Articoli di riviste sul tema "Theraputic use"

Thyroid nodules are very common in clinical practice, with an overall prevalence that varies from 4% by palpation to 67% by ultrasonography. The annual incidence by palpation has been estimated at 0.09% by the Framingham study,1which translates into approximately 300,000 new nodules in the US in 2005. Despite their high frequency, only a small fraction (~5%) of thyroid nodules harbor cancer. Because only malignant or large, symptomatic nodules will require surgical excision, a systematic approach to their evaluation is important to avoid unnecessary surgery. Certain aspects in the evaluation and management of thyroid nodules remain controversial or represent clinical dilemmas.

Abstract Abstract 4996 The application of monoclonal antibodies represents an increasingly powerful weapon in the arsenal against hematologic diseases. With the advent of new therapies come previously unrecognized laboratory interference that if not properly identified could have clinical repercussions. We encountered two patients, neither of whom had a history of plasma cell dyscrasia, who underwent treatment with rituximab for immune thrombocytopenic purpura (ITP) and were discovered to have a monoclonal IgG kappa band on serum protein electrophoresis (SPEP) followed by immunofixation (IFX). Both patients had severe, steroid-resistant ITP and received rituximab on an empiric basis, at a weekly dose of 375 mg/m2 IV. In Patient #1, an evaluation for secondary causes of thrombocytopenia included SPEP and IFX. The IFX yielded a faint, atypical IgG kappa band that migrated to the far cathodal zone of the gel. No band was seen on SPEP alone. Since the patient was treated with rituximab the day before these studies were performed, we considered the possibility that the IgG kappa band was due to circulating rituximab. Rituximab is a chimeric antibody composed of human IgG1 kappa chain constant regions and heavy- and light-chain variable regions from a murine anti-CD20 antibody. The elimination half-life of this therapeutic antibody increases with subsequent doses and is approximately 60 hours for the first dose and 174 hours for the fourth dose (range 26 to 442 hours). An aliquot of rituximab was obtained from pharmacy and analyzed by SPEP/IFX, showing an IgG kappa monoclonal protein band identical to the M-protein in the patient's serum. Repeat assessment of serum from this patient obtained immediately prior to her fourth treatment with rituximab demonstrated that the IgG kappa paraprotein was less intense on IFX compared to the first IFX. Several hours after the fourth rituximab infusion was completed, a more intense band corresponding to the IgG kappa paraprotein was detected again on IFX. In Patient #2, who also received rituximab for steroid-resistant ITP, a similar circulating rituximab-related protein was detected on IFX performed one hour after his fourth rituximab infusion. IFX performed on a sample obtained immediately before treatment did not demonstrate a paraprotein, and testing one week after treatment showed that the band had resolved. We believe that awareness of the presence of a faint monoclonal protein by SPEP/IFX following recent administration of rituximab is important to avoid unnecessary further evaluation for a pathologic monoclonal gammopathy. Alternatively, if suspicion exists, SPEP/IFX should be conducted prior to the initiation of treatment with rituximab or after the treatment course is completed in order to avoid uncertainty. Furthermore, it is important to be cognizant of this finding in patients on maintenance rituximab for an indolent lymphoma and an associated paraprotein who may undergo interval monitoring of the monoclonal gammopathy. It is possible that a similar phenomenon may be seen with other therapeutic monoclonal antibodies with a dosing regimen and half-life that is similar to rituximab, such as cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor. Finally, the presence of a characteristic band on immunofixation may allow for the qualitative assessment of the presence of a therapeutic monoclonal antibody in the serum. Further studies are necessary to determine the sensitivity and specificity of such a laboratory test. Disclosures: Off Label Use: Rituximab is an anti-CD20 chimeric antibody and is used for the treatment of immune thrombocytopenic purpura.

The domain of Physics covers vast area of scientific knowledge. Basic research on assemblies of atomic or nuclear radiation and gyromagnetic moments led to powerful technique for studying molecular structure as well as solid lattices. It led to invention and development of modern medical diagnostic and theraputic tools which have revolutionized the medical practices. Advancement in medical researches as seen today will be well-nigh impossible without the use of the finding of Physics. The funding made on Physics is in fact another way of funding made on human health.Keywords: Radioactivity; Crystallography; Radioimmune assay; MRI; CAT; PETThe Himalayan PhysicsVol.2, No.2, May, 2011Page: 43-46Uploaded Date: 1 August, 2011

Abstract Brain cancers remain some of the most challenging tumors to treat. The goal of our research is to use a 3D in vitro model to acquire in-depth understanding of the unique environment of brain tumors in order to find new biomarkers of disease and develop more efficient therapeutic approaches. Glioblastomas (GBM) present a very poor prognosis, they exhibit high infiltration into brain parenchyma, impairing surgical resection and leading to recurrence. The recurrent tumor is predominantly more aggressive and resistant to available therapeutic strategies. Brain extracellular matrix (ECM) plays a key role in glioblastoma invasion and therapeutic resistance. In particular, the aberrant biosynthesis of the main component of brain ECM, hyaluronic acid (HA), has been associated to pathological conditions. We investigate the influence of tumor extracellular microenvironment in glioblastoma progression. We focus on the tumor-associated HA biosynthesis in response to biophysical alterations, such as hypoxia and stiffness, and after radio and chemotherapeutic interventions. The ability to manipulate tumor ECM can improve therapeutic outcomes and restrict glioblastoma growth and infiltration. Citation Format: Joseph Mueller, Ryan Yao, Kim Selting, Catherine Best-Popescu, Brendan Harley, Sara Pedron-Haba. Engineered systems for tumor modeling facilitate the assessment of theraputic interventions [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A045.

Abstract This is a fully automated system for determining six common antiepileptic drugs and two principal metabolites of carbamazepine in serum. It is based on "high-performance" liquid chromatography (HPLC), with column switching. TSKprecolumn BSA-ODS and TSKgel ODS-120A (both from Toyo Soda) were used as the precolumn and analytical column, respectively. The former contains octadecylsilyl resins treated with bovine serum albumin (BSA), and does not adsorb macromolecules such as serum proteins but retains small lipophilic molecules such as antiepileptic drugs. Serum samples are directly injected onto the precolumn. After washing out the serum proteins from the precolumn with sodium phosphate buffer, we switch the column connections to introduce the retained substances onto the analytical column and elute with a step-gradient of acetonitrile/sodium phosphate buffer. The high analytical recovery (95-102%) and the reproducibilities (CV less than 5% within-run) indicate that this system is suitable for use in theraputic drug monitoring in clinical laboratories.

Introduction: Therapeutic contact lens (TCL) is indicated to relieve pain, promote corneal wound healing, provide mechanical protection and support, maintain corneal hydration, improve vision and seal or splint cornea in various ocular surface disorders. Till date no study has been reported about use of contact lenses for these purposes in Nepalese population. is study thus aims to evaluate the outcome of TCL in ocular surface disorders in Nepalese population. Methods: A prospective analysis of patients fitted with TCL for various ocular surface disorders was done at B.P. Koirala Lions centre for Ophthalmic Studies. All the subjects were fitted with Poly-2-hydroxy ethyl methacrylate (70% water content); information on clinical conditions were evaluated and recorded at initial and final treatment visit. Results: Of 57 eyes fitted with TCL, corneal laceration caused by mechanical injury (22.8%) and vernal keratoconjunctivitis (21.1%) were the most common ocular surface disorders. The common indications for applying TCLs were to alleviate pain and discomfort (31.5%) and corneal thinning impending to perforation (26.3%). Subjects’ clinical conditions and symptoms were resolved partially to completely in 89.4%. Dry eye was a common cause of contact lens associated therapeutic failure. Conclusion: Poly-2-hydroxy ethyl methacrylate contact lenses are safe and effective in alleviating symptoms and healing of various ocular surface disorders in Nepalese population.

Abstract Inflammatory bowel disease (IBD) is a complex, multifactorial set of diseases defined by chronic and relapsing inflammation of the gut. Changes in oxidative stress, inflammation, and metabolism are central to the disease process, linking mitochondrial health to IBD pathogenesis. Mitophagy is a quality-control mechanism that selectively removes dysfunctional mitochondria. Multiple mitophagy pathways co-exist in the intestine, including the canonical PINK1/PARKIN pathway and NIX. We have previously shown that NIX is increased in IBD, removing damaged mitochondria in the epithelium. Whether this translates to a physiologic increase in mitochondrial turnover remains unanswered. We hypothesized that mitophagy within the intestinal epithelium represents a key homeostatic response to inflammation. To study this hypothesis, we employed the use of a novel transgenic mouse expressing the pH-dependent fluorescent protein, mt-Keima, tethered to the mitochondria. Adult mt-Keima mice were subjected to chemically induced colitis (3% DSS) for 7 days to induce intestinal inflammation. In vivo mitophagic flux, measured via live-cell confocal microscopy, was increased nearly 4-fold (n=3, p<0.05) in DSS-treated animals compared to controls. Despite this consistent elevation, NIX expression varied in both human and mouse tissue, suggesting that other mitophagy pathways, like PARKIN, may be involved. Interestingly, activated PARKIN (pSer65-PARKIN) was higher in inflamed tissues of humans and mice as compared to controls, though variation was present. To determine the functional importance of PARKIN, Parkin-/- mice were subjected to a 7-day treatment of 2% DSS. These mice developed a more severe colitis, suggesting that Parkin-mediated mitophagy contributes to the mitochondrial damage response in IBD. These data collectively indicate that mitophagy is elevated in IBD, and both NIX and PARKIN likely work in parallel to respond to the elevated mitophagic demand. Interestingly, both NIX and pSer65-PARKIN expression are co-expressed in human control tissues, while both were generally expressed in inflamed biopsies, and at higher levels. We speculate that the mechanism of mitophagy may not necessarily be important, but that it is elevated in response to intestinal inflammation. To address this aim, we administered a known mitophagy inducer, urolithin A, to mice on a 7-day course of DSS. Urolithin A + DSS-treated mice had elevated NIX and pSer65-PARKIN expression compared to vehicle + DSS controls. This elevation correlated with decreased disease activity and improved O2 mitochondria respiration. We conclude that mitophagy is an imperative homeostatic response to remove superfluously damaged mitochondria in IBD and is amenable to therapeutic intervention. Elevating mitophagic flux might be a potential therapeutic option to help improve disease outcomes in IBD.

Glioblastoma multiforme (GBM) is the most common and malignant type of brain tumor. In fact, tumor recurrence usually appears a few months after surgical resection and chemotherapy, mainly due to many factors that make GBM treatment a real challenge, such as tumor location, heterogeneity, presence of the blood-brain barrier (BBB), and others. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) represent the most promising carriers for therapeutics delivery into the central nervous system (CNS) owing to their inherent ability to cross the BBB. In this review, we present the main challenges in GBM treatment, a description of SLNs and NLCs and their valuable role as drug carriers in GBM treatment, and finally, a detailed description of all modification strategies that aim to change composition of SLNs and NLCs to enhance treatment outcomes. This includes modification of SLNs and NLCs to improve crossing the BBB, reduced GBM cell resistance, target GBM cells selectively minimizing side effects, and modification strategies to enhance SLNs and NLCs nose-to-brain delivery. Finally, future perspectives on their use are also be discussed, to provide insight about all strategies with SLNs and NLCs formulation that could result in drug delivery systems for GBM treatment with highly effective theraputic and minimum undesirable effects.

Introduction: Treatment of the cryptorchid testicle is essential due to the increased risk of infertility and malignancy as well as the risk of testicular trauma and psychological stigma on patients and their parents. Approximately 20% of cryptorchid testicles are impalpable. In these cases, the laparoscopy is the method of choice for both diagnostic and theraputic requirements. Materials and Methods: Between 1, April 2009 to 31, October 2010, 37 testicles of 30 patients were submitted to diagnostic laparoscopy for impalpable testes. This was a prospective study to evaluate the diagnostic accuracy and therapeutic outcomes of use of laparoscopy in impalpable testes. Age, operative techniques, complications, the cosmetic aspect and outcomes were also recorded. Results: Mean age was 6.64 ± 3.96 years and 23% cases were bilateral. Twenty one cases had primary orchiopexy, 9 had 1 st stage Fowler-Stephens (FS) procedure, 3 had 2nd stage FS, 13 cases needed inguinal exploration and there was I vanishing testicles. Average operating time was 40 minutes for diagnostic laparoscopy, 90 minutes for unilateral and 120 minutes for the bilateral cases. Two of the patients had late postoperative complications e.g. one uretereral obstruction and one recurrence. Conclusions: In pediatric age group, the laparoscopic approach is safe and feasible. The purpose of study is to observe whether the laparoscopic procedure presents excellent results in terms of diagnosis and therapy of the impalpable testis. Journal of Paediatric Surgeons of Bangladesh (2017) Vol. 8 (1): 15-19

Marma Science, an extraordinary gem in the vast treasure of Ayurvedic knowledge, represents the science of specific vital places in the body (Marmas), that are the ‘seats of life’ (Prana - the vital life force). As any injury to these parts may lead to severe pain, disability, loss of function, loss of sensation, or death, therefore, they hold an important place in the science of surgery. The ancient scriptures have strictly prohibited causing any injury to the Marmas. However, recent researches have used Marma stimulation for theraputic benefits, with encouraging outcomes. Looking at these mutually conflicting, important applications of Marma Science, the present study was undertaken for its in-depth analysis. Previously, we have explored different aspects of Marma Science in ancient and classical Indian scriptures. In addition, our other study have provided detailed description of the number of Marmas, their location, structures involved, classification, effect of trauma, etc., as per classical texts, as well as correlation with modern science. Previously, we also published its use in Yoga and other ancient Indian traditions, both as a therapeutic technique, as well as for self-defense and inflicting injury on the opponents. The present article explored its application as a therapeutic procedure (Marma Therapy). Different methods of Marma stimulation have been compiled. Therapeutic classification and applications of Marmas have been listed, and several research studies on Marma Therapy have been presented. Several mechanisms for the mode of action of Marma Therapy have been discussed. It is concluded that Marma Science holds significant promise as an effective therapeutic procedure.

185 Background: Advances in breast cancer screening and treatment have fostered the use of surgical procedures that increasingly optimize cosmetic outcome, while ensuring oncologic safety remains the primary concern of the oncologic surgeon. The role of nipple-sparing mastectomy (NSM) for risk-reducing surgery and breast cancer is evolving. It can be difficult to demonstrate involvement of the nipple-areolar complex (NAC) preoperatively, and and in this report we examine the utility of intraoperative subareolar frozen section (FS). Methods: Records of patients undergoing NSM at the NYU Langone Medical Center from 2006-2011 were reviewed retrospectively. Use of subareolar FS was at surgeon’s discretion. Results: 237 NSM were performed (146 prophylacytic, 91 theraputic). FC was not utilized in 58 mastectomies (28 prophylactic), with 2 (+) on paraffin. Among the remaining 180 mastectomies, 11 biopsies were (+)(7.2%); 5 subareolar biopsies were (+) on FS and paraffin histologic slides (PS) (2.8%); 6 were negative on FS and (+) on PS. Among the 3 prophylactic NSM with (+) subareolar biopsies there was 1 (+) FS, 1 (-) FS, and 1 with no FS performed. There were no false (+) FS. Four of the 5 patients with (+)FS underwent simultaneous excision of the NAC. The 5th patient had atypia on FS and DCIS on PS, and returned to the OR during the same hospitalization for removal of NAC. The remaining patients underwent subsequent excision of the NAC either during planned 2nd stage reconstruction or following completion of chemotherapy. 8 NAC were free of disease and 5 were positive for in situ or invasive disease. There has been no local recurrence in these patients to date. Conclusions: The rate of NAC involvement is low, 5.5% in this series, and FS, while utilized in the majority of these cases, detected only 46% of subareolar disease. While FS can direct intraoperative decision making, the predictive power is low, and these considerations must be addressed in preoperative patient discussions. Furthermore, among those patients with (+) subareolar biopsies, only 39% had residual disease on NAC excision. Thus, optimal oncologic management of the NAC must still be considered an unresolved issue.

Abstract One common feature of high-risk pediatric B-cell acute lymphoblastic leukemia (B-ALL) is impaired function of the Ikaros (IKZF1) tumor suppressor gene. Ikaros encodes a DNA-binding, zinc finger protein that regulates expression of its target genes. Using chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-SEQ) we determined that Ikaros targets multiple genes that regulate cell cycle progression. Functional studies provided evidence that Ikaros acts as a transcriptional repressor of several key cell cycle-promoting genes. We hypothesize that Ikaros’ ability to regulate transcription is reduced in leukemia and that restoration of Ikaros function as transcriptional repressor of cell cycle-promoting genes will have a strong anti-leukemia effect. We have previously shown that Casein Kinase II (CK2) directly phosphorylates Ikaros in vivo and that this phosphorylation impairs Ikaros function. Here, we show that the activity of Casein Kinase II (CK2) is more than 5-fold increased in primary B-ALL cells as compared to normal bone marrow in kinase assays. We tested whether CK2 inhibition can enhance the binding of Ikaros to cell cycle-promoting genes and enhance Ikaros transcriptional repressor activity. Treatment of leukemia cell lines, as well as primary B-ALL cells, with different CK2 inhibitors resulted in enhanced Ikaros binding to its target genes, as evidenced by quantitative chromatin immunoprecipitation (qChIP). This was associated with transcriptional repression of the Ikaros target genes that function as cell cycle promoters, as evidenced by quantitative real-time PCR (qRT-PCR), and by cell cycle arrest in treated cells. CK2 inhibition had a particularly pronounced effect on Ikaros activity in cells of primary high-risk B-ALL, which carry a deletion of one Ikaros allele. When these cells were untreated Ikaros was unable to bind promoters of its target genes. CK2 inhibition restored Ikaros binding to promoters of the cell cycle-promoting genes resulting in their repression. These results suggest that CK2 inhibition has an anti-proliferative effect on leukemia cells and that these effects occur via enhanced Ikaros tumor suppressor activity as a transcriptional repressor of cell cycle-promoting genes. We tested whether CK2 inhibition can produce an anti-leukemia effect in vivo using two preclinical human-mouse xenograft models of B-ALL: Nalm6 xenografts and primary patient-derived xenografts produced from high-risk leukemia cells that have a deletion of one Ikaros allele. Our results demonstrate that CK2 inhibition results in a potent anti-leukemia therapeutic effect in both xenograft models as evidenced by a reduction of leukemia burden in bone marrow and in spleen of treated mice, along with their prolonged survival as compared to controls. In summary, our results demonstrate the therapeutic efficacy of a novel therapeutic approach for high-risk leukemia – restoration of Ikaros tumor suppressor activity via inhibition of CK2. These results provide a rationale for the use of CK2 inhibitors in clinical trial for high-risk leukemia, including cases with deletion of one Ikaros allele. Supported by the National Institutes of Health R01 HL095120, and the Four Diamonds Fund Endowment. Disclosures No relevant conflicts of interest to declare.

Abstract Carcinoembryonic antigen associated cell adhesion molecule 1 (CEACAM-1) belongs to a family of carcinoembryonic antigen-associated glycoproteins. It is expressed on leukocytes, endothelium, and epithelium. Microarray analysis showed that CEACAM-1 mRNA is increased in the small bowel during gut graft-versus-host-disease (GVHD) after allogeneic bone marrow transplantation (allo-BMT). Using CEACAM-1−/− mice as recipients or sources of donor bone marrow or T cells caused significantly worse GVHD mortality (p<0.05) compared to wildtype (WT) controls. Histopathological analysis of GVHD target organs from CEACAM-1−/− recipients of WT T cells or WT recipients of CEACAM-1−/− T cells revealed increased GVHD of the large bowel (p<0.05) but not liver or small bowel compared to WT control. Alloreactive splenic CD8 CEACAM-1−/− T cells from recipients with GVHD had increased levels of α4β7 integrin compared to WT controls. We also found increased numbers of small bowel intraepithelial lymphocytes and mesenteric lymph node cellularity in CEACAM-1−/− recipients of WT T cells and WT recipients of CEACAM-1−/− T cells, with a corresponding decrease of cellularity in peripheral lymph nodes and the liver. Adoptive transfer of CFSEhi CEACAM-1−/− T cells into WT hosts, or of WT T cells into CEACAM 1−/− hosts revealed more profound activation of T cells in CEACAM-1 deficient settings, shown by increased early CD25 expression and CD62L down-regulation on splenic CFSEdim alloreactive T cells. We found no significant differences in serum levels of TNF or IFNγ, T cell proliferation kinetics upon adoptive transfer, percentages of alloactivated CD4 or CD8 cells, intracellular levels of T-bet or IFNγ, CD8 T cell cytolytic efficiency, percentages of splenic regulatory T cells, or levels of T cell apoptosis in WT recipients of CEACAM-1−/− T cells or CEACAM-1−/− recipients of WT T cells with GVHD as compared with controls. Finally, irradiation of non-transplanted CEACAM-1−/− mice revealed increased radiation sensitivity, shown by earlier and greater lethality and increased small bowel crypt apoptosis, suggesting a role for CEACAM-1 in conditioning-related toxicity and subsequent GVHD amplification. We conclude that CEACAM-1 deficiency on donor T cells or transplant recipients results in increased gut and systemic GVHD due to increased T cell activation and elevated expression of the gut homing integrin α4β7. This suggests that the use of CEACAM-1 agonists could be a novel theraputic strategy for ameliorating acute intestinal and systemic graft-versus-host-disease.

Sodium Glucose Co-transporter2 inhibitors are one of the latest anti diabetic drugs that are approved by USFDA. It include Dapagliflozin, Canagliflozin , Ipragliflozin,Empagliflozin, Tofogliflozin,and Luscogliflozin. They act by inhibiting tubular reabsorption of glucose in kidney and increasing urinary excretion of glucose. SGLT2 inhibitors reduce the workload of the proximal tubules and improve tubulointerstitial hypoxia, and allow fibroblasts to start normal erythropoietin production, and thereby exhibit renoprotection .These drugs have beneficial role in the reduction of HbA1c, cardiovascular risk factors and proteinuria. Use of SGLT2 inhibitor is contraindicated in patients with estimated GFR less than 30 mL/min or End stage renal failure Genitourinary infections are most common adverse effects associated with these drugs, predominantly in female. Keywords: Diabetes Mellitus, Diabetic Nephropathy, Hyperfiltration, Natriuresis, Macroalbuminuria, Endothelial dysfunction, Intraglomerular filtration, ketoacidosis, amputations, apoptosis

The doctors’ clinical time collides with the increasing of the use of telecare technologies in our digital era, reducing the actual doctor-patient interaction and the potential to engage with therapeutic doctor-patient communication. In our qualitative study, we followed a collaborative German-Israeli project that trained medical students to use complementary and integrative medicine (CIM) methods in order to improve doctor-patient communication. Interviews with the participants and participatory observation revealed the ways the mentors taught CIM methods, the meaning of therapuitic doctor-patient communication and how the students learned and implemented these skills in different ways. Our findings show that students expand their communication channels and skills, notice their own somatic-sensory states, and engage with somatic knowledge in different interactions. Our findings correspond with, and signify the intercorporeal space of doctor-patient interaction in the way in which doctors’ and patients’ soma-sensual aspects are interact, influence each another, and enable therapeutic communication.

The goals and recommendations for ICU (Intensive Care Unit) patients’ sedation and analgesia should be to have adequately sedated patients who are calm and arousal, so that they can guarantee a proper evaluation and an adequate control of pain. This way, it is also possible to perform their neurological evaluation, preserving intellectual faculties and helping them in actively participating to their care. Dexmedetomidine is a selective alpha-2 receptor agonist, member of theraputical cathegory: “other hypnotics and sedatives” (ATC: N05CM18). Dexmedetomidine is recommended for the sedation of adult ICU patients who need a sedation level not deeper than arousal in response to verbal stimulation (corresponding to Richmond Agitation-Sedation Scale 0 to -3). After the EMA approval, some European government authorities have elaborated HTA on dexmedetomidine, based on clinical evidence derived from Prodex and Midex trials. Dexmedetomidine resulted to be as effective as propofol and midazolam in maintaining the target depth of sedation in ICU patients. The mean duration of mechanical ventilation with dexmedetomidine was numerically shorter than with propofol and significantly shorter than with midazolam. The resulting favourable economic profile of dexmedetomidine supported the clinical use in ICU. Dexmedetomidine seems to provide clinical benefits due to the reduction of mechanical ventilation and ventilator weaning duration. Within the present review, an economic analysis of costs associated to the use of dexmedetomidine was therefore performed also in the Italian care setting. Thus, four different analyses were carried out based on the quantification of the total number of days in ICU, the time spent on mechanical ventilation, the weighted average number of days with mechanical ventilation or not and TISS points (Therapeutic Intervention Scoring System). Despite the incremental cost for drug therapy associated with dexmedetomidine, a reduction of the management costs for ICU has been estimated, with savings ranging between € 800 and € 1,400 per patient.

Abstract All trans retinoic acid (ATRA) has been used in differentiation therapy for APL and other types of cancers. However, the rapid emergence of ATRA resistance due in part to ATRA-induced acceleration of ATRA metabolism limits its use. A novel strategy to overcome the limitation associated with exogenous ATRA therapy has been developed by inhibiting the cytochrome P450-dependent ATRA-4-hydroxylase enzyme responsible for ATRA metabolism. These inhibitors are referred to as RAMBAs. Novel RAMBAs were developed which demonstrated a superior apoptosis, cell growth inhibition, in vivo anti-tumor effect in addition to the differentiation effect in breast cancer cell lines (Patel JB et al. J. Med. Chem2004,47:6716). We tested 3 RAMBAs, VN/14-1, 50-1, and 66-1 to investigate their activities against APL cell lines. RAMBAs did not confer cytotoxicity or apoptosis induction in vitro at the concentration between 0.5 to 5 μM as opposed to breast or prostate cancer cell lines. However, the differentiation effect was demonstrated by morphological and phenotypic changes using Wright-Giemsa stain and CD11b staining measured by flow cytometric analysis. VN/14-1 and VN/66-1 induced differentiation and apoptosis morphologically and phenotypically in HL60 cells. VN/14-1 and VN/50-1 showed superior differentiation in NB4 cell line compared to ATRA (70%, 69%, and 45%, respectively). Interestingly, HL60 ATRA resistant cell line was induced to undergo differentiation by VN/14-1 (0.5μM) at 55% whereas ATRA (0.5, 1, 5μM) showed less than 5% by flow cytometry analysis. VN/14-1 inhibited cell cycle at S phase whereas ATRA did not attenuate the cell cycle at the same concentration. We also tested the effect of RAMBAs on human CD34+ enriched cell colony formation. RAMBAs were added to the methylcellulose culture plates with CD34+ cells and colonies were determined after 14 days. There was no difference in the CFU-GM or BFU-E colony count between the control and the RAMBAs group. In summary, RAMBAs are promising differentiation agents in the treatment of APL, possibly through an inhibition of Cyp26A leading to increased endogenous ATRA levels. In addition, cell cycle inhibition may be a mechanism of differentiation induction in ATRA resistant cell lines. RAMBAs did not affect normal hematopoietic stem cells. We are currently testing whether RAMBAs can induce acetylation of histones in APL cell lines.

PURPOSE: The Coronavirus 2019 (COVID-19) pandemic is an international public health emergency. Vaccines, and acute infection drugs are currently unknown, and when available, expense and distribution issues may impede distribution in undeserved areas. The aim of this systematic review was to summarize the evidence regarding cinchona bark (CB) for its potential anti-viral properties against COVID-19 STUDY DESIGN: A current literature and historical text review was conducted, limited to articles having full text or abstracts available in English, using Google Scholar, Pubmed-NCBI, ScienceDirect, and WebMD, and online book publications, with key search words, including synthetic CB analogues: chloroquine-hydroxychloroquine (CQ/HCQ) derivatives. RESULTS: Several related in-vitro studies, editorials, and expert consensus papers on quinine analogue anti-viral treatment papers and historical treatises have been published. A March 2020 CQ drug trial ongoing in China, has just reported breakthrough efficacy evidence for COVID-19 pneumonia. However, there are severe CQ shortages and direct evidence for the anti-viral therapeutic use of CB is sparse, several centuries old, and controversial. CONCLUSION: CB was for centuries known to be a natural source of quinine from which modern synthetically manufactured analogues anti-viral purposed drugs such as CQ/HCQ are based. CB may also possess anti COVID-19 activity as its historical derivatives, but with the same potential for life-threatening adverse reactions and severe drug interaction complications akin to its analogues. Issues with herbal quality control, prescriber dose inexperience, perceived risk underestimation by self-prescribers, and a misinformed propensity for consumer fraud are other concerns. However, analogue drug risk-benefit ratios indicate CB may also have some value for acute COVID-19 (cytokine storm) infection management. The existing evidence and evolving breakthrough CQ efficacy findings in China, shadowed by CQ shortage, highlight a need for modern and timely investigation of CB as cost-effective alternative COVID-19 pneumonia monotherapy.

Abstract Introduction Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), CD19 directed CAR T cells, are effective treatments (tx) for relapsed/refractory (R/R) aggressive B-cell lymphomas (B-NHL). We present a multicenter retrospective study of safety, patterns of use, resource utilization, and efficacy with commercial axi-cel and tisa-cel in 7 US centers that offer both products for R/R B-NHL. Methods Data collection included all patients (pts) who underwent apheresis from 5/1/2018 (when centers had a choice of either axi-cel or tisa-cel) through 7/31/2019, with a data cutoff of 12/31/20. Pt and tx characteristics are summarized descriptively. Cytokine release syndrome (CRS) and neurologic toxicity (NT) were graded per ASTCT consensus. Pt selection, toxicity management, and response assessment followed institutional practices. Univariable and multivariable analyses (MVA) with forward selection were performed to determine the association between baseline/tx characteristics, and response and toxicity. Results 251 pts underwent apheresis, 161 (64%) for axi-cel, and 90 (36%) for tisa-cel. Twelve (7%) axi-cel and 8 (9%) tisa-cel pts died from lymphoma progression prior to infusion. Among infused pts, the median age at apheresis was 59 years (range: 18-86) for axi-cel pts and 67 years (range: 37-89) for tisa-cel pts, with 35% of axi-cel and 61% of tisa-cel pts aged ≥ 65 years. By histology, 81% of axi-cel pts had either DLBCL or HGBL, compared to 91% of tisa-cel pts. Median number of prior therapies was 3 (range: 2-10) for axi-cel and 4 (range: 2-7) for tisa-cel pts, with 72% of axi-cel and 85% of tisa-cel pts receiving ≥ 3 prior therapies. Forty percent of axi-cel and 21% of tisa-cel pts had primary refractory disease. Bridging therapy was given in 63% of axi-cel and 73% of tisa-cel pts. Median time from apheresis to infusion was 28 days for axi-cel and 44 days for tisa-cel. Sixty-one percent of axi-cel and 44% of tisa-cel pts would have been ineligible for ZUMA-1 and JULIET, respectively. CRS occurred in 123 (83%) axi-cel pts; Grade ≥3 CRS in 13 (9%) (Table 1). CRS occurred in 29 (35%) tisa-cel pts; Grade ≥3 CRS in 2 (2%). NT occurred in 72 (48%) axi-cel recipients; Grade ≥3 NT in 47 (32%). NT occurred in 7 (9%) tisa-cel recipients; Grade ≥3 NT in 1 (1%). Median onset of CRS and NT was 3 and 6 days, respectively, with axi-cel, and 3 and 4 days, respectively, with tisa-cel. Tocilizumab was administered in 61% of axi-cel pts with 54% receiving steroids. In tisa-cel pts, tocilizumab was administered in 15% of cases, with 7% receiving steroids. Inpatient CAR T-cell infusion occurred in 92% of axi-cel and 38% of tisa-cel pts. The median hospital length of stay (LOS) was 18 days for axi-cel pts and 15 days in tisa-cel pts. Intensive care unit (ICU) transfer occurred in 40% of axi-cel pts and 6% of tisa-cel pts. Response for infused pts was assessed at day 90 or at time of clinical progression. Of 142 axi-cel pts evaluable at day 90, the ORR was 53% with 42% achieving a CR. Of 81 tisa-cel pts evaluable at day 90, the ORR was 44% with 36% achieving a CR. With a median follow-up of 12.2 months in axi-cel recipients, the 12-month PFS was 44% with 12-month OS of 62%. With median follow-up of 13 months in tisa-cel recipients, the 12-month PFS was 34% with 12-month OS of 58%. On MVA, peak ferritin ≥ 5000 ng/ml was associated with worse PFS (HR 2.19; 95% CI, 1.34-3.59; P=0.002) and OS (HR 3.44; 95% CI, 1.98-5.97; P&lt;0.001). Tx with tisa-cel was associated with a lower incidence of ≥ Grade 3 NT (OR 0.03; 95% CI, 0.01-0.25; P=0.001), while an elevated LDH prior to lymphodepleting chemotherapy (OR 3.75; 95% CI, 1.35-10.43; P=0.011) and an ECOG PS &gt;1 (OR 5.83; 95% CI, 1.12-30.45; P=0.037) were associated with severe NT. Conclusions In this retrospective multicenter analysis by centers with prescription choice of either axi-cel or tisa-cel for R/R B-NHL, baseline characteristics differed between recipients of axi-cel and tisa-cel. Tisa-cel recipients were more likely to be older and heavily pretreated, and less likely to have primary refractory disease. In an unmatched comparison, ORR, PFS, and OS appeared comparable between axi-cel and tisa-cel recipients. Safety appeared more favorable than reported in the pivotal trials. In comparison to axi-cel, tisa-cel was associated with a lower incidence and severity of CRS and NT, lower utilization of tocilizumab and steroids, lower rate of ICU transfer, and shorter median hospital LOS. Figure 1 Figure 1. Disclosures Riedell: Xencor: Research Funding; Calibr: Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, 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; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite/Gilead: Research Funding, Speakers Bureau; Tessa Therapeutics: Research Funding; MorphoSys: Research Funding. Nastoupil: Denovo Pharma: Other: DSMC; Janssen: Honoraria, Research Funding; Bayer: Honoraria; Gilead/Kite: Honoraria, Research Funding; Caribou Biosciences: Research Funding; Novartis: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; IGM Biosciences: Research Funding; MorphoSys: Honoraria; ADC Therapeutics: Honoraria. Perales: Novartis: Honoraria, Other; Equilium: Honoraria; Karyopharm: Honoraria; Miltenyi Biotec: Honoraria, Other; Incyte: Honoraria, Other; Merck: Honoraria; Medigene: Honoraria; Kite/Gilead: Honoraria, Other; Cidara: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; MorphoSys: Honoraria; Nektar Therapeutics: Honoraria, Other; NexImmune: Honoraria; Omeros: Honoraria; Takeda: Honoraria; Servier: Honoraria; Sellas Life Sciences: Honoraria. Maziarz: Athersys: Other: Data and Safety Monitoring Board, Patents & Royalties; Artiva Therapeutics: Consultancy; Allovir: Consultancy, Research Funding; Bristol-Myers, Squibb/Celgene,, Intellia, Kite: Honoraria; CRISPR Therapeutics: Consultancy; Omeros: Research Funding; Intellia: Honoraria; Novartis: Consultancy, Other: Data and Safety Monitoring board, Research Funding; Incyte Corporation: Consultancy, Honoraria; Vor Pharma: Other: Data and Safety Monitoring Board. McGuirk: Allovir: Consultancy, Honoraria, Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding; EcoR1 Capital: Consultancy; Astelllas Pharma: Research Funding; Fresenius Biotech: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Novartis: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding. Bachanova: FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schuster: Genentech/Roche: Consultancy, Research Funding; Loxo Oncology: Consultancy; Tessa Theraputics: Consultancy; Pharmaclyclics: Research Funding; Juno Theraputics: Consultancy, Research Funding; BeiGene: Consultancy; Alimera Sciences: Consultancy; Acerta Pharma/AstraZeneca: Consultancy; Abbvie: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Nordic Nanovector: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Adaptive Biotechnologies: Research Funding; Merck: Research Funding; Incyte: Research Funding; TG Theraputics: Research Funding; DTRM: Research Funding. Bishop: Arcellx, Autolus, Bristol-Myers Squibb, CRISPR, Kite/Gilead, and Novartis: Consultancy, Research Funding; Bristol-Myers Squibb and Kite/Gilead: Other: fees for non-CME/CE services . Porter: Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Unity: Patents & Royalties; Wiley and Sons Publishing: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; GenenTech: Current Employment, Current equity holder in publicly-traded company; DeCart: Membership on an entity's Board of Directors or advisory committees; ASH: Membership on an entity's Board of Directors or advisory committees; American Society for Transplantation and Cellular Therapy: Honoraria.

Introduction: Globally, stroke is the second leading cause of death. Despite the burden of illness and death, few acute interventions are available to patients with ischemic stroke. Over 1,000 potential neuroprotective therapeutics have been evaluated in preclinical models. It is important to use robust evidence synthesis methods to appropriately assess which therapies should be translated to the clinical setting for evaluation in human studies. This protocol details planned methods to conduct a systematic review to identify and appraise eligible studies and to use a network meta-analysis to synthesize available evidence to answer the following questions: in preclinical in vivo models of focal ischemic stroke, what are the relative benefits of competing therapies tested in combination with the gold standard treatment alteplase in (i) reducing cerebral infarction size, and (ii) improving neurobehavioural outcomes? Methods: We will search Ovid Medline and Embase for articles on the effects of combination therapies with alteplase. Controlled comparison studies of preclinical in vivo models of experimentally induced focal ischemia testing the efficacy of therapies with alteplase versus alteplase alone will be identified. Outcomes to be extracted include infarct size (primary outcome) and neurobehavioural measures. Risk of bias and construct validity will be assessed using tools appropriate for preclinical studies. Here we describe steps undertaken to perform preclinical network meta-analysis to synthesise all evidence for each outcome and obtain a comprehensive ranking of all treatments. This will be a novel use of this evidence synthesis approach in stroke medicine to assess pre-clinical therapeutics. Combining all evidence to simultaneously compare mutliple therapuetics tested preclinically may provide a rationale for the clinical translation of therapeutics for patients with ischemic stroke. Dissemination: Review findings will be submitted to a peer-reviewed journal and presented at relevant scientific meetings to promote knowledge transfer. Registration: PROSPERO number to be submitted following peer review.

Abstract Background: Patients (pts) with cancer are at higher risk for complications and mortality related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although mRNA vaccines have been granted Food and Drug Administration emergency use authorization (EUA) for prevention of COVID-19, the pivotal trials largely excluded pts with active cancer. Emerging data suggests suboptimal efficacy of these vaccines in pts with hematologic malignancies. There are also theoretical concerns that programmed cell death protein 1 inhibitors (PD-1i) could potentiate vaccine-related adverse events (AEs); conversely, these vaccines could activate the immune system, increasing the risk for immune-related reactions (IRRs) after PD-1i treatment. Pts with classic Hodgkin lymphoma (cHL) receiving PD-1i represent a unique cohort and should be investigated for safety and efficacy issues with SARS-CoV-2 vaccines. Methods: We conducted a retrospective analysis of pts with cHL who were treated with PD-1i within the past 12 months. Our primary objective was to determine the frequency of vaccine-related AEs and also subsequent IRRs to PD-1i after vaccination as reported in the medical records. Our secondary objective was to determine efficacy based on post-vaccine COVID-19 infection rates and by presence of adequate receptor binding domain (RBD) IgG antibody level to the SARS-CoV-2 spike protein. This assay was a clinically available institutional assay developed under EUA. While the level of antibody that is associated with immune protection has not yet been defined, we used RBD IgG &gt; 0.700 AU as positive since it was previously correlated with virus neutralization titer in vitro. Results: From July 1, 2020 through June 31, 2021, we identified 27 pts who received PD-1i for cHL and were seen at the University of Pennsylvania. Seventeen (63%) pts received nivolumab and 10 (37%) received pembrolizumab. The median age was 42 years (23-86), median number of therapies was 4 (2-15), and 7 (26%) had prior history of COVID-19 infection (none required hospitalization). Twenty-three pts (85% of total) were vaccinated: 17 (74%) received Pfizer-BioNTech BNT162b2 and 6 (26%) had Moderna mRNA-1273 formulations. Of 19 (83%) pts who received at least one dose of PD-1i prior vaccine, the median time between last PD-1i infusion and first vaccine administration was 20 days (2-157). Of 19 (83%) pts who received any PD-1i after vaccine, the median time to infusion was 18 days (4-89). In pts who had prior COVID-19 infection, the median time between the prior infection and vaccine was 91 days (range 78-350). There were no unexpected toxicities noted and no severe adverse events or hospitalizations directly related to vaccination. No patient discontinued the vaccination series due to side effects. In 12 vaccinated pts who had vaccine-related AEs solicited by the medical provider, 7 (58%) developed injection site reaction/pain: grade 1 (6/12) and grade 2 (1/12). Six (50%) pts had systemic AEs: grade 1 fatigue (4/12), grade 2 fatigue (1/12), transient generalized lymphadenopathy (1/12), fever (1/12). No new IRRs occurred in pts receiving subsequent PD-1i after vaccination. Two weeks after second vaccination, 1 patient developed worsening cough with imaging suggestive of pneumonitis but improved with antibiotics. There were no post-vaccine COVID-19 infections noted. RBD IgG antibody levels were available in 12/23 (52%) of all vaccinated pts; 11/12 (92%) pts had positive antibody titers. The only patient who did not mount positive RBD IgG antibody titers received brentuximab vedotin concurrently with PD-1i prior to vaccination. There were insufficient events to correlate pre-vaccine factors with AEs or efficacy. Conclusion: Pts with relapsed/refractory cHL on PD-1i who received SARS-CoV-2 vaccines had no unexpected toxicities and tolerated subsequent PD-1i without new IRRs. The efficacy based on post-vaccination COVID-19 rates and RBD IgG levels is encouraging in these heavily pretreated pts. We plan an additional prospective component of this study using patient reported outcomes and long-term safety and efficacy follow-up. Disclosures Svoboda: Incyte: Research Funding; Genmab: Consultancy; Merck: Research Funding; Pharmacyclics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; TG: Research Funding; Imbrium: Consultancy; Seattle Genetics: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Atara: Consultancy; Adaptive: Consultancy, Research Funding. Dwivedy Nasta: Roche: Research Funding; Merck: Other: Data safety monitoring board; Incyte: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; ATARA: Research Funding; Millenium: Research Funding; Rafael: Research Funding; Debiopharm: Research Funding. Ruella: AbClon: Consultancy, Research Funding; BMS, BAYER, GSK: Consultancy; Novartis: Patents & Royalties; Tmunity: Patents & Royalties; viTToria biotherapeutics: Research Funding. Landsburg: Triphase: Research Funding; Takeda: Research Funding; Curis: Research Funding; ADCT: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; Morphosys: Membership on an entity's Board of Directors or advisory committees. Barta: Seagen: Honoraria; Daiichi Sankyo: Honoraria; Acrotech: Honoraria; Kyowa Kirin: Honoraria. Gerson: TG Therapeutics: Consultancy; Kite: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy. Schuster: Loxo Oncology: Consultancy; Nordic Nanovector: Consultancy; Genentech/Roche: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acerta Pharma/AstraZeneca: Consultancy; BeiGene: Consultancy; Juno Theraputics: Consultancy, Research Funding; Tessa Theraputics: Consultancy; Pharmaclyclics: Research Funding; Abbvie: Consultancy, Research Funding; Alimera Sciences: Consultancy; Adaptive Biotechnologies: Research Funding; Merck: Research Funding; Incyte: Research Funding; TG Theraputics: Research Funding; DTRM: Research Funding.

e20500 Background: Despite recent therapeutic advances, PNA remains a significant source of morbidity and mortality among CLL pts. We determined population-level estimates for the incidence and outcome of PNA hospitalizations. We further investigated secular trends in care by comparing cohorts before (1994) and after (2004) the widespread use of multiagent chemoimmunotherapy. Methods: Using data from the U.S. Nationwide Inpatient Sample and ICD-9CM diagnosis codes, we identified all non-governmental hospitalizations of CLL pts for a primary dx of PNA in calendar years 1994 and 2004. Admissions were described by pt demographics (age, gender, race) and comorbidity (Charlson index, presence of chronic lung disease). Ten-year prevalence estimates for CLL were obtained from NCI SEER data and used as denominators in incidence calculations. Outcomes studied included need for intubation, in-hospital mortality, and length of stay (LOS). All analyses were sample weighted. Estimates and 95% confidence limits are reported. Results: PNA was the primary dx for 7316 (13.1%) and 7651 (11.2%) CLL pt admissions in 1994 and 2004, respectively. Incidence of PNA admission was similar in 1994 (140/per 1000 pts, 95%CI 130–151) and 2004 (129/per 1000 pts, 95%CI 119–138). CLL pts admitted in 2004 were older (75.7 v. 74.2 years, p<0.001) and more likely to have at least one Charlson comorbidity (67.6% v. 56.2%, p<0.001) or comorbid chronic lung disease (40.6% v. 28.3%, p<0.001) than pts in 1994. Intubation was rare in both cohorts (<1%) and did not significantly differ by year, but in-hospital mortality was significantly higher in 2004 (11.3% v. 8.2%, p=0.005). However, LOS decreased significantly between 1994 and 2004 (9.2 v. 6.4 days, p<0.001). Conclusions: PNA hospitalization rates for CLL pts have not significantly increased over the last decade despite more aggressive therapies, likely secondary to improved supportive care. However, CLL pts hospitalized for PNA are now older, increasingly likely to suffer from chronic medical illness, and significantly more likely to die while in hospital. Therapuetic strategies targeting older pts with significant comorbidities are needed. No significant financial relationships to disclose.

Background. Hydroxyurea reduces pain crises, acute chest syndrome and blood transfusions in sickle cell disease (SCD), but potential detrimental effects on fertility and birth outcomes are an impediment to its use. Patient data on the effects of hydroxyurea when taken during conception and pregnancy are scarce. The Sickle Cell Disease Implementation Consortium (SCDIC) is a cooperative research program of eight clinical centers, a data coordinating center, and the National Heart, Lung, and Blood Institute (NHLBI). One of the SCDIC programs is an SCD patient registry including at least 300 participants from each center. Methods. The SCDIC Registry retrospectively questioned participants regarding pregnancy history, hydroxyurea use and pregnancy outcomes. Of 2436 subjects 15-45 years of age, 2375 answered at least one pregnancy-related question, including hydroxyurea use during conception, the month and year the pregnancy ended, the outcome (live birth, stillbirth, miscarriage, abortion, currently pregnant), hydroxyurea use during pregnancy and what trimester (females only), and for live births - prematurity, birth weight &lt; 5.5 lbs, and medical complications in the baby. The primary outcome was miscarriage or stillbirth, with separate analyses for males and females. Univariate logistic regression was used to identify significant covariates and predictors, and multivariate logistic regression was used to select the best fitting models. All models included severe sickle cell genotype, pregnancy order (1-3, 4-6, &gt;6) and history of miscarriage or stillbirth at each pregnancy WResults. Among 1,357 women, 1797 pregnancies were reported for a crude rate of 1.32 pregnancies per woman; among 1018 men, 620 pregnancy conceptions were reported for a rate of 0.61 per man. Overall, in 221 (12.3%) of reported pregnancies in women and in 122 (19.7%) of reported pregnancies conceived by men, conception occurred while on hydroxyurea (P&lt;0.001). We further analyzed 2062 pregnancies that did not end in elective abortion as reported by 920 individuals. Pregnancy order, severe sickling genotype of the parent and prior history of still birth or miscarriage were significantly associated with stillbirth or miscarriage in univariate analyses. After adjustment for these covariates, hydroxyurea use at conception was associated with a 2.1-fold increase in the odds of miscarriage or stillbirth in pregnancies conceived by males (P = 0.046) and hydroxyurea use at conception and during the first trimester was associated with a 3.3-fold increase in the odds of miscarriage or stillbirth in pregnancies conceived by women (P&lt;0.001). Hydroxyurea use at conception and during the first trimester was also independently associated with birth weight &lt;5.5 lbs (OR 2.4, P=0.01), but not prematurity or medical problems in the newborn. Discussion. There are important limitations to our study. The pregnancy history is self-reported and therefore complicated by recall bias. The completion of the reproductive history form varied by age. The dates of pregnancies ending in miscarriage were more often missing than other outcomes, so we could not use age at pregnancy in statistical analyses. Males may not have known or remembered all of the pregnancies they conceived that did not end in live birth, and we did not collect information about the female partners of males with SCD. Furthermore, the availability and use of hydroxyurea has increased over time. Nevertheless, our results suggest that the use of hydroxyurea at conception in males and at conception and the first trimester in females may be associated with adverse pregnancy outcomes. Our findings support advising patients who plan a pregnancy to temporarily discontinue hydroxyurea before attempting to conceive and during the first trimester in females, and to provide alternative approaches to prevent SCD complications during this time. Disclosures Gordeuk: Novartis: Consultancy; Ironwood: Research Funding; Imara: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding. Hankins:Novartis: Research Funding; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria; LINKS Incorporate Foundation: Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; Global Blood Therapeutics: Consultancy, Research Funding; UptoDate: Consultancy. Kutlar:Novartis Pharmaceuticals: Consultancy, Research Funding; Global Blood Therapeutics: Research Funding, Speakers Bureau; Micelle Biopharma: Consultancy; NIH/NHLBI (SCDIC): Research Funding; Novo Nordisk: Research Funding; Forma Therapeutics: Research Funding; REACH: Other: DSMB Member; NOHARM: Other: DSMB Member; Bluebird Bio: Other: DSMB Member. King:Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; RiverVest: Consultancy; Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company. Shah:Alexion: Speakers Bureau; Bluebird Bio: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy. Kanter:BEAM: Membership on an entity's Board of Directors or advisory committees; SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; bluebird bio, inc: Consultancy, Honoraria; Novartis: Consultancy; Sanofi: Consultancy; Medscape: Honoraria; Guidepoint Global: Honoraria; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees. Treadwell:UpToDate: Honoraria; Global Blood Therapeutics: Consultancy.

Background: Clinical factors including previous history of AF, heart failure, hypertension, valvular heart disease, increased age and male gender increase the risk of AF in CLL patients (Shanafelt, Leukemia and Lymphoma 2017). Treatment with Bruton tyrosine kinase inhibitors (BTKi) such as ibrutinib has also been associated with an increased risk of AF in CLL. We evaluated the role of artificial intelligence electrocardiography (AI-ECG) in predicting ibrutinib-induced AF (and, for reference, AF unrelated to ibrutinib) in patients with CLL. Methods: We identified two cohorts of CLL patients using the Mayo Clinic CLL Database. Cohort 1 included patients evaluated within 12 months of CLL diagnosis who did not ever receive ibrutinib. Cohort 2 included patients who were treated with ibrutinib. The electrocardiographic signature of AF in sinus rhythm was detected by an AI-ECG algorithm previously developed using a convolutional neural network (Attia, Lancet 2019). The baseline AI-ECG AF score (positive defined as &gt;0.10 on a scale of 0-1 which offers best balance between sensitivity and specificity per Attia et al.) was computed based on ECGs obtained within 10 years prior to CLL diagnosis (Cohort 1) or 10 years prior to initiation of ibrutinib therapy (Cohort 2). Patients with AF at baseline, missing data, or with ECGs previously used to train the AI algorithm were excluded. Reverse Kaplan Meier diagrams were plotted for both cohorts grouped by AI-ECG positivity. Cox proportional hazards were fitted to assess the predictive ability of AI-ECG in both cohorts. Results: After screening 2,739 patients and applying exclusion criteria (126 patients had baseline AF) a total of 1,149 patients with median 4 (interquartile range [IQR] 2-9) baseline ECGs were included in the analysis (Figure 1A). Cohort 1 included 951 patients with a median follow up of 3.0 (IQR 0.6-7.0) years and positive baseline AI-ECG in 546 (57%) patients. Cohort 2 included 198 patients with a median follow up of 1.6 (IQR 0.7-3.2) years and positive baseline AI-ECG in 91 (46%) patients. In Cohort 1, the median age was 67 years (IQR 58-72), 681 (72%) of patients were men, 68% had low/intermediate risk CLL-International Prognostic Index (IPI), and 32% had high/very high-risk CLL-IPI. In Cohort 2, the median age was 69 years (IQR 62-75), 139 (70%) of patients were men, 13% had low/intermediate risk CLL-IPI, and 87% had high/very high-risk CLL-IPI. AF occurred during follow up in 164 patients (17%) in Cohort 1 and 46 patients (23%) in Cohort 2. In both Cohorts 1 and 2, a positive baseline AI-ECG significantly increased the incidence of AF during follow up (log rank &lt;0.001) (Figure 1B and C). Hazard ratios (for positive vs. negative AI-ECG) were 33.9 (95% confidence interval [CI] 15.0-76.6) for Cohort 1 and 14.8 (95% CI 5.3-41.3) for Cohort 2. Conclusion: The addition of AI to a standard 12-lead ECG obtained during normal sinus rhythm - an inexpensive and ubiquitous test - predicts the occurrence of future AF in patients with CLL. This holds true irrespective of BTKi -based therapy and has important implications for the management of CLL patients. Disclosures Ding: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Astra Zeneca: Research Funding; Abbvie: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees. Kenderian:BMS: Research Funding; Gilead: Research Funding; Novartis: Patents & Royalties, Research Funding; Mettaforge: Patents & Royalties; Juno: Research Funding; MorphoSys: Research Funding; Lentigen: Research Funding; Sunesis: Research Funding; Tolero: Research Funding; Kite: Research Funding; Humanigen: Consultancy, Patents & Royalties, Research Funding; Torque: Consultancy. Wang:Novartis: Research Funding; Innocare: Research Funding; Incyte: Research Funding. Kay:Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Abbvie: Research Funding; MEI Pharma: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Cellectar: Consultancy; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Celgene: Honoraria; GlaxoSmithKline: Research Funding. Parikh:MorphoSys: Research Funding; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Merck: Research Funding; AbbVie: Honoraria, Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; Verastem Oncology: Honoraria; GlaxoSmithKline: Honoraria; TG Therapeutics: Research Funding; Pharmacyclics: Honoraria, Research Funding.

Abstract Background: CD19-directed CAR-T cell therapy has shown promising efficacy in relapsed/refractory (R/R) B-cell malignancies in clinical trials resulting in the approval and commercialization of two products (tisagenlecleucel/Tisa-cel and axicabtagene ciloleucel/Axi-cel) for R/R diffuse large B cell lymphoma (DLBCL) and primary mediastinal large B cell lymphoma (PMBCL). However, relapses occur in 60-65% of patients (pts) and thus a better understanding of the early determinants of response is critical to improve long-term survival in the real-world scenario. Aims of the study: To assess whether CAR-T cell expansion after infusion represents a crucial determinant to sustain effective anti-tumor responses to both Tisa-cel and Axi-celTo evaluate differences in CAR-T cell kinetics due to the use of CD28 or 4-1BB costimulatory moleculesTo identify immune phenotypic features of infusion products accounting for CAR-T cell expansion and survival probability Methods: We analyzed samples from 43 pts [29 DLBCL, 8 high grade B-cell lymphoma (HGBCL) and 6 PMBCL] treated with Axi-cel (n=22) and Tisa-cel (n=21) at the Fondazione IRCCS Istituto Nazionale Tumori prospectively collected between November 2019 and April 2021. CAR-T cells were monitored in the peripheral blood (PB) on days 0, 4, 7, 10, 14, 21, 28 and monthly post infusion by flow cytometry (FCM). Cells were stained with CD19 CAR Detection Reagent (Miltenyi), CD3, CD4, CD8, CD45, CD14, CD45RO, CD62L, CD197, CD279, CD223 and CD366. Residual cells obtained from washings of 32 infused commercial CAR-T bags (10 Tisa-cel and 22 Axi-cel) were also analyzed by FCM. Data were acquired on a BD FACSCanto II (BD Biosciences) and a MACSQuant® Analyzer MQ10 (Miltenyi) and analyzed using FlowJo software, version 10. Results: The median time to maximal expansion of CAR-T cells was at day 10 post infusion with no differences between Axi-cel and Tisa-cel [median concentration at day 10 (C 10) 25 for Axi-cel vs 26 CAR-T cells/µl for Tisa-cel; p, ns], nor among the different histologies (median C 10 33 for DLBCL vs 19 for HGBCL vs 18 CAR-T cells/µl for PMBCL; p, ns). On the contrary, CAR-T peak concentration (C max) was higher in responders at 3 months post infusion (RE, n=28) (defined as pts achieving complete or partial response by PET/CT) than in non responders (NR, n=13) (median C max 87 in RE vs 26 in NR CAR-T cells/µl; p&lt;0.01; Fig 1A). Consistently, the magnitude of CAR-T cell expansion in the first 30 days was higher in RE than in NR [median area under the curve (AUC 0-30) 189 vs 50; p&lt;0.005; Fig 1B]. Circulating CAR-T cells were enriched in subpopulations representing naïve T cells (CD8+ T N; CD45RO−/CD62L+) in RE (median 0.4% in RE vs 0.04% in NR, p&lt;0.05) while NR had significantly higher levels of effector memory T cells (CD8+ T EM; CD45RO+/CD62L+) (median 26.5% in RE vs 66.2% in NR, p&lt;0.05). Additionally, the extent of CAR-T cell expansion predicted the progression free survival (PFS), but not the overall survival (OS), irrespective of the product used (Fig 2, p&lt;0.05) and the overall survival was improved by salvage treatment with bispecifc antibodies. Finally, we evaluated whether CAR-T cell expansion was influenced by the immune phenotypic attributes of the infused products. A significant enrichment of central memory populations (CD8+ T CM; CD45RO−/CCR7+/CD62L+) among CAR-T cells within the infusion products of pts with longer PFS was documented, as compared with those with shorter PFS (CD8+ T CM; median 15.2% vs 3.1%; p&lt;0.005). Conclusion: To the best of our knowledge, this is the first study assessing the clinical utility of early CAR-T cell monitoring in lymphoma pts receiving both commercial anti-CD19 CAR-T cell therapies. We provide evidence that in pts treated with Axi-cel and Tisa-cel: i) the in vivo kinetics of the CAR-T cell products are similar, consistent with the fact that no differences in the outcome of Axi-cel and Tisa-cel treated pts were detected; ii) CAR-T cell expansion is critical for efficacy and predicts the PFS; iii) circulating CAR-T cells in responders have a naïve phenotype; iv) a memory signature in the CAR-T cell product before infusion is associated with in vivo expansion and survival. Figure 1 Figure 1. Disclosures Chiappella: Celgene Bristol Myers Squibb: Other: lecture fee, advisory board; Incyte: Other: lecture fee; Novartis: Other: lecture fee; Astrazeneca: Other: lecture fee; Servier: Other: lecture fee; Takeda: Other: advisory board; Gilead Sciences: Other: lecture fee, advisory board; Clinigen: Other: lecture fee, advisory board; Roche: Other: lecture fee, advisory board; Janssen: Other: lecture fee, advisory board. Corradini: AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Consultancy; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Honoraria; KiowaKirin; Incyte; Daiichi Sankyo; Janssen; F. Hoffman-La Roche; Kite; Servier: Consultancy; Novartis; Gilead; Celgene: Consultancy, Other: Travel and accommodations; BMS: Other: Travel and accommodation; Sanofi: Consultancy, Honoraria; Amgen; Takeda; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations; Incyte: Consultancy; Novartis, Janssen, Celgene, BMS, Takeda, Gilead/Kite, Amgen, AbbVie: Other: travel and accomodations.

Abstract Background: Targeted therapies including ibrutinib, acalabrutinib and venetoclax (ven) have fundamentally changed the treatment of patients (pts) with chronic lymphocytic leukemia (CLL) leading to improved outcomes and durable remissions for many pts. However, CLL remains an incurable disease and a subset of pts will ultimately have progressive CLL following treatment with a covalent Bruton's Tyrosine Kinase inhibitor (cBTKi, e.g., ibrutinib, acalabrutinib) and ven. Data on efficacy of therapies for "double exposed" pts (i.e., pts exposed to both a cBTKi and ven) are extremely limited. Available approved options include chemoimmunotherapy (CIT) and phosphatidylinositol 3-kinase inhibitors (PI3Ki). However, the landmark clinical trials leading to the approvals of CIT and PI3Kis did not include pts treated with either cBTKi or ven (Furman et al. NEJM 2014, Flinn et al. Blood 2018). Non-covalent BTKis (ncBTKi) and chimeric antigen receptor (CAR) T-cell therapy have demonstrated promising clinical activity in double exposed CLL pts in clinical trials (Mato et al. Lancet 2021, Siddiqi et al. ASH 2020), but have not yet been compared to other novel agents or CIT in clinical trials or real-world analyses. We sought to describe outcomes of therapies for "double exposed" CLL pts. Methods: A retrospective, international, multicenter study was conducted. CLL pts were included if they received a cBTKi and ven and then a subsequent CLL-directed therapy. Therapies for Richter Transformation were excluded. Investigators identified pts at each site and collected data on demographics, disease characteristics, prior therapies, subsequent therapies and response assessments. Information was collected on up to three subsequent lines of therapy (LOT 1-3) per patient. The primary study endpoint was investigator-assessed overall response rate (ORR) per iwCLL 2018 criteria to therapies (LOT 1-3) following both cBTKi and ven. Kaplan-Meier method was used to estimate progression free survival (PFS). All other analyses were descriptive. Analyses were performed using STATA 17.0. Results: We report outcomes on 125 CLL pts who had prior cBTKi and ven and received a subsequent LOT. Baseline characteristics are presented in Table 1. ORR to prior cBTKi was 84.7% and 69.6% to prior ven. The most common reason for discontinuation of prior cBTKi and ven was CLL progression (71.1% cBTKi, 68.8% ven) followed by toxicity (25.6% cBTKi, 16.8% ven). Most common treatment strategies included ncBTKi (n=45), cBTKi (n=43), CIT (n=23), PI3Ki (n=24), alloSCT (n=17), CAR T-cell therapy (n=9), ven re-treatment (n=6), and other (n=44). ORR for selected agents following cBTKi and ven are presented in Table 2. ORR and PFS estimates were as follows: CAR T-cell therapy (85.7%, median PFS 4 months), alloSCT (76.5%, median PFS 11 months), ncBTKi (75.0%, median PFS not reached), PI3Ki (40.9%, median PFS 5 months), CIT (31.8%, median PFS 3 months) and ven re-treatment (ORR 40%, median PFS 14 months). ORR to cBTKi was 53.7%; however, median PFS for pts who discontinued a previous cBTKi for PD was 1 month versus 7 months for pts who discontinued due to AE. Figure 1 shows Kaplan-Meier estimated PFS for ncBTKi, PI3Ki, alloSCT, and CIT. Conclusions: In the largest series of "double exposed" CLL pts, several key findings warrant further investigation and discussion. Practice patterns are variable and no standard of care exists for CLL pts previously treated with a cBTKi and ven. Additionally, approved standard therapies including CIT combinations and PI3Kis yield poor outcomes with responses which are not durable. The low response rates and short PFS for PI3Ki and CIT call into question the use of these therapies as standard comparator arms in planned randomized trials. At this time, ncBTKi has a high ORR with durable responses (median PFS not reached). There appears to be a promising role for alloSCT in select, fit patients (ORR 76.5%, median PFS 11 months), and CAR T-cell therapy should be further explored in this population (ORR 85.7%, median PFS 4 months). Overall, this study highlights a continued unmet need for therapies for "double exposed" CLL pts. Figure 1 Figure 1. Disclosures Thompson: MJH Life Sciences: Honoraria; VJHemOnc: Honoraria; Curio Science: Honoraria. Roeker: Abbot Laboratories: Current equity holder in publicly-traded company; Pharmacyclics: Consultancy; Loxo Oncology: Consultancy; TG Therapeutics: Consultancy; AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy; Pfizer: Consultancy, Research Funding. Coombs: LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Genentech: Honoraria; MEI Pharma: Honoraria. Kamdar: AbbVie: Consultancy; TG Therapeutics: Research Funding; SeaGen: Speakers Bureau; ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy; Celgene: Other; Celgene (BMS): Consultancy; Kite: Consultancy; KaryoPharm: Consultancy; Genentech: Research Funding; Genetech: Other. Pagel: Epizyme: Consultancy; Incyte/MorphoSys: Consultancy; BeiGene: Consultancy; Pharmacyclics/AbbVie: Consultancy; Actinium Pharmaceuticals: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Kite, a Gilead Company: Consultancy; MEI Pharma: Consultancy. Jacobs: MEI Pharma: Research Funding; Adaptive Biotechnologies: Consultancy; Genentech: Consultancy; TG Therapeutics: Research Funding, Speakers Bureau; Verastem: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy; TeneoBio: Research Funding; AbbVie: Consultancy, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Jannsen: Speakers Bureau; SecuraBio: Consultancy, Speakers Bureau. Hill: Gentenech: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Brander: AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; AstraZeneca: Research Funding; BeiGene: Research Funding; ArQule: Research Funding; DTRM: Research Funding; LOXO: Research Funding; Verastem: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Ascentage: Research Funding; MEI Pharma: Research Funding; Genentech: Consultancy, Research Funding; NCCN: Other: panel member; Pfizer: Consultancy, Other: Biosimilars outcomes research panel; ArQule/Merck: Consultancy. Shadman: Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding; Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy. Ujjani: AbbVie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Research Funding; Adaptive Biotechnologies: Research Funding; Atara Bio: Consultancy; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; TG Therapeutics: Honoraria; Gilead: Honoraria; ACDT: Honoraria; Kite, a Gilead Company: Honoraria. Battiato: Abbvie: Honoraria; Janssen: Honoraria. Rhodes: AbbVie, Genentech, Pharmacyclics, TG Therapeutics: Other: Consultant; Conquer Cancer Foundation Young Investigator Award: Other: Grant/Research Support. Fakhri: Loxo/Lilly: Research Funding. Barr: Morphosys: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; Beigene: Consultancy; Bristol Meyers Squibb: Consultancy; Abbvie/Pharmacyclics: Consultancy; Genentech: Consultancy. Portell: TG Therapeutics: Honoraria, Research Funding; SeaGen: Research Funding; Kite: Honoraria, Research Funding; Xencor: Research Funding; Abbvie: Research Funding; Pharmacyclics: Honoraria; Merck: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; Acerta/AstraZeneca: Research Funding; Aptitude Health: Honoraria; Targeted Oncology: Honoraria; Morphosys: Honoraria; Genentech: Research Funding; VelosBio: Research Funding. Lamanna: AbbVie: Consultancy, Research Funding; Verastem Oncology: Research Funding; BeiGene: Consultancy; Pharmacyclics: Consultancy; Celgene Corporation: Consultancy; Oncternal Therapeutics: Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy; Gilead Sciences, Inc.: Consultancy; MingSight Pharmaceuticals, Inc.: Research Funding; Genentech, Inc.: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; TG Therapeutics, Inc: Research Funding; Juno Therapeutics, Inc.: Research Funding. Zelenetz: MorphoSys: Honoraria; Verastem: Honoraria; LFR: Other; Gilead: Honoraria, Research Funding; NCCN: Other; AstraZeneca: Honoraria; MEI Pharma: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Janssen: Honoraria; Gilead: Honoraria; Pharmacyclics: Honoraria; BMS/Celgene/JUNO: Honoraria, Other; Novartis: Honoraria; SecuraBio: Honoraria; Genentech/Roche: Honoraria, Research Funding; MethylGene: Research Funding; Amgen: Honoraria; Beigene: Honoraria, Other, Research Funding. Schuster: Abbvie: Consultancy, Research Funding; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; Adaptive Biotechnologies: Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; DTRM: Research Funding; Genetech: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Incyte: Research Funding; Juno Theraputics: Consultancy, Research Funding; Loxo Oncology: Consultancy; Merck: Research Funding; Nordic Nanovector: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Pharmaclcyclics: Research Funding; Tessa Theraputics: Consultancy; TG Theraputics: Research Funding. Eyre: Secura Bio: Consultancy, Honoraria; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Research Funding; Incyte: Consultancy; Beigene: Honoraria, Research Funding; Roche: Consultancy, Honoraria; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Janssen: Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel to conferences. Mato: MSKCC: Current Employment; AstraZeneca: Consultancy; Genmab: Research Funding; LOXO: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Nurix: Research Funding.

Abstract Neutropenia is common in patients receiving myelotoxic chemotherapy. Benefilgrastim, an rhG-CSF dimer (rhG-CSF-FC fusion protein), is a once-per-cycle therapy for prophylactic neutrophil support. In this Phase II trial, 230 women with stage I-IV breast cancer are to be treated for 4 chemotherapy cycles with either docetaxel/cyclophosphamide (TC) or doxorubicin/docetaxel/cyclophosphamide (TAC) chemotherapy, with each cycle lasting approximately 21 days. Patients will be randomized to receive either benefilgrastim or pegfilgrastim (Neulasta; 6 mg fixed dose) one day after chemotherapy during each cycle, as a subcutaneous injection. Dose levels of benefilgrastim examined are 80 µg/kg (TC patients only), and 240 and 320 µg/kg (TC and TAC patients). The primary endpoint is the duration of grade 3/4 neutropenia in chemotherapy cycle 1. As of August 1, 2014, 232 patients have completed chemotherapy cycle 1; safety and efficacy were analyzed for these enrolled patients. For the TC chemotherapy regimen, a total of 141 patients were randomized (ratio = 1:1:1:1) into 4 arms (80, 240, and 320 µg/kg benefilgrastim or 6 mg pegfilgrastim). In the TAC chemotherapy regimen, a total of 91 patients were randomized (ratio = 1:1:1) into 3 arms (240 and 320 µg/kg benefilgrastim or 6 mg pegfilgrastim). The incidence of grade 3/4 and grade 4 neutropenia and their mean durations in cycle 1 are provided in Table 1. There were higher incidences of grade 3/4 and grade 4 neutropenia in the TAC regimen compared to the TC regimen. The safety profiles of benefilgrastim and pegfilgrastim were similar. A total of 10 SAEs were reported in 6 patients with the majority (7 SAEs in 4 patients) occurring in those receiving pegfilgrastim. The most commonly observed treatment emergent adverse events (>10% of total TC + TAC patients) were: alopecia, nausea, asthenia, neutropenia, bone pain, and fatigue. The rates were similar amongst treatment regimens and treatment groups. In summary, a single subcutaneous injection of benefilgrastim 240 or 320 µg/kg provided neutrophil support to patients treated with both the TC and TAC chemotherapy regimens. The safety profile of benefilgrastim was comparable to that of pegfilgrastim during multiple chemotherapy cycles. The results suggest a potential use of benefilgrastim for the management of severe neutropenia in cancer patients undergoing high dose chemotherapy. Abstract 1584. Table 1: Preliminary Results TC Regimen TAC Regimen Benefilgrastim Pegfilgrastim 6 mg (N=35) Benefilgrastim Pegfilgrastim 6 mg (N=29) 80 µg/kg (N=35) 240 µg/kg (N=37) 320 µg/kg (N=34) 240 µg/kg (N=29) 320 µg/kg (N=30) Grade 3/4 neutropenia n/N (%) 10/35 (28.6) 10/37 (27.0) 7/34 (20.6) 7/35 (20.0) 17/25 (68.0) 19/26 (73.1) 17/24 (70.8) Duration (days) Mean (SD) 95% CI 2.4 (2.07) 1.2, 3.6 2.2 (0.79) 1.7, 2.7 1.9 (0.38) 1.6, 2.1 1.4 (0.79) 0.9, 2.0 2.8 (1.67) 2.1, 3.5 2.6 (1.07) 2.2, 3.1 2.2 (0.73) 1.9, 2.5 Grade 4 neutropenia n/N (%) 4/35 (11.4) 7/37 (18.9) 6/34 (17.6) 3/35 (8.6) 14/25 (56.0) 17/26 (65.4) 15/24 (62.5) Duration (days) Mean (SD) 95% CI 2.0 (1.15) 0.6, 3.4 2.1 (0.90) 1.5, 2.8 1.2 (0.41) 0.8, 1.5 1.0 (0.00) 1.0, 1.0 1.9 (1.33) 1.3, 2.6 2.0 (0.87) 1.6, 2.4 1.5 (0.64) 1.2, 1.8 SAEs n (%) # SAEs 0 0 1 (2.7) 1 0 0 2 (5.7) 3 0 0 1 (3.3) 2 2 (6.9) 4 CI=confidence interval; SAE=serious adverse event; SD=standard deviation Disclosures Glaspy: Generon (Shanghai) Corporation Ltd.: Research Funding. Tang:Generon (Shanghai) Corporation Ltd.: Employment. Rutty:Everest Clinical Research Services Inc.: Employment; Generon (Shanghai) Corporation Ltd.: Consultancy; Schering Corporation: Consultancy; Roche: Consultancy; Methylgene: Consultancy; Steba Biotech SA: Consultancy; Aderans Research Institute Inc: Consultancy; Stem Cell Theraputics: Consultancy; Genentech: Consultancy; Pearly Therapeutics: Consultancy; Sundise Chinese Medicine Technology Development Corp: Consultancy; Endocyte, Inc: Consultancy; Hutchison Medipharma: Consultancy; Nutrition Science Partners Limited: Consultancy. Yan:Generon (Shanghai) Corporation Ltd.: Employment.

Chronic Lymphocytic Leukemia (CLL) is an indolent lymphoproliferative disorder commonly managed in community centers. Ibrutinib revolutionized the management of patients with CLL (2). Ibrutinib was initially considered an easy to administer, well tolerated oral medication with excellent efficacy. It was the first clinically available Bruton's Tyrosine Kinase (BTK) inhibitor widely used to treat CLL (3). Recently there have been concerns about cardiovascular toxicities leading to the use of alternative BTK inhibitors (5). Where alternative BTK inhibitors are available these toxicity concerns have led to a decline in the use of ibrutinib to treat CLL. The population served is ethnically diverse consisting of 52% South East Asian with a significant population of African origin. We suspected that the concerns regarding Ibrutinib toxicity were not seen in our patient population prompting a retrospective review of our experience. Ibrutinib therapy A total of 106 CLL patients treated with Ibrutinib were identified from which data was extracted. The mean age was 63.4 years. Patients with CLL treated with Ibrutinib from 2014 to 2021 were identified using OPIS and Meditech and data was extracted manually. Table 1 60% of patient received their initial drug funding through compassionate access, 2% via private insurance and the remaining 38% through the provincial health system. The majority of patients who received funding through compassionate access were eventually transitioned to the provincial health system for drug funding. Toxicity and outcomes Table 2 81% of treated patients never required a dose adjustment of Ibrutinib. The majority of dose reductions were of a temporary nature. We were unable to obtain accurate response data in our retrospective review. 82 of the 106 patients continue on ibrutinib therapy. It is presumed that these patients continue to benefit from therapy without disease progression although response data details were poorly recorded in the medical record. Conclusions There is a lack of data of community real world experience with Ibrutinib particularly in the Canadian setting. Community centers generally are lacking in information technology required to do retrospective audits. Our data shows that ibrutinib therapy for CLL is a reasonable and effective option with good tolerability in a patient population with high cardiovascular risk. The data is limited by the retrospective data collection. The efficacy of therapy is likely comparable to that of the published literature. These data suggest that the tolerability of Ibrutinib therapy seems better than that of the published literature (1) with a low incidence of atrial fibrillation, dose adjustments and low drug discontinuation rate. Of note Richter's transformation was also uncommon in our patient population. This is particularly of interest as our study did capture patients in the early days of ibrutinib therapy when there were concerns that Richter's transformation was more common than seen today. Many of the patients who were treated with ibrutinib would not have received the drug today because of cardiovascular concerns (4). At that time, it was the only available oral targeted agent for the treatment of chronic lymphocytic leukemia. Other agents such as Venetoclax, Acalabrutinib, Zanubrutinib and novel combinations were unavailable at that time or were not funded. These lack of options likely contribute to the persistence of Ibrutinib therapy in our patients. These data suggest that ibrutinib can be used in a high cardiovascular risk population with good efficacy and tolerability. 1.Alloucjery, M., Tomowiak, C., Lombard, T., & et al. (2021). Safety Profile of Ibrutinib: An Analysis of the WHO Pharmacovigilance Database. Front Pharmacology, 12:769315. 2.Byrd, J. C., Brown, J. R., O'Brien, S., & et al. (2014). Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. NEJM, 371(3):213-223. 3.Byrd, J. C., Furman, R. R., & Coutre, S. S. (2013). Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. NEJM, 369(1):32-42. 4.Lovell, A. R., Jammal, N., & Bose, P. (2022). Selecting the optimal BTK inhibitor therapy in CLL: rationale and practical considerations. Therapueltic Advances in Hematology, 13:1177/20406207221116577. 5.Salem, J. E., Manouchehri, A., & Bretagne, M. (2019). Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. J Am Coll Cardiol, 74:1667-1678.

Abstract Introduction: There is increased risk of congestive heart failure (CHF) following anthracycline-based chemotherapy in patients with Diffuse Large B-cell lymphoma (DLBCL). Other than increased cumulative anthracycline dose, little is known about risk factors for developing CHF and other cardiovascular events (CVE). Methods: We conducted a retrospective analysis of 539 DLBCL patients diagnosed at University Hospitals Seidman Cancer Center between 2002 - 2016. Baseline patient and disease characteristics, patterns of treatment and outcomes after therapy, including response, survival, relapse, CVE, and causes of death were collected. Time-to-CVE was measured from the date of DLBCL diagnosis to the date of CVE diagnosis and censored at the date of last follow-up for those without CVE, considering death as competing risk. The cumulative incidence of CVE was estimated taking death as competing risk into account. Univariate and multivariable analysis on time-to-CVE was done using Gray's method. Multicollinearity was tested and some of the highly correlated covariables were excluded in the final analysis. CVE risk scores were computed for each patient as a linear combination of the factors included in the multivariable model and their respective coefficients. The optimal cutoff point was identified by searching the spectrum of the risk scores to have the best discrimination of time-to-CVE among patients at low/high risks. All tests were two-sided and p-value ≤ 0.05 were considered statistically significant. Results: We identified 463 patients who received anthracycline to be included in the statistical analysis. Baseline clinical and disease characteristics including comorbidities, clinical risk factors are outlined in Table 1. After a median follow up of 71.1 (range: 0.3 - 216.1) months, 5-year PFS was 59% with median PFS of 82.7 (95% Cl: 71.1 - 115.7) months and 5-year OS was 71% with median OS of 152.6 (95% CI: 127.5 - 162) months. CVE were identified in 92 patients (19.9%), with 128 events identified. The most common CVE was new onset of CHF in 10.4% of patients, followed by atrial fibrillation (4.9%) and asymptomatic heart failure ( 3%) (Table 2). The 3, 6 and 9-year cumulative incidence of CVE for early stage was 13.1%, 15.2% and 18.5%, respectively and 22.2%, 31.4% and 36.5% for advanced stage, respectively (p-value = 0.026). Similarly, the cumulative incidence of CVE was increased in patients with diabetes, with a 3-year cumulative incidence of CVE of 9.4% vs. 17.5% in patients with and without diabetes, respectively. Proportional hazards regression for time-to-CVE identified age &gt;65 years, CD10 expression by IHC, diabetes, and hypertension as significant predictors of time-to-CVE on univariate analysis. On multivariable regression analysis with advanced age at diagnosis, stage, baseline lymphocyte count, and diabetes; stage was still significant in predicting time-to- CVE controlling the effects of advanced age and diabetes, which were also marginally significant. A predictive formula was created to help identify patients at highest risk for cumulative incidence of CVE. Using advanced age (over 65 years of age), baseline lymphocyte count above 800/µL, advanced stage at diagnosis and history of diabetes patients could be stratified into groups with low, intermediate and high risk for CVE (Table 4 and Figure 1). Risk score = Age &gt;65 (3 points) + Lymphocyte count &gt; 800/µL (-1 point) + Stage III/IV(8 points) + Diabetes (3 points) (Table 3) One-year cumulative incidence of CVE was 5.3% for low-risk patients, 7.9% for intermediate risk patients and 13.4% for high risk patients (Figure 1). Conclusions: Our analysis indicates a high risk of CVE in anthracycline treated DLBCL patients, with 19.9% of patients having a CVE in our cohort. The proposed CVE predictive score uses clinical and laboratory parameters routinely collected on all new DLBCL patients and can be easily assessed in the clinical setting. Patients in the high-risk group have a cumulative incidence of CVE of 13.4% at 1 year and would likely benefit from surveillance and interventions. Use of a clinical risk score can aid in the identification of patients at highest CVE risk to conduct studies of surveillance and prevention of this common complication. Figure 1 Figure 1. Disclosures Boughan: Beigene: Speakers Bureau. Caimi: Seattle Genetics: Consultancy; Verastem: Consultancy; Amgen Therapeutics.: Consultancy; Kite Pharmaceuticals: Consultancy; TG Therapeutics: Honoraria; ADC Theraputics: Consultancy, Research Funding; Genentech: Research Funding; XaTek: Patents & Royalties: Royalties from patents (wife).

Background: Patients with acute myeloid leukemia (AML) receiving intensive chemotherapy face a life-threatening illness, experience a prolonged, isolating hospitalization, and endure substantial physical and psychological symptoms. Some patients with AML experience traumatic stress as a result of their diagnosis and illness course. As traumatic stress reactions can negatively impact patients' QOL, mood, and clinical outcomes, it is essential to understand the extent of this trauma, its clinical manifestations, and risk factors to inform targeted management strategies. Post-traumatic stress disorder (PTSD), characterized by experiencing a traumatic event, is a common stress related disorder in cancer populations. Despite the potential link between AML and PTSD, data are limited regarding risk and risk factors of PTSD symptoms in this population. Methods: We conducted a secondary analysis of 160 patients with high-risk AML hospitalized to receive intensive chemotherapy. We used the Post-Traumatic Stress Disorder Checklist-Civilian Version to assess PTSD symptoms at one month after diagnosis of AML. We used the Brief COPE, and Functional Assessment of Cancer Therapy-Leukemia at baseline and week-2 during hospitalization to assess coping and quality of life (QOL), respectively. We then used multivariate regression models to assess the relationship between PTSD symptoms at one month and patient baseline sociodemographic factors, coping, and QOL. Results: Twenty-eight percent of patients reported clinically significant PTSD symptoms, describing high rates of intrusion (92%), avoidance (100%), and hypervigilance (97%). Among those who did not have clinically significant PTSD symptoms, 27%, 26%, and 23% of patients reported clinically significant intrusion, avoidance, and hypervigilance symptoms, respectively. In adjusted analyses, higher baseline QOL (B= -.22, p= &lt;.001) and less decline in QOL during hospitalization (B= -.17, p=.018) were associated with fewer PTSD symptoms. The use of approach-oriented coping (B= -.72; p= .018) was also associated with fewer PTSD symptoms, while the use of avoidant coping was not significantly associated with PTSD symptoms. Conclusion: A substantial proportion of patients with AML report clinically significant PTSD symptoms at one month after initiating intensive chemotherapy. These findings highlight the need to routinely screen, assess, and manage PTSD symptoms in all patients with AML. Patients' baseline QOL, coping strategies, and extent of QOL decline during hospitalization are important risk factors for PTSD symptoms, underscoring potential intervention targets in future studies to reduce the impact of PTSD in this population. Disclosures LeBlanc: Heron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Medtronic: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Welvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; American Cancer Society: Research Funding; BMS: Research Funding; Duke University: Research Funding; NINR/NIH: Research Funding; Jazz Pharmaceuticals: Research Funding; UpToDate: Patents & Royalties; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; CareVive: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Flatiron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Helsinn: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hobbs:Merck: Research Funding; Incyte: Research Funding; Celgene/BMS: Honoraria; Novartis: Honoraria; Jazz: Honoraria; Bayer: Research Funding; Constellation: Honoraria, Research Funding. Brunner:Novartis: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Luger:Daiichi-Sankyo: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Acceleron: Honoraria; Agios: Honoraria; Loxo Oncology: Honoraria; Onconova: Research Funding; Kura: Research Funding; Hoffman La Roche: Research Funding; Ariad: Research Funding; Biosight: Research Funding. Bhatnagar:KITE: Membership on an entity's Board of Directors or advisory committees; KaryoPharm Therapuetics: Research Funding; Cell Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

Intro: Relapse post allogeneic transplant is the leading cause of early mortality in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Known risk factors of relapse include persistent disease at the time of transplant, use of anti-thymocyte globulin, reduced intensity conditioning, and absence of chronic graft versus host disease (GVHD). Early infection has been reported to increase non-relapse mortality (NRM) while protecting against hematologic disease relapse (Auletta et al., Blood 2016). We sought to determine the influence of patient features and post-transplant early infection (bacterial, fungal, and viral) on acute GVHD, relapse, and mortality. Methods: Adult patients (N=146) with myeloid disorders (AML, MDS, MPN/CMML) who received an initial allogeneic transplantation from 2013-2018 at Oregon Health & Science University were retrospectively identified and followed until 6/30/20 for acquired infections, hematologic relapse, and survival outcomes. Time-to-event endpoints, starting from transplant date, were modeled with Cox regression for single events (overall survival [OS], cause-specific hazards for competing events) and Fine-Gray subdistribution regression for events with a competing risk (early infection vs. death, acute GVHD vs. death, relapse vs. NRM). Infection status (one or more confirmed infections) in the first 100 days post-transplant was considered as a time-dependent covariate. Results: Among 146 adult patients, 77% had AML, 54% were male, and the median age was 59 years (range 18 - 72). The Karnofsky score was 90-100 in 44% and 60-80 in 51% of patients. Using 2017 ELN risk guidelines for AML and IPSS-R for MDS and MDS/MPN, 11% of patients were classified as low risk, 33% as intermediate, and 50% as adverse. The median time from diagnosis to transplant was 5 months (range 2 - 203). At the time of transplant, 63% of patients had attained some degree of response (i.e., complete remission [CR] or hematologic improvement). However, 66% had minimal residual disease (defined as persistent cytogenetic abnormalities or leukemia-associated mutations detected by NGS). Fifty-one percent of patients had myeloablative conditioning and 90% received peripheral blood stem cell grafts with methotrexate and calcineurin-based GVHD prophylaxis. Donors were HLA-matched in 86% of patients, with haploidentical and umbilical cord blood grafts representing 10% and 3%, respectively. Forty-six percent of donors were positive for cytomegalovirus (CMV). Seventy-five percent (n=109) of patients had at least one infection in the first 100 days after transplant. Cumulative incidence rates of any infection are displayed in Table 1. The median time from transplant to first infection was 22 days, ranging from 0 to 73 days. Forty-three patients (29%) relapsed during study follow-up. The median time from transplant to relapse was 6.1 months (IQR 3.1 - 12.0). Over a median follow-up time of 18.7 months, 78 patients (53%) died, with median time to death of 4.1 months after transplant. Forty-six (59%) of the deaths were attributed to causes other than hematologic disease (i.e., infection, GVHD, other cancer). Low prognostic risk and total body irradiation during conditioning were associated with early infection (Table 2). In the multivariable setting, a higher rate of death was associated with male gender (HR=1.67; p=0.040), having at least a 6-month lag between diagnosis and transplant (HR=2.79; p&lt;0.001), and contracting an infection of any type (HR=2.54; p=0.003; Table 3). There was no association between early infection and acute GVHD, which occurred in 85 patients (58.2%) with a median time to onset of 34 days. A greater incidence of acute GVHD was related to older recipient age (HR=1.88 for ≥50 years vs. &lt;50; p=0.014), being male (HR=2.62; p&lt;0.001), not having achieved a CR (HR=1.66; p=0.020), and undergoing transplant ≥ 6 months after diagnosis (HR=1.72; p=0.014). Infection did not correlate with the rate of relapse (HR=1.02, p=0.942) but significantly elevated the rate of NRM (HR=5.72, p&lt;0.001). Time-independent variables associated with a higher probability of relapse were failure to attain a pre-transplant CR (HR=1.87; p=0.038) and having a CMV-positive donor (HR=2.11; p=0.016). Conclusion: Our retrospective study found that post-transplant early infection in AML and MDS/MPN patients did not impact relapse rate but drastically increased the rate of NRM. Disclosures Saultz: Kyn Theraputics: Research Funding. Maziarz:Novartis, Incyte, CRISPR Therapeutics, Artiva Biotherapeutics, and AlloVir: Consultancy; Novartis and Athersys: Other: DSMB participant; Novartis and Juno: Research Funding; Incyte, Kite, BMS/Celgene, PACT Pharma, Orca BioSystems, and Omeros: Honoraria; Athersys: Patents & Royalties.

Introduction Sickle cell disease (SCD) is the most common inherited blood disorders in the United States. The disease predominantly affects African Americans with 1 out of every 365 individuals born with SCD. The disease is characterized by vascular inflammation and vaso-occlusion leading to numerous complications and multi-organ dysfunction. Previous studies have shown women with SCD tend to outlive their male counterparts. Other than the increased life expectancy, sex-based clinical outcome differences in SCD remain largely unknown. To better characterize sex-based differences in SCD, we assessed sociodemographic characteristics, pain, treatment characteristics, laboratory measures and complications among males and females currently enrolled in the Sickle Cell Disease Implementation Consortium (SCDIC) registry. Methods The SCDIC consists of eight academic and comprehensive SCD centers, and one data-coordinating center that received funding from the National Heart Lung and Blood Institute to improve outcomes for individuals with SCD. Participants were eligible for the enrollment in the SCDIC registry if they were 15 to 45 years of age and had a confirmed diagnosis of SCD. Participants were excluded if they had sickle cell trait or had a successful bone marrow transplant. Enrolled participants completed surveys. Data were also abstracted from the participants' medical records. Data were entered into a REDCap database and analyzed using SAS version 9.4 (SAS Institute; Cary, NC). Categorical variables were presented as frequencies and percentages, continuous variables were presented as medians and interquartile ranges (IQR) or means and standard deviations. Categorical variables were analyzed using Chi-Square or Fisher exact tests when appropriate. Continuous variables were compared using the Mann-Whitney U test or independent sample t-tests depending on the distribution. A two-sided p-value less than 0.05 was deemed significant. Results A total of 2,124 participants were included in the study. The mean (SD) age of our participants was 27.8 (7.9) years. Almost all (95.6%) were Africa American, female (56%) and had hemoglobin SS (68.2%) SCD genotype. More males (55.4 % vs. 44.6%, p &lt;0.0001) were taking hydroxyurea. Females had significantly worse reports of pain frequency and severity (p=0.0002 and &lt;0.0001 respectively), more vaso-occlusive episodes (p=0.01) and a higher occurrence of 3 or more hospital admissions in the past year (30.9 % vs. 25.5, p= 0.03). Males had significantly more skin ulcers and respiratory, musculoskeletal, genitourinary and cardiovascular complications while females had more anxiety, depression and autoimmune conditions. Males also had significantly higher creatinine, blood urea nitrogen, albumin and liver enzymes (alkaline phosphatase, aspartate and alanine aminotransferases). Females had higher fetal hemoglobin levels with and without hydroxyurea use. There were no statistical differences in ethnicity, marital and employment status. Conclusion Key differences in SCD presentation and occurrence of complications exist among males and females. Females had higher rates of depression and anxiety while males had more chronic end-organ complications that are life threatening. Our findings emphasize the need for stratification of data analysis by sex in future SCD studies. Disclosures Hankins: Global Blood Therapeutics: Consultancy, Research Funding; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; LINKS Incorporate Foundation: Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria; MJH Life Sciences: Consultancy, Patents & Royalties; UptoDate: Consultancy; Novartis: Research Funding. Treadwell:UpToDate: Honoraria; Global Blood Therapeutics: Consultancy. King:Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company; RiverVest: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioline: Consultancy; Novimmune: Research Funding; Amphivena Therapeutics: Research Funding. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Kanter:bluebird bio, inc: Consultancy, Honoraria; SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Sanofi: Consultancy; Medscape: Honoraria; Guidepoint Global: Honoraria; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees. Glassberg:Eli Lilly and Company: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Consultancy. Shah:Bluebird Bio: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy; Alexion: Speakers Bureau.

Background: Fetal hemoglobin (HbF) is the most influential modifier of the clinical and hematologic phenotype of sickle cell disease (SCD) and is highly heritable. Low HbF is independently associated with increased white matter changes on brain imaging and poorer performance on neurocognitive measures (Ruffiuex, Child Neuropsychology, 2013). Our previous work has shown that 11 SNPs in three genes (BCL11A, MYB, and β-globin), contribute over 20% of the variance in HbF (Rampersaud, Kang. et al., 2020, under review). Clinically, these HbF-associated SNPs are associated with disease severity and frequency of pain events. However, the neurocognitive implications of these SNPs have yet to be explored. As part of a prospective longitudinal cohort study, the Sickle Cell Clinical Research and Intervention Program (SCCRIP), we evaluated the relationship between HbF-associated SNPs and neurocognitive functioning in SCD patients. Methods: We included 257 patients with SCD (69% HbSS/HbSβ0-thalassemia). The median age of participants was 13 years (range 4 - 25). We extracted genotypes for the 11 HbF-associated SNPs from whole genome sequencing data and analyzed them based on an additive genetic model. Following informed consent, patients completed a battery of gold-standard neurocognitive measures, supervised by a psychologist, assessing IQ, verbal and perceptual reasoning, working memory, processing speed, sustained attention, and executive functioning skills. HbF was the average value of measurements collected within 3 months of neurocognitive assessment, or the closest value. In univariate analyses, Kruskal-Wallis rank sum test was used to assess the associations of the 11 HbF-associated SNPs with neurocognitive measures. Linear regression was used to examine these associations adjusting for age, sickle genotype, hydroxyurea exposure, socioeconomic status (index of social vulnerability) and 5 principal components to adjust for population stratification. Benjamini and Hochberg false discovery rate (FDR) was used for multiple corrections and FDR adjusted p (pFDR)&lt;0.05 was considered significant for all analyses. Mediation analyses (Imai, Psychological Methods, 2010) were used to evaluate the indirect effects of HbF-associated SNPs on neurocognitive outcomes via HbF. Results: One SNP in the β-globin gene, rs968857, was associated with performance on measures of IQ, verbal reasoning, working memory, and executive functioning by Kruskal-Wallis rank sum test (Figure 1) and by linear regression adjusting for covariates listed above at pFDR &lt;0.05. HbF expression was positively associated with IQ and verbal reasoning scores at pFDR &lt;0.05 using linear regression adjusting for age, sickle genotype, hydroxyurea exposure, and socioeconomic status. HbF mediated the relationship between rs968857 and scores on IQ and verbal reasoning measures at pFDR &lt;0.05 (Figure 2). The direct effect of rs968857 on neurocognitive functioning remained significant following inclusion of HbF at pFDR &lt;0.05, indicating partial mediation. Full linear regression models with rs968857, HbF, and covariates accounted for 10.8%, 14.5%, 6.4%, and 8.3% of the variance in IQ, verbal reasoning, working memory, and executive functioning measures, respectively. Conclusions: This is the first study to demonstrate a relationship between genetic modifiers of SCD and neurocognitive functioning. Beyond findings on neuroimaging and sociodemographic factors, there is little known about risk for neurocognitive deficits in SCD. The present results suggest an influence of SNP rs968857 on cognitive function, which was partially mediated by expression of HbF. rs968857, is one of four SNPs that defines almost all β-globin gene cluster haplotypes and influences HbF levels in SCD. How this SNP effects HbF and neurocognition is unknown and requires further investigation of its mechanism. The highly heritable nature of HbF may allow for future use of precision medicine. SCD patients could be stratified according to risk for neurocognitive deficits to utilize early intervention strategies, informed by genetic polymorphisms. Correlation with neuroimaging will help further elucidate the relationship between genetic modifiers and neurocognitive functioning. Future trials with larger samples are needed to validate our findings and investigate if the observed relationships differ by age or hydroxyurea treatment status. Disclosures Estepp: Daiichi Sankyo, Esperion, Global Blood Therapeutics: Consultancy; Global Blood Therapeutics, Forma Therapeutics, Pfizer, Eli Lilly and Co: Research Funding; ASH, NHLBI: Research Funding. King:Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; RiverVest: Consultancy; Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company. Hankins:Novartis: Research Funding; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; UptoDate: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; American Society of Pediatric Hematology/Oncology: Honoraria; LINKS Incorporate Foundation: Research Funding.

Introduction Pregnancy in sickle cell disease (SCD) is associated with an exacerbation of SCD-related complications and an increased risk of maternal complications. The increased risk is partly due to physiologic adaptations in pregnancy, which include increased metabolic demands and a hypercoagulable state. The maternal death rate for SCD is 629 per 100,000 deliveries, compared to 12 per 100,000 deliveries in black women and 6 per 100,000 deliveries in the general population (Raider et al., 2016). Studies on maternal and perinatal outcomes of patients with SCD present inconsistent and conflicting results. Some studies have reported an increase in maternal complications such as pre-eclampsia, acute chest syndrome and thromboembolic events, while other studies have reported no significant risk in adverse maternal outcomes. The inconsistent findings reported in prior studies may be attributed to small sample sizes and single-centered sites. Our study aims to determine the prevalence and predictors of maternal morbidity among participants enrolled in the SCD Implementation Consortium (SCDIC) registry, which is the largest, most geographically diverse SCD participant sample in the United States. Methods This cross-sectional study included women enrolled in the SCDIC registry who had at least one pregnancy event. The SCDIC is composed of eight academic SCD centers across the United States and one data-coordinating center. Participants were enrolled in the SCDIC registry if they were 18 to 45 years of age and had a confirmed diagnosis of SCD. Enrolled participants completed a series of surveys that collected sociodemographic information, SCD and pregnancy history and data abstractions of participants' medical records was completed. Medical complications queried during pregnancy included: vaso-occlusive episodes, acute chest syndrome, blood transfusion requirement, preeclampsia, maternal diabetes and deep venous thrombosis. Descriptive analysis of sociodemographic, clinical and maternal characteristics was conducted. Bivariate analysis was performed using Chi-Square test, Mann-Whitney U test, t-test, and logistic regressions, as appropriate. A p-value of ≤ 0.05 was considered statistically significant for all analysis. Results The study sample included 743 women who had at least one pregnancy event, and a total of 1066 live births. Almost all women (96.3%) were African American, with a median age of 21 years (inter-quartile range of 19 to 23 years) at first birth. The majority had Hb SS SCD genotype (69.5%; 513 of the 738 with SCD genotype data). Of all reported pregnancies, participants did not use hydroxyurea during conception (78%), and pregnancy (84.5%). Only 2.7 % of the women reported using fertility drugs or assisted reproductive procedures. Seventy five percent of the pregnancies that ended in live births had maternal complications. The leading complications were vaso-occlusive episodes (61.2%), pregnancy requiring blood transfusion(s) (33.2%), preeclampsia (15.4%), deep venous thrombosis (5.6%) and acute chest syndrome (7.7%). When the pregnancies were stratified by SCD genotype, women with Hb SS had a higher occurrence of acute chest syndrome (63.4% vs. 26.7%), transfusion requirement (70.8% vs. 21%) and preeclampsia (66.7% vs 22.4%). In the univariate logistic regressions, multiparous women, with a history of adverse maternal outcomes in a previous pregnancy, had higher odds of vaso-occlusive episodes (OR: 3.42; 95% CI: 2.42-4.94) acute chest syndrome (OR:4.99; 95% CI:2.56- 9.48), transfusion requirement (OR:3.86; 95% CI:2.64- 5.69), and pre-eclampsia (OR:3.36; 95% CI:2.05-5.45). Conclusion In this large multicenter registry, we found pregnant women with SCD have significant maternal complications. Early antenatal care by healthcare providers knowledgeable about risk factors for adverse maternal outcomes in SCD is essential improve maternal and fetal outcomes and reduce the maternal death rate for SCD. Disclosures Hankins: Novartis: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; UptoDate: Consultancy; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; LINKS Incorporate Foundation: Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria. Treadwell:Global Blood Therapeutics: Consultancy; UpToDate: Honoraria. King:Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; RiverVest: Consultancy; Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Kanter:SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; Medscape: Honoraria; Guidepoint Global: Honoraria; bluebird bio, inc: Consultancy, Honoraria; Sanofi: Consultancy. Glassberg:Pfizer: Research Funding; Global Blood Therapeutics: Consultancy; Eli Lilly and Company: Research Funding. Shah:Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; CSL Behring: Consultancy; Bluebird Bio: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau.

Introduction: Chronic Lymphocytic Leukemia (CLL) is characterized by the accumulation of mature-appearing malignant lymphocytes (CLL B-cells) in the blood, marrow, lymph nodes, and spleen. Despite improved outcome with the introduction of novel BCR and BCL-2 inhibitors, disease progression is still a therapeutic challenge from either differential responses or acquired drug resistance. Recent studies in CLL reported alterations of the epigenetic landscape as well as mutations of genes encoding key chromatin machineries. These aberrant chromatin structures may provide novel therapeutic targets for CLL. Here, we identify aberrant chromatin features in CLL B-cells as novel therapeutic targets. Methods: Histones were extracted by acid from B cells derived from 10 random selected CLL patients and 10 normal donors and histone modifications were checked by western blot. For ChIP-seq study, published H3K27me3 ChIP-seq data (GSE113336) were downloaded from and analyzed (Control samples, n= 6; CLL samples, n=16). Gene ontology analysis used the Panther Classification System. Cell Survival was determined by CellTiter 96® AQueous Assay (Promega). Results: While most histone modifications do not vary between CLL and controls, H3K27me3 and H3.3S31ph are increased and decreased respectively, albeit variably, in CLL B-cells (Fig1. A and B). Notably, the low level of H3.3S31ph was observed in a subset of samples (7 of 10 CLL samples tested). To further investigate the biology and role of H3K27me3 in CLL, we analyzed its genome-wide distribution by chromatin immunoprecipitation followed by sequencing (ChIP-seq). Our analysis showed that the genes with increased H3K27me3 occupancy were mostly enriched in tumor suppression pathways (e.g., negative regulation of PI3K-Akt pathway) or down-regulated genes in CLL such as genes involved in the pro-apoptotic pathway (FAS) (Fig1. C and D). These results suggested that high enrichment of H3K27me3 may regulate the expression of these genes, contributing to CLL survival. H3K27 methylation, an important suppressive histone modification that is associated with transcription repression, is catalyzed by Polycomb Repressive Complex 2 (PRC2). Therefore, inhibition of Enhancer of Zeste Homolog 2 (EZH2), the catalytic subunit of PRC2, could be explored as a therapy approach in CLL. However, feedback activation of H3K27 acetylation (H3K27ac) can promote expression of pro-survival genes that confers EZH2 inhibitor (EZH2i) resistance, which limits its use in human malignancy. Thus, the epigenetic determinants that reliably overcome EZH2i resistance or sensitize cells to EZH2 inhibition have yet to be identified. As we observed that the CLL B-cells in a subset of CLL patients have low levels of H3.3S31ph, and a recent study showed the importance of H3.3S31ph for the enzymatic activity of p300 to acetylate H3 at lysine 27(Martire S et al., Nat Genet. 2019), we assessed the role of H3.3S31ph in the process of EZH2 inhibitor-mediated H3K27ac. Our results showed that inhibition of H3.3S31ph by CHK1 inhibitor MK-8776 abolished the activation of H3K27ac by EZH2i in MEC1 cells, which represents the patients who have CLL cells with relatively high level H3.3S31ph. However, we did not see a major increase of H3K27ac and H3.3S31ph in primary CLL B-cells with EZH2 inhibition (Fig. 1E), consistent with the relatively low expression of CHK1 protein in these cells (Fig. 1F). Because our data shows the requirement of H3.3S31ph in H3K27ac activation by EZH2 inhibition, we next tested if H3.3S31ph inhibition could overcome H3K27ac induced EZH2 inhibition resistance. We found that suppression of H3.3S31ph by CHK1 inhibitor MK-8776 sensitizes the CLL-like line MEC1 to EZH1/2 inhibition (Fig. 1 G). We then showed that an EZH2 inhibitor, Valemetostat, reduce the survival of the primary CLL B-cells (Fig. 1 H). These results suggest that the low level of H3.3S31ph may provide a therapeutic opportunity for CLL treatment with EZH inhibition. Conclusion: In summary, we have elucidated how epigenetic features in leukemic CLL B-cells (H3K27me3 and H3.3S31ph), can provide novel treatment targets for CLL (Fig. 1 I). Moreover, this study may provide a proof of concept to develop new treatment strategies based on epigenetic vulnerabilities in other hematological malignancies. Disclosures Parikh: GlaxoSmithKline: Honoraria; MorphoSys: Research Funding; Genentech: Honoraria; Ascentage Pharma: Research Funding; AbbVie: Honoraria, Research Funding; TG Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Verastem Oncology: Honoraria; Merck: Research Funding. Kenderian:Kite: Research Funding; MorphoSys: Research Funding; Tolero: Research Funding; Humanigen: Consultancy, Patents & Royalties, Research Funding; BMS: Research Funding; Gilead: Research Funding; Juno: Research Funding; Lentigen: Research Funding; Mettaforge: Patents & Royalties; Novartis: Patents & Royalties, Research Funding; Torque: Consultancy; Sunesis: Research Funding. Ding:Beigene: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; DTRM: Research Funding; Abbvie: Research Funding. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Kay:Oncotracker: Membership on an entity's Board of Directors or advisory committees; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; MEI Pharma: Research Funding; Abbvie: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding.

INTRODUCTION T-cell prolymphocytic leukemia (T-PLL) is a rare, aggressive malignancy of mature T-cells. Although responses may been seen with initial alemtuzumab-based therapy, relapse is inevitable and relapsed/refractory disease carries a dismal prognosis. T-PLL has shown in vitro sensitivity to venetoclax, and short-lived clinical responses to venetoclax monotherapy (Smith, Blood Advances 2020; Boidol, Blood 2017) or when given in combination with pentostatin (Alfayez, Leukemia & Lymphoma 2020). Given the lack of standard treatment options, we reviewed the outcomes of patients (pts) with relapsed T-PLL on venetoclax-based therapy. METHODS Using an institutional clinical database of pts with T-PLL seen in the Division of Hematology at Mayo Clinic, Rochester, MN, all pts treated with venetoclax or venetoclax-based therapies in a relapsed/refractory setting were identified. Clinical, laboratory, and pathology data, as well as treatment dosing and toxicity were ascertained retrospectively from the medical records. Diagnostic criteria and response definitions were utilized as per the T-PLL International Study Group (Staber, Blood 2019). RESULTS Between 8/2017 and 5/2020, 9 pts with relapsed/refractory T-PLL treated with venetoclax were identified. The median age was 63 years (range 49-75), and one-third were male. Baseline characteristics are detailed in Table 1. Rearrangement of TCL1 family genes was present in all 8 pts evaluated with fluorescence in situ hybridization (FISH). Using conventional cytogenetics, a complex karyotype was present in 4/6 pts tested. The median prior lines of therapy was 3 (range 1-4), including alemtuzumab in 8 of 9 pts (intravenous 7/8); and two pts had undergone prior hematopoietic stem cell transplantation (1 allogeneic; 1 autologous) after achieving a complete remission. Additional individual pt details are included in Table 2. Prior to venetoclax therapy initiation, 2 pts had B-symptoms (2 night sweats; 1 fever) and 6 pts had an ECOG score ≥ 2. Lymphadenopathy and splenomegaly were present in 6 and 9 pts, respectively. Extranodal involvement included 3 pts with cutaneous involvement and 5 pts with effusions (4 ascites; 1 pleural). The target maximum dose of venetoclax (800 mg [n=4]; 400 mg [n=1]) was reached by 5 pts at a median of 12 days (range 7-40 days). The other 4 pts had disease progression after a median of 10 days (range 5-22 days) during the dose ramp-up, including 2 pts undergoing rapid dose escalation. Altogether, 6 of the 9 pts initiated venetoclax with a rapid dose escalation. Bendamustine was given with venetoclax in 5/9 pts; median number of cycles 1 (range 1-4) with variable starting dosing (range 60-100 mg/m2). The disease control rate was 56%; best response was partial remission (PR) in 4 (44%) pts and stable disease (SD) in 1 (11%) pt. The 1 pt with SD received venetoclax monotherapy; however, the overall response rate among pts who received the combination of venetoclax and bendamustine was 80% (4/5 pts). One pt with a partial remission met all criteria for complete remission but did not have a confirmatory bone marrow biopsy. Cutaneous disease improved in 2 of 3 pts (both with PR as best response), and effusions improved in 2 of 5 pts (1 PR and 1 SD as best response). Among those in PR, the median decrease in absolute lymphocyte count was 67x109/L and the median decrease in lactate dehydrogenase was 1,162 U/L (normal range 122-222 U/L). Median duration of treatment for all pts was 42 days (range 4-201 days). All pts ultimately died during follow-up with a median overall survival of 53 days (range 4-464 days); Figure 1. All pts experienced at least one adverse event and 8 of 9 pts had a grade ≥ 3 toxicity, most commonly edema (n=7) and neutropenia (n=6). Five pts required dose interruptions due to neutropenia (n=3), tumor lysis syndrome (n=1), and edema (n=1). Three pts had dose reductions, all from 800 mg dosing, due to hematologic toxicity (n=2) and nausea (n=1). No pts discontinued venetoclax as a result of adverse events. CONCLUSION Treatment of pts with relapsed/refractory T-PLL remains a significant unmet need. The 9 pts described herein represent the largest cohort of pts treated with venetoclax-based therapy in this setting to the current date. Despite initial reports of clinical efficacy, our results show that venetoclax (with or without bendamustine) has modest efficacy in the treatment of relapsed/refractory T-PLL after prior alemtuzumab exposure. Disclosures Parikh: TG Therapeutics: Research Funding; Verastem Oncology: Honoraria; GlaxoSmithKline: Honoraria; AbbVie: Honoraria, Research Funding; Genentech: Honoraria; Merck: Research Funding; MorphoSys: Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Ascentage Pharma: Research Funding; AstraZeneca: Honoraria, Research Funding. Shah:Dren Bio: Consultancy. Bennani:Verastem: Other: Advisory Board; Affimed: Research Funding; Purdue Pharma: Other: Advisory Board; Kite/Gilead: Research Funding. Wang:Incyte: Research Funding; Novartis: Research Funding; Innocare: Research Funding. Kenderian:MorphoSys: Research Funding; Lentigen: Research Funding; Gilead: Research Funding; Juno: Research Funding; BMS: Research Funding; Tolero: Research Funding; Sunesis: Research Funding; Kite: Research Funding; Novartis: Patents & Royalties, Research Funding; Torque: Consultancy; Humanigen: Consultancy, Patents & Royalties, Research Funding; Mettaforge: Patents & Royalties. Kay:MEI Pharma: Research Funding; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; Cytomx: Membership on an entity's Board of Directors or advisory committees; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Ding:Octapharma: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; alexion: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Abbvie: Research Funding. OffLabel Disclosure: Venetoclax: off-label use in treatment of relapsed/refractory T-cell prolymphocytic leukemia

Introduction: BCMA is a tumor necrosis factor (TNF) receptor superfamily transmembrane glycoprotein essential for the maturation and survival of plasma cells. CC-93269 is an asymmetric 2-arm humanized IgG TCE that binds bivalently to BCMA and monovalently to CD3ε in a 2+1 format (Seckinger A, et al. Cancer Cell. 2017;31:396-410). The CC-93269-mediated interaction between T cells and BCMA-expressing myeloma cells induces T cell receptor/CD3 crosslinking leading to T cell activation, and release of proinflammatory cytokines and cytolytic enzymes, resulting in myeloma cell death. In preclinical studies with CC-93269 and related molecules, 2+1 BCMA TCEs induced tumor regression in animal models and promoted myeloma cell death in primary pt myeloma cells. Here we report interim results from a phase 1 dose-finding study (CC-93269-MM-001; NCT03486067) evaluating CC-93269 in pts with RRMM. Methods: Eligible pts had RRMM and had received ≥ 3 prior regimens without prior BCMA-directed therapy. In dose escalation, CC-93269 was administered intravenously over 2 hours on Days 1, 8, 15, and 22 for Cycles 1-3; Days 1 and 15 for Cycles 4-6; and on Day 1 for Cycle 7 and beyond, all in 28-day cycles. Dose escalation involved 2 stages: in stage 1, CC-93269 was given in fixed doses; in stage 2, pts received a fixed first dose on Cycle 1 Day 1, followed by intrapatient dose escalation on Cycle 1 Day 8. Primary objectives were to assess the safety and tolerability of CC-93269 and define the maximum tolerated dose (MTD), non-tolerated dose (NTD), and/or recommended phase 2 dose (RP2D). Minimal residual disease (MRD) was assessed after clinical response in pt bone marrow aspirate samples by Next Generation Flow using the EuroFlow panel. MRD negativity was reported only if a minimum sensitivity of &lt; 1 tumor cell in 105 nucleated cells was achieved. Results: As of May 24, 2019, 19 pts had received CC-93269. Median age was 64 years (range 51-78), with a median of 6.2 years (range 1.4-13.9) since initial diagnosis. The median number of prior regimens was 6 (range 3-12) and included treatment with autologous stem cell transplantation (73.7%), allogenic stem cell transplantation (10.5%), lenalidomide (100%), pomalidomide (84.2%), bortezomib (100%), carfilzomib (84.2%), and daratumumab (DARA; 94.7%). All pts had MM refractory to their last line of therapy, with 16 (88.9%) refractory to DARA, 17 (89.5%) to their last proteasome inhibitor, and 16 (84.2%) to their last immunomodulatory agent. CC-93269 doses ranged from 0.15 to 10 mg; median duration of treatment was 14.6 weeks (range 1.6-32.0) with pts receiving a median of 4 cycles (range 1-8). Grade 3-4 treatment-emergent adverse events were reported in 15 (78.9%) pts and included 10 (52.6%) pts with neutropenia, 8 (42.1%) with anemia, 5 (26.3%) with infections, and 4 (21.1%) with thrombocytopenia. No pt required dose modifications. Cytokine release syndrome (CRS) was reported in 17 (89.5%) pts, the majority of whom reported a maximum grade 1 (n = 11 [57.9%]) or grade 2 (n = 5 [26.3%]), and occurred most frequently with the first or second dose (n = 22 of 27 events [81.5%]). CRS prophylaxis was implemented with dexamethasone for first dose and dose increases in pts receiving ≥ 6 mg. Of 27 CRS events, 8 (29.6%) were managed with dexamethasone and 10 (37.0%) with tocilizumab. One pt receiving 6 mg CC-93269 as first dose and 10 mg on Cycle 1 Day 8 died on study in the setting of CRS, with a potential infection as a contributing factor. Dose-related pharmacodynamic activity, including peripheral blood immune cell redistribution and transient release of pro- and anti-inflammatory cytokines, was observed in pts. Of the 12 pts treated with ≥ 6 mg CC-93269 in Cycle 1, 10 pts achieved a partial response (PR) or better (overall response rate; 83.3%), including 7 (58.3%) with a very good partial response (VGPR) or better and 4 (33.3%) with a stringent complete response (sCR) (Table); 9 (75.0%) pts achieved MRD negativity. The median time to response was 4.2 weeks (range 4.0-13.1), and 10 of 10 responses were ongoing with follow-up ranging from 2.1 to 4.7 months. The NTD, MTD, and RP2D have not yet been reached. Conclusions: CC-93269, a 2+1 BCMA TCE, shows a manageable safety profile and promising efficacy, including MRD-negative sCRs, in pts with heavily pretreated RRMM. The study continues to enroll in the dose escalation phase. Updated safety and efficacy data will be presented at the meeting. Disclosures Costa: Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Karyopharm: Consultancy; Abbvie: Consultancy; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau. Wong:Genentech: Research Funding; Janssen: Research Funding; Celgene Corporation: Research Funding; Fortis: Research Funding; Juno: Research Funding. Bermúdez:MSD: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Fresenius: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. de la Rubia:AMGEN: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Mateos:Pharmamar: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; EDO: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ocio:BMS: Honoraria; Sanofi: Research Funding; Mundipharma: Research Funding; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding; Pharmamar: Consultancy; Novartis: Consultancy, Honoraria; AbbVie: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Rodríguez-Otero:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Takeda: Consultancy; BMS: Honoraria; Kite Pharma: Consultancy. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Li:Celgene Corporation: Employment, Equity Ownership. Sarmiento:Celgene Corporation: Employment. Lardelli:Celgene Corporation: Employment, Equity Ownership. Gaudy:Celgene Corporation: Employment, Equity Ownership. Boss:Celgene Corporation: Employment, Equity Ownership. Kelly:Celgene Corporation: Employment. Burgess:University of California: Other: Volunteer clinical faculty, without salary, Patents & Royalties: Patent - T315A and F317I mutations of BCR-ABL kinase domain; Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: Patent - CD47 antibodies and methods of use thereof. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant.

Background: Cluster of differentiation 47 (CD47), a widely expressed cell-surface ligand,is overexpressed in various malignancies and is correlated with worse outcomes in NHL. Interaction of CD47 and signal regulatory protein-α (SIRPα) delivers an antiphagocytic 'don't eat me' signal to promote tumor cell evasion from macrophages. CC-90002 is a humanized IgG4-PE CD47 antibody that inhibits CD47-SIRPα interaction and enabled phagocytosis across a panel of cancer cell lines (Narla et al. AACR.2017). In addition to high binding affinity, CC-90002 is potentially differentiated from other CD47 immunotherapies by its lack of ability to induce hemagglutination of red blood cells or hemolysis in nonclinical studies. CD47 antibodies can synergize with the CD20 antibody rituximab to induce phagocytosis of NHL cells in vitroand to eliminate lymphoma in mouse models (Chao et al. Cell.2010). We therefore examined CC-90002 plus rituximab for treatment of R/R NHL. Methods: This 2-part, phase I, multicenter study (CC-90002-ST-001; NCT02367196) is evaluating CC-90002 in subjects with advanced solid and hematologic malignancies. Part B of the study (reported here) is examining CC-90002 in combination with rituximab in subjects with CD20-positive R/R NHL. Dose escalation followed a modified 3+3 design. Subjects received escalating doses of CC-90002 intravenously at 4, 8, 15, 20, or 30 mg/kg every 2 weeks (Q2W) on days 1 and 15 plus rituximab 375 mg/m2 given on days −15, −8, and −1 and day 8 of cycles 1-6, 8, 10, and 12 in 28-day cycles. Primary endpoints are dose-limiting toxicities (DLTs), nontolerated dose (NTD), and maximimum tolerated dose. Secondary endpoints are pharmacokinetics, preliminary efficacy per International Working Group Response Criteria for NHL (Cheson et al. J Clin Oncol.2014), and frequency of antidrug antibodies. Results: Overall, 28 subjects have been enrolled and 24 were treated. As of July 5, 2019, 20 subjects had discontinued the study, most commonly for progressive disease (PD; n=9) or death (n=7). The median age at enrollment was 64 years (range, 27−81), and subjects had received a median of 3 prior systemic therapies (range, 2−9). Subjects received a median of 2 cycles of CC-90002 plus rituximab (range, 1−18). There were no CC-90002 dose reductions but 7 subjects had their dose interrupted, mostly because of thrombocytopenia and neutropenia. The NTD was established as 30 mg/kg Q2W.DLTs occurred in 3 subjects; 1 subject developed dyspnea attributed to an infusion-related reaction at 15 mg/kg Q2W CC-90002 and 2 subjects had grade 3 thrombocytopenia requiring platelet transfusion occurring at 30 mg/kg Q2W CC-90002. The most common adverse events (AEs) were hematologic (Table). Although anemia was common, there was no evidence of hemolysis. The most frequent grade 3/4 AEs were neutropenia (38%) and thrombocytoenia (21%). Seven deaths occurred on study or in follow-up, 6 from PD or complications related to NHL and 1 due to an AE (cytokine release syndrome in a subject who discontinued CC-90002 for PD and enrolled in another trial within the follow-up period). There were no treatment-related deaths. The overall response rate was 13% (95% CI, 2.7−32.4) and the disease control rate was 25% (95% CI, 9.8−46.7; Figure). One subject achieved a durable complete response (8 mg/kg; ongoing in cycle 18) and 2 had partial responses (15 mg/kg and 20 mg/kg); 3 subjects had stable disease. Among responders, the median duration of response was 3.9 months (95% CI, 1.9−3.9). CC-90002 exhibited linear pharmacokinetics at doses ≥15 mg/kg, suggesting target saturation at 15 mg/kg. In addition, a longer half-life was observed at higher (≥15 mg/kg) versus lower doses (t1/2≈ 3−7 days vs 1 day). Conclusions: The CD47-SIRPα checkpoint inhibitor, CC-90002,plus rituximab demonstrated tolerability and modest clinical activity in this early-phase study of heavily pretreated R/R NHL subjects. AEs were predominantly grade 1/2; cytopenias were the most common AEs with dose-limiting thrombocytopenia observed at 30 mg/kg Q2W. In contrast to other CD47-targeting immunotherapies and consistent with results of preclinical studies of CC-90002, hemolysis at a starting dose of up to 30 mg/kg CC-90002 was not observed. These preliminary data support further evaluation of targeting the CD47-SIRPα pathway in combination with rituximab in NHL. Disclosures Abrisqueta: Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau. Sancho:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Other: Advisory board; Novartis: Honoraria; Kern Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Celltrion: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squib: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cordoba:Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Speakers Bureau; Kyowa-Kirin: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Roche: Honoraria, Speakers Bureau; FUNDACION JIMENEZ DIAZ UNIVERSITY HOSPITAL: Employment; Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy. Persky:Sandoz: Consultancy; Morphosys: Other: Member, Independent Data Monitoring Committee; Debiopharm: Other: Member, Independent Data Monitoring Committee; Bayer: Consultancy. Andreadis:Juno: Research Funding; Pharmacyclics: Research Funding; Roche: Equity Ownership; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Research Funding; Kite: Consultancy; Gilead: Consultancy; Merck: Research Funding; Genentech: Consultancy, Employment. Huntington:Pharmacyclics: Honoraria; Genentech: Consultancy; Bayer: Consultancy, Honoraria; DTRM Biopharm: Research Funding; AbbVie: Consultancy; Celgene: Consultancy, Research Funding. Carpio:University Hospital Vall D'Hebron: Employment. Morillo Giles:Hospital Universitario Fundacion Jimenez Diaz: Honoraria. Wei:Celgene Corp.: Employment, Equity Ownership. Li:Celgene Corp.: Employment, Equity Ownership. Zuraek:Celgene Corp.: Employment, Equity Ownership, Other: Travel, Accommodations, Expenses. Burgess:University of California: Other: Volunteer clinical faculty, without salary, Patents & Royalties: Patent - T315A and F317I mutations of BCR-ABL kinase domain; Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: Patent - CD47 antibodies and methods of use thereof. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees. Martín:iQone: Consultancy; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: Travel Expenses; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Kiowa Kirin: Consultancy; Servier: Honoraria, Other: Travel Expenses; Teva: Research Funding; Janssen: Honoraria, Other: Travel Expenses, Research Funding.

Introduction: CAR-T cells targeting the CD19 antigen are approved to treat children and young adults with relapsed and refractory B-cell ALL, in whom response rates are &gt;80%. Acute toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) complicate CAR-T therapy in most patients. Though most patients with CRS or ICANS experience toxicities that can be managed with supportive care including corticosteroids and tocilizumab, 46% experience grade 3-4 CRS and 13% experience grade 3 ICANS (Maude SL et al N Engl J Med 2018; 37:439). Thus, novel approaches to address the management of high grade toxicities are needed. Donor T lymphocytes engineered to express human caspase 9 fused to a modified human FK-binding protein that induces caspase-dependent apoptosis when exposed to the dimerizing drug rimiducid (Di Stasi A et al. N Engl J Med 2011; 365:1673). We hypothesized that the inducible caspase 9 safety switch (iC9) coupled with CAR19 could mitigate severe CRS or ICANS in patients treated with CAR-T cells. We initiated a phase I trial to test the safety and efficacy of autologous T lymphocytes, genetically modified to express both iC9 and CAR19 administered to patients with relapsed and refractory B-ALL. Methods: Subjects with B-cell ALL in 2nd or greater bone marrow (BM) relapse, relapse &gt;100 days after allogeneic stem cell transplant, disease refractory to ≥2 induction therapies, or with measurable residual disease (MRD) persistence/recurrence were enrolled in a phase I dose escalation trial. Autologous T-lymphocytes were collected, and CAR-T cell products generated by gene modification with a γ-retroviral vector encoding for iC9, ΔNGFR (for selection and tracking purposes) and CAR.CD19 (encoding 4-1BB) genes (Diaconu I et al Mol Ther 2017; 25:580). Subjects underwent lymphodepletion with fludarabine and cyclophosphamide and CAR-T cells were subsequently infused at one of two dose levels (DL1: 5 x 105 CAR-T cells/kg; DL2: 1 x 106 CAR-T cells/kg). Toxicities were graded by CTCAE v5 or ASBMT consensus grading for CRS and ICANS. Dose limiting toxicities (DLT) were grade 3-4 CRS or ICANS lasting &gt;7 days despite standard of care intervention or grade 3 or higher autoimmune or non-CRS/ICANS organ toxicity. CAR-T cell expansion in peripheral blood (PB) was determined by flow cytometry (FC) and Q-PCR. Leukemia response was determined by NCCN criteria at 4 and 8 weeks after CAR-T infusion. Results: Nine products from 9 consecutive patients have been successfully manufactured in a median of 14 days (range 13-22), with transduction efficiency of 83 ± 6% after specific ΔNGFR selection. Six subjects have been enrolled to date, three in each cohort. Median age of subjects was 32 years (range 21-41). Median number of prior therapies was 3 (range 2-5). One subject had Philadelphia chromosome positive ALL. Maximum grade CRS was 2 in two subjects and 1 in three subjects. Median duration of any grade CRS was 4 days (range 2-7). One subject in DL1 experienced grade 1 ICANS for 2 days. All CRS/ICANS resolved with standard of care supportive measures, and no subject received rimiducid. No subject experienced DLT. CAR-T cells were found to be increased by PB Q-PCR, peaking at week 2 post infusion (7.9 x 104 ± 3.4 x 104 copies/μg of DNA). This trend paralleled the detection of CAR-T cells by FC. At 4 weeks post infusion, CAR-T cell signals were also detectable in BM samples, and BM B cells comprised &lt;0.01% of BM cellularity in 5/6 subjects. All six subjects experienced response, with best response of CR (n=2), CRi (n=3) and morphologic leukemia-free state (n=1). At time of best response, all subjects were MRD negative by FC and 2 of 3 were MRD negative by molecular MRD assays. Conclusions: iC9-CAR19 cells can be safely administered to adult patients with relapsed and refractory B-ALL. The use of iC9 as a safety switch has not been required due to the absence of patients with high-grade CRS/ICANS . Preliminary antileukemic activity was observed. The recommended phase 2 cell dose, 1 x 106 transduced cells/kg is being tested in an expansion cohort. A dose finding study to determine the effects of rimiducid on CRS/ICANS grade, CAR-T cell persistence and cytokine levels is being conducted among expansion cohort patients who experience CRS/ICANS not responding to standard supportive care. Introduction: CAR-T cells targeting the CD19 antigen are approved to treat children and young adults with relapsed and refractory B-cell ALL, in whom response rates are &gt;80%. Acute toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) complicate CAR-T therapy in most patients. Though most patients with CRS or ICANS experience toxicities that can be managed with supportive care including corticosteroids and tocilizumab, 46% experience grade 3-4 CRS and 13% experience grade 3 ICANS (Maude SL et al N Engl J Med 2018; 37:439). Thus, novel approaches to address the management of high grade toxicities are needed. Donor T lymphocytes engineered to express human caspase 9 fused to a modified human FK-binding protein that induces caspase-dependent apoptosis when exposed to the dimerizing drug rimiducid (Di Stasi A et al. N Engl J Med 2011; 365:1673). We hypothesized that the inducible caspase 9 safety switch (iC9) coupled with CAR19 could mitigate severe CRS or ICANS in patients treated with CAR-T cells. We initiated a phase I trial to test the safety and efficacy of autologous T lymphocytes, genetically modified to express both iC9 and CAR19 administered to patients with relapsed and refractory B-ALL. Methods: Subjects with B-cell ALL in 2nd or greater bone marrow (BM) relapse, relapse &gt;100 days after allogeneic stem cell transplant, disease refractory to ≥2 induction therapies, or with measurable residual disease (MRD) persistence/recurrence were enrolled in a phase I dose escalation trial. Autologous T-lymphocytes were collected, and CAR-T cell products generated by gene modification with a γ-retroviral vector encoding for iC9, ΔNGFR (for selection and tracking purposes) and CAR.CD19 (encoding 4-1BB) genes (Diaconu I et al Mol Ther 2017; 25:580). Subjects underwent lymphodepletion with fludarabine and cyclophosphamide and CAR-T cells were subsequently infused at one of two dose levels (DL1: 5 x 105 CAR-T cells/kg; DL2: 1 x 106 CAR-T cells/kg). Toxicities were graded by CTCAE v5 or ASBMT consensus grading for CRS and ICANS. Dose limiting toxicities (DLT) were grade 3-4 CRS or ICANS lasting &gt;7 days despite standard of care intervention or grade 3 or higher autoimmune or non-CRS/ICANS organ toxicity. CAR-T cell expansion in peripheral blood (PB) was determined by flow cytometry (FC) and Q-PCR. Leukemia response was determined by NCCN criteria at 4 and 8 weeks after CAR-T infusion. Results: Nine products from 9 consecutive patients have been successfully manufactured in a median of 14 days (range 13-22), with transduction efficiency of 83 ± 6% after specific ΔNGFR selection. Six subjects have been enrolled to date, three in each cohort. Median age of subjects was 32 years (range 21-41). Median number of prior therapies was 3 (range 2-5). One subject had Philadelphia chromosome positive ALL. Maximum grade CRS was 2 in two subjects and 1 in three subjects. Median duration of any grade CRS was 4 days (range 2-7). One subject in DL1 experienced grade 1 ICANS for 2 days. All CRS/ICANS resolved with standard of care supportive measures, and no subject received rimiducid. No subject experienced DLT. CAR-T cells were found to be increased by PB Q-PCR, peaking at week 2 post infusion (7.9 x 104 ± 3.4 x 104 copies/μg of DNA). This trend paralleled the detection of CAR-T cells by FC. At 4 weeks post infusion, CAR-T cell signals were also detectable in BM samples, and BM B cells comprised &lt;0.01% of BM cellularity in 5/6 subjects. All six subjects experienced response, with best response of CR (n=2), CRi (n=3) and morphologic leukemia-free state (n=1). At time of best response, all subjects were MRD negative by FC and 2 of 3 were MRD negative by molecular MRD assays. Conclusions: iC9-CAR19 cells can be safely administered to adult patients with relapsed and refractory B-ALL. The use of iC9 as a safety switch has not been required due to the absence of patients with high-grade CRS/ICANS . Preliminary antileukemic activity was observed. The recommended phase 2 cell dose, 1 x 106 transduced cells/kg is being tested in an expansion cohort. A dose finding study to determine the effects of rimiducid on CRS/ICANS grade, CAR-T cell persistence and cytokine levels is being conducted among expansion cohort patients who experience CRS/ICANS not responding to standard supportive care. Disclosures Foster: Bellicum Pharmaceuticals: Research Funding; Daiichi Sankyo: Consultancy; Macrogenics: Consultancy, Research Funding. Roehrs:Spark Therapeutics: Consultancy; Gamifant: Speakers Bureau. Grover:Tessa: Consultancy; Genentech: Research Funding. Armistead:GeneCentric: Consultancy; Cell Microsystems: Patents & Royalties: Patent application U.S. 16/347,104 "Automated collection of a specified number of cells". Morrison:Vesselon: Consultancy. Dotti:Tessa Therapeutics: Consultancy, Research Funding; Bellicum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Savoldo:Bellicum Inc: Research Funding; Bluebirdbio: Research Funding; Tessa theraputics: Consultancy, Patents & Royalties, Research Funding; Cell Medica: Ended employment in the past 24 months, Research Funding. OffLabel Disclosure: Rimiducid will be mentioned in management of toxicities of cellular therapies.

Abstract Background: Pts with LBCL primary refractory to or relapsed ≤ 12 mo after first-line (1L) therapy may have poor outcomes with SOC, including salvage CT and ASCT, which underscores a critical unmet need. Liso-cel is an autologous CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. In the TRANSCEND NHL 001 study (NCT02631044) in pts with R/R LBCL (≥ 2 prior lines of therapy), liso-cel treatment resulted in an ORR of 73% (CR rate, 53%), 2% grade ≥ 3 cytokine release syndrome (CRS), and 10% grade ≥ 3 neurological events (NE) (Abramson et al. Lancet 2020). Here we present a prespecified interim analysis of TRANSFORM (NCT03575351; SOC vs liso-cel as 2L therapy in pts with R/R LBCL). Methods: TRANSFORM is a pivotal, global, randomized, multicenter, phase 3 study comparing efficacy and safety of SOC (Arm A; R-DHAP, R-ICE, or R-GDP per investigator choice followed by BEAM + ASCT) vs liso-cel (Arm B). Pts were adults (aged ≤ 75 years), eligible for ASCT, and with LBCL primary refractory to or relapsed ≤ 12 mo after 1L therapy. Key inclusion criteria were ECOG PS ≤ 1 and adequate organ function (LVEF ≥ 40%; serum CrCl &gt; 45 mL/min); pts with secondary CNS lymphoma were allowed. Key exclusion criteria were prior gene or anti-CD19-targeted therapy, and active infection. Pts in Arm A were to receive 3 cycles of CT. Responding pts (CR or PR) were to proceed to BEAM + ASCT. Pts in Arm B were to undergo lymphodepletion with fludarabine/cyclophosphamide followed by liso-cel at a target dose of 100 × 10 6 CAR + T cells. Bridging therapy with an Arm A CT regimen was allowed. Crossover to receive liso-cel was allowed in Arm A for pts not achieving CR or PR after 3 cycles of CT or not in CR after ASCT, or demonstrating PD at any time. Primary endpoint is event-free survival (EFS) based on independent review committee per Lugano 2014 criteria, defined as time from randomization to death from any cause, PD, failure to achieve CR or PR by 9 weeks after randomization, or start of new antineoplastic therapy, whichever occurred first. Key secondary endpoints included in the testing strategy are CR rate, PFS, and OS. P value significance threshold for endpoints to reject the null hypothesis was ≤ 0.012. Results: A total of 184 pts were randomized, with 92 pts in each arm. Baseline characteristics were well balanced between both arms (Table). Of 91 treated pts in Arm A (1 pt withdrew consent), 43 received BEAM + ASCT, of which 28 achieved CR with CT. Fifty pts crossed over to receive liso-cel. In Arm B, 90 pts received liso-cel infusion; 58 pts (63%) received bridging therapy. Two Arm B pts were not infused (1 each due to manufacturing failure and rapid progression). Median EFS and PFS were significantly longer, and CR rate was significantly improved for Arm B vs Arm A. For Arms A and B, respectively, median EFS was 2.3 vs 10.1 mo (HR, 0.349; P &lt; 0.0001), median PFS was 5.7 vs 14.8 mo (HR, 0.406; P = 0.0001), and CR rate was 39% vs 66% (P &lt; 0.0001). OS data were immature at the time of this analysis with a median follow-up of 6.2 mo (range, 0.9-20.0), but a numerical trend favored Arm B (HR, 0.509; 95% CI, 0.258-1.004; P = 0.0257). Cellular kinetics in Arm B showed a median t max of 10 d (range, 6‒22). No new liso-cel safety signals were detected in the 2L setting. In Arm B, any-grade CRS was reported in 49% of pts, with grade 1 in 37% and grade 2 in 11%. Only 1 pt had grade 3 CRS (onset at Day 9, which resolved in 2 days). Any-grade NEs were reported in 12% of pts and were also primarily low grade (grade 3, 4%). No grade 4 or 5 CRS or NEs were reported. In Arm B, 24% of pts received tocilizumab, 17% received corticosteroids, and none received vasopressors. The most common TEAEs in both arms were cytopenias. Prolonged cytopenias in Arm B (ie, grade ≥ 3 at 35 d after infusion) were reported in 43% of pts; the majority recovered within 2 mo after infusion. Conclusions: In the TRANSFORM study, liso-cel demonstrated statistically significant and clinically meaningful improvement in the primary endpoint, EFS, as well as in key secondary efficacy endpoints (CR rate and PFS) compared with SOC as 2L therapy in pts with LBCL primary refractory to or relapsed ≤ 12 mo after 1L therapy. Safety results in the 2L setting were consistent with the liso-cel safety profile in 3L or later LBCL, and no new safety concerns were identified. Liso-cel improved outcomes vs SOC and exhibited a favorable safety profile, providing support for liso-cel as a potential new SOC for 2L treatment in pts with R/R LBCL. Figure 1 Figure 1. Disclosures Kamdar: SeaGen: Speakers Bureau; ADC Therapeutics: Consultancy; Celgene: Other; TG Therapeutics: Research Funding; KaryoPharm: Consultancy; Celgene (BMS): Consultancy; Genetech: Other; Genentech: Research Funding; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy; Kite: Consultancy; AstraZeneca: Consultancy. Arnason: Juno/BMS: Honoraria. Glass: BMS: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; Riemser: Research Funding; Kite: Consultancy; Novartis: Consultancy; Helios Klinik Berlin-Buch: Current Employment. Bachanova: KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ibrahimi: Karyopharm Theraputics: Divested equity in a private or publicly-traded company in the past 24 months. Mielke: Immunicum: Other: Data safety monitoring board; Novartis: Speakers Bureau; Miltenyi: Other: Data safety monitoring board; DNA Prime SA: Speakers Bureau; Gilead/KITE: Other: Travel support, Expert panel ; Celgene/BMS: Speakers Bureau. Mutsaers: BMS: Consultancy; AstraZeneca: Research Funding. Hernandez-Ilizaliturri: Kite: Other: Advisory Boards; Amgen: Other: Advisory Boards; Pharmacyclics: Other: Advisory Boards; BMS: Other: Advisory Boards; Celgene: Other: Advisory Boards; Incyte: Other: Advisory Boards; AbbVie: Other: Advisory Boards; Gilead: Other: Advisory Boards; Epyzime: Other: Advisory Boards. Izutsu: Novartis: Honoraria, Research Funding; MSD: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Huya Biosciences: Research Funding; Genmab: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; Allergan Japan: Honoraria; AbbVie: Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Pfizer: Research Funding; Solasia: Research Funding; Symbio: Honoraria; Takeda: Honoraria, Research Funding; Yakult: Research Funding. Morschhauser: Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Janssen: Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; Chugai: Honoraria; Servier: Consultancy; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lunning: Karyopharm: Consultancy; AstraZeneca: Consultancy; Legend: Consultancy; Verastem: Consultancy; Janssen: Consultancy; Myeloid Therapeutics: Consultancy; Daiichi-Sankyo: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; AbbVie: Consultancy; Acrotech: Consultancy; Beigene: Consultancy; ADC Therapeutics: Consultancy; TG Therapeutics: Consultancy; Morphosys: Consultancy; Kite, a Gilead Company: Consultancy; Kyowa Kirin: Consultancy. Maloney: Amgen: Honoraria; Celgene: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; A2 Biotherapeutics: Honoraria, Other: Stock options; BMS: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; Celgene: Other: Research funding was paid to my institution, Research Funding; Umoja: Honoraria; Janssen: Honoraria; Legend Biotech: Honoraria; Genentech: Honoraria; Novartis: Honoraria; MorphoSys: Honoraria; Juno therapeutics: Other: Research funding was paid to my institution, Research Funding; Navan Technologies: Honoraria, Other: Stock options; Kite Pharma: Honoraria, Other: Research funding was paid to my institution, Research Funding; Juno Therapeutics: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb. Crotta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Montheard: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Previtali: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Stepan: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ogasawara: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Mack: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Abramson: Bluebird Bio: Consultancy; EMD Serono: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Morphosys: Consultancy; C4 Therapeutics: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Genmab: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. OffLabel Disclosure: Liso-cel is a CAR T cell therapy approved for use in the third line for R/R LBCL. This trial reports data from the pivotal trial in the second line.

Background : CD47 is a transmembrane protein ubiquitously expressed in human cells. CD47 is overexpressed in various malignancies and is correlated with negative prognosis in AML and MDS (Chao et al. Curr Opin Immunol.2012; Majeti et al. Cell.2009). Interaction of CD47 with signal-regulatory protein alpha (SIRPα) expressed on macrophages inhibits phagocytosis (Kim et al. Leukemia.2012). CC-90002, a humanized anti-CD47 monoclonal antibody, blocks CD47/SIRPα interactions, thereby enabling macrophage-mediated killing of tumor cells. In preclinical studies, CC-90002 demonstrated antibody-mediated phagocytosis of several hematologic cancer cell lines, including AML cells. CC-90002 also demonstrated a rapid and substantial reduction in tumor burden in AML xenograft models. Herein, we report results from CC-90002-AML-001 evaluating CC-90002 in patients (pts) with R/R AML and high-risk MDS. Methods : In this phase I multicenter study (NCT02641002), CC-90002 was administered intravenously once/week for 4 weeks of each 42-day cycle during cycles 1−4 then once every 4 weeks during a maintenance phase of 28-day cycles. Pts were enrolled in cohorts of escalating dose levels using a modified 3+3 design. The primary objectives were to determine preliminary safety and tolerability, non-tolerated dose (NTD), maximum tolerated dose (MTD), and/or recommended phase 2 dose. Secondary objectives were to measure preliminary efficacy, pharmacokinetics, and the presence and frequency of anti-drug antibodies (ADAs). Results: As of July 18, 2018, 24 pts with R/R AML and 4 pts with high-risk R/R MDS were enrolled. Pts received CC-90002 at 0.1 mg/kg (n=6), 0.3 mg/kg (n=6), 1 mg/kg (n=6), 2 mg/kg (n=4), and 4 mg/kg (n=6). Median age was 70 years (range, 28-85) and 16 (57%) were male. The most common AML subtypes were AML with myelodysplasia-related changes (n=9) and AML not otherwise specified (n=9). All 4 pts with MDS were classified as having refractory anemia with excess blasts-2 and high- or very high-risk disease per the Revised International Prognostic Index Scoring System. The median number of prior systemic anticancer regimens was 3 (range, 1-10), and 29% of pts had prior stem cell transplants. The median treatment duration was 6.9 weeks (range, 2-44). Four pts experienced a dose-limiting toxicity, consisting of grade 4 disseminated intravascular coagulation and grade 4 cerebral hemorrhage in 1 pt (0.1 mg/kg), grade 3 purpura in 1 pt (0.3 mg/kg), grade 4 congestive cardiac failure and grade 4 acute respiratory failure in 1 pt (1 mg/kg), and grade 4 sepsis in 1 pt (4 mg/kg). The most common (≥30%) any-grade treatment-emergent adverse events (TEAEs) were diarrhea (46%); thrombocytopenia (39%); febrile neutropenia and aspartate aminotransferase increased (36% each); and anemia, alanine aminotransferase increased, and cough (32% each). A total of 23 pts (82%) had serious TEAEs with febrile neutropenia (n=10), bacteremia (n=4), pneumonia (n=4), and general physical health deterioration (n=3) occurring in&gt;2 pts. No TEAEs led to dose reductions; however, 7 pts (25%) discontinued due to TEAEs. Overall, 82% of pts were dependent on red blood cell (RBC) transfusions and CC-90002 treatment did not interfere with continued RBC transfusion in pts on study. No pts experienced hemolysis, tumor lysis syndrome, or macrophage activation/cytokine release syndrome. Sixteen pts died during the study. The best overall response observed was stable disease in 2 pts with MDS. CC-90002 serum exposures appeared to increase with doses above 0.3−4.0 mg/kg and the terminal half-life ranged from 4.6−17.0 hours. Development of ADAs targeting CC-90002 occurred at all dose levels tested and the proportion of pts testing positive for ADAs in cycle 1 increased over time (4/27 pts at day 8, 6/25 pts at day 15, and 8/22 pts at day 22). ADAs continued to be present across different doses with increases in median serum ADA titers after cycle 1. No apparent dose-ADA relationship was observed. Conclusion: CC-90002 showed a lack of objective responses in pts with R/R AML and high-risk MDS. The MTD and NTD were not established. The CC-90002-AML-001 study was discontinued in dose escalation for lack of preliminary monotherapy activity and evidence of ADAs in most pts. CC-90002 in combination with rituximab is being explored in CD20+ NHL to enhance efficacy of CD47 blockade while reducing ADAs (CC-90002-ST-001; NCT02367196). Disclosures Zeidan: BeyondSpring: Honoraria; Seattle Genetics: Honoraria; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria. DeAngelo:Novartis: Consultancy, Research Funding; Jazz Pharmaceuticals Inc: Consultancy; Shire: Consultancy; Incyte: Consultancy; Blueprint: Consultancy, Research Funding; Pfizer: Consultancy; Amgen: Consultancy; GlycoMimetics: Research Funding; Celgene: Consultancy; Abbvie: Research Funding; Takeda Pharmaceuticals: Consultancy. Seet:University of California, Los Angeles: Employment. Tallman:Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Cellerant: Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biosight: Research Funding; Biosight: Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; UpToDate: Patents & Royalties; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding. Wei:Celgene Corp.: Employment, Equity Ownership. Li:Celgene Corp.: Employment, Equity Ownership. Hock:Celgene Corp.: Employment, Equity Ownership. Burgess:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: Patent - CD47 antibodies and methods of use thereof; University of California: Other: Volunteer clinical faculty, without salary, Patents & Royalties: Patent - T315A and F317I mutations of BCR-ABL kinase domain. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees. Stock:Agios: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; UpToDate: Honoraria; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Standard of care (SOC) for second-line (2L) therapy (tx) of relapsed/refractory aggressive B-cell non-Hodgkin lymphomas (R/R aNHL) includes platinum-based chemotherapy (PCT) followed by autologous hematopoietic cell transplantation (aHCT) in responders. Outcomes are poor for patients (pts) with R/R aNHL who experience progression during or within 12 months (mo) of 1L tx. Tisagenlecleucel (tisa-cel) is an autologous chimeric antigen receptor (CAR) T-cell tx targeting CD19 approved for pts with large B-cell lymphoma (LBCL; US) and diffuse LBCL (non-US) after ≥2 lines of tx. BELINDA (NCT03570892) is a Phase III, randomized, global (18 countries) study of tisa-cel vs SOC as 2L tx for R/R aNHL. Methods: Adults with confirmed R/R aNHL within 12 mo after 1L chemo-immunotherapy were eligible. All pts underwent leukapheresis for tisa-cel production and were randomized 1:1 to receive tisa-cel (Arm A) or SOC (Arm B) and stratified by 1L duration of response, International Prognostic Index (IPI), and geographic region. Arm A received optional bridging tx (investigator choice of protocol-defined PCT regimens) followed by lymphodepletion (LD; generally, fludarabine 25 mg/m 2/day [d] + cyclophosphamide 250 mg/m 2/d for 3 d) and followed by a single tisa-cel infusion (0.6-6×10 8 CAR-T cells). Arm B received investigator choice of PCT regimen followed by aHCT in responders or a second PCT in nonresponders. Disease assessments were performed at 6 and 12 weeks (wk), then planned every 3 mo for year (y) 1 and every 6 mo for y 2. The primary endpoint was event-free survival (EFS), defined as time from randomization to stable disease (SD) or progressive disease (PD) at or after wk 12 assessment or death at any time. SD/PD at wk 6 was not considered an event on either Arm. Arm A's wk 6 assessment evaluated disease burden before tisa-cel infusion and after bridging if administered. Arm B's wk 6 assessment determined if response was sufficient for aHCT or if a second PCT regimen was needed prior to aHCT. Results: As of May 6, 2021, 322 pts were randomized: 162 to Arm A and 160 to Arm B. In Arms A and B, 33% and 29% were ≥65 y, and 66% and 67% had primary refractory disease, respectively. Baseline characteristics indicated imbalances with more high-grade B-cell lymphomas (24% vs 17%) and IPI ≥2 (65% vs 58%) in Arm A vs B. In Arm A, 47% received ≥2 cycles of bridging PCT, 36% received 1 cycle, and 17% received 0. In Arm A, 96% received tisa-cel; the median dose was 2.9×10 8 cells. In Arm B, 96% received ≥2 PCT cycles and 54% received ≥2 different PCT regimens; 33% received aHCT, including 10% requiring ≥2 different PCT regimens before aHCT. Median time from randomization to aHCT was 92 d (range, 61-158 d). Median follow-up was 10 mo (range, 2.9-23.2 mo). At wk 6 assessment, 26% had PD in Arm A vs 14% in Arm B. Median EFS in Arms A and B was 3 mo (HR 1.07; 95% CI, 0.82-1.40; P=0.69); Arm A pts with PD at wk 6 had shorter EFS. Overall response rate (ORR) at wk 12 in Arm A was 46% vs 43% in Arm B; complete response rate in both arms was 28%. Some pts responded to tisa-cel after SD/PD at wk 12 without additional tx but were counted as an event in EFS analysis. In Arm B, 81 pts (51%) crossed over to receive tisa-cel, 71 without receiving aHCT. Of 72 crossover pts with response assessment, ORR to tisa-cel was 40%. Overall survival was immature at data cutoff. In Arm A, 84% had a grade ≥3 adverse event (AE; vs 90% in Arm B), including grade ≥3 cytokine release syndrome in 5% (CRS; Lee 2014) and grade ≥3 neurologic events (NE) in 3% (CTCAE v5.0), with no grade 5 CRS/NE. Median times to CRS and NE onset were 4 and 5 d, respectively; median time to resolution was 5 and 9 d. Fifty-two (32%) and 45 (28%) pts in Arms A and B died on study, including 42 (26%) and 32 (20%) deaths due to PD, respectively. Ten pts in Arm A and 13 in Arm B died of AEs. Conclusions: Tisa-cel as 2L tx in R/R aNHL pts did not have a higher EFS vs SOC. Possible contributing factors include study design elements, such as optional PCT bridging tx in Arm A with potential delay of tisa-cel infusion until after wk 6 assessment, allowance of a different PCT regimen to reach aHCT in Arm B after inadequate response to first PCT, and imbalances in relevant pt characteristics. Insights from this randomized Phase III study will inform use of cellular tx in the 2L R/R aNHL setting and the design of future CAR-T trials. Figure 1 Figure 1. Disclosures Bishop: Arcellx, Autolus, Bristol-Myers Squibb, CRISPR, Kite/Gilead, and Novartis: Consultancy, Research Funding; Bristol-Myers Squibb and Kite/Gilead: Other: fees for non-CME/CE services . Dickinson: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Research Funding; Celgene: Research Funding; Amgen: Honoraria. Purtill: Novartis: Honoraria; Gilead: Honoraria; BMS Celgene: Honoraria. Barba: Amgen, Celgene, Gilead, Incyte, Jazz Pharmaceuticals, MSD, Novartis, Pfizer and Roche, Jazz Phar,aceuticals: Honoraria; Cqrlos III heqlth Institute, aSOCIACION espanola contra el cancer, PERIS: Research Funding. Santoro: Arqule: Consultancy, Speakers Bureau; Sanofi: Consultancy; Takeda: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau; AbbVie: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eli-Lilly: Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kato: Abbvie: Consultancy, Research Funding; AstraZeneca: Consultancy; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Dainippon-Sumitomo: Honoraria; Eisai: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; MSD: Honoraria; Mundi: Honoraria; Novartis: Consultancy, Research Funding; Ono: Honoraria, Research Funding. Sureda: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Bluebird: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy. Greil: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding. Thieblemont: Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Janssen: 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; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Morschhauser: F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, 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; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: 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; Chugai: Honoraria; Janssen: Honoraria; Genmab: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees. Janz: Janssen: Honoraria, Other: Meeting Fees; Novartis: Honoraria; Takeda: Honoraria, Other: Travel Accommodations, Expenses, Meeting fees; Roche: Honoraria; Gilead: Other: Travel Accommodations, Expenses, Meeting fees. Flinn: Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Seattle Genetics: Research Funding; Sarah Cannon Research Institute: Current Employment; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding. Kwong: Novartis: Consultancy, Honoraria, Research Funding. Kersten: Novartis: Consultancy, Honoraria, Other: Travel support; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding; Celgene: Research Funding; Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Other: Travel support; BMS/Celgene: Consultancy, Honoraria. Minnema: Janssen: Consultancy, Honoraria; Celgene: Other: Travel expenses; BMS: Consultancy; Kite/Gilead: Consultancy; Alnylam: Consultancy. Holte: Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Nanovector: Membership on an entity's Board of Directors or advisory committees, Other: lectures honorarias; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Nordic: Membership on an entity's Board of Directors or advisory committees. Martinez-Lopez: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: 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; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: 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; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: 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; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maziarz: Novartis: Consultancy, Other: Data and Safety Monitoring board, Research Funding; Incyte Corporation: Consultancy, Honoraria; Bristol-Myers, Squibb/Celgene,, Intellia, Kite: Honoraria; Allovir: Consultancy, Research Funding; Artiva Therapeutics: Consultancy; CRISPR Therapeutics: Consultancy; Intellia: Honoraria; Omeros: Research Funding; Athersys: Other: Data and Safety Monitoring Board, Patents & Royalties; Vor Pharma: Other: Data and Safety Monitoring Board. McGuirk: Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Novartis: Research Funding; Fresenius Biotech: Research Funding; Astelllas Pharma: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding; Gamida Cell: Research Funding; Pluristem Therapeutics: Research Funding. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Dreyling: Amgen: Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Gilead Kite: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; AbbVie: Research Funding; BeiGene: Consultancy, Speakers Bureau; Genmab: Consultancy; MorphoSys: Consultancy. Harigae: Bristol Myers Squibb: Honoraria; Novartis Pharma: Honoraria, Research Funding; Chugai Pharma: Honoraria; Janssen Pharma: Honoraria; Ono pharma: Honoraria, Other: Subsidies or Donations; Astellas Pharma: Other: Subsidies or Donations; Kyowakirin: Other: Subsidies or Donations. Bond: Kite/Gilead: Honoraria. Andreadis: Merck: Research Funding; BMS: Research Funding; CRISPR Therapeutics: Research Funding; GenMAB: Research Funding; Novartis: Research Funding; Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Epizyme: Honoraria; Incyte: Honoraria; TG Therapeutics: Honoraria; Kite: Honoraria; Karyopharm: Honoraria; Atara: Consultancy, Honoraria. McSweeney: Kite-Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gamida: Consultancy, Honoraria; TG Theraputics: Consultancy, Honoraria; Autolous Limited: Research Funding; Novartis: Research Funding; NKARTA: Research Funding; Allovir: Research Funding. Newsome: Novartis: Current Employment. Degtyarev: Novartis: Current Employment, Current equity holder in publicly-traded company. Del Corral: Novartis: Current Employment. Andreola: Novartis: Current Employment, Current holder of stock options in a privately-held company. Masood: Novartis: Current Employment, Current holder of stock options in a privately-held company. Schuster: AbbVie, Acerta, Celgene/Juno, DTRM Bio, Genentech, Incyte, Merck, Novartis, Portola, and TG Therapeutics: Research Funding; Acerta, AlloGene, AstraZeneca, BeiGene, Celgene/Juno, Genentech/Roche, LoxoOncology, Novartis, and Tessa Therapeutics: Consultancy; Acerta, AlloGene, AstraZeneca, BeiGene, Celgene, Genentech/Roche, LoxoOncology, Novartis, Nordic Nanovector, Pfizer, and Tessa Therapeutics;: Honoraria; Novartis: Other: Personal fees, Patents & Royalties; AbbVie, Celgene, Novartis, Juno, Nordic Nanovector, and Pfizer: Other: Steering Committee Participation. Jaeger: BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Norvartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: 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; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Westin: Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Umoja: Consultancy; Iksuda Therapeutics: Consultancy; Curis: Research Funding; Morphosys: Research Funding; 47 Inc: Research Funding.

The nature made world is graduallyeyeing towards plant based natural system of medicine like Ayurveda. The novel healing approach of Ayurveda founded on evidence based fundamental approaches are gaining interest of the scientific communities globally. There are various interesting therapies are in the ocean of Ayurveda, still looking for scientific exploration in order to serve the people worldwide. The plant Rohitaka botanically identified as Tecomellaundulata Sm. which is commonly distributed in drier part of North-West and western India, is such an example. The present review aimed to analyze the ancient therapeutic uses of Rohitaka mentioned in classical texts of Ayurveda and systematically categorized them in term of contemporary practices. The review suggests that in spite of various published study there are still scope of exploration different novel use of Rohitaka mentioned in classical Ayurveda texts. The present reviews may perform an optimistic role for Researcher, Physician and Industries. It may also provide the future leads and scope for drug development and product marketing.

Abstract Objection To explore the effects of combinations of antiangiogenic agents and chemotherapy agents on non-small cell lung cancer (NSCLC) patients and indirectly compare the therapeutic effect of Endostar combined with chemotherapy and bevacizumab combined with chemotherapy on NSCLC. Methods We searched 3 electronic databases: PubMed, Web of Science and the Cochrane Library. The ORRs, HRs and 95% confidence intervals of OS and PFS were used to compare the efficacy of Endostar combined with chemotherapy and bevacizumab combined with chemotherapy. We use the Bayesian network meta-analysis method to make indirect comparisons and obtain rank probabilities; in addition, we used single-arm meta-analysis to synthesize the existing data. Results A total of 29 studies were included in the analysis. Among them, we included a total of 14 interventions. A total of 12,862 patients participated in this analysis. The single-arm meta-analysis showed that the pooled ORR and 95% CI were 0.35 (0.31, 0.39), the pooled HR of OS and 95% CI were 0.89 (0.81, 0.98), and the pooled HR of PFS and 95% CI were 0.67 (0.56, 0.81). According to the results of network meta-analysis, there were no significant differences between the 5 kinds of bevacizumab combined with chemotherapy regimens and the 4 kinds of Endostar combined with chemotherapy regimens for improving ORR and prolonging OS and PFS. The rank probabilities suggested that in terms of ORR, Pla + Pem + Bev was the first-ranked intervention (0.288). Pla + Pem + Endo was the first-ranked intervention for prolonging OS (0.423) and Pla + Gem + Endo was the first-ranked intervention for prolonging PFS (0.302). Conclusion Antiangiogenic agents combined with platinum-containing dual drugs can provide benefits to NSCLC patients. In addition, bevacizumab combined with chemotherapy regimens has better theraputic effect on ORR while Endostar combined with chemotherapy may have better effects on OS and PFS for the treatment of NSCLC patients.

Abstract Background A growing number of compassionate phage therapy use cases reported in the last decade, with only a limited number of clinical trials conducted and very few unsuccessful clinical trials reported. However, the limited understanding of individual clinical cases and lack of successful published clinical trials provides little evidence on the role of phages in refractory infections. Our objective was to bridge between single cases to early clinical trials and to describe the compassionate use of a single same phage - PASA16 - in sixteen patients with non-resolving Pseudomonas aeruginosa infections. Methods We have collected all cases in which PASA16 was used and summarized clinical microbiology data, administration protocol, clinical data and outcome. In all instances involving intravenous phage administration (14 out of 16 cases), PASA16 phage was manufactured and provided pro-bono by Adaptive Phage Therapeutics. Results PASA16 was administered either IV, locally to infection site or by topical use to 16 patients, with data available for 15 patients, mainly for osteoarticular and foreign device associated infections. Few minor side effects were noted including elevated liver function enzymes and a transient reduction in white blood cell count. Good clinical outcome was documented in 13 out of 15 (86%). Two clinical failures were reported. Conclusion PASA16 with antibiotics was found to be relatively successful in patients who have failed previously in traditional approaches. Minimal successful duration of phage therapy was 8 days with once to twice a day administration. Such pre-phase 1 cohorts can outline the potential clinical protocols to be used and facilitate the design of future clinical trials. Disclosures Ran Nir-Paz, MD, Adaptive phage theraputics: Supplied the phage product for this study|BiomX: Advisor/Consultant|Technophage: Grant/Research Support