ALBERT

Description: Post-transplant cyclophosphamide (PTCy) based GVHD prevention regimens are an emerging platform in allogeneic transplantation for hematological malignancies and are being prospectively compared to traditional standards. We present a single-center retrospective series of adult allogeneic bone marrow transplantation with the use of post-transplant cyclophosphamide in the setting of benign hematological conditions. Ten patients were treated between 2013 to 2019. Non-myeloablative conditioning consisted of rATG 0.5mg/kg on day (D) -9, 2mg/kg on D-7,-8 (ATG was in one patient with DBA), fludarabine 30mg/m2 daily from D-6 to D-2, cyclophosphamide 14.5mg/kg D-6 and D-5, and 200cGy of total body irradiation D-1. The bone marrow graft was administered on D0. GVHD prophylaxis consisted of post-transplant cyclophosphamide at 50mg/kg/day IV D+3, and +4 mycophenolate mofetil (MMF) at 15 mg/kg 3 times daily (maximum daily dose 3000 mg) starting on D+5 with taper beginning at D+35 to be off around D+100, and tacrolimus on D+5 with a target trough of 5-10 ng/mL with tapering beginning at D+180 with a goal to be off at D+360 in the absence of any GVHD. The median age at the time of transplantation was 42 (range 24-73) and 4 of 10 were female. Diagnoses include severe aplastic anemia (n=6), Diamond-Blackfan Anemia (n=2), paroxysmal nocturnal hemoglobinuria (n=1), and pure red cell aplasia (n=1). Median Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) was 0 (range 0-5). Bone marrow donors were haploidentical donors (n=6), fully matched unrelated donors(n=3), and fully matched sibling (n=1). The median donor age was 31 (range 22-53). Donor marrow grafts had a median CD34+ cell count of 4.41 x 106/kg recipient ideal body weight (range 1.12 x 106 to 20.5 x 106). At a median follow-up of 17 months (range 3, 63) after transplantation, all patients are alive, with donor-derived hematopoiesis and free of significant acute or chronic GVHD. Neutrophil and platelet engraftment occurred at a median of 21 (range 16-34) days and 33 (21-65) days, respectively, after transplantation. The patient with pure red cell aplasia developed secondary graft failure and required a second transplant using a peripherally collected graft with the same fully matched unrelated donor. For all recipients, median day +30 unsorted chimerism was 100% (range 71-100%). Patients have not experienced significant acute or chronic GVHD. There were no cases of grade II-IV acute GVHD observed. Chronic GVHD was observed in 3 patients with ocular disease (two mild, one moderate). All patients who are over 12 months after transplantation are off systemic immunosuppression. Three patients experienced CMV reactivation, two required preemptive treatment with oral valganciclovir, while the third had a single positive low level positive CMV PCR that resolved spontaneously. Three patients had low level positive EBV viremia, none of which required pre-emptive treatment. Other significant infectious complications before day +100 included BK cystitis in three patients, influenza, adenovirus cystitis, clostridium difficile colitis, streptococcal and enterococcal polymicrobial endocarditis, and enterococcal bacteremia. Significant non-infectious complications were rare. One patient experienced engraftment syndrome which resolved quickly with systemic steroid administration. Another patient suffered a small spontaneous subdural hemorrhage day +10 after transplantation, but subsequently made a full neurologic recovery. Post-transplant cyclophosphamide based non-myeloablative allogeneic bone marrow transplantation appears safe and effective for patients with non-malignant hematologic conditions and should be prospectively compared to historical regimens. Table 1. Cohort Characteristics. SAA - Severe aplastic anemia, DBA - Diamond Blackfan anemia, ATG- anti-thymocyte globulin, CSA- cyclosporine, Cy-cyclophosphamide, haplo- haploidentical Disclosures Defilipp: Incyte: Research Funding. Frigault:Nkarta: Consultancy; Novartis: Consultancy; Foundation Medicine: Consultancy; Xenetic: Consultancy; Juno/Celgene: Consultancy; Kite/Gilead: Honoraria; Incyte: Consultancy. Chen:Incyte: Consultancy; Magenta: Consultancy; Takeda: Consultancy; Kiadis: Consultancy; Abbvie: Consultancy.

Description: Chimeric antigen receptor (CAR) T cells targeting CD19 have emerged as a leading engineered T-cell therapy for relapsed/refractory B-cell non-Hodgkin lymphoma. The phase 1/2 clinical trials that led to US Food and Drug Administration approval excluded patients with central nervous system (CNS) involvement, due to strict eligibility criteria. Here, we report on our institutional experience with 8 secondary CNS lymphoma patients treated with commercial tisagenlecleucel. No patient experienced greater than grade 1 neurotoxicity, and no patient required tocilizumab or steroids for CAR T-cell–mediated toxicities. Biomarker analysis suggested CAR T-cell expansion, despite the absence of systemic disease, and early response assessments demonstrated activity of IV infused CAR T cells within the CNS space.

Description: Chimeric antigen receptor (CAR) T cells have emerged as a novel form of treatment of patients with B-cell malignancies. In particular, anti-CD19 CAR T-cell therapy has effected impressive clinical responses in B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma. However, not all patients respond, and relapse with antigen loss has been observed in all patient subsets. Here, we report on the design and optimization of a novel CAR directed to the surface antigen CD37, which is expressed in B-cell non-Hodgkin lymphomas, in chronic lymphocytic leukemia, and in some cases of cutaneous and peripheral T-cell lymphomas. We found that CAR-37 T cells demonstrated antigen-specific activation, cytokine production, and cytotoxic activity in models of B- and T-cell lymphomas in vitro and in vivo, including patient-derived xenografts. Taken together, these results are the first showing that T cells expressing anti-CD37 CAR have substantial activity against 2 different lymphoid lineages, without evidence of significant T-cell fratricide. Furthermore, anti-CD37 CARs were readily combined with anti-CD19 CARs to generate dual-specific CAR T cells capable of recognizing CD19 and CD37 alone or in combination. Our findings indicate that CD37-CAR T cells represent a novel therapeutic agent for the treatment of patients with CD37-expressing lymphoid malignancies.

Description: Characterization of molecular alterations in acute myeloid leukemia (AML) has led to development of targeted therapies, including FLT3 and IDH1/2 inhibitors. Maintenance therapy following hematopoietic cell transplantation (HCT) has shown substantial promise. Enasidenib (ENA), a selective IDH2 inhibitor, was associated with impressive rates of response in relapsed/refractory (R/R) AML and is now FDA-approved for this indication. We sought to assess the tolerability and define the maximum tolerated dose (MTD) of ENA as maintenance following HCT for IDH2-mutated myeloid malignancy. HCT-eligible patients (pts) ≥ 18 years with AML in remission, or myelodysplastic syndrome (MDS) with 1000/µL and platelets 〉 50000/µL). Those with prior HCT, active disease, QTc ≥450ms, and active infections were excluded. ENA was initiated between day 30 and 90 after HCT, at which time the following were required: chimerism ≥70% of donor origin among blood/marrow cells, no acute graft versus host disease (aGVHD) requiring ≥0.5mg/kg/day prednisone or equivalent, and no relapse. ENA was taken orally (po) daily (qd) in 28-day cycles. The period for dose-limiting toxicity (DLT) evaluation was the first cycle, escalation to successive levels was guided by DLT incidence, and 2 levels (50mg,100mg) were studied. Following establishment of MTD or recommended phase 2 dose (RP2D), 10 pts would be enrolled in an expansion cohort. Pts were monitored for relapse and toxicity and continued until disease progression, intolerable toxicity, or receipt of 12 cycles. Nineteen pts have been registered prior to HCT at 3 sites, Massachusetts General Hospital, Dana Farber Cancer Institute, and Johns Hopkins Hospital. Three pts could not initiate ENA following HCT; 2 due to logistic challenges of the COVID pandemic and 1 due to relapse. The remaining 16 pts initiated ENA treatment. The median age was 61 years (range 31-76); 12 (75%) were male, and 13 (81%) were Caucasian. Fourteen (88%) had AML, of which 6 were AML with MDS related changes and 2 had antecedent myeloproliferative neoplasm. Two pts (13%) had MDS. Among these 16 pts, 9 (56%) had IDH2 R140, and 5 (25%) had IDH2 R172 mutations. IDH2 subtype data was unavailable for 2 pts. Of 15 pts with available data from time of diagnosis, 11 (73%) had intermediate-risk and 4 (27%) had adverse-risk cytogenetics. Among these 15 pts, common concurrent mutations were DNMT3A (47%), SRSF2 (33%), and RUNX1 (33%). Eleven AML pts (85%) received intensive versus non-intensive therapies (15%) prior to HCT, and among all pts, 7 (44%) had received ENA prior to HCT. HCT data was available for all 16 pts; 4 pts (25%) received myeloablative, and 12 (75%) received reduced-intensity conditioning. Nine pts (56%) had a matched unrelated, 6 (38%) had haploidentical, and 1 (6%) had a matched related donor HCT. Three pts were enrolled at the 50mg dose level, 6 pts at 100mg, and after no DLTs were detected, the remaining were enrolled in an expansion cohort at 100mg qd. Median follow-up (F/U) for surviving patients is currently 11.7 months (range 1.5-18.9). 2 pts (13%) have relapsed during F/U, at 96 and 364 days post HCT. Additional ≥grade (G) 3 toxicities detected during treatment, possibly or probably related to ENA, included neutropenia, anemia, and bilirubinemia. Six pts (38%) required dose interruptions lasting a median 19 days (range 7-25), 4 required a dose reduction to 50mg, and 1 stopped treatment due to G3 bilirubinemia. In total, 3 pts (18%) discontinued study treatment, 1 for aforementioned G3 bilirubinemia, 1 to pursue a GVHD trial, and 1 for relapse. Six pts have completed the 12-month f/u without relapse, and 7 remain on study. 15 of 16 pts remain alive. Thus far, 3 pts have experienced ≥ G2 aGVHD, and 4 had moderate chronic GVHD. Serial measurement of 2HG is being conducted on samples, and these will be reported. Enasidenib is well-tolerated as post-HCT maintenance therapy for myeloid malignancy at the RP2D of 100mg qd. No DLTs have been detected, and a low rate of post-HCT relapse has been identified to date, although longer f/u is needed. Larger, randomized studies of ENA in the post-SCT setting would determine the true efficacy of this agent as maintenance therapy. Disclosures Fathi: Blueprint: Consultancy; Jazz: Consultancy; Amgen: Consultancy; Newlink Genetics: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Seattle Genetics: Consultancy, Research Funding; Agios: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Takeda: Consultancy, Research Funding; Boston Biomedical: Consultancy; Amphivena: Consultancy; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Trovagene: Consultancy; Forty Seven: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Trillium: Consultancy; Kura Oncology: Consultancy. Soiffer:Gilead: Consultancy; Novartis: Consultancy; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; VOR Biopharma: Consultancy; alexion: Consultancy; Rheos Therapeutics: Consultancy; Cugene: Consultancy; Precision Bioscience: Consultancy; Be the Match/ National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Consultancy. Levis:Menarini: Honoraria; Amgen: Honoraria; FujiFilm: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria. Mims:Novartis: Speakers Bureau; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Agios: Consultancy; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Abbvie: Membership on an entity's Board of Directors or advisory committees. Devine:Magenta Therapeutics: Consultancy. Defilipp:Incyte: Research Funding; Regimmune: Research Funding; Syndax Pharmaceuticals: Consultancy. Spitzer:Jazz Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees. Frigault:Celgene: Consultancy; Arcellx: Consultancy; Novartis: Consultancy, Research Funding; Gilead/Kite: Consultancy, Research Funding. Amrein:Amgen: Research Funding; AstraZeneca: Consultancy, Research Funding; Takeda: Research Funding. Hobbs:Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding; Constellation: Honoraria, Research Funding; Jazz: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria. Brunner:Janssen: Research Funding; Acceleron Pharma Inc.: Consultancy; GSK: Research Funding; Xcenda: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz Pharma: Consultancy; Forty Seven, Inc: Consultancy; Celgene/BMS: Consultancy, Research Funding; Biogen: Consultancy; Astra Zeneca: Research Funding. Narayan:Genentech: Other: Prior Spouse employment within 24 months and prior spouse equity divested within past 24 months; Takeda: Other: Prior Spouse employment within 24 months; Sanofi-Genzyme: Other: Current Spouse employment . Chen:AbbVie: Other: Data and Safety Monitoring Board Member; Incyte Corporation: Consultancy; Takeda: Consultancy; Actinium: Other: Data and Safety Monitoring Board Member; Equillium: Other: Data and Safety Monitoring Board Member; Magenta: Consultancy; Kiadis: Consultancy. OffLabel Disclosure: Enasidenib as post-transplant maintenance therapy

Description: Diagnosing primary central nervous system lymphoma (PCNSL) frequently requires neurosurgical biopsy due to nonspecific radiologic features and the low yield of cerebrospinal fluid (CSF) studies. We characterized the clinical evaluation of suspected PCNSL (N=1007 patients) and designed a rapid multiplexed genotyping assay for MYD88, TERT promoter, IDH1/2, H3F3A, and BRAF mutations to facilitate the diagnosis of PCNSL from CSF and detect other neoplasms in the differential diagnosis. Among 159 patients with confirmed PCNSL, the median time to secure a diagnosis of PCNSL was 10 days, with a range of 0-617 days. Permanent histopathology confirmed PCNSL in 142/152 biopsies (93.4%), whereas CSF analyses were diagnostic in only 15/113 samplings (13.3%). Among 86 archived clinical specimens, our targeted genotyping assay accurately detected hematologic malignancies with 57.6% sensitivity and 100% specificity (95% CI: 44.1-70.4% and 87.2-100%, respectively). MYD88 and TERT promoter mutations were prospectively identified in DNA extracts of CSF obtained from patients with PCNSL and glioblastoma, respectively, within 80 minutes. Across 132 specimens, hallmark mutations indicating the presence of malignancy were detected with 65.8% sensitivity and 100% specificity (95% CI: 56.2-74.5% and 83.9-100%, respectively). This targeted genotyping approach offers a rapid, scalable adjunct to reduce diagnostic and treatment delays in PCNSL.

Description: Introduction: Chimeric Antigen Receptor (CAR) T cell therapies directed against B-cell maturation antigen (BCMA) have demonstrated compelling clinical activity and manageable safety in subjects with relapsed and refractory Multiple Myeloma (RRMM). These CAR T cells encode humanized or murine scFvs, or camelid heavy chain antibody fragments with CD3-zeta in combination with 41BB or CD28 co-stimulatory domains. In contrast, CART-ddBCMA is an anti-BCMA investigational CAR T cell therapy encoding a non-scFv, synthetic binding domain targeting BCMA with a 4-1BB costimulatory motif and CD3-zeta T cell activation domain. The binding domain is a small stable protein comprising 73 amino acids engineered to reduce the risk of immunogenicity. CART-ddBCMA is being studied as part of a Master Phase 1 Cell Therapy protocol for RRMM and is a first-in-human clinical study to assess the safety, pharmacokinetics, immunogenicity, efficacy, and duration of effect. Methods: ARC-101 (NCT04155749), ARM 1 (CART-ddBCMA) is a Phase 1, multi-center, open label, dose escalation trial enrolling approximately 12 subjects with RRMM who have received ≥ 3 prior regimens, including a proteasome inhibitor, an immuno-modulatory agent, and a CD38 antibody or are triple-refractory. There is no prescreening or requirement for BCMA expression on tumor cells. Peripheral blood mononuclear cells are collected via leukapheresis and sent to a central facility for selection, transduction, and expansion on the CliniMACS Prodigy® system. The drug product is cryopreserved and undergoes release testing prior to being returned to the site for infusion. Subjects undergo lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) daily for 3 days, then receive CART-ddBCMA as a single infusion. Planned dose levels are 100, 300, and 900 x 106 CAR+ T cells. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures are quality and duration of clinical response assessed according to the IMWG Uniform Response Criteria for MM, evaluation of minimal residual disease (MRD), progression-free and overall survival, and quantification of CAR+ cells in blood. Results: As of July 1, 2020, 4 subjects (median age 73.5 [min;max 73 to 75]) were enrolled and 4 received CART-ddBCMA. Median follow-up after CART-ddBCMA infusion was 100 days (min:max 9 to 142 days), 3 subjects were evaluable for initial safety and clinical response and 1 subject was pending assessment. All subjects received a dose of 100 x 106 CAR+ T cells±20%, median drug product CAR+ expression was 76% (min:max 72-78%) of total CD3+ T cells. Subjects had a median of 5 (min;max 5 to 7) prior lines of therapy and one had prior autologous stem cell transplant; one had high-risk cytogenetics. All 4 subjects had previously received Bort/Len/Car/Pom/Dara and 2 were penta-refractory. Three subjects had high tumor burden, with 95, 95, and 70% bone marrow plasma cells pre-infusion, respectively. Three subjects developed Grade 2 cytokine release syndrome (CRS) and 1 subject developed Grade 2 ICANS. These adverse effects resolved quickly after intervention; 3 subjects received tocilizumab and 2 received steroids (dexamethasone). All 3 evaluable subjects have demonstrated clinical response per IMWG criteria: currently 1 sCR (MRD-10-4), 1 sCR, 1 sCR (MRD-10-6). MRD negative results were obtained by next-generation sequencing (Adaptive clonoSEQ), 1 subject did not have baseline bone marrow involvement. Extramedullary disease resolved in three subjects. CAR+ T cell expansion during the first 30 days was observed in evaluable subjects by ddPCR. No post treatment ADA were detected in the first 3 subjects, through M1. Conclusions: In the initial cohort receiving 100 x 106 CAR+ T cells of CART-ddBCMA, no subjects experienced severe CRS and/or ICANs. Early efficacy results are encouraging, with all 3 evaluable subjects demonstrating deep clinical responses of sCR, with 2 MRD negative bone marrow responses at 1 month. No evidence of ADA has been detected to date. These data are encouraging in a small group of elderly subjects who did not initially receive autologous transplant following induction therapy. Subjects continue to be enrolled and treated. Additional subjects, and longer follow-up will establish whether treatment with CART-ddBCMA results in durable CAR+ T responses. Disclosures Frigault: Celgene: Consultancy; Novartis: Consultancy, Research Funding; Arcellx: Consultancy; Gilead/Kite: Consultancy, Research Funding. Bishop:Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Autolus: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; CRSPPR Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Speakers Bureau. O'Donnell:Celgene: Consultancy. Raje:Celgene: Consultancy. LeFleur:Arcellx: Current Employment, Current equity holder in private company. Buonato:arcellx: Current Employment, Current equity holder in private company. Edwards:arcellx: Current Employment, Current equity holder in private company. Richman:arcellx: Current equity holder in private company. Polianova:arcellx: Current Employment, Current equity holder in private company. Sabatino:Arcellx: Current equity holder in private company. Currence:Arcellx: Current Employment, Current equity holder in private company. Shen:Arcellx: Current Employment, Current equity holder in private company. Quigley:Arcellx: Current Employment, Current equity holder in private company. Maus:arcellx: Consultancy, Research Funding; kite: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.