60% and 9% n=6 Ki67&lt;30%, p=0.04) and MED12mut (13% n=5 vs. 3% n=2 30%&gt;= Ki67 &lt; 60% and no cases with Ki67&lt;30%, p=0.006). There were 23 patients with sequential biopsies with a median time difference of 37m (IQR 18-57) between samples. pre-Tx and POD sequential samples had strikingly similar genomic alterations (figure 2). Furthermore, the mutation landscape of these pre-Tx samples was highly similar to that seen in the overall POD samples. For example, TP53mut were observed in 48% of sequential pre-Tx samples, similar to 49% seen in overall POD samples and not to the 22% seen in overall pre-Tx samples. Genomic clustering identified four distinct clusters of patients with ATMmut (BIRC3mut; KMT2Dmut; NOTCH1/CCND1 and None) a cluster of WHSC1mut and a cluster of TP53mut associated with SMARCA4mut (figure 3). Survival analysis was limited to 151 pre-Tx patients and who had completed treatment or managed expectantly (20%, n=30). With a median follow-up of 49m, TP53mut was associated with shorter OS (HR 4.15; 1.9-9.0) corresponding to a 4yOS of 63% vs. 92% in TP53wt (figure 4). In 22 patients (15%) with BIRC3mut, no deaths were observed (p=0.03). Notably, however, the rate of BIRC3mut at POD was similar to pre-Tx and not associated with superior outcomes. CONCLUSIONS Our data suggests that the ultimate outcome of MCL is driven by clones present at diagnosis and in most cases is not the result of clonal evolution. As with former studies TP53mut is the strongest driver of poor outcome. Still a considerable subset of patients fares well. BIRC3mut seemed to confer a good prognosis, however this observation needs to be validated in a dedicated study as the rate of BIRC3mut was similar between pre-Tx and POD and not associated with a better prognosis in the latter. We identify several genomic clusters associated with targetable mutations. Figure Disclosures Kumar: Seattle Genetics: Research Funding. Straus:Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria; Elsevier (PracticeUpdate): Consultancy, Honoraria. Palomba:Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights . Noy:Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Horwitz:Forty-Seven: Research Funding; Kura: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Astex: Consultancy; Innate Pharma: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; Astex: Consultancy; Trillium: Research Funding; Trillium: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Innate Pharma: Consultancy; Kura: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Innate Pharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Mundipharma: Consultancy; Aileron: Research Funding; ADCT Therapeutics: Research Funding; Forty-Seven: Research Funding; Affimed: Consultancy; Miragen: Consultancy; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; ADCT Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; Kura: Consultancy; Celgene: Consultancy, Research Funding; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Mundipharma: Consultancy; Miragen: Consultancy; Affimed: Consultancy; Affimed: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Kyowa Hakko Kirin: Consultancy; Miragen: Consultancy; Innate Pharma: Consultancy; Forty-Seven: Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy; Forty-Seven: Research Funding; Affimed: Consultancy; Trillium: Research Funding; Portola: Consultancy; Trillium: Research Funding; Portola: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Portola: Consultancy; Portola: Consultancy; Seattle Genetics: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moskowitz:miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Merck: Research Funding; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy. Matasar:Bayer: Other: Travel, accommodation, expenses; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Rocket Medical: Consultancy, Research Funding; Teva: Consultancy; Merck: Consultancy, Equity Ownership; Juno Therapeutics: Consultancy; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. von Keudell:Genentech: Consultancy; Bayer: Consultancy; Pharmacyclics: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy; Bayer: Consultancy. Dogan:Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Corvus Pharmaceuticals: Consultancy; Roche: Consultancy, Research Funding. Younes:Janssen: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; HCM: Consultancy; BMS: Research Funding; Syndax: Research Funding; Merck: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Xynomics: Consultancy; Celgene: Consultancy, Honoraria; Biopath: Consultancy. Zelenetz:Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Introduction Brentuximab vedotin (BV) targets CD30, a receptor expressed on the Reed-Sternberg cells of classic Hodgkin lymphoma (cHL). Nivolumab (Nivo) restores antitumor immunity by blocking the PD-1 receptor on activated T-cells. In this phase 1/2 study, combination treatment (tx) with BV + Nivo demonstrated durable efficacy in patients (pts) with relapsed/refractory (R/R) cHL (Herrera, Blood 2018; NCT02572167). Biomarkers consistent with innate and adaptive immune activation were observed in the peripheral blood of pts treated with the combination regimen. Herein, we associate biomarkers in the peripheral blood with clinical response, and present follow-up results for pts who received BV + Nivo under staggered and concurrent dosing schedules. Methods Enrolled pts had cHL that relapsed or was refractory to frontline chemotherapy. In Parts 1 and 2 (staggered dosing), pts received up to 4 cycles of BV 1.8 mg/kg and Nivo 3.0 mg/kg given on Days 1 and 8 of Cycle 1, respectively, and together on Day 1 of Cycles 2-4. Pts in Part 3 (concurrent dosing) received the same dose of both agents on Day 1 of all 4 cycles. After investigators assessed response (Cheson 2014, with the incorporation of LYRIC [Cheson 2016] for pts in Part 3), pts could undergo ASCT. Results Demographics and baseline characteristics were similar across all treated pts (N=91) in the staggered and concurrent dosing cohorts; median age 34 years (yrs, range; 18-69), 42% with primary refractory disease, and 30% with relapse within 1 yr of frontline therapy. All 91 pts are off-tx and have been observed through the 100-day safety reporting period. A total of 86 pts (92%) completed all 4 cycles of BV + Nivo. Early tx discontinuations were due to; AE (peripheral neuropathy and increased GGT [1 pt each]), progressive disease (PD), investigator decision, and pt decision (1 pt each). Most common AEs prior to ASCT or additional salvage therapy were nausea (52%) and infusion-related reactions (IRRs, 43%). Excluding IRRs, 14% of pts had immune-related AEs requiring tx with systemic steroids, including rash (8%), pneumonitis (4%), and AST increased, diarrhea, and Guillain-Barre syndrome (1% each). The ORR for all-treated pts was 85%, with 67% complete response (CR). A total of 67 pts (74%) underwent ASCT after tx with BV + Nivo. There were 22 pts who received additional salvage therapy after BV + Nivo (7 PD, 6 partial response, 5 stable disease, and 4 CR at EOT), 17 of whom later underwent ASCT. At a median of 22.6 months (range; 1.2, 41.2) from the start of tx, the estimated 2-yr PFS rate in all treated pts was 78%, and for pts who underwent ASCT after tx with BV + Nivo was 91% (Figure 1). At 2 years, the estimated OS rate for all treated pts was 93%. Staggered and concurrent dosing of BV + Nivo resulted in increased levels of activated and dividing CD4+ T cells, activated and dividing CD8+ T cells (concurrent dosing-only), regulatory T cells (Tregs), and circulating plasmablasts in blood. We did not observe any associations between the magnitude of these changes and clinical response. Pts with CR exhibited trends for higher pre-tx blood levels of CD30+ Tregs and CD30+ Th subsets compared to pts without CR, suggesting BV depletion of these populations may have a role in the clinical mode of action of BV + Nivo. Although pre-tx levels of cytotoxic lymphocytes (CTLs) in blood did not differentiate pts with CR from other pts, pts in the lower quartile of pre-tx CTL levels showed significantly shorter PFS than other pts, suggesting a potential association between CTLs and disease control. Changes in blood cytokine and chemokine levels were observed after BV + Nivo, including increased levels of IL-18, IP-10, I-TAC, and sCD30, and decreased levels of TARC, IL-2Ra, and IL-6. Our analyses support strong correlations between pre-tx cytokine/chemokine levels and clinical benefit including trends linking lower pre-tx levels of IL-18, I-TAC, and IL-2RA to achieving CR and longer PFS. Conclusion BV + Nivo, both staggered and current dosing, showed tolerability and high CR rates with durable remissions among pts with R/R cHL. Analysis of blood biomarkers identified trends potentially linking baseline levels of CD30+ immune cells and the baseline pt inflammatory state with the activity of BV + Nivo. Together, these encouraging results support further investigation of BV + Nivo as initial salvage therapy in pts with R/R cHL. Figure 1 Disclosures Moskowitz: Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Merck: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Incyte: Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding. Advani:Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Forty-Seven: Research Funding; Infinity Pharma: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Merck: Research Funding; Kura: Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agensys: Research Funding; Cell Medica, Ltd: Consultancy; Stanford University: Employment, Equity Ownership; Seattle Genetics: Consultancy, Research Funding; Millennium: Research Funding; Janssen: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bartlett:Affimed Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Dynavax: Research Funding; Forty-Seven: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medimmune: Research Funding; Merck: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Vose:Acerta Pharma: Honoraria, Other: Grants, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Celgene Corporation: Research Funding; Incyte Corporation: Research Funding; Kite Pharma: Honoraria, Other: Grants, Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; AbbVie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Legend Pharmaceuticals: Honoraria. Ramchandren:Genentech: Research Funding; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Pharmacyclics LLC, an Abbvie company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Sandoz-Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Feldman:Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Pfizer: Research Funding; Portola Pharma: Research Funding; Roche: Research Funding; Trillium: Research Funding; Viracta: Research Funding. LaCasce:BMS: Consultancy; Research to Practice: Speakers Bureau; Humanigen: Consultancy; Seattle Genetics: Consultancy, Research Funding. Christian:Bristol-Myers Squibb: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Research Funding; Janssen: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Acerta: Research Funding; Triphase: Research Funding; Millennium Pharmaceuticals Inc: Research Funding; Merck: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding. Moskowitz:ADC Therapeutics: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding. Brown:Seattle Genetics, Inc.: Employment, Equity Ownership. Taft:Seattle Genetics, Inc.: Employment, Equity Ownership. Ansari:Seattle Genetics, Inc.: Employment, Equity Ownership. Zak:Seattle Genetics, Inc.: Employment, Equity Ownership. Sacchi:Seattle Genetics, Inc.: Research Funding. Manley:Seattle Genetics: Employment, Equity Ownership. Herrera:Merck: Consultancy, Research Funding; AstraZeneca: Research Funding; Adaptive Biotechnologies: Consultancy; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding.

Background: Angioimmunoblastic T-cell lymphoma (AITL) is a relatively common subtype of peripheral T-cell lymphoma (PTCL) that typically presents with lymphadenopathy, extranodal disease, including rash, and is associated with frequent infections due to immune dysregulation. Patients with AITL generally have a poor prognosis, even with aggressive chemotherapy as responses to standard chemotherapy are often suboptimal. Recent advances in cancer biology suggest that AITL is derived from T-follicular helper cells and is often characterized by gross epigenetic dysregulation. Histone deacetylase (HDAC) inhibitors have demonstrated significant activity in T-cell neoplasms. The BELIEF trial established an overall response rate of 25% in patients with relapsed/refractory PTCL who were treated with belinostat, with a duration of response of about 1 year, leading to accelerated approval. Herein, we present a subset analysis of the data for patients with AITL. Methods: Patients with histologically confirmed PTCL (N = 129) who experienced failure with or refractory to ≥ 1 prior systemic therapy received belinostat 1,000 mg/m(2) as daily 30-minute infusions on days 1 to 5 every 21 days. Central assessment of response used International Working Group criteria. Primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response (DoR) and progression-free and overall survival (PFS). Results: Of 129 patients, 22 patients had AITL; most had advanced disease (91% stage III/IV; 36% with bone marrow involvement). The median number of prior therapies was 2 (range, 1-5), and 3 (14%) patients were refractory to their last line of therapy. The ORR for patients with AITL was 46% (10/22; 95%CI: 24 - 68%), with a complete response (CR) in 4 of 22 patients (18%). Of the ten responders, the median time to response of 11.3 weeks (range, 4.7 - 24.4 weeks) in the AITL subgroup. After a median follow up of 21.5 months, the median PFS was 4.2 months (95%CI: 1.5 -13.9) and the median DOR was 13.6 months (95%CI: 1.4 - 29.4) as shown in Figure 1. For all patients with AITL treated with belinostat, the median OS was 9.2 months (95%CI: 6.8 - 21.5). The most common grade 3 to 4 adverse events were asthenia (n=2), fatigue (n=2), anemia (n=2), thrombocytopenia (n=2), neutropenia (n=2), and septic shock (n=2). Conclusions: Single-agent belinostat induced rapid and durable responses in patients with relapsed/refractory AITL. At the end of the study, there were 37% patients with ongoing responses at 2 years. Patients with clinical benefit from belinostat continued treatment until progression of disease. These results support the use of belinostat in relapsed/refractory AITL as a single agent and provide rationale for combination therapies in clinical trials. Disclosures Sawas: Seattle Genetics, Gilead, Daiichi Sanko: Consultancy; Affimed: Research Funding. Shustov:Spectrum Pharmaceuticals: Consultancy, Research Funding. Hsu:Spectrum Pharmaceuticals: Employment. Bhat:Spectrum Pharmaceuticals: Employment. Acosta:Acrotech Biopharma: Employment. Horwitz:Astex: Consultancy; Kyowa Hakko Kirin: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Innate Pharma: Consultancy; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Kura: Consultancy; ADCT Therapeutics: Research Funding; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Aileron: Research Funding; Trillium: Research Funding; Miragen: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kura: Consultancy; Forty-Seven: Research Funding; Millennium/Takeda: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Mundipharma: Consultancy; Kura: Consultancy; Miragen: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy; Astex: Consultancy; Seattle Genetics: Consultancy, Research Funding; Astex: Consultancy; Portola: Consultancy; Celgene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Aileron: Research Funding; Trillium: Research Funding; Forty-Seven: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Innate Pharma: Consultancy; Miragen: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; Portola: Consultancy; Mundipharma: Consultancy; Portola: Consultancy; Aileron: Research Funding; Forty-Seven: Research Funding; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Seattle Genetics: Consultancy, Research Funding; Portola: Consultancy; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Innate Pharma: Consultancy; Kyowa Hakko Kirin: Consultancy; Miragen: Consultancy; Affimed: Consultancy; Affimed: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Innate Pharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Forty-Seven: Research Funding; Affimed: Consultancy; Millennium/Takeda: Consultancy, Research Funding. O'Connor:Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADCT Therapeutics, Affimed, Agensys, Merck, Seattle Genetics, Spectrum, Trillium, and Verastem Oncology.: Research Funding; TG Therapeutics: Other: Travel Support, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Introduction: MAVORIC was an open-label, multicenter, randomized phase 3 study evaluating the safety and efficacy of mogamulizumab (moga) compared to vorinostat (vori) in patients with mycosis fungoides (MF) or Sézary syndrome (SS) who had failed at least one prior course of systemic therapy (NCT01728805). Primary results have been reported (Kim et al. Lancet Oncol 2018) and were based on a data cutoff date of December 31, 2016. The primary endpoint was progression-free survival (PFS); patients in the moga treatment arm experienced significantly longer PFS compared to patients in the vori treatment arm (median 7.7 months vs 3.1 months; p<0.0001). The most common treatment-emergent adverse events (TEAEs) of any cause or grade reported in patients randomized to moga were: infusion-related reaction (33.2%), drug eruption (ie, skin rash attributed to moga [23.9%]), diarrhea (23.4%), and fatigue (23.4%). This report provides the final safety results of MAVORIC as of the data available on January 3, 2019. Methods: Patients were randomized 1:1 to moga 1.0 mg/kg administered intravenously on Days 1, 8, 15, and 22 of the first cycle and on Days 1 and 15 of subsequent cycles or vori 400 mg administered orally once daily. Patients randomized to vori were allowed to cross over to moga upon progression or intolerable toxicity. Safety was assessed by reported adverse events (AEs), changes in physical examinations, vital sign measurements, electrocardiograms, and laboratory analyses. Results: In total, 372 patients were randomized (moga, 186; vori, 186), of whom 370 received study drug and were included in the safety analysis (moga, 184; vori, 186). For the final safety analysis, median duration of follow-up was 34.5 months (range, 0.13-70.0) in the randomized part of the study. Median treatment exposure was 170 days (range, 1-1813) for moga and 84 days (4-1230) for vori, which represent the same median values but broader ranges compared to the primary analysis (primary analysis, 170 days [1-1379] for moga and 84 days [4-1058] for vori). The type and frequency of AEs in either the moga or vori treatment groups (Table) were consistent with those reported in the primary analysis. TEAEs, regardless of causality, that were reported at similar rates in the two treatment groups included constipation, peripheral edema, headache, and anemia. TEAEs (all causality) that occurred at higher frequency in the moga vs vori arm included infusion-related reaction (33.2% vs 0.5%) and drug eruption (25.0% vs 1.1%); the majority of these events were grade 1 or 2 (Table). The types and frequencies of AEs attributable to moga (per Investigator assessment) included infusion-related reaction (33.2% [61/184]), drug eruption (23.9% [44/184]), and fatigue (18.5% [34/184]), and for vori, diarrhea (55.4% [103/186]), nausea (38.2% [71/186]), and fatigue (33.3% [62/186]). In patients who crossed over from the vori to moga arm and received study drug (n=135), the most frequently reported AEs attributable to moga were infusion-related reaction (37.8% [51/135]), drug eruption (24.4% [33/135]), fatigue (7.4% [10/135]), increased alanine aminotransferase (7.4% [10/135]), and increased aspartate aminotransferase (7.4% [10/135]). Discontinuation rates due to AEs were similar between treatment arms and in crossover patients (moga, 21.7% [40/184]; vori, 23.7% [44/186]; crossover, 25.9% [35/135]). The most common AEs leading to discontinuation were drug eruption in the moga arm (7.1% [13/184]) and fatigue in the vori arm (4.3% [8/186]). Overall, the rates of drug-related serious TEAEs were similar between treatment arms and in crossover patients (moga, 19.6% [36/184]; vori, 16.7% [31/186]; crossover, 11.9% [16/135]). After the data cutoff for the primary analysis, 1 additional patient randomized to moga (decreased appetite, general physical health deterioration, hypoalbuminemia) and 1 crossover patient (cerebral hemorrhage) experienced TEAEs with an outcome of death, all considered unrelated to study treatment per Investigator. Conclusions: This final safety analysis from the MAVORIC study in patients with previously treated MF and SS demonstrates that moga was generally well tolerated. Longer follow-up and treatment exposure did not identify any new safety signals. The type and incidence of treatment-related AEs among patients receiving moga after crossover were similar to those observed for patients initially randomized to moga. Disclosures Kim: Merck: Research Funding; Portola Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon: Research Funding; Corvus: Honoraria, Membership on an entity's Board of Directors or advisory committees; Galderma: Research Funding; Elorac: Research Funding; Soligenix: Research Funding; Kyowa Hakko Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medivir: Honoraria, Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Neumedicine: Research Funding; miRagen: Research Funding. Bagot:Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zinzani:MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Duvic:Seattle Genetics: Consultancy, Honoraria, Research Funding; Eisai: Research Funding; Shape: Research Funding; UT MD Anderson Cancer Center: Employment; USCLC Registry: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Secretary/treasurer of Item h; Spatz Foundation: Research Funding; Tetralogic: Research Funding; Millennium (formerly Takeda): Research Funding; Mallinckrodt Pharmaceuticals (formeraly Therakos, Inc): Research Funding; Kyowa Hakko Kirin Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees; PleXus Communications: Speakers Bureau; Guidepoint Global: Consultancy; Evidera, Inc.: Consultancy; Cell Medica Inc.: Consultancy; Allos: Research Funding; Rhizen Pharma: Research Funding; Oncoceuticals: Research Funding; Soligenetics: Research Funding; Cell Medica Ltd.: Honoraria; Therakos: Speakers Bureau; Jonathan Wood & Assoc.: Speakers Bureau; Hawaiian Dermatology Society: Speakers Bureau; Hemedicus: Speakers Bureau; Janssen Pharmaceuticals (div of Johnson & Johnson): Speakers Bureau. Morris:Guys Hospital: Employment. Kim:Medimmune: Research Funding; Soligenix: Research Funding; Kyowa Kirin: Research Funding; Galderma: Consultancy, Research Funding; Actelion: Consultancy, Research Funding. Musiek:Menlo: Other: Investigator; Helsinn: Membership on an entity's Board of Directors or advisory committees; Soligenix: Other: Investigator; Pfizer: Other: Investigator; Elorac: Other: Investigator; Kyowa: Honoraria, Other: Above honoraria: for Ad Board; miRagen: Other: Investigator. Ortiz-Romero:Actelion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kyowa: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; PLCG1: Patents & Royalties; miRagen: Membership on an entity's Board of Directors or advisory committees; MEDA: Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; 4SC: Membership on an entity's Board of Directors or advisory committees. Eradat:Kyowa: Research Funding; Kite: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Research Funding; Genentech: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Research Funding. Magnolo:University Hospital of Muenster, Center of Innovative Dermatology: Employment. Scarisbrick:Kyowa Kirin: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Recordat: Consultancy; 4SC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Helsinn: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dalle:Kyowa: Other: Principal Investigator in clinical trials promoted by Kyowa. Fisher:Kyowa Kirin: Consultancy. Poligone:Stemline Therapeutics: Consultancy, Speakers Bureau; Regeneron: Consultancy, Speakers Bureau; Actelion: Consultancy, Speakers Bureau; Astex Pharmaceuticals: Research Funding; Bioniz: Research Funding; Celgene: Consultancy; Helsinn: Research Funding, Speakers Bureau; Innate Pharma: Research Funding; Kyowa Hakko Kirin: Consultancy, Honoraria, Research Funding, Speakers Bureau; miRagen: Research Funding; Soligenix: Research Funding. Pro:Takeda: Consultancy, Honoraria, Other: Travel Expenses; Celgene: Consultancy, Honoraria; Kyowa Hakka Kirin: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Quaglino:Actelion: Honoraria, Other: Advisory Board; Innate Pharma: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Kyowa Kirin: Honoraria, Other: Advisory Board; Helsinn: Honoraria, Other: Advisory Board; Therakos: Honoraria, Other: Advisory Board. Reddy:AbbVie: Honoraria; Janssen: Honoraria; KITE: Honoraria; Merck: Research Funding; Celgene: Honoraria, Speakers Bureau. Geskin:Merck: Other: Supported/Contracted Research; UpToDate: Patents & Royalties: Royalty, Receipt of Intellectual Property Rights / Patent Holder; Actelion: Other: Supported/Contracted Research; Helsinn: Consultancy, Honoraria, Other: Supported/Contracted Research; Stratpharma: Other: Supported/Contracted Research; Mallinckrodt: Consultancy, Honoraria, Other: Supported/Contracted Research; Medscape: Speakers Bureau; Medivir: Consultancy, Honoraria. Halwani:Amgen: Other: Investigator; Takeda: Other: PI; Seattle Genetics: Other: PI; Pharmacyclics: Other: Investigator; miRagen: Other: PI; Kyowa Hakko Kirin: Other: PI; Immune Design: Other: PI; Genentech, Inc.: Other: Investigator; Bristol-Myers Squibb: Other: PI; AbbVie: Other: PI. Khot:Peter MacCallum Cancer Centre: Employment; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy; Janssen: Consultancy; Kyowa Hakko Kirin: Consultancy. Korman:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dermira: Research Funding; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa: Research Funding; Leo: Research Funding; Menlo: Research Funding; Merck: Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Research Funding; Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Research Funding; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rhizen: Research Funding; Sun: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syntimmune: Research Funding; UCB: Research Funding; Valeant: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Horwitz:Seattle Genetics: Consultancy, Research Funding; Affimed: Consultancy; Astex: Consultancy; Portola: Consultancy; ADCT Therapeutics: Research Funding; Kyowa Hakko Kirin: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Forty-Seven: Research Funding; Celgene: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Miragen: Consultancy; Innate Pharma: Consultancy; Kura: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Miragen: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Portola: Consultancy; Kura: Consultancy; Celgene: Consultancy, Research Funding; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Aileron: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Portola: Consultancy; Aileron: Research Funding; Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Mundipharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Portola: Consultancy; Kura: Consultancy; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Aileron: Research Funding; Affimed: Consultancy; Trillium: Research Funding; Innate Pharma: Consultancy; Affimed: Consultancy; Astex: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Miragen: Consultancy; Trillium: Research Funding; Innate Pharma: Consultancy; Forty-Seven: Research Funding; Forty-Seven: Research Funding; Innate Pharma: Consultancy; Astex: Consultancy; Seattle Genetics: Consultancy, Research Funding. Lamar:Seattle Genetics: Consultancy; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moskowitz:Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding. Wells:Takeda Pharmaceuticals Australia Pty Limited: Membership on an entity's Board of Directors or advisory committees; MSD Australia: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Akilov:Trillium Therapeutics: Consultancy, Other: PI on the clinical trials, Research Funding; Pfizer: Research Funding. Cowan:Kyowa Kirin: Consultancy. Dummer:Merck Sharp & Dohme: Other: Intermittent, project focused consulting and/or advisory relationships; Novartis: Other: Intermittent, project focused consulting and/or advisory relationships; Bristol-Myers Squibb: Other: Intermittent, project focused consulting and/or advisory relationships; Roche: Other: Intermittent, project focused consulting and/or advisory relationships; Amgen: Other: Intermittent, project focused consulting and/or advisory relationships; Takeda: Other: Intermittent, project focused consulting and/or advisory relationships; Pierre Fabre: Other: Intermittent, project focused consulting and/or advisory relationships; Sun Pharma: Other: Intermittent, project focused consulting and/or advisory relationships; Sanofi: Other: Intermittent, project focused consulting and/or advisory relationships; Catalym: Other: Intermittent, project focused consulting and/or advisory relationships; Second Genome: Other: Intermittent, project focused consulting and/or advisory relationships. Lechowicz:Kyowa Kirin Inc: Consultancy; Spectrum: Consultancy. Foss:Eisai: Consultancy; Seattle Genetics: Consultancy, Other: fees for non-CME/CE services ; miRagen: Consultancy; Acrotech: Consultancy; Mallinckrodt: Consultancy; Spectrum: Other: fees for non-CME/CE services . Wilcox:University of Michigan: Employment. Porcu:Innate Pharma: Honoraria, Other: Scientific Board, Research Funding; Viracta: Honoraria, Other: Scientific Board, Research Funding; BeiGene: Other: Scientific Board, Research Funding; Incyte: Research Funding; Daiichi: Research Funding; Kyowa: Honoraria, Other: Scientific Board, Research Funding; ADCT: Research Funding; Spectrum: Consultancy. Vermeer:Kyowa: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Abhyankar:Therakos: Other: Consulting, Speakers Bureau; Incyte: Speakers Bureau. Pacheco:University of Colorado: Employment. William:Techspert: Consultancy; Guidepoint Global: Consultancy; Defined Health: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy. Fukuhara:Kyowa-Hakko Kirin: Honoraria; Bayer: Research Funding; Mundi: Honoraria; Janssen Pharma: Honoraria; Mochida: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Eisai: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Nippon Shinkyaku: Honoraria; Zenyaku: Honoraria; AbbVie: Research Funding; Gilead: Research Funding; Solasia Pharma: Research Funding. Munoz:Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Portola: Research Funding; Incyte: Research Funding; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Pfizer: Consultancy. Querfeld:Elorac: Other: Investigator, Research Funding; Trillium: Consultancy, Other: Investigator, Research Funding; Medivir: Consultancy; miRagen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Helsinn: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Soligenix: Other: Investigator; City of Hope Cancer Center and Beckman Research Institute: Employment; Celgene: Other: Investigator, Research Funding; Kyowa: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Eisai: Other: Investigator; Bioniz: Membership on an entity's Board of Directors or advisory committees, Other: Investigator. Uhara:Kyowa Kirin Co., Ltd: Honoraria, Research Funding. Huen:Innate Pharmaceuticals: Research Funding; Galderma Inc: Research Funding; Rhizen Pharmaceuticals: Research Funding; Glaxo Smith Kline Inc: Research Funding. Tobinai:Meiji Seika: Honoraria; Takeda Pharmaceutical: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Janssen Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Ono Pharmaceutical: Consultancy, Honoraria, Research Funding; Zenyaku Kogyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Mundi Pharma: Consultancy, Honoraria, Research Funding; Eisai: Honoraria, Research Funding; HUYA Bioscience: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; AbbVie: Research Funding; Verastem: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Yakult: Honoraria; Solasia: Honoraria. Tokura:Kyowa Kirin Pharmaceutical Development, Inc.: Honoraria. Boh:Actelion: Other: Principal Investigator; Tulane University School of Medicine: Employment; Celgene: Other: Principal Investigator, Speaker, Grants; Sun: Other: Speaker; Janssen: Other: Principal Investigator, Speaker, Grants; Novartis: Other: Principal Investigator, Speaker, Grants; Soligenix: Other: Principal Investigator; Incyte: Other: Principal Investigator; Regeneron: Other: Principal Investigator, Grants; Ortho Dermatologics: Other: Speaker, Grants; Pfizer: Other: Principal Investigator; UCB: Other: Speaker, Grants; Elorac: Other: Principal Investigator; Abbvie: Other: Principal Investigator. Nicolay:Teva Pharmaceutical Industries: Honoraria, Other: Conference participation fees; Novartis AG: Consultancy, Honoraria; Biogen GmbH: Consultancy, Honoraria; Almirall Hermal AG: Consultancy, Honoraria; Actelion Pharmaceuticals: Consultancy, Honoraria; Innate Pharma: Consultancy; Kyowa Hakko Kirin: Consultancy, Honoraria; Takeda Pharmaceuticals: Consultancy. Leoni:Kyowa Kirin Pharmaceutical Development, Inc.: Employment. Ito:Kyowa Kirin Pharmaceutical Development, Inc.: Employment. Herr:Kyowa Kirin, Inc.: Employment. Sokol:EUSA: Consultancy.

Perennial ryegrass (PR) (Lolium perenne L.) is often used as a low-mowed turf in the transition climatic zone. However, control of the fungal disease gray leaf spot (Pyricularia grisea (Cooke) Sacc.) has drastically increased the cost of PR management. Seeded bermudagrasses (SB) [Cynodon dactylon (L.) Pers.] are viable options for turfgrass management operations with limited pesticide budgets. Field trials in 2000 and 2001 tested the effects of two herbicides and several plant growth regulators (PGR) during renovation of mature PR to either of two cultivars of SB. The herbicides glyphosate and pronamide, and the PGR's trinexapac-ethyl, ethephon, paclobutrazol, and flurprimidol were applied at label rates to mature stands of PR. `Mirage' and `Yukon' SB were seeded separately either 1 or 7 days after applications (DAA) of chemicals. SB establishment, first-winter survival, and turfgrass quality (TQ) were rated and compared to an untreated control. Results indicated that only applications of glyphosate resulted in acceptable renovation of PR to SB, but also resulted in significantly lower (P< 0.05) TQ during the transition. Applications of pronamide resulted in significantly less (P < 0.05) SB transition than did applications of glyphosate, but pronamide plots maintained higher TQ. None of the PRG treatements had a significant effect (P < 0.05) on SB transition. There were no consistent significant effects (P < 0.05) due to DAA among any of the chemicals evaluated. First-winter survival was significantly higher (P < 0.05) with `Yukon' than with `Mirage' in both years. We conclude that among the chemicals tested, only applications of glyphosate resulted in acceptable transition of PR to SB, but a significant reduction of TQ should be expected during the transition. Chemical names used: [N-(phosphonomethyl) glycine] (glyphosate); [3.5-dichloro-N-(1,1-dimethyl-2-propynyl)-benzamide] (pronamide); [(2-chloroethyl) phosphonic acid] (ethephon); [4-(cyclopropyl-α-hydroxy-methylene)-3,5-dioxo-cyclohexane-cabroxylic acid ethyl ester] (trinexapac-ethyl); [(±)-(R*R*)β-[(4-chlorophenyl)-methyl]-α-(1,1-dimethylethyl)-1H-1,2,4-triazole-1-ethanol] (paclobutrazol); [α-(1-methylethyl)-α-[4-(trifluromethoxy)phenyl]-5-pyrmidinemethanol] (flurprimidol).

SummaryIn this article, the history of the so-called ablative absolute as a descriptive category is traced from the 3rd to the 20th century. Texts by Sacerdos, Diomedes, Priscian, Alberic of Montecassino, Kühner & Stegmann and Harm Pinkster illustrate how the ablative absolute is recognized long before it get its name, and how its role in grammatical description is invented, changes, and disappears again in accordance with the grammatical systems adopted by the respective grammarians. The ablative absolute starts as a kind of appendix to the doctrine of the parts of speech, is moved from the description of the noun to that of the participle, and eventually just fades away as a descriptive label in its own right in the context of Functional Grammar. Its history cannot, of course, prove that the ‘God’s Truth’ metaphysics of grammar is wrong, but it certainly looks like a series of manifestations of grammatical ‘Hocus Pocus’.RésuméDans cet article, on suit l’histoire de la description du soi-disant ablatif absolu du troisième au vingtième siècle. Des textes de Sacerdos, Diomède, Priscien, Alberic de Montecassino, Kühner & Stegmann et de Harm Pinkster rendent compte de la reconnaissance de l’existence de l’ablatif absolu avant qu’on ne l’appelle ainsi. On montre comment son rôle dans la description grammaticale se voit inventé, se transforme et ensuite disparaît selon le système de catégories grammaticales des divers grammairiens. L’ablatif absolu, à l’origine sorte d’appendice à la doctrine des ‘parties du discours’, passe de la description du nom à celle du participe, et enfin disparaît en tant que terme descriptif sui iuris dans le contexte de la grammaire fonctionnelle. Son histoire ne prouve nullement que la métaphysique de la vérité objective, en grammaire, est fausse, mais elle semble bien montrer l’existence de ‘mirages’ linguistiques.ZusammenfassungIn diesem Beitrag wird die Geschichte der deskriptiven Kategorie desablativus absolutusvom dritten bis zum zwanzigsten Jahrhundert geschildert. Texte von Sacerdos, Diomedes, Priscianus, Alberic von Montecassino, Kühner & Stegmann und Harm Pinkster illustrieren die Art und Weise, wie derablativus absolutuserkannt wurde, bevor er seinen technischen Namen erhielt; wie seine Rolle in der grammatischen Deskription entdeckt wurde, wie sich diese allmählich änderte, und wie sie schliesslich verschwand, immer in Übereinstimmung mit den grammatischen Systemen des jeweiligen Grammatikers. Derablativus absolutusist ursprunglich eine Art von Appendix zur Lehre der Redeteile, zieht sich von der Beschreibung des Nomens bis zu der des Partizipiums hin und verschwindet schliesslich einfach wie ein eigenständiges deskriptives Etikett inm Kontext der funktionellen Grammatik. Obwohl seine Geschichte natürlich kein Argument gegen die grammatische Metaphysik der ‘God’s Truth’ sein kann, sieht sie sicherlich eher aus wie eine Serie von Manifestationen des grammatischen ‘Hocus Pocus’.

The Ivory Coast was lauded as a development ‘success’ for 20 years after independence in 1960. In fact, the 1978 World Bank report on the Ivory Coast was sub-titled ‘the challenge of success’. Six years after the publication of this economic study, the so-called ‘miracle’ looked more like a mirage, so much so that an analyst could write: ‘no African country's creditworthiness has fallen more spectacularly than that of the Ivory Coast’. Domestically, it has been obliged to implement a severe austerity programme, and externally, to request a rescheduling of its debt. From a real growth rate of G.N.P. that had averaged more than 7 per cent a year since 1960, growth fell to 2 per cent in 1981, to zero per cent in 1982, and to −4.3 per cent in 1983.

Celebrity Manufacture Theory postulates that both the emergence of celebrities and our fascination with them are shaped by the media. Another premise of the theory is that a person’s fame does not necessarily correlate with the talent or achievements of that person. Rather, it often depends on the way the media manufacture that person as a celebrity. Today’s celebrity culture extols a particular type of fame ‐ one created and sustained by media production. Hence, there is a painstaking method of personification and commodification at work. The pursuit for authenticity is not the objective of Celebrity Manufacture Theory. For this reason, the theory is an example of a ‘manipulation theory’. It describes how media industries manipulate audiences through mass-mediated celebrity production. To best understand Celebrity Manufacture Theory, four major tenets are thoroughly described in this article: (1) media mirage, (2) democratization of spotlight, (3) commodity and (4) cultural mutation.

255 Background: Magnetic resonance imaging (MRI) guidance offers several theoretical advantages over computed tomography (CT) guidance in the context of stereotactic body radiotherapy (SBRT) for intact prostate cancer. Here we report the results of an interim analysis of the phase III MIRAGE trial, which directly compared MRI- and CT-guidance with a pragmatic primary endpoint of acute grade ≥2 genitourinary (GU) toxicity. Methods: MIRAGE is a single center, randomized phase 3 trial. Men undergoing SBRT for localized prostate cancer were randomly assigned to either CT-guidance or MRI-guidance. Planning margins of 4 mm (CT-arm) and 2 mm (MRI-arm) were placed around the prostate and proximal seminal vesicles, and this volume received 40 Gy in five fractions. Elective nodal radiotherapy and rectal spacers were allowed per physician discretion. The primary outcome was the incidence of acute (i.e., within 90 days of SBRT) grade ≥2 GU physician-reported toxicity (by CTCAE version 4.03). Secondary outcomes of interest included the incidence of acute grade ≥2 GU physician-reported toxicity, changes in IPSS scores at 1 and 3 months, and changes in EPIC-26 bowel domain summary scores at 1 and 3 months. A pre-specified efficacy analysis was planned once the 100th patient was eligible for evaluation of the primary endpoint. Results: On 9/1/2021, 100 patients became eligible for evaluation for the interim analysis (51 CT arm, 49 MRI arm). Acute grade ≥2 GU toxicity was significantly reduced in men receiving MRI-guided SBRT (incidence of 24 (47.1%) vs. 11 (22.4%), p = 0.01). Acute grade ≥2 GI toxicity was also significantly reduced in men receiving MRI-guided SBRT (incidence of 7 (13.7%) vs. 0 (0%), p = 0.01.). The increase in IPSS scores from baseline was significantly higher in men receiving CT-guided SBRT at 1 month post-SBRT (median change of 10 vs. 6, p = 0.03), but not at 3 months (median change of 3 vs. 2, p = 0.3). The decrement in EPIC-26 bowel domain scores was significantly greater at 1 month in men receiving CT-guided SBRT (median change of -8.3 vs. 0, p = 0.03), but not at 3 months (median change of -2.3 vs. 0, p = 0.4). Given the large primary endpoint signal seen, our protocol was amended to reduce the projected sample size to 154 while still maintaining 89% power to detect a difference. Conclusions: This interim analysis demonstrates a statistically significant reduction in acute grade ≥2 GU toxicity with MRI-guidance versus CT-guidance in the context of prostate SBRT. Patient-reported urinary and bowel function metrics are also better preserved at the 1 month time point with MRI-guidance, though this difference dissipates (potentially due to side-effect management) at the 3 month time point. Accrual has been completed as of October 2021 and a final analysis for the primary endpoint is anticipated in early 2022. Clinical trial information: NCT04384770.

Introduction Relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) carries a poor prognosis, with most approved therapies having response rates of &lt; 30% and limited progression-free survival (PFS). Duvelisib (DUV), a dual PI3K-δ,γ inhibitor, is FDA approved at 25 mg twice daily (BID) for the treatment of R/R chronic lymphocytic leukemia or small lymphocytic lymphoma after ≥ 2 lines of prior therapy and R/R follicular lymphoma after ≥ 2 prior systemic therapies. DUV exhibited potent activity against T-cell lymphoma cell lines in vitro, and DUV monotherapy at 25 or 75 mg BID demonstrated clinical activity in patients (pts) with R/R peripheral T-cell lymphoma (PTCL) in phase 1 studies [overall response rate (ORR), 50%] across multiple subtypes (Horwitz et al. Blood 2018; Horwitz et al. 2019 ICML). The phase 2 PRIMO trial was designed to determine an optimal regimen of DUV monotherapy in R/R PTCL and characterize the efficacy and tolerability of DUV in this disease. We report the results for the dose-optimization phase of the PRIMO trial (NCT03372057). Methods In the dose-optimization phase, pts with R/R PTCL, ECOG performance score of ≤ 2, and no history of allogeneic stem cell transplant were randomized to receive DUV 25 mg BID with an option for dose escalation (cohort 1) or DUV 75 mg BID (cohort 2) continuously until development of progressive disease or unacceptable toxicity (cycle = 28 days). The primary endpoint was investigator-assessed ORR, and secondary endpoints included duration of response and safety. Results A total of 33 pts (cohort 1, n = 20; cohort 2, n = 13) were treated in the dose-optimization phase (Table). Pts had a median of 1.5 years (range, 0.3-12.7 years) from initial diagnosis and a median of 2 prior therapies (range, 1-8). Patients were evaluable if they completed 1 cycle of DUV and had ≥ 1 efficacy assessment. Nonevaluable patients could be replaced. Response was assessed in the evaluable and overall populations. All patients in cohort 2 and 13 of 20 patients in cohort 1 were able to complete 1 cycle of therapy. Seven patients in cohort 1 discontinued therapy early due to disease progression and/or toxicity. Low CD4 counts (&lt; 50 cells/mm3; Common Terminology Criteria for Adverse Events grade 4) were associated with early discontinuation of DUV. Most responses (cohort 1, 5/7; cohort 2, 6/7) were observed at the end of cycle 1. At a median follow-up of 20 weeks, the majority of responders (cohort 1, 4/7; cohort 2, 6/7) were still in response at the time of their last assessment. ORR as assessed by blinded independent central review could be determined for 31 patients and was 42% in cohort 1 and 67% in cohort 2. Table. Analysis Populations and Investigator-Assessed Response Pharmacokinetic analysis demonstrated a dose-related increase in exposure, with ≈ 2-fold increase in the steady-state exposure of DUV at the 75 vs 25 mg BID dosage, suggesting that adequate exposure can be more rapidly and reliably achieved with a higher dose of DUV. No differences were observed in pharmacodynamic markers (pAKT in monocytes and B cells) at 25 and 75 mg dose levels. The most common (≥ 3 patients) grade ≥ 3 adverse events (AEs) in all patients receiving DUV were neutropenia (7), thrombocytopenia (5), and sepsis (4), with disease progression, pneumonia, aspartate aminotransferase elevation, lymphopenia, dyspnea, and rash observed in 3 patients. Serious AEs occurring in ≥ 2 patients were colitis, pyrexia, disease progression, sepsis, pneumonia, hyponatremia, dyspnea, pneumonitis, and respiratory failure. Overall, 12% of pts receiving DUV discontinued due to an AE. Conclusions These findings confirm that both 25 and 75 mg BID starting dosages of DUV are clinically active in pts with R/R PTCL, with complete responses in both cohorts. There were no unexpected toxicities. Early progression was seen more frequently in the 25 mg cohort, and higher initial exposure may be important in aggressive diseases. The expansion phase of the PRIMO trial will investigate DUV starting at 75 mg BID for 2 cycles to achieve rapid tumor response, followed by 25 mg BID to maintain long-term disease control and mitigate the potential for later onset toxicity. Disclosures Horwitz: Miragen: Consultancy; Celgene: Consultancy, Research Funding; Aileron: Research Funding; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin: Consultancy; Astex: Consultancy; Affimed: Consultancy; Kura: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Portola: Consultancy; Affimed: Consultancy; Celgene: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Innate Pharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; ADCT Therapeutics: Research Funding; Portola: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Portola: Consultancy; Forty-Seven: Research Funding; Trillium: Research Funding; Aileron: Research Funding; Celgene: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Kura: Consultancy; Seattle Genetics: Consultancy, Research Funding; Astex: Consultancy; Forty-Seven: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADCT Therapeutics: Research Funding; Astex: Consultancy; Miragen: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Miragen: Consultancy; Mundipharma: Consultancy; Innate Pharma: Consultancy; Forty-Seven: Research Funding; Celgene: Consultancy, Research Funding; Innate Pharma: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Research Funding; Affimed: Consultancy; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Forty-Seven: Research Funding; Kyowa Hakko Kirin: Consultancy; Kura: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Miragen: Consultancy; Trillium: Research Funding; Kura: Consultancy; Mundipharma: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Trillium: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Portola: Consultancy; ADCT Therapeutics: Research Funding. Mehta-Shah:Kiowa Hakka Kirin: Consultancy; Roche/Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Verastem Pharmaceuticals: Research Funding; Celgene: Research Funding; Innate Pharmaceuticals: Research Funding. Pro:Takeda: Consultancy, Honoraria, Other: Travel Expenses; Celgene: Consultancy, Honoraria; Kyowa Hakka Kirin: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Jacobsen:Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Honoraria; Acerta: Consultancy; Astra-Zeneca: Consultancy; F. Hoffmann-LaRoche: Research Funding. Casulo:Celgene: Research Funding; Gilead: Honoraria, Other: Travel, accommodation, expenses; Roche: Other: Travel, accommodation, expenses. Brammer:Celgene: Research Funding; Seatlle Genetics: Honoraria, Speakers Bureau. Haney:Verastem Inc: Employment, Equity Ownership. Youssoufian:Verastem Oncology: Consultancy, Equity Ownership. Weaver:Verastem Oncology: Employment, Equity Ownership, Patents & Royalties: Inventor; Hillstream Biopharma: Consultancy, Equity Ownership; FemtoDx: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor. Baglio:Verastem Oncology: Employment. Narasimhan:Verastem: Employment, Equity Ownership. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy. OffLabel Disclosure: Duvelisib (DUV), a dual PI3K-delta,gamma inhibitor, is US FDA approved at 25 mg twice daily (BID) for the treatment of R/R chronic lymphocytic leukemia or small lymphocytic lymphoma after at least 2 lines of prior therapy and R/R follicular lymphoma after at least two prior systemic therapies.

Poverty often leads people to kufr and leads them into a life of mirage and imagination. The phenomenon of life with this ornate fantasy seems to be found on the followers of Mukrominiyyah understanding or teachings led by Mr. Mukromin in the Jangga Village, Jangga Distric, Indramayu. The approach used in this research is a qualitative approach. by using primary and secondary data with data collecting technique through: library research, participant observation, open interview and depth. Research conclusion 1. Genealogy Mukrominiyyah. Mukrominiyyah is a religious group that begins with the emergence of a thought named Mukromin. Mukrominiyah is located in Jangga Village, Jangga District, Indramayu. 2. Doctrine and teachings Mukrominiyyah include: Treasure, character, fiqh, Sufism and monotheism. 3. Implications of Mukrominiyyah doctrine and teachings. 1. Positive implications include: Mukrominiyyah followers who are patient, wise and generous. While the negative implications are: the followers Mukrominiyyah have the nature of the dreamer, lazy to work and disturbed his faith.

This article is devoted to the analysis of the formal content structure V. Nabokov / Sirin’s second novel “King, Queen, Knave” (1928). The “realistic” narration about adultery is here сlosely connected with metaphysical themes and the features of game poetics. The theme of mannequins, dolls and maps is interpreted here in a quite new way. It is shown that, contrary to popular belief, not the figures of mannequins and dolls highlight the images of the characters, their soulless and mechanistic, but, conversely, the novel “King, Queen, Knave” shows how the blanks of literary heroes types, with a wave of the Author’s magic wand, turn into real people. From the stereotypical figures of the triangle husband – wife – lover and the banal plot about adultery, V. Sirin created a fresh and unusual story with non-standard and accurately drawn characters, with a non-trivial structure of the plot and original narrative models. From the sketchy narrative of adultery, the true dominant theme of the novel emerges – the revival of the inanimate, the creation of the “living life” of a literary text. In every episode, in every moment of the narrative, in every plot course, the Author emphasizes his dominant, organizing and creating role. The law of the Author’s willfulness dominates over the eventual field of the novel and forms game poetics of the novel. The elements of the game and the chance reign here and control the logic of the plot development, the atmosphere is created by the card name, the crazy old man-illusionist, various models of sports games (tennis, mountain skiing, sports equipment store, etc.) and children’s (dolls), dressing up and carnival masks, etc. The Author, in the face of chance / or fate, throws trick-mirages (a pistol that turned out to be a lighter, etc.) to the heroes, and then brutally exposes them; organizes driving rain or sends deadly disease. From the game in the play quite naturally emerge two Russians – the “representatives” of the Author in the text.

O melão (Cucumis melo) apresenta elevados gastos com adubos minerais, evidenciando a possibilidade da utilização de produtos alternativos como os biofertilizantes. Este experimento teve como objetivo avaliar a produtividade e a pós-colheita da cultura do melão cultivar Mirage seguimento Harper, submetida a doses e tipos de biofertilizantes na presença e ausência de adubação mineral. O delineamento experimental foi em blocos casualizados no arranjo fatorial 4×2+2, referentes a quatro doses de biofertilizantes (0,5, 1,0, 1,5 e 2,0 L/semana), dois tipos de biofertilizantes líquidos (misto de fermentação aeróbica e bovino simples de fermentação anaeróbica) com dois tratamentos adicionais: controle e adubação mineral recomendada. As variáveis analisadas foram produtividade, massa média de frutos, diâmetro de frutos, sólidos solúveis, acidez titulável, firmeza, espessura da polpa e cavidade da polpa. O biofertilizante misto mostrou-se mais eficiente do que o bovino na maioria das variáveis analisadas. A maior produtividade do meloeiro (32,62 t/ha) foi alcançada com a dose de 1,08 L/planta/semana para o biofertilizante misto e com 1,41 L/planta/semana para o bovino (25,87 t/ha). O biofertilizante misto e bovino com a dose 2,0 L/planta/semana foi melhor que o controle e a adubação mineral para espessura e cavidade de polpa.

Background: Interleukin-2-Inducible T-Cell Kinase (ITK) is a Tec-family, non-receptor tyrosine kinase expressed in T-cells that plays a key role in T-cell receptor (TCR) signaling, which is required for development and differentiation of T-cells. In T-cell lymphoproliferative disorders, expression of the TCR and its downstream signaling components are maintained, which suggests malignant cells may exploit this growth and survival pathway to their advantage. Professional antigen-presenting cells abundant in the lymphoma microenvironment may provide antigen to drive TCR signaling through ITK, which is expressed in a variety of T-cell lymphomas. CPI-818 is a first-in-class, irreversible ITK inhibitor with a high degree of selectivity for ITK. By inhibiting ITK, CPI-818 blocks signaling pathways and is efficacious in murine models of T-cell lymphomas. Furthermore, the safety and efficacy of CPI-818 in companion dogs with spontaneously-occurring T-cell lymphomas have been evaluated. Following oral, BID dosing of CPI-818 to dogs, evidence of anti-tumor activity including complete and partial responses was observed. CPI-818 was well tolerated in dogs with no change in normal lymphocyte counts. Thus, the preclinical evidence supports the evaluation of CPI-818 in clinical trials in patients with T-cell malignancies. To test this clinically, a phase 1/1b dose-escalation and dose-expansion trial of CPI-818 has been initiated in patients with relapsed/refractory T-cell lymphoma. Methods: The trial will enroll patients with various types of T-cell lymphoma (PTCL and CTCL) who have progressed on, refractory to, relapsed, or intolerant to at least 2 standard therapies; age ≥ 18 years; have ECOG status 0-1; adequate organ function; and without any other condition that would contraindicate the use of the investigational product. A dose Escalation part with 3 + 3 (+ optional 3) design will consist of up to 6 ascending dose levels (100, 200, 400, 600, 900, and 1200 mg) of CPI-818. In the Dose Expansion part, there will be 4 disease-specific expansion cohorts (AITL, PTCL-NOS, CTCL and other T-cell lymphoma), and each cohort may enroll up to a maximum of 28 subjects/cohort based on a two-stage expansion design- Study Details in Figure 1. Patients will receive CPI-818 orally BID at the assigned dose level continuously up to sixteen 21-day cycles, until progression or unacceptable toxicity. The primary objectives of the study are to evaluate the safety and tolerability of CPI-818 in ascending dose levels and to establish the maximum tolerated dose or the maximum administered dose of CPI-818. Secondary objectives include evaluating pharmacokinetics/ pharmacodynamics, assessing the anti-tumor activity of CPI-818 and identifying potential biomarker signals. Adverse events and dose-limiting toxicities of CPI-818 will be assessed. The PK profile of CPI-818 will be characterized by PK parameters in plasma. Efficacy will be assessed by the investigator using standard response criteria: Lugano Classification for PTCL patients, Consensus Statement for Response for CTCL patients, and the international consensus modification of Japan Clinical Oncology Group criteria for adult T-cell lymphoma patients. ITK occupancy/engagement in peripheral blood T cells and potential predictive biomarkers associated with anti-tumor activity in tumor tissue and blood samples will be evaluated. Study Status: This study is currently enrolling. US NIH Clinical Trials Registration Number NCT03952078. Disclosures Mobasher: Corvus Pharmaceuticals: Employment, Equity Ownership. Miller:Corvus Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Janc:Corvus Pharmaceuticals: Employment, Equity Ownership. Kwei:Corvus Pharmaceuticals: Employment, Equity Ownership. Buggy:Corvus Pharmaceuticals: Employment, Equity Ownership. Luciano:Corvus Pharmaceuticals: Employment, Equity Ownership. Mohammady:Corvus Pharmaceuticals: Employment, Equity Ownership. Kim:F. Hoffmann-La Roche Ltd: Research Funding; Celltrion: Research Funding; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding. Kim:Portola Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medivir: Honoraria, Membership on an entity's Board of Directors or advisory committees; Neumedicine: Research Funding; Elorac: Research Funding; Corvus: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Hakko Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding; Horizon: Research Funding; Galderma: Research Funding; Merck: Research Funding; Trillium: Research Funding; miRagen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Soligenix: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Khodadoust:Corvus Pharmaceuticals: Research Funding. Horwitz:Portola: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Affimed: Consultancy; Seattle Genetics: Consultancy, Research Funding; Astex: Consultancy; Kyowa Hakko Kirin: Consultancy; ADCT Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Affimed: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty-Seven: Research Funding; ADCT Therapeutics: Research Funding; Trillium: Research Funding; Mundipharma: Consultancy; Kyowa Hakko Kirin: Consultancy; Miragen: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Mundipharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Forty-Seven: Research Funding; Aileron: Research Funding; Miragen: Consultancy; Mundipharma: Consultancy; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Forty-Seven: Research Funding; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADCT Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; Affimed: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy; Astex: Consultancy; Trillium: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Trillium: Research Funding; Forty-Seven: Research Funding; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Portola: Consultancy; Astex: Consultancy; Innate Pharma: Consultancy; Celgene: Consultancy, Research Funding; Kura: Consultancy; Innate Pharma: Consultancy; Innate Pharma: Consultancy; Kura: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Kura: Consultancy; Innate Pharma: Consultancy; Trillium: Research Funding; Miragen: Consultancy; Mundipharma: Consultancy; Portola: Consultancy. Radeski:Corvus Pharmaceuticals: Research Funding.

The results of studying the variability of a number of quantitative and qualitative characteristics in a model sample of varieties of herbaceous peony with a Japanese flower shape to identify genotypes that differ in variety-specific characteristics are presented. The investigated sample is formed on the basis of the collection of the genus Paeonia L. laboratory of ornamental plants MBG. In the course of the study, variety-specific characteristics were established for a number of cultivars. 2 short ('Bu-Te', 'West Elkton') and 3 tall ('Yellow King', 'Hit Parade', 'Lotus Queen') varieties were selected. 3 grades are marked — 'Mrs. Wilder Bankroft', Midnight Sun, 'Neon' — with consistently low absolute values of the peduncle diameter at the base. 2 large-flowered ('Gold Standard', 'Surprise') and 2 small-flowered ('Bu-Te', 'Gay Paree') cultivars were identified. It was found that the largest sizes of the staminodium zone are distinguished by 'Hit Parade' and 'John van Leeuwen'. The least common variations of the bush type (in the full flowering phase) were recorded in 4 varieties 'Rahoomon', 'Feather Top', 'Largo' (compact) and 'Mr. G.F. Hemerik' (spreading). There are 2 cultivars ('Isani Gidui', 'Fairy') with probably not typical for representatives of this garden group, the type of leaf shape — Paeonia mlokosewitschii. 8 varieties were identified ('Philomele', 'Fairy', 'Okinava', 'Mirage', as well as 'Isani Gidui','Yellow King','Bu-Te', 'Walter Mains'), characterized by relatively sparsely distributed morphological characteristics associated with the shape of the leaf segment. The variety 'Akron' with the original (for the sample under study) variant of stem pigmentation was selected.

Protein–protein interactions (PPIs) are the vital engine of cellular machinery. After virus entry in host cells the global organization of the viral life cycle is strongly regulated by the formation of virus-host protein interactions. With the advent of high-throughput -omics platforms, the mirage to obtain a “high resolution” view of virus–host interactions has come true. In fact, the rapidly expanding approaches of mass spectrometry (MS)-based proteomics in the study of PPIs provide efficient tools to identify a significant number of potential drug targets. Generation of PPIs maps by affinity purification-MS and by the more recent proximity labeling-MS may help to uncover cellular processes hijacked and/or altered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), providing promising therapeutic targets. The possibility to further validate putative key targets from high-confidence interactions between viral bait and host protein through follow-up MS-based multi-omics experiments offers an unprecedented opportunity in the drug discovery pipeline. In particular, drug repurposing, making use of already existing approved drugs directly targeting these identified and validated host interactors, might shorten the time and reduce the costs in comparison to the traditional drug discovery process. This route might be promising for finding effective antiviral therapeutic options providing a turning point in the fight against the coronavirus disease-2019 (COVID-19) outbreak.

Protein–protein interactions (PPIs) are the vital engine of cellular machinery. After virus entry in host cells the global organization of the viral life cycle is strongly regulated by the formation of virus-host protein interactions. With the advent of high-throughput -omics platforms, the mirage to obtain a “high resolution” view of virus–host interactions has come true. In fact, the rapidly expanding approaches of mass spectrometry (MS)-based proteomics in the study of PPIs provide efficient tools to identify a significant number of potential drug targets. Generation of PPIs maps by affinity purification-MS and by the more recent proximity labeling-MS may help to uncover cellular processes hijacked and/or altered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), providing promising therapeutic targets. The possibility to further validate putative key targets from high-confidence interactions between viral bait and host protein through follow-up MS-based multi-omics experiments offers an unprecedented opportunity in the drug discovery pipeline. In particular, drug repurposing, making use of already existing approved drugs directly targeting these identified and validated host interactors, might shorten the time and reduce the costs in comparison to the traditional drug discovery process. This route might be promising for finding effective antiviral therapeutic options providing a turning point in the fight against the coronavirus disease-2019 (COVID-19) outbreak.