Auswahl der wissenschaftlichen Literatur zum Thema „Nanovectors,g“

Polydopamine (pDA)-modified iron oxide core-shell nanoparticles (IONPs) are developed and designed as nanovectors of drugs. Reactive quinone of pDA enhances the binding efficiency of various biomolecules for targeted delivery. Glutathione disulfide (GSSG), an abundant thiol species in the cytoplasm, was immobilized on the pDA-IONP surface. It serves as a cellular trigger to release the drug from the nanoparticles providing an efficient platform for the drug delivery system. Additionally, GSSG on the surface was further modified to form S-nitrosoglutathione that can act as nitric oxide (NO) donors. These NPs were fully characterized using a transmission electronic microscopy (TEM), thermogravimetric analysis (TGA), dynamic light scattering (DLS), zeta potential, X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FTIR) and UV-vis spectroscopies. Doxorubicin (DOX) and docetaxel (DTX) are two anticancer drugs, which were loaded onto nanoparticles with respective loading efficiencies of 243 and 223 µmol/g of IONPs, calculated using TGA measurements. DOX release study, using UV-vis spectroscopy, showed a pH responsive behavior, making the elaborated nanocarrier a potential drug delivery system. (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl) -2H-tetrazolium (MTS) and apoptosis assays were performed on PC3 cell lines to evaluate the efficiency of the developed nanocarriers. These nanoparticles thus can prove their worth in cancer treatment on account of their easy access to the site and release of drug in response to changes to internal parameters such as pH, chemicals, etc.

Abstract Nanotechnology is a promising branch of the medical field, directed to improve diagnostic and therapeutics strategies, applying nanovectors as drug delivery systems. Efficient encapsulation of anticancer drugs in nanocolloids and microcapsules was recently developed by G. Ciccarella research group (1). Based on our collaboration with the Nantional Nanotechnology Laboratory of the University of Salento and our previous experience with target therapies, we encapsulated BEZ235, a phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR). BEZ235 efficiently blocks the dysfunctional activation of the PI3K/mTOR pathway in cellular and in vivo settings, thus inhibiting the growth and proliferation of various cancer cells, and phase I/II clinical trials were open in solid cancer. However the scarse solubility limited further development of this promising compound. In order to overcome the solubility issue BEZ235-loaded nanocapsules were generated by the stepwise adsorption of oppositely charged polyelectrolytes into biocompatible CaCO3 cores. First nanocapsules were tested for biocompatibility. The exposition of lymphoma cell lines to empty nanocapsules up to 48 hours, did not induce any cititoxicity, confirming their biocompatibility. Second, encapsulated BEZ235 was compared with free-drug to test the cytotoxicity in a T lymphoma cell line (HUT78) by MTT assay (Fig. 1). The results suggested that nanoencapsulated-BEZ235 was extremely efficient compared with free-BEZ235, reaching IC50 just after 5 hours of exposure compared with an IC65% at 48 hours with the free drug. A validated LC-MS/MS method was developed in order to quantify intracellular concentration of BEZ235 over time. Intracellular concentration of BEZ235 in the lymphoma cell line was consistent with biological results since the internalization kinetic and efficiency was increased by the coating. In order to confirm that the encapsuled-BEZ235 was still effective on cell apoptosis, we tested free BEZ and encapsulated BEZ235 at a concentration of 1µM in T cell lymphoma cell lines. Encapsulated-BEZ235 induced apoptosis evidenced by the cleavage of caspase 8, 9 and 3 at an earlier time point compared with free BEZ235 and at significantly lower concentration. We also confirmed that the encapsulated-BEZ235 maintained its effect on the target mTOR/AKT pathway: p-AKT was dephosphorylated at 5h while the free BEZ235 operates at least after 24 hours at concentrations 100 times higher, as previously demonstrated (2). Keeping in mind a future clinical application of these polymeric particles/capsules, our data can be regarded as a promising new nanotechnology-based strategy to improve the efficacy and bioavailability of old and new drugs. Functional biological studies of BEZ235-encapsulated carrier and its mechanism of internalization are already under way, and animal in vivo studies to evaluated toxicity and distribution of the nanocapsuled compound are ongoing. 1 F. Baldassare et al., Macromolecular Bioscience, Volume 12, Issue 5, pages 656-665, 2012 2 Civallero M, Cosenza M, Marcheselli L, Pozzi S, Sacchi S. Expert Opin Investig Drugs. 2012 Nov;21(11):1597-606. Disclosures No relevant conflicts of interest to declare.

Abstract Background: CD37 is an internalizing transmembrane antigen highly expressed by normal B cells and on most of B-cell malignancies, and represents an interesting therapeutic target for the treatment of B-cell NHL. 177Lu-DOTA-HH1 (Betalutin®) is a novel CD37-targeting antibody radionuclide conjugate in clinical development. It consists of a CD37-binding murine IgG1 antibody HH1 labelled with the short-ranged beta-emitter lutetium-177 (T½ = 6.7 days) chelated to DOTA. 177Lu-DOTA-HH1 is delivered in a ready-to-use formulation. Efficacy and safety data of patients (pts) receiving 177Lu-DOTA-HH1 with HH1 pre-dosing, as well as new efficacy and safety data from pts receiving 177Lu-DOTA-HH1 without HH1 pre-dosing will be presented. Methods: Pts with relapsed incurable CD37 positive NHL of follicular grade I-IIIA, marginal zone, mantle cell, lymphoplasmacytic and small lymphocytic subtypes and with platelet counts ≥ 150 x109/l were eligible for inclusion in the study. In a 3+3 study design pts received rituximab (375 mg/m2) day 1 and 8 in order to deplete normal B cells. On day 29 pre-dosing with HH1 (50 mg, cold CD37 antibody) was administered before 177Lu-DOTA-HH1 injection (Arm 1). In Arm 2 177Lu-DOTA-HH1 was administered without HH1 pre-dosing on day 29. The starting doses for Arm 1 and 2 were 10 MBq/kg b.w. and 15 MBq/kg b.w, respectively. Pts enrolment has been completed (n=13) in Arm 1 with the dose-limiting toxicity (DLT) observed at 20 MBq/kg bw and a dose expansion cohort is currently open for enrollment at 15 MBq/kg with HH1 pre-dosing. Arm 2 is currently open for enrollment. Tumour response was assessed by FDG PET/CT scans (Cheson 2007), and pts will be followed for 5 years. Results: Arm 1:A total of13 (M/F 11/2) pts, median age 68 years, follicular lymphoma (n=12), and mantle cell lymphoma (n=1) have been enrolled since the study start in December 2012. The range of prior therapies was 1 to 8, where 5 of 13 pts were refractory to rituximab. The most common toxicities observed were hematologic and all DLTs were reversible and manageable. At 20 MBq/kg (n=3) G 3/4 neutropenia and/or thrombocytopenia were observed in all pts and platelet transfusions were required in 2 pts. At 15 MBq/kg (n=6) DLTs were: 1 G 3 thrombocytopenia lasting >14 days and 1 G 4 neutropenia/ thrombocytopenia lasting >7 days. The median time to nadir for platelets and neutrophils was 40 and 49 days, respectively. No pts experienced febrile neutropenia. Serious AEs were reported in 5 pts: at 10 MBq/kg pneumonia (possibly related) and pulmonary embolism (PE) unrelated, in the same pt, with history of PE; thrombocytopenia requiring platelet transfusions (2 pts) and epistaxis in 1 of them (20 MBq/kg), possibly related; transient atrial fibrillation (2 pts) at 15 MBq/kg, possibly related. No secondary malignancies or other long term events have been observed. Best overall tumor response observed across all dose levels were 4 complete and 3 partial remissions, 2 stable disease and 4 progression of disease (one pt had confirmed transformed lymphoma at 3 months). The duration of response (complete and partial remissions) ranged from 6 to more than 21 months. One patient is still in remission after 2 years. The median response duration has not yet been reached. Arm 2: Inclusion in this arm is ongoing. Data on efficacy and safety will be presented and compared with the pts receiving pre-dosing. Conclusions: 177Lu-DOTA-HH1, which is a single dose ready-to-use formulation, has a predictable and manageable safety profile. Most AEs were hematological in nature, all transient and reversible. Promising efficacy and durable responses have been observed. 177Lu-DOTA-HH1 has the potential to be a novel therapy for B-cell malignancies. Disclosures Kolstad: Nordic Nanovector ASA: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bolstad:Nordic Nanovector ASA: Employment. Bruland:Nordic Nanovector ASA: Equity Ownership. Dahle:Nordic Nanovector ASA: Employment, Equity Ownership. Hartvig Larsen:Nordic Nanovector ASA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: Most indolent NHL patients (pts) have advanced stage disease at diagnosis, and no curative therapy exists. The mainstay of both first- and second-line (2L) therapy is anti-CD20 chemo-immunotherapy, and although initially effective, most pts relapse, with median PFS decreasing markedly after 2L and 3rd-line therapies. In addition, many pts eventually develop resistance to rituximab (RTX)/RTX-containing regimens, thus therapeutic targets other than CD20 are important. Those who develop resistance to RTX, especially the elderly, need new treatment approaches. With a median age at diagnosis of 67 (seer.gov), NHL is a disease of the elderly, who are at risk of developing cumulative myelosuppression, cardiac toxicity, and severe infections with currently available therapies. CD37 is highly expressed (>90%) in B-cell NHL, providing an alternative target to CD20. Lutetium (177Lu) lilotomab satetraxetan (Betalutin®) is a beta-emitting anti-CD37 ARC in a ready-to-use formulation. LYMRIT 37-01 is a phase I/II open-label, multicenter, dose-escalation study to determine the safety, pharmacokinetics (PK), and preliminary efficacy of a single dose of Betalutin in pts with relapsed iNHL, and to establish a recommended phase II dose (RP2D). We present updated efficacy and safety data for the phase I/IIa part of the study (Part A) as of 22 June 2018; all pts have ≥ 6 months (m) of follow-up, except for 3 (will be completed in August). Methods: Pts with histologically confirmed iNHL relapsing after ≥1 prior therapy with <25% bone marrow involvement, platelets (plt) >150 x 109/L, no prior SCT/RIT, and a life expectancy of ≥3 months were enrolled into 1 of 4 dose-escalation arms (Part A) to determine the optimal lilotomab pre-dose and Betalutin dose for further evaluation in an expanded phase II cohort. A fifth arm collected additional PK data. All pts received pre-treatment with RTX. Responses were assessed using Cheson IWG response criteria (including CT and FDG PET/CT scans) beginning at week 12. Results: 74 pts [57 follicular (FL), 7 mantle cell (MCL), 9 marginal zone (MZL), 1 small lymphocytic (SLL)] were enrolled at 13 sites from Dec 2012 to Feb 2018. Median age was 68 (range 38-87; 55% ≥ 65); the median no. of prior therapies was 3 (range 1-9); 48 pts (65%) had received ≥2 prior therapies. Two RP2Ds emerged: a lilotomab pre-dose of 40 mg + 15 MBq/kg Betalutin ("40/15"; Arm 1) and a lilotomab pre-dose of 100 mg/m2 + 20 MBq/kg Betalutin ("100/20"; Arm 4). For all pts, the overall response rate (ORR) was 61%, with 26% complete responses (CR). By subtype, the ORR was 65% (CR 24%) for FL, and 78% (CR 44%) for MZL. FL with ≥2 prior therapies (n=37) had an ORR of 70% (CR 27%). With a median follow-up of 9.1 m (range 4.9-49.5 m), the median duration of response for all pts is 13.3 m (20.5 m for those with a CR); 26 pts (35%) have remained free of disease progression for >12 m [CR(15)/PR(5)/SD(6)]. For the 36 pts receiving the "40/15" regimen, the ORR was 58% (CR 28%), and 64% (CR 28%) for FL (n=25). The ORR was 63% (CR 21%) for 19 pts receiving the "100/20" regimen, and 69% (CR 19%) for FL (n=16). Betalutinwas well-tolerated. The most common grade (G) 3/4 AEs were neutropenia (53%) and thrombocytopenia (48%); 5 pts (7%) had G3/4 infections (pneumonia, UTI, pharyngitis (G3), 2 G4 sepsis). No febrile neutropenia was reported. Four pts had plt transfusions [low plt count (2), epistaxis (1), hematuria (1)]; 3 received G-CSF. Two pts had infusion reactions; both were related to RTX. SAEs occurred in 14 pts (19%); SAEs in ≥2 pts were atrial fibrillation, thrombocytopenia, lymphoma progression and sepsis (all n=2). Five pts developed transient anti-drug antibodies. One case of CMML occurred 24 m after Betalutin (18 m after subsequent bendamustine-RTX therapy). There were no study drug-related deaths in the treatment period. G3/4 neutropenia and thrombocytopenia occurred in 56%/56% (40/15 regimen) and 47%/42% (100/20 regimen). Conclusions: Betalutin is well tolerated and has promising antitumor activity in recurrent iNHL, especially in FL and MZL. Use of a higher lilotomab pre-dose resulted in a lower incidence of G3/4 hematologic AEs. With a single administration, Betalutin has the potential to be a novel, safe, and effective therapy for pts with B-cell malignancies. The 2 RP2Ds from Part A of the study are now being compared in a randomized phase 2b cohort (Part B: "PARADIGME") in relapsed, RTX/anti-CD20 refractory FL pts who have received ≥2 prior therapies. Disclosures Kolstad: Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche: Research Funding. Illidge:Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria. Hajek:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Jurczak:European Medicines Agency: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Consultancy; Acerta: Consultancy, Research Funding; Sandoz-Novartis: Consultancy; Afimed: Research Funding; Bayer: Research Funding; BeiGene: Research Funding; Celgene: Research Funding; Epizyme: Research Funding; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Nordic Nanovector: Research Funding; Merck: Research Funding; Morphosys: Research Funding; Pharmacyclics: Research Funding; Servier: Research Funding; Roche: Research Funding; TG Therapeutics: Research Funding. Rojkjaer:Nordic Nanovector: Employment. Østengen:Nordic Nanovector: Employment.

Global gene expression profiling of the tumor microenvironment in diffuse large B-cell lymphoma (DLBCL) has revealed broad innate immune signatures that distinguish the heterogeneous disease subtypes and correlate with good treatment outcome. However, we still lack tools to identify the relatively large group of patients that are refractory to initial therapy and have a dismal prognosis. Here, we used mass cytometry and serum profiling in a systems-level approach to analyze immune responses in 36 patients with aggressive B cell lymphoma and age- and sex-matched healthy controls. Stochastic neighbor embedding (t-SNE) analysis of protein profiles divided patients into two distinct clusters, with cluster 2 representing patients with a more severe deviation in their protein expression compared to healthy controls. Patients in cluster 2 showed a more dramatic perturbation of their immune cell repertoires with expansion of myeloid-derived suppressor cells (MDSCs), increased T cell differentiation and significantly higher expression of metabolic markers such as GLUT-1 and activation markers, including Ki67, CD38 and PD-1. An extended analysis of serum protein profiles in two independent cohorts (n=69 and n=80 patients, respectively) revealed that that the identified systemic immune signatures were linked to poor progression free survival (PFS) and inferior overall survival (OS). Immune monitoring during chemo-immunotherapy showed that most patients normalized their serum protein profiles. Notably, non-responding patients retained higher than normal expression of several proteins, including PD-L1, CD70, IL-18, granzyme A and CD83. These studies demonstrate distinct patterns of disease-driven alterations in the systemic immune response of DLBCL patients that are associated with poor survival and persist in patients who are refractory to therapy. Figure 1 System-level immune signatures associated with poor prognosis in DLBCL. A) Altered serum profiles in patients compared to healthy controls. Two clusters of patients were identified based on t-SNE analysis of serum profiles. B) Patients in cluster 2 had bulky disease and B symptoms. C) t-SNE map of all patients (n=36) and controls (n=17). Relative abundance of cells from healthy controls and patients in all areas of the t-SNE clustering, highlighting cell subsets that are larger or smaller in patients compared to healthy donors. Colors indicate the difference in kernel density estimation of the t-SNE data for patients and healthy controls. D) Abundance of monocytic myeloid-derived suppressor cells as percentage of all CD45+ cells in healthy donors and the two patient clusters. White, Healthy controls; Blue, Cluster 1; Red, Cluster 2. E) Major phenotypic differences between patient clusters shown as mean mass intensity (MMI) or percent positive cells for selected markers (CD38 and PD-1) across multiple subsets. White, Healthy controls; Blue, Cluster 1; Red, Cluster 2. F-G) Overall survival in patients with serologically defined immune signatures belonging to cluster 1 or 2. H) Abundance of serum proteins in patients that stayed in remission (n=24) compared to those that did not (n=6). Figure 1 Disclosures Olweus: Gilead Kite: Research Funding; Intellia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Wahlin:Roche and Gilead: Consultancy. Fehniger:Cyto-Sen Therapeutics: Consultancy; Horizon Pharma PLC: Other: Consultancy (Spouse). Holte:Novartis: Honoraria, Other: Advisory board. Kolstad:Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding. Malmberg:Fate Therapeutics, Inc.: Consultancy, Research Funding; Vycellix: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: Primary mediastinal large B-cell lymphoma (PMBL) is a rare non-Hodgkin lymphoma subtype that occurs predominantly in young adults, with an overall favorable prognosis. The cell of origin is presumed to be thymic medullary B-cells and the gene expression profile of PMBL is similar to classic Hodgkin lymphoma. Recent studies have begun unravelling the genomic alterations underlying PMBL. Frequent, recurrent mutations (e.g. B2M, TNFAIP3, SOCS1, STAT6, GNA13) have been reported, but most of the studies have analyzed a small number of cases. To gain further insights into disease biology, we recruited 63 cases of PMBL as part of the Atlas of Blood Cancer Genomes (ABC-G) initiative, a consortium consisting of 25 institutions. Methods: Formalin-fixed paraffin-embedded (FFPE) biopsies and clinical data were collected. All cases were subjected to centralized review by an experienced panel of hematopathologists to ensure accurate diagnosis. Whole-exome DNA and RNA sequencing was performed using the Illumina platform and the DNA and RNA reads aligned to the GRCh38 genome and transcriptome respectively. Exonic variants were filtered using a set of paired normal samples and population-based databases to identify putative driver mutations, which were then aggregated at the gene level. Mutational analysis was performed on 56 samples that passed quality filtering and expression analysis on 45 samples. RNAseq data was normalized using DESeq2. Results: The cohort included samples from 16 males and 24 females, with a median age of 33 years (range 16 - 72) at the time of diagnosis. The majority of patients were treated with R-CHOP (47%) or R-EPOCH (43%), with 93% of patients surviving through the end of follow-up (median follow-up: 60.1 months). Besides the known recurrent mutations involving the JAK-STAT (STAT6 -21%, SOCS1 - 26%), NFKB (TNFAIP3 - 27%, NFKB1A - 7%), immune escape (B2M - 20%, LTB - 11%, IRF8 - 9%, IRF4 -9%), and chromatin modification (ZNF217 - 16%, CREBBP - 11%, KMT2D -11%) pathways , we discovered recurrent somatic variants in novel candidate driver genes in this disease, including NOTCH4 (7%), DICER1 (11%), MCL1 (7%), amongst others. EZH2, EP300, and XPO1 mutations were not detected. CIITA mutations and fusions were observed in 14% and 11% of cases, respectively, with novel partner genes (IGHA2, IGHG1, CDC6) detected in 67% of the fusion positive cases. Copy number alterations included gains at 2p16.1 (REL - 20%) and 9p24.2 (JAK2/PDL1/PDL2 - 24%), as well as loci not previously implicated in PMBL, 8q24.3 and 9q34.3 (each in 20%). Of note, CIITA alterations and 9p24 gains were virtually mutually exclusive, highlighting diverse mechanisms of immune escape in this entity. The transcriptomes of cases harboring CIITA alterations demonstrated differential enrichment of genes involved in protein glycosylation. The PMBLs in our series showed significant enrichment of the reported PMBL genetic classifier score, compared to nodal diffuse large B cell lymphoma (DLBCL) (p=0.0003). Finally, the gene expression profile of thymic B cells was more similar to that of PMBL than nodal DLBCL (p=0.0144). Conclusions: Our study, representing one of the largest comprehensive genomic and transcriptomic analyses of PMBL, expands the mutational landscape of PMBL, provides evidence for biologically distinct disease subsets and suggests an origin of PMBLs from thymic B-cells. Disclosures Hsi: AbbVie: Research Funding; Eli Lilly: Research Funding; Cytomx: Honoraria; Seattle Genetics: Honoraria. McKinney: BTG: Consultancy; Celgene: Consultancy, Research Funding; Epizyme: Consultancy; Genetech: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria, Speakers Bureau; Molecular Templates: Consultancy, Research Funding; Nordic Nanovector: Research Funding; Novartis: Research Funding; Pharmacyclics: Consultancy; Verastem: Consultancy; Beigene: Research Funding; ADC Therapeutics: Consultancy, Speakers Bureau. Jaye: Stemline Therapeutics: Honoraria. Cohen: Genentech, Takeda, BMS/Celgene, BioInvent, LAM, Astra Zeneca, Novartis, Loxo/Lilly: Research Funding; Janssen, Adaptive, Aptitude Health, BeiGene, Cellectar, Adicet, Loxo/Lilly, AStra ZenecaKite/Gilead: Consultancy. Behdad: Lilly: Speakers Bureau; Roche/Foundation Medicine: Speakers Bureau; Thermo Fisher: Speakers Bureau. Dave: Data Driven Bioscience: Current equity holder in publicly-traded company.

Abstract Background Management of patients (pts) with primary central nervous system lymphoma (PCNSL) and those with secondary CNS involvement by diffuse large B cell lymphoma (DLBCL) present a therapeutic challenge. There is no clear standard of care but traditionally initial treatment of PCNSL involves induction with intravenous high-dose methotrexate (HD-MTX) followed by consolidation including whole brain radiation therapy (WBRT), cytarabine, or autologous stem cell transplant. This approach has been associated with significant toxicities, especially the risk of cognitive dysfunction with WBRT. Treatment of secondary CNS involvement by DLBCL may depend on the extent of concomitant systemic disease, but HD-MTX is often the backbone of therapy. We report results of our institutional approach in pts with PCNSL and secondary involvement of the CNS by DLBCL using a prolonged course of rituximab, temozolamide, and HD-MTX (RTM) without consolidation. Methods We conducted a retrospective cohort study describing outcomes of pts with PCNSL or secondary CNS DLBCL who were treated on the RTM protocol. Eligible pts are treated with rituximab 375 mg/m2 on day 1 in combination with HD-MTX 8 g/m2 (days 1 and 15) and temozolamide 150 mg/m2 (days 1-5) in 28-day cycles. HD-MTX is administered with leucovorin rescue and adjusted for creatinine clearance. Initial response assessment is usually after 2 cycles with brain MRI. Once a complete response (CR) has been achieved, the day 15 HD-MTX is omitted from future cycles. Pts typically complete a total of 6-12 cycles, at the discretion of the clinician, without further planned consolidation. Descriptive and survival analyses using the Kaplan-Meier methodology were performed (STATA 13). The primary endpoints, overall survival (OS) and progression free survival (PFS) were estimated from the date of the first treatment with RTM to death, progression, or date of last follow-up. A log-rank test was utilized to compare OS/PFS between pts with PCNSL versus secondary CNS DLBCL. A Cox proportional hazard analysis was performed to evaluate the effect of patient level variables on OS. Clinical response was evaluated using International Workshop on Response Criteria for PCNSL (Abrey, J Clin Oncol 2005). Results We identified 46 pts who received RTM at our institution between 2009 and 2014. Twenty-seven (59%) pts had PCNSL and 19 (41%) pts had secondary CNS DLBCL. The median age at diagnosis was 61 years (range 21-85) with 50% males. Treatment was well tolerated. Two (4%) pts discontinued treatment prematurely and 7 (15%) pts required a dose reduction in HD-MTX due to toxicity. Toxicities included transaminitis, acute renal failure, infection, fatigue, and cytopenias. In pts with PCNSL, all received RTM as their initial treatment. Best response to therapy in this group was as follows: 19 (70%) had a CR, 3 (11%) had PR, 3 (11%) had SD and 2 (7%) had PD. The overall response rate was 81%. All patients with secondary CNS DLBCL had received prior systemic therapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. Best CNS response to therapy in this group was as follows: 7 (37%) had CR, 2 (11%) had PR, 1 (5%) had SD, and 9 (47%) had PD. The overall response rate was 47%. For the entire cohort, the median OS was 41 months (m) and median PFS was 8 m. Compared with secondary CNS DLBCL, patients with PCNSL had a significantly longer median OS (54 m vs. 5 m; p<0.01) (Figure 1). PFS was also significantly longer for pts with primary versus secondary CNS DLBCL (22 m vs. 2 m; p=0.02) (Figure 2). Univariate cox analysis demonstrated that sex and age did not impact OS but pts who were in a CR or PR at initial response assessment compared to SD or PD had a hazard ratio for OS of 0.12 (95% CI: 0.05 to 0.29, P<0.01). Conclusions In our cohort, pts with PCNSL had excellent outcomes using a prolonged course of the RTM regimen without the toxicities of consolidation with radiation or high dose chemotherapy. These outcomes did not translate to pts with secondary CNS DLBCL, which may be consistent with the different biology and aggressive nature of this subgroup in addition to the prior therapies received. Early response assessment is vital to assess prognosis pts as those who respond within 2 cycles of therapy have an improved OS. This data suggests that RTM without further consolidation is an acceptable alternative regimen for PCNSL. Future prospective studies are needed to validate our findings. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Ganetsky: Onyx: Speakers Bureau. Dwivedy Nasta:Millenium: Research Funding; BMS: Research Funding. Mato:Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; Celgene Corporation: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy. Schuster:Gilead: Research Funding; Janssen: Research Funding; Hoffman-LaRoche: Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Svoboda:Celgene: Research Funding; Seattle Genetics: Research Funding; Immunomedics: Research Funding; Celldex: Research Funding.

Background: Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor (CAR)-T cell therapy that is approved for adult patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). In the phase 2 JULIET trial, pts could receive bridging therapy (BT), when needed, to permit flexibility in scheduling and maintain disease control. Lymphodepleting chemotherapy (LDC) was started 5-14 days prior to CAR-T cell infusion. Here we present baseline characteristics, efficacy/safety outcomes, and cellular kinetics by BT and type of LDC used in the JULIET trial. Methods: Pts were categorized based on BT or no BT, as well as LDC (cyclophosphamide/fludarabine [Cy/Flu; 250 and 25 mg/m2 IV daily for 3 doses, respectively] or bendamustine [90 mg/m2 IV daily for 2 days]) or no LDC, received prior to tisagenlecleucel infusion. Cy/Flu was the proposed regimen for LDC, followed by bendamustine (if the pt experienced previous grade [G] 4 hemorrhagic cystitis with Cy or demonstrated resistance to a previous Cy-containing regimen). LDC was not required if white blood cell count was <1000 cells/μL within 1 week prior to infusion. Best overall response rate (ORR) was defined as complete response (CR) + partial response (PR). Event-free probability estimates and their 95% confidence intervals (95% CI) were obtained using Kaplan-Meier method. The 95% CIs for ORR were obtained using exact Clopper-Pearson method. The time course of transgene copies per microgram of genomic DNA, as measured by quantitative polymerase chain reaction (qPCR), was utilized to estimate the cellular kinetic parameters (maximal expansion of CAR-T cells in vivo, Cmax; time to maximal expansion, Tmax; and area under the curve from time of infusion to day 28, AUC0-28d). Results: Of the 115 pts infused, 104 received BT (90 systemic therapy alone, 13 systemic therapy in combination with radiation therapy, and 1 radiation therapy alone) and 11 pts did not receive BT. For LDC, 85 pts received Cy/Flu, 22 bendamustine, and 8 pts did not receive LDC. Baseline and disease characteristics across the different BT and LDC categories are presented (Table). Of note, 90.9% (10/11) of pts who did not receive BT had baseline ECOG performance status 0, whereas 52.9% of pts who received BT had ECOG 0. Pts who did not receive BT had an ORR of 81.8% (63.6% complete response [CR]); in pts who received BT, the ORR was 49.0% (35.6% CR) (Table). Progression-free survival (PFS) rate at 12 months was 60.6% in pts who did not receive BT and 32.0% in pts who received BT. Among LDC groups, pts who received Cy/Flu had an ORR of 57.6% (41.2% CR) and 12-month PFS rate of 39.1%, whereas those who received bendamustine had an ORR of 40.9% (31.8% CR) and 12-month PFS rate of 21.2%. These differences were not statistically significant. Among pts who did not receive LDC, only 2/8 achieved a response (ORR 25% [25% CR]) and 12-month PFS rate was 25%. Rates of selected adverse events reported within ≤8 weeks post-infusion, >8 weeks to ≤1 year post-infusion, >1 year post-infusion, and any time after infusion were generally consistent across BT and LDC groups for prolonged cytopenias, neurological events (NE), cytokine release syndrome (CRS), and infection (Table). Of note, among pts who did not receive BT, only 1 G3 CRS and 1 G3 NE were reported, and no G4 CRS or NE were reported. Additionally, the rate of cytopenias not resolved by day 28 post-infusion was lowest among pts who did not receive BT (1/11 pts). However, cytopenias resolved to ≤G2 by month 3 or month 6 in the majority of pts. Cmax, Tmax, and exposure (AUC0-28d) were similar between LDC groups (Table). Cmax and AUC0-28d were also similar between pts who received BT and those who did not. Additional analyses of subgroups will be presented at the congress. Conclusions: The majority of pts enrolled in the JULIET trial received BT and LDC, indicating high tumor burden and aggressive disease in this pt population with r/r DLBCL. Although the sample size is small (n=11), pts not requiring BT appeared to have less aggressive disease, achieved high response rates, and had no G4 CRS or NE. Pts who did not receive LDC (n=8) seemed to have low response rates, suggesting either the impact of prior therapy, the importance of LDC, or both. Further evaluation of the impact of BT and LDC on clinical outcomes on larger patient population will be possible with the availability of registry data. Clinical trial information: NCT02445248 Table Disclosures Andreadis: Genentech: Consultancy, Employment; Merck: Research Funding; Roche: Equity Ownership; Novartis: Research Funding; Celgene: Research Funding; Juno: Research Funding; Pharmacyclics: Research Funding; Gilead: Consultancy; Kite: Consultancy; Jazz Pharmaceuticals: Consultancy. Tam:BeiGene: Honoraria; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie company: Honoraria; AbbVie: Honoraria, Research Funding. Borchmann:Novartis: Honoraria, Research Funding. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees. McGuirk:Astellas: Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Research Funding. Holte:Novartis: Honoraria, Other: Advisory board. Waller:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents & Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents & Royalties: Patents, royalties or other intellectual property ; Amgen: Consultancy; Kalytera: Consultancy. Jaglowski:Unum Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding; Juno: Consultancy, Other: advisory board; Kite: Consultancy, Other: advisory board, Research Funding. Bishop:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: 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, Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Foley:Celgene: Speakers Bureau; Amgen: Speakers Bureau; Janssen: Speakers Bureau. Westin:Curis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Celgene: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Genentech: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Unum: Research Funding; Kite: Other: Advisory Board, Research Funding. Fleury:Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; AstraZeneca: Consultancy. Ho:Novartis: Other: Trial Investigator meeting travel costs; La Jolla: Other: Trial Investigator meeting travel costs; Janssen: Other: Trial Investigator meeting travel costs; Celgene: Other: Trial Investigator meeting travel costs. Mielke:DGHO: Other: Travel support; IACH: Other: Travel support; EBMT/EHA: Other: Travel support; Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau; Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau; ISCT: Other: Travel support; Bellicum: Consultancy, Honoraria, Other: Travel (via institution). Teshima:Novartis: Honoraria, Research Funding. Salles:Epizyme: Consultancy, Honoraria; Amgen: Honoraria, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events. Schuster:Novartis: Patents & Royalties: Combination Therapies of CAR and PD-1 Inhibitors (royalties to Novartis); i3Health, Dava Oncology, Novartis, OncLive, PER Oncology: Speakers Bureau; AbbVie, Acerta, Celgene, DTRM Bio, Genentech, Incyte, Merck, Novartis, Portola, TG therapeutics: Research Funding; AbbVie, Celgene, Novartis, Nordic Nanovector, Pfizer: Other: steering committee; Acerta, AstraZeneca, Celgene, Juno, LoxoOncology, Novartis: Other: advisory board; i3Health, Acerta, AstraZeneca, Celgene, Dava Oncology, Juno, LoxoOncology, Novartis, Nordic Nanovector, OncLive, PER Oncology, Pfizer: Honoraria. Bachanova:Kite: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Gamida Cell: Research Funding; GT Biopharma: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Maziarz:Novartis: Consultancy, Research Funding; Incyte: Consultancy, Honoraria; Celgene/Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees. Van Besien:Miltenyi Biotec: Research Funding. Izutsu:Eisai, Chugai, Zenyaku: Honoraria; Kyowa Kirin, Eisai, Takeda, MSD, Chugai, Nihon Medi-physics, Janssen, Ono, Abbvie, Dainihon Sumitomo, Bayer, Astra Zeneca, HUYA Japan, Novartis, Bristol-Byers Squibb, Mundi, Otsuka, Daiichi Sankyo, Astellas, Asahi Kasei: Honoraria; Celgene: Consultancy; Eisai, Symbio, Chugai, Zenyaku: Research Funding; Chugai, Celgene, Daiichi Sankyo, Astra Zeneca, Eisai, Symbio, Ono, Bayer, Solasia, Zenyaku, Incyte, Novartis, Sanofi, HUYA Bioscience, MSD, Astellas Amgen, Abbvie, ARIAD, Takeda, Pfizer: Research Funding. Wagner-Johnston:Gilead: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Corradini:Amgen: Honoraria; Celgene: Honoraria, Other: Travel Costs; AbbVie: Consultancy, Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Gilead: Honoraria, Other: Travel Costs; Janssen: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; KiowaKirin: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Servier: Honoraria; Takeda: Honoraria, Other: Travel Costs; BMS: Other: Travel Costs. Tiwari:Novartis: Employment. Awasthi:Novartis: Employment. Lawniczek:Novartis: Employment. Eldjerou:Novartis Pharmaceuticals Corporation: Employment. Kersten:MSD: Other: Travel grants, honorarium, or advisory boards; Janssen/Cilag: Other: Travel grants, honorarium, or advisory boards; Kite: Consultancy, Other: Travel grants, honorarium, or advisory boards; Roche: Consultancy, Research Funding, Travel grants, honorarium, or advisory boards; Bristol Myers Squibb: Other: Travel grants, honorarium, or advisory boards; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel grants, honorarium, or advisory boards; Celgene: Other: Travel grants, honorarium, or advisory boards; Gilead: Other: Travel grants, honorarium, or advisory boards; Amgen: Other: Travel grants, honorarium, or advisory boards; Roche: Other: Travel grants, honorarium, or advisory boards; Celgene: Consultancy, Research Funding.

Abstract Background: Cellular therapy using anti-CD19 autologous chimeric antigen receptor modified T (CART19) cells demonstrates promising outcomes in several hematologic malignancies of B-cell origin, but this therapy has not been studied in HL patients (pts). While neoplastic HL Reed-Sternberg (HRS) cells are considered CD19 negative, circulating CD19 positive clonal HRS cell precursors and CD19 positive reactive cells within the HRS tumor microenvironment represent potential therapeutic targets for CART19 in HL. Methods: We designed companion pediatric (NCT02624258) and adult (NCT02277522) open-label pilot studies to estimate the feasibility, safety, and efficacy of CART19 cell infusions in pts with relapsed/refractory HL lacking curative treatment options. To allow transient CD19 targeting and limit the window for acute toxicity and B cell aplasia, we used autologous T-cells electroporated with mRNA encoding chimeric anti-CD19 immunoreceptor scFv (RNA CART19) cells in lieu of permanently modified cells engineered by viral transduction. The scFv is derived from a murine monoclonal antibody. Following pheresis and manufacturing of RNA CART19 cells, pts undergo up to 6 infusions of 8x105-1.5x106 RNA CART19 cells/kg/dose for pts &lt;80kg and 1x108 RNA CART19 cells/dose (±20%) for pts ≥80kg. Intravenous cyclophosphamide (30mg/kg) is administered prior to the first and fourth infusion to enhance engraftment. Safety, response assessments (Cheson 2007 criteria), and ancillary studies are measured at defined time points. The primary objective is to describe manufacturing feasibility, safety, and persistence of RNA CART19 cells in HL. Secondary objectives are to estimate efficacy by overall response rates (ORR) and the effect of RNA CART19 on immune factors. Results: To date, 5 pts have been enrolled and had RNA CART19 manufactured. Four pts were infused with RNA CART19 and are evaluable for toxicity/response. Characteristics of the 5 pts include: median age 24 years (range 21-42), 4 (80%) with stage IV, median number of previous therapies 5 (range 4-9), 4 (80%) had stem cell transplant (SCT): 3 had auto SCT, 1 had both auto and allo SCT. Three pts previously progressed on PD-1 inhibitor. All 5 pts underwent successful manufacturing of RNA CART19. One pt developed MDS prior to RNA CART19 infusions and was taken off study. Four patients who underwent RNA CART19 infusions were treated with cyclophosphamide as per protocol. The median number of infused CART19 cells/kg/dose was 1.5x106 (range 7.3x105 -1.5x106). Each patient (pt) received 6 infusions over 2 weeks. Using qRT-PCR, RNA CART19 was detected in 80% of peripheral blood samples drawn within 2 hours after each infusion (Figure 1). RNA CART19 was also detected in 20% of samples drawn immediately prior each infusion reflecting persistence of RNA CART19 from previous infusion at 48 or more hours ago. No pt had RNA CART19 detected by Day (D) 21. There were no study related deaths or grade (G) 3/4 non-hematologic toxicities. Most common G1/2 toxicities at least possibly related to the RNA CART19 therapy occurring in &gt; 1 pt included transient headache in 3 and insomnia in 2. There was no evidence of cytokine release syndrome or significant elevation in cytokines at any point. The ORR at D28 was 50%: 1 complete (CR) and 1 partial response (PR). One pt had stable disease (SD) and one pt had progressive disease (PD). The CR pt (#3) was noted to have persistent RNA CART19 cells in 3 samples drawn at about 48 hours after the prior infusion compared with the PD pt (#1) who had no RNA CART19 detected by this time point on any measurement. In 2 pts who responded (#3 and #4), number of CD19-positive B-cells by flow cytometry as % of total leukocytes declined by 50% on D28 when compared to baseline. There was no evidence of B cell aplasia. The pt in CR progressed at 3 months and the pt in PR was taken off study. As part of routine clinical care, the 2 responding pts (#3 and #4) are currently in CR on PD-1 inhibitor (one underwent auto SCT). The pt with SD is in PR on lenalidomide and the pt with PD died of disease progression. Conclusion: Targeting CD19 positive cells with non-viral, RNA-electroporated, transiently expressed CART19 cells is a feasible and safe strategy in pts with relapsed/refractory HL. We saw encouraging responses, but these were short-lived. We are planning a study for HL pts utilizing virally transduced CART19 cells that are capable of in vivo expansion in combination with PD-1 inhibitors. Disclosures Svoboda: Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Research Funding; Kite: Consultancy; Pharmacyclics: Research Funding. Gill: Novartis Pharmaceuticals: Patents & Royalties, Research Funding. Grupp: Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties; Jazz Pharmaceuticals: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Other: grant. Lacey: Novartis: Research Funding; Genentech: Honoraria. Melenhorst: Novartis: Research Funding. Mato: DTRM: Research Funding; AstraZeneca: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Regeneron: Research Funding; Acerta: Research Funding; Portola: Research Funding; Kite: Consultancy; AbbVie: Consultancy, Research Funding; Gilead Sciences, Inc.: 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. Dwivedy Nasta: Takeda: Research Funding; Incyte: Research Funding; Immunogen: Research Funding. Landsburg: Takeda: Research Funding; Curis: Consultancy, Research Funding. Levine: GE Healthcare: Consultancy; Tmunity Therapeutics: Equity Ownership, Research Funding; Brammer Bio: Consultancy; Novartis Pharmaceuticals Corporation: Patents & Royalties, Research Funding. Porter: Immunovative Therapies: Other: Member DSMB; Novartis: Honoraria, Patents & Royalties, Research Funding; Genentech/Roche: Employment, Other: Family member employment, stock ownship - family member; Servier: Honoraria, Other: Travel reimbursement; Incyte: Honoraria. June: Novartis: Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Research Funding; WIRB/Copernicus Group: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celldex: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Design: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Schuster: Genentech: Consultancy, Research Funding; Merck: Research Funding; Celgene: Consultancy, Research Funding; Nordic Nanovector: Consultancy; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria.

Introduction: Marginal zone lymphoma (MZL) and lymphoplasmacytic lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM) comprise approximately 7% and 2%, respectively, of non-Hodgkin's lymphomas (NHL) (Teras 2016). MZL is further subclassified as splenic MZL (sMZL), nodal MZL (nMZL), or extranodal MZL (eMZL). Standard first-line therapies for LPL/WM include rituximab plus an alkylating agent and/or proteasome inhibitor or ibrutinib (Castillo 2017), while standard first-line treatment for MZL varies by subtype (Rosand 2017). There are limited treatment options for patients who have relapsed after first-line therapy. Idelalisib, a selective oral inhibitor of PI3Kδ, demonstrated efficacy in indolent NHL (iNHL), including MZL and LPL/WM, at a median follow-up of 9.7 months (mos) in a phase 2 study (NCT01282424; 101-09; Gopal 2014). Here, we present the final, long-term results for patients with double-refractory MZL and LPL/WM from the 101-09 study. Methods: Eligible iNHL patients had measurable disease and were refractory to both rituximab and an alkylating agent. Refractory status was defined as lack of response to or progression of lymphoma within 6 mos of completion of preceding therapy, documented by imaging. Oral idelalisib 150 mg twice daily was administered continuously until disease progression or intolerance. Responses were evaluated by an independent review committee using standard criteria (Cheson 2007; Owen 2013). Endpoints included overall response rate (ORR), time to response, duration of response (DOR), lymph node response, progression-free survival (PFS), overall survival, and safety. The final data cutoff date was 22 Oct 2018. Results: Of 125 patients enrolled, 15 (12%) had MZL (sMZL, n = 1; nMZL, n = 5; eMZL, n = 9) and 10 (8.0%) had LPL/WM. Median age was 65 years and most were non-Hispanic (n = 24; 96%) and White (n = 23; 92%). At diagnosis, 80% of MZL and 100% of LPL/WM patients had stage IV disease. The largest lesion at baseline was ≥5 cm for 5 (33%) MZL and 3 (30%) LPL/WM patients. Baseline median IgM level was elevated for 80% of LPL/WM patients (median 1.9, IQR 1.0-2.7 g/dL). Baseline beta2-microglobulin level was >3 µg/mL for 1 of 9 LPL/WM patients with values recorded (median 2.5 [range 1.7-3.1] µg/mL). For MZL and LPL/WM patients, 7 (47%) and 7 (70%) had ≥3 prior therapies, respectively. Common regimens for all 25 patients included rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (44%), rituximab-cyclophosphamide-vincristine-prednisone (40%), rituximab only (28%), bendamustine only (24%), and bendamustine-rituximab (20%). For MZL, the ORR (95% confidence interval [CI]) was 47% (21%, 73%), with median duration of therapy of 6.4 (range 1.8-37) mos. Of 7 responders, 1 had a complete response and 6 had partial responses (PR). Seven had stable disease (SD) and 1 had progressive disease (PD). Fourteen (93%) patients had reduction in lymph nodes, with 8 (53%) having ≥50% reduction in the sum of the products of the greatest perpendicular diameters (SPD). Median PFS was 6.6 (95% CI 3.5, 22) mos and median DOR was 18 (range 0-18) mos (Table). For LPL/WM, the ORR (95% CI) was 80% (44%, 98%), with a median duration of therapy of 29 (range 6.4-51) mos. Of 8 responders, 7 had PR and 1 had a minor response. There was 1 SD and 1 PD. Nine (90%) patients had lymph node reduction, with 5 (50%) having ≥50% reduction in SPD. Median PFS was 22 (95% CI 1.4, 56) mos and median DOR was 20 (range 1.7-50) mos (Table). All 25 patients had ≥1 treatment-emergent adverse event (TEAE), 16 (64%) had a serious AE, and 11 (44%) had dose reduced due to a TEAE. Grade ≥3 TEAEs occurred for 22 (88%) patients; neutropenia (n = 7, 28%), diarrhea (7, 28%), alanine aminotransferase increased (4, 16%), asthenia (3, 12%), and pneumonia (3, 12%) were the most frequent. All patients eventually discontinued treatment due to disease progression (14, 56%), AE (6, 24%), death (3, 12%), investigator request (1, 4%), or other (1, 4%). Ten patients have died, 3 during the study and 7 during the long-term follow-up. Conclusions: Monotherapy with idelalisib showed high rates of antitumor activity in this small subset of patients with MZL and LPL/WM refractory to prior therapy with rituximab and an alkylating agent; prolonged disease control was achieved for LPL/WM patients. No new safety signals were identified despite longer follow-up. Disclosures Wagner-Johnston: Bayer: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Schuster:Genentech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination Therapies of CAR and PD-1 Inhibitors with royalties paid to Novartis, Research Funding; AstraZeneca: Honoraria; Pharmacyclics: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Loxo Oncology: Honoraria; Nordic Nanovector: Honoraria; Pfizer: Honoraria; AbbVie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. de Vos:Verastem: Consultancy; Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy. Salles:Epizyme: Consultancy, Honoraria; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jurczak:Bayer: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Celtrion: Research Funding; MorphoSys: Research Funding; Gilead: Research Funding; Roche: Research Funding; Servier: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Rajakumaraswamy:Gilead Sciences, Inc.: Employment. Xing:Gilead Sciences, Inc.: Employment. Gopal:Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria. OffLabel Disclosure: Idelalisib is a selective oral inhibitor of PI3K-delta that has shown antitumor activity in previously treated indolent non-Hodgkins lymphomas in phase 1 and 2 studies. It is approved for treatment of relapsed follicular lymphoma that has progressed on 2 prior systemic therapies, relapsed chronic lymphocytic leukemia in combination with rituximab when rituximab alone would be considered appropriate due to other comorbidities, and relapsed small lymphocytic lymphoma that has progressed on 2 prior systemic therapies. In this presentation, we provide results of 2 less common subgroups of indolent non-Hodgkins lymphoma, Âmarginal zone lymphoma and lymphoplasmacytic lymphoma/Waldenstrom's Macroglobulinemia, Âfrom the completed phase 2 trial with long-term follow-up.

La polykystose rénale autosomique dominante (PKRAD) est une maladie héréditaire caractérisée par la présence de kyste au niveau des reins et par des atteintes cardiovasculaires. Elle est responsable d’environ 5 à 10 % des insuffisances rénales terminales. Il n’existe, à l’heure actuelle, aucun traitement permettant la prise en charge thérapeutique des atteintes rénales et cardiovasculaires de la PKRAD. Elle se caractérise par un dysfonctionnement des polycystines au niveau des cils des cellules endothéliales vasculaires et tubulaires rénales jouant un rôle dans la détection de stimuli mécanique. De nombreux travaux ont mis en évidence l’intérêt thérapeutique de la stimulation des récepteurs dopaminergiques de type 5 (D5), permettant de restaurer la mécanosensibilité des cellules endothéliales. Parmi les agonistes dopaminergiques, le fénoldopam se démarque de par sa sélectivité des récepteurs D5. Toutefois ses propriétés physicochimiques, en particulier sa faible demi-vie et sa sensibilité au métabolisme, en font une molécule peu adaptée à une administration per os, voie privilégiée dans le cas des maladies chroniques. Dans ce contexte, le fénoldopam a fait l’objet d’une formulation sous forme de nanoémulsions et de liposomes. Ces 2 formulations ont permis l’encapsulation de fénoldopam. Si les nanoémulsions ont montré une instabilité dans les milieux biomimétiques, confirmée par l’absence d’amélioration du profil pharmacocinétique, les liposomes, quant à eux se sont montrés plus stables. Ils ont également permis de modifier le devenir du fénoldopam, en comparaison à sa forme libre en solution, après administration par voie orale, laissant présager la possibilité d’obtenir une libération prolongée
Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disorder characterized by the presence of cysts in the kidneys and associated cardiovascular complications. It is responsible for about 5 to 10% of end-stage renal failure cases. Currently, there is no treatment available for the therapeutic management of renal and cardiovascular complications of ADPKD. The disease is characterized by dysfunction of polycystins in the cilia of vascular endothelial and renal tubular cells, which play a role in detecting mechanical stimuli. Numerous studies have highlighted the therapeutic potential of stimulating dopamine type 5 receptors (D5), which can restore the mechanosensitivity of endothelial cells. Among dopamine agonists, fenoldopam stands out due to its selectivity for D5 receptors. However, its physicochemical properties, particularly its short half-life and sensitivity to metabolism, make it poorly suited for oral administration, a preferred route for chronic diseases. In this context, fenoldopam has been formulated into nanoemulsions and liposomes. Both formulations allowed for the encapsulation of fenoldopam. While the nanoemulsions showed instability in biomimetic media, confirmed by the lack of improvement in the pharmacokinetic profile, the liposomes demonstrated greater stability. They also modified the fate of fenoldopam compared to its free form in solution after oral administration, suggesting the possibility of achieving prolonged release