Abstract: Background: The proteasome inhibitor (PI) bortezomib is active in AL amyloidosis. Carfilzomib (CFZ) is a novel irreversible PI approved for relapsed/refractory multiple myeloma, with less neurologic toxicity than bortezomib, but its safety and efficacy in AL amyloidosis is not known. We report the first results of a multi-center, Phase I, dose-finding study of CFZ in AL (NCT01789242). Methods: Patients had relapsed AL after ≥1 prior therapy. Patients with advanced cardiac involvement (Mayo stage III, LVEF 〈 40%, or NYHA Class III/IV) were excluded. A standard 3+3 dose escalation schedule was used, with planned cohorts of 27, 36, 45, and 56 mg/m2. CFZ was given as a 30-minute infusion on days 1, 2, 8, 9, 15, 16 of a 28-day cycle, starting at 20 mg/m2 on cycle 1, days 1,2, then escalating starting day 8. Primary objectives were safety, tolerability, and determination of MTD. DLTs were defined in Cycle 1 only. Adverse events (AEs) were graded by NCI-CTCAE v4. Serial echocardiograms were performed at baseline, after cycle 3, and every 4 cycles thereafter. Hematologic and organ responses were assessed by updated AL Consensus criteria. Dexamethasone 20mg with each CFZ dose was added for patients without VGPR after cycle 4. After 8 cycles, patients could continue on a reduced-frequency (day 1, 2, 15, 16) schedule at investigator discretion. Two expansion cohorts (PI-naïve and PI-exposed, n=12 each) are currently enrolling at MTD. Results: As of 7/17/14, 12 patients have enrolled. Median age was 62 (range 58–81); 50% were male. Median time from diagnosis was 2.8 years, with median of 2 prior regimens (range 1-4). Eleven patients (92%) had prior bortezomib (5 were refractory); 50% prior IMiDs; 50% prior stem cell transplant. Median # of involved organs was 1 (range 1-2), including 5 patients with heart, 5 kidney, 1 liver, 2 GI tract, and 4 peripheral/autonomic nerve. Median NT-proBNP was 854 pg/ml (range 93 – 9702); 3 and 9 patients were Mayo cardiac stage I and II, respectively. Three patients each were treated at 20/27 and 20/36 mg/m2, with no DLTs. In the 20/45 mg/m2 cohort, there were 2 DLT's of grade 3 fatigue ≥7 days in 4 patients, establishing 20/36 mg/m2 as the MTD. Two additional patients have enrolled at MTD in the PI-exposed expansion cohort. Median number of cycles is 5 (range 1+-13+), with 7 patients still on study, and 5 discontinuing (3 AE, 2 patient withdrawal). Drug-related AEs occurring in 〉 20% of patients (n=11 evaluable) included fatigue (45%), nausea (36%), anemia, dyspnea, and diarrhea (27% each). Seven patients had at least one Grade ≥3 AE (any cause), including cardiac events (n=4 patients), fatigue (n=3), diarrhea (n=2), and nausea, hypoalbuminemia, and pneumonia (n=1 each). There have been 3 cardiac events possibly related to drug: 1 grade 4 cardiac arrest due to ventricular tachycardia during cycle 5; 1 grade 4 restrictive cardiomyopathy and CHF after cycle 3 (with negative endomyocardial biopsy for amyloid); 1 grade 3 drop in ejection fraction after cycle 7. Rising NTproBNP levels correlated with clinical and/or echocardiographic manifestations of CHF in these latter 2 patients. A 4th patient had exacerbation of atrial fibrillation during pneumonia, deemed unrelated. No deaths have occurred. Of 9 evaluable patients, 7 have responded hematologically, including 6 VGPR (≥PR rate=78%; Table 1). Responses have been seen at all dose levels, with median response duration of 3.8 months (range 0.3+ –10.9+) and no hematologic progression. Two patients had dexamethasone added after cycle 4, both improving response to VGPR. With median follow-up of 5.1 months (range 0.2 to 12.3), no organ responses have yet been observed. Conclusions: Carfilzomib monotherapy is feasible and effective in relapsed/refractory AL amyloidosis, with MTD identified as 20/36 mg/m2 as a 30-minute infusion. Cardiac events are common in this population, and may be related to drug, underlying disease or both, suggesting a role for monitoring with cardiac biomarkers and serial echocardiograms. Preliminary hematologic response rates are promising in this bortezomib-exposed population, and organ assessments are ongoing. Further study is warranted. Table 1: Preliminary response data Carfilzomib Dose Cohort Hematologic response 20/27 (n=3) 20/36 (n=5) 20/45 (n=4) Total (n=12) VGPR 2 1* 3** 6 PR 0 1 0 1 SD 1 0 1 2 Not evaluable/ too early 0 3 0 3 *Dex added. **1 had dex added. Never escalated above 20mg/m2 Disclosures Cohen: Celgene: Member, Independent Response Adjudication Committee Other; Janssen: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Advisory Board, Advisory Board Other, Research Funding; Onyx Pharmaceuticals: Advisory Board, Advisory Board Other. Off Label Use: Carfilzomib treatment in amyloidosis . Scott:Onyx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Liedtke:Onyx: Membership on an entity's Board of Directors or advisory committees. Kaufman:Spectrum: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Millennium: The Takeda Oncology Co.: Consultancy, Honoraria; Merck: Research Funding. Landau:Onyx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Vesole:Onyx Pharmaceuticals: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Speakers Bureau. Gasparetto:Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lentzsch:Celgene: Consultancy, Research Funding; Novartis: Consultancy; Bristol Myers Squibb: Consultancy. Rosenzweig:Celgene: Speakers Bureau. Sanchorawala:Celgene: Research Funding; Millennium Pharmaceuticals: Research Funding; Onyx: Research Funding. Comenzo:Millennium Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Durie:Millennium Pharmaceuticals: IRC, IRC Other; Onyx Pharmaceuticals: IRC Other.

Abstract: This is the first clinical trial to investigate CPD in multiple myeloma. Results suggest that the regimen is a well-tolerated and highly active combination for patients with relapsed/refractory multiple myeloma.

Abstract: Background Carfilzomib, a novel proteasome inhibitor (PI), and pomalidomide, an IMiD® immunomodulatory agent, have both demonstrated efficacy as single agents or in combination with dexamethasone in relapsed/refractory multiple myeloma(RRMM). IMiD compound+PI combinations including lenalidomide/dex and thalidomide/dex in combination with bortezomib and carfilzomib, have had high response rates and good tolerability. We aimed to combine carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) for the first time and hypothesized that this regimen would be highly effective in patients RRMM. In the Phase I, dose-escalation of carfilzomib started with 27mg/m2 carfilzomib/4mg pomalidomide/40 mg dexamethasone using a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. The MTD presented previously was 27mg/m2 Carfilzomib /4mg pomalidomide/40 mg dexamethasone. Here, we report our combined findings from the additional Phase II expansion cohort of the first phase I/II trial of Car-Pom-d in patients with RRMM (NCT01464034). Methods The primary objective of the phase II portion was to determine the overall response rate (ORR). Secondary objectives included time to progression(TTP), progression free survival(PFS), overall survival (OS)and time to next therapy. All patients had to be refractory to prior lenalidomide, and must have relapsed or were refractory to their most recent therapy. Phase II patients had to be both pomalidomide and Carfilzomib naïve. Treatment consisted of 28-day cycles of oral pomalidomide once daily on days 1-21, intravenous (IV) carfilzomib over 30 minutes on days 1, 2, 8, 9, 15, and 16, and oral or IV dexamethasone 40 mg on days 1, 8, 15, and 22 Carfilzomib was initiated at 20 mg/m2 for Cycle 1, days 1-2 at all dose levels. Investigators were permitted to adjust the dose of dexamethasone at any point based on their discretion. Adverse events (AEs) were graded by NCI-CTCAE v4. Response was assessed by the modified International Uniform Response Criteria. Results In the Phase I dose-escalation portion of the trial a total of 12 patients were enrolled. The MTD was established as the starting dose level (carfilzomib 20/27 mg/m2, pomalidomide 4mg, dexamethasone 40 mg). We enrolled an expansion cohort of 20 patients at MTD for a total of 30 toxicity-evaluable patients from 8 centers. In Phase II we enrolled 40 of 82 planned patients resulting in a total study population of 72 patients, with 29 still receiving treatment. Five patients out of the 72 were not yet evaluable for efficacy. Data cut-off was June 15, 2013. The median age was 64 years (range 41–78), 63% were male. The median number of prior regimens was 6 (range 2–15), median time from diagnosis was 5.1 years and median follow-up was 6.0 months (range: .5 to 16.1 months). Two-thirds of patients had a prior stem cell transplant, 87% had prior bortezomib, and all were lenalidomide-refractory. Cytogenetic abnormalities included 16 patients with del(17p), 6 patients with t(4;14), and 23, 14, and 5 patients each with del(13), t(11;14), and t(14;16), respectively. Patients received a median of 5 cycles (range 1–18 cycles). Ten patients have died, 6 from progressive multiple myeloma. Best response assessments in 67 out of 72 patients showed 1 CR, 18 VGPR, 24 PR, 11 MR, 11 SD, and 2 PD for an ORR of 64% and a ≥MR rate of 81%. Grade ≥3 drug-related AEs occurring in 〉 20% of patients included fatigue (48%), neutropenia (40%), anemia (34%), thrombocytopenia (34%), and diarrhea (20%). Sixty-two percent of patients experienced grade ≥3 AEs including neutropenia, anemia, and diarrhea. Median PFS and OS were 12.0 and 16.3 months, respectively, for the entire cohort. Patients with intermediate- or high-risk cytogenetics (mSMART criteria, N=33) had a median PFS of 9.6 months and a ≥MR rate of 84%. Conclusions The Car-Pom-d regimen is a well-tolerated regimen and achieves a high response rate (ORR of 64%; ≥MR rate of 81%) in a heavily pre-treated Lenalidomide-refractory population with prior bortezomib exposure, with a median of 6 lines of prior therapy. Importantly, we have seen responses in patients with poor risk cytogenetics, specifically del (17p) with prolonged disease control. We would like to acknowledge Onyx Pharmaceuticals, Inc. and Celgene Corporation for their support of this study. Disclosures: Shah: Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Stadtmauer:Celgene: Consultancy, Speakers Bureau; Millenium: Consultancy, Speakers Bureau. Abonour:Onyx: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Cohen:Millennium: Honoraria; Onyx: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees. Bensinger:Celgene: Consultancy, Honoraria, Research Funding. Gasparetto:Onyx: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Kaufman:Onyx: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy; Jansenn: Consultancy; Merck: Research Funding. Lentzsch:Celgene: Research Funding. Vogl:Acetylon Pharmaceuticals, Inc: Research Funding; Millennium: Research Funding; Celgene: Consultancy; Otsuka: Consultancy. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Durie:Celgene: Consultancy; Onyx: Consultancy; Millennium: Consultancy; Amgen: Consultancy.

Abstract: Introduction: Geriatric assessment (GA) is a multidimensional evaluation of patient health and function that may detect impairments not identified as part of routine care, predict treatment-related morbidity and mortality, and inform treatment plans. Given evidence of these benefits, the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend GA for older candidates of hematopoietic stem cell transplantation (HCT). However, both older and younger HCT candidates will often receive multiple rounds of chemotherapy before HCT, leading to functional impairments in all age groups. Furthermore, HCT patients often experience a significant gap between when they are first evaluated and actually proceed to transplant (e.g., while a donor search is conducted), creating an opportunity to identify impairments and optimize function prior to transplant. Methods: To address this opportunity, we created a clinical pre-HCT optimization program (C-POP) to evaluate physical function, cognitive function, nutritional status, and mental health in all adults who were deemed potential candidates for allogeneic HCT by a HCT physician. We applied this standard of care program to all adult candidates for HCT, regardless of age, with the goal of identifying functional impairments and then referring patients to services to optimize those impairments prior to HCT. We defined impairments using validated measures and compared results to established norms or scoring, controlling for age and gender where appropriate (e.g., the cut-off for six-minute walk distance was adjusted for age, gender, height, and weight, while the cut-off for falls was any fall regardless of characteristics). Patients with impairments were referred to the appropriate supportive care (e.g., physical function impairment - 〉 referral to physical therapy). Results were prospectively analyzed at new patient evaluation (NPE), which was the first time the patient met a HCT physician and sign-off, which occurred within a week before starting transplant. While the program is ongoing, we present here the results of patients evaluated between October 16th, 2017 and July 1st, 2019. Patients are divided into three pre-specified age groups: 〈 40 years old, 40-59 years old, and 〉 =60 years old, with results compared using a chi-squared test. Results: We evaluated 115 patients: 21 (18%) 〈 40 years, 40 (35%) 40-59 years, and 54 (47%) 〉 =60 years). There were no differences between the age groups in other demographics (gender, race, and ethnicity). At NPE, 93 (81%) met criteria for at least 1 impairment in physical function, cognitive function, nutritional status, or mental health; 62 (54%) met criteria for impairments in 2 or more areas. Surprisingly, patients 〈 40 years were more likely to screen positive for physical function (20/21, 95%) than patients 40-59 years (26/40, 65%) and patients 〉 =60 years (36/54, 67%) (p=0.03). Of those 115 patients, 52 (45%) proceeded to HCT, including 12 (57%) 〈 40 years, 18 (45%) 40-59 years, and 22 (41%) 〉 =60 years (p=0.75); of those patients who have not proceeded to HCT, 40 (35%) will never proceed to HCT (e.g., deemed not a candidate after functional evaluation or died of disease prior to HCT) while 23 (20%) are still awaiting HCT (e.g., donor search ongoing). Patients who proceeded to HCT were less likely to have mental health impairments (2/52, 4% vs. 9/40, 23%, p=0.006). Of the 52 who were seen at new patient evaluation and proceeded to transplant, 40 (77%) were seen at sign off. Of those who had impairments at NPE, 12/23 (52%) improved their physical function to normal limits, 4/9 (44%) improved their cognitive function, and 9/13 (69%) improved their nutritional status by the time of sign-off (of those who were seen at sign-off, none had mental health impairments at NPE). Discussion: These results demonstrate that younger as well as older candidates for HCT exhibit a high degree of functional impairment. However, this impairment could be amenable to improvement prior to HCT. These findings support application of GA to all HCT candidates regardless of age. We will investigate the effect of referred interventions (e.g., physical therapy, seeing a dietician) in improving functional impairments in future studies, as well as look at the effect of these findings on HCT outcomes. Disclosures Wiggins: Incyte, Inc.: Speakers Bureau. Gasparetto:Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Rizzieri:Millennium: Speakers Bureau; Novartis: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Incyte: Consultancy, Speakers Bureau; TEVA: Consultancy; Spectrum: Consultancy; Kite Pharma: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau. Horwitz:Abbvie Inc: Membership on an entity's Board of Directors or advisory committees. Sung:Novartis: Research Funding; Merck: Research Funding; Seres: Research Funding.

Abstract: CD19-specific chimeric antigen receptor (CAR) T cell therapies have been highly effective against B cell malignancies. We previously demonstrated that differential responses to anti-CD19 CAR T cell therapy in chronic lymphocytic leukemia (CLL) are associated with early memory T cell signature in apheresed, pre-manufacturing T-cells (CAR T-cell precursors). We tested the hypothesis that the composition of CAR-T precursor cells determines clinical efficacy in adult and pediatric Acute Lymphoblastic Leukemia (ALL), Non-Hodgkin's Lymphoma (NHL), Multiple Myeloma (MM), and CLL. Apheresed T cells were engineered to express 4-1BB plus CD3-zeta-signaling CARs targeting CD19, or B cell maturation antigen (BCMA). The same 9-day manufacturing process was used for all trials. CAR T cell kinetics were monitored using a CAR gene-specific quantitative PCR assay and standard clinical response assessments were performed. Apheresed T cells from 36 CLL, 30 adult ALL, 58 pediatric ALL, 33 NHL, and 25 MM patients were immunophenotyped by flow cytometry. The CLL cohort was used to discover phenotypically distinct subpopulations associated with the two main response groups; these associations were validated in the remaining patient cohorts. Eight CD8+ T cell populations or clusters were identified using the shared-nearest-neighbor clustering method (PMID: 31178118) in the CLL cohort. T cell subsets exhibiting naive (cluster 6) or early memory (cluster 4) features were significantly enriched in responding patients, whereas an effector memory CD8 subpopulation (cluster 2) marked the non-responding patients. Mapping these clusters onto apheresed CD8+ T cells from the other four diseases showed that cluster 4 predicted response to CAR T cell therapy in NHL and myeloma but not in adult and pediatric ALL. We also examined the expression of activation-regulated molecules including HLA-DR, Ki67, and exhaustion-related molecules PD1, CTLA4, TIM3, and LAG3. A CD27+ CD8+ population expressing low level CTLA4 but none of the activation or negative regulatory molecules was significantly enriched in responding CLL patients; this cluster validated in NHL and myeloma. A similar analysis on apheresed CD4+ T cells identified an early memory population (cluster 6) enriched in CLL responders, which expresses CCR7 and CD27 but not CD45RO, CD127, CD28, or other late memory/effector molecules. However, this population did not validate in any of the other diseases. Though not statistically significant, the CD4+ clusters with the largest effect size for enrichment in responders from NHL and myeloma trials exhibited early memory T cell features and lack of HLA-DR expression, suggesting that quiescent early memory state in CD4 may also be associated with clinical responses. A separate analysis of checkpoint inhibitory receptors and activation markers in memory CD4 T cell subsets confirmed the early memory, non-activated state of this population in CLL and was validated in myeloma but none of the other diseases. In vivo activation was a shared theme in CD4+ T cells for non-responding patients as well, though these CLL-defined CD4+ apheresed T cells clusters did not significantly validate in other diseases. In summary, our data confirm and extend our predictive biomarker profile in CLL to mature B cell and plasma cell malignancies by showing that a non-cycling, non-activated early memory CD8+ T cell population in pre-manufacturing cells was validated as a biomarker in myeloma, and NHL. We also showed that responder-associated apheresed CD4+ T cells with early memory features identified in CLL after CD19 CAR T infusions are validated in myeloma after BCMA CAR T. Thus, differentiation state and in vivo activation, and potentially exhaustion, separate response groups. Our findings inform next-generation CAR T-cell manufacturing using the populations identified herein as a starting population. Disclosures Pruteanu: Novartis: Employment. Cohen:Poseida Therapeutics, Inc.: Research Funding. Garfall:Surface Oncology: Consultancy; Novartis: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Tmunity: Research Funding. Milone:Novartis: Patents & Royalties: patents related to tisagenlecleucel (CTL019) and CART-BCMA; Novartis: Research Funding. Gill:Novartis: Research Funding; Tmunity: Research Funding; Carisma: Equity Ownership, Research Funding; Sensei: Consultancy; Aro: Consultancy; Fate: Consultancy. Frey:Novartis: Research Funding. Ruella:Nanostring: Consultancy, Speakers Bureau; Novartis: Patents & Royalties: CART for cancer; AbClon: Membership on an entity's Board of Directors or advisory committees. Lacey:Novartis: Patents & Royalties: Patents related to CAR T cell biomarkers; Tmunity: Research Funding; Novartis: Research Funding. Svoboda:Merck: Research Funding; BMS: Consultancy, Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Celgene: Research Funding; Kite: Consultancy; Seattle Genetics: Consultancy, Research Funding; Kyowa: Consultancy; AstraZeneca: Consultancy. Chong:Tessa: Consultancy; Novartis: Consultancy; Merck: Research Funding. Fraietta:LEK Consulting: Consultancy; Cabaletta: Research Funding; Tmunity: Research Funding. Davis:Cabaletta: Research Funding; Tmunity: Research Funding. Nasta:Rafael: Research Funding; Aileron: Research Funding; Takeda/Millennium: Research Funding; Incyte: Research Funding; Roche/Genentech: Research Funding; Merck: Consultancy; Atara: Research Funding; Debiopharm: Research Funding. Levine:CRC Oncology: Consultancy; Vycellix: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership; Novartis: Consultancy, Patents & Royalties, Research Funding; Cure Genetics: Consultancy; Avectas: Membership on an entity's Board of Directors or advisory committees; Brammer Bio: Membership on an entity's Board of Directors or advisory committees; Incysus: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Maude:Kite: Consultancy; Novartis: Consultancy. Schuster:Nordic Nanovector: Honoraria; Pfizer: Honoraria; AstraZeneca: Honoraria; Pharmacyclics: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Loxo Oncology: Honoraria; Merck: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination Therapies of CAR and PD-1 Inhibitors with royalties paid to Novartis, Research Funding; AbbVie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Stadtmauer:Celgene: Consultancy; Tmunity: Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Abbvie: Research Funding. Grupp:Novartis: Consultancy, Research Funding; Roche: Consultancy; GSK: Consultancy; Cure Genetics: Consultancy; Humanigen: Consultancy; CBMG: Consultancy; Novartis: Research Funding; Kite: Research Funding; Servier: Research Funding; Jazz: Other: study steering committees or scientific advisory boards; Adaptimmune: Other: study steering committees or scientific advisory boards. Porter:Incyte: Membership on an entity's Board of Directors or advisory committees; American Board of Internal Medicine: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Glenmark Pharm: Membership on an entity's Board of Directors or advisory committees; Immunovative: Membership on an entity's Board of Directors or advisory committees; Genentech: Employment; Wiley and Sons: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. June:Novartis: Research Funding; Tmunity: Other: scientific founder, for which he has founders stock but no income, Patents & Royalties. Melenhorst:Novartis: Research Funding, Speakers Bureau; Parker Institute for Cancer Immunotherapy: Research Funding; Stand Up to Cancer: Research Funding; Incyte: Research Funding; IASO Biotherapeutics, Co: Consultancy; Simcere of America, Inc: Consultancy; Shanghai Unicar Therapy, Co: Consultancy; Colorado Clinical and Translational Sciences Institute: Membership on an entity's Board of Directors or advisory committees; Genentech: Speakers Bureau; National Institutes of Health: Research Funding.

Abstract: The prognostic relevance of diagnosis to treatment interval (DTI) in patients with newly diagnosed mantle cell lymphoma (MCL) is unknown. Hence, we sought to evaluate the impact of DTI on outcomes in MCL using 3 large datasets (1) the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource, (2) patients enrolled in the ALL Age Asthma Cohort/CALGB 50403, and (3) a multisitecohort of patients with MCL. Patients were a priori divided into 2 groups, 0 to 14 days (short DTI) and 15 to 60 days (long DTI). The patients in whom observation was deemed appropriate were excluded. One thousand ninety-seven patients newly diagnosed with MCL and available DTI were included in the study. The majority (73%) had long DTI (n=797). Patients with short DTI had worse eastern cooperative oncology group performance status (ECOG PS ≥2), higher lactate dehydrogenase, bone marrow involvement, more frequent B symptoms, higher MCL International Prognostic Index (MIPI ≥6.2), and were less likely to receive intensive induction therapy than long DTI group. The median progression-free survival (2.5 years vs 4.8 years, p & lt;0.0001) and overall survival (7.8 years vs. 11.8 years, p & lt;0.0001) were significantly inferior in the short DTI group than the long DTI cohort and remained significant for progression-free survival and overall survival in multivariable analysis. We show that the DTI is an important prognostic factor in patients newly diagnosed with MCL and is strongly associated with adverse clinical factors and poor outcomes. DTI should be reported in all the patients newly diagnosed with MCL who are enrolling in clinical trials and steps must be taken to ensure selection bias is avoided.

Abstract: A subset of DHL patients may be cured, and some patients may benefit from intensive induction. Further investigations into the roles of SCT and novel agents are needed.

Abstract: Introduction Omidubicel is a hematopoietic stem cell graft derived from umbilical cord blood, composed of an ex vivo nicotinamide-expanded CD133+ stem cell fraction and a non-expanded CD133- T-cell-containing fraction. Omidubicel was the first ex vivo expanded stem cell graft to demonstrate durable engraftment and the first to be transplanted as a single, stand-alone graft following myeloablative conditioning. Recent prospective clinical trials have established the short-term safety and efficacy of hematopoietic cell transplantation (HCT) with omidubicel, both as a stand-alone graft and in conjunction with an unmanipulated cord blood unit (Horwitz et al, 2014, 2019, and 2021). This retrospective study reports on the long-term experience with omidubicel HCT in patients with advanced hematologic malignancies at a single institution. Methods All patients with hematologic malignancies who had undergone HCT and engrafted with omidubicel between November 2010 and January 2020 were eligible for analysis. Patients who experienced primary graft failure or engrafted with an unmanipulated unit were excluded. A retrospective review was performed under the auspices of an IRB approved protocol to determine their long-term outcomes. The primary endpoints were survival and long-term hematopoiesis. Secondary endpoints included immune reconstitution, disease relapse, chronic graft versus host disease (GVHD), and secondary hematologic malignancies. R 4.1.0 was used to perform Kaplan Meier survival analysis and competing risk analyses of cumulative incidence via Gray's method. Results A total of 26 patients received an omidubicel graft during the study period, of whom 22 were eligible for analysis. Three patients engrafted with an unmanipulated cord blood graft and 1 patient experienced primary graft failure. The median age of the eligible patients was 48 yrs (range, 18 - 62 yrs) and 8 patients (36%) were non-white. The most common disease types were AML (36%), MDS (32%), and ALL (18%). By disease risk index, 5 patients (23%) were considered high risk, 13 (59%) were intermediate risk, 3 (14%) were low risk, and 1 (5%) was unevaluable. At the time of data cutoff, the median follow-up was 2.3 yrs (range, 0.1 - 10 yrs) for all eligible patients and 7.4 yrs (range, 1.8 - 10 yrs) for the 11 survivors. At last follow-up, 11 patients had passed away due to disease relapse (64%), acute GVHD (27%), or infection (9%). The estimated 10-year overall survival and disease-free survival were 48.5% (95% CI, 31.0% - 75.7%) (Fig 1A) and 43.6% (95% CI, 26.8% - 70.9%), respectively. Durable omidubicel-derived trilineage hematopoiesis was observed at up to ten years of follow-up (Fig 2A-2C). Serial quantitative assessments of lymphocyte subsets suggest stability of the median CD3+, CD4+, and CD8+ T cell, as well as CD19+ B cell and NK cell counts. These levels were within normal ranges starting at 6 months post-transplant and up until 8 years of follow-up. Using competing risk analysis, the 10-year estimated cumulative incidence of relapse was 31.8% (95% CI, 13.6% - 51.8%). The 10-year estimated cumulative incidence of chronic GVHD was 31.8% (95% CI, 13.4% - 52.1%). Of the 7 patients who experienced chronic GVHD, only 2 still required systemic immunosuppression at last follow-up. One patient experienced secondary graft failure requiring a rescue haploidentical transplant on day 202. There were no cases of secondary hematologic malignancies. Conclusions This study suggests that omidubicel provides long-term sustainable hematopoiesis and immune competence at follow-up periods of up to 10 years. This is the first characterization of the long-term safety of an ex vivo expanded hematopoietic stem cell graft. While there has been concern that ex vivo expansion approaches may compromise the integrity of long-term repopulating hematopoietic stem cells, there was only one documented case of secondary graft failure in this cohort. Furthermore, there was no evidence for the development of clonal hematopoiesis, however molecular testing was not performed to confirm this observation. Chronic GVHD was observed, but most patients were able to wean off immunosuppression. In summary, omidubicel is a safe and reliable stem cell source for patients in need of hematopoietic cell transplantation, particularly for underrepresented racial and ethnic minorities. Figure 1 Figure 1. Disclosures Choi: Janssen Biotech: Speakers Bureau. Gasparetto: Janssen: Consultancy; Sanofi: Consultancy, Honoraria, Speakers Bureau; Oncopeptide: Consultancy, Honoraria, Speakers Bureau; Gsk: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Speakers Bureau. Lopez: PhosphoGam: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Rizzieri: AbbVie: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Acrotech: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Karyopharm: 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; Celltrion: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria; Pharmacyclics: Honoraria. Sarantopoulos: Rigel: Other: Advisory Board. Sung: Merck: Research Funding; Novartis: Research Funding; Enterome: Research Funding; Seres: Research Funding; AVROBIO: Consultancy; Abbott Nutrition: Honoraria; Clasado: Other: Research Product; DSM: Other: Research Product. Galamidi-Cohen: Gamida Cell, Ltd: Current Employment. Schwarzbach: Gamida Cell: Current Employment. Horwitz: Gamida Cell: Research Funding.

Abstract: Leukemic cells from 30% of patients with acute myeloid leukemia (AML) have an activating mutation in the FLT3 (fms-like tyrosine kinase) gene, which represents a target for drug therapy. We treated 20 patients, each with mutant FLT3 relapsed/refractory AML or high-grade myelodysplastic syndrome and not believed to be candidates for chemotherapy, with an FLT3 tyrosine kinase inhibitor, PKC412 (N-benzoylstaurosporine), at a dose of 75 mg 3 times daily by mouth. The drug was generally well tolerated, although 2 patients developed fatal pulmonary events of unclear etiology. The peripheral blast count decreased by 50% in 14 patients (70%). Seven patients (35%) experienced a greater than 2-log reduction in peripheral blast count for at least 4 weeks (median response duration, 13 weeks; range, 9-47 weeks); PKC412 reduced bone marrow blast counts by 50% in 6 patients (2 of these to & lt; 5%). FLT3 autophosphorylation was inhibited in most of the Corresponding patients, indicating in vivo target inhibition at the dose schedule used in this study. PKC412 is an oral tyrosine kinase inhibitor with clinical activity in patients with AML whose blasts have an activating mutation of FLT3, suggesting potential use in combination with active agents, such as chemotherapy.

Abstract: Background: Autologous stem cell transplantation (ASCT) can be curative for patients (pts) with relapsed/refractory Hodgkin lymphoma (HL) who are sensitive to salvage therapy, particularly for pts who achieve a complete metabolic response (CMR) before ASCT. Pts who fail multiple salvage regimens have inferior outcomes and are generally considered poor candidates for ASCT. Recent studies suggest that anti-PD-1 monoclonal antibodies (mAbs) may restore sensitivity to cytotoxic therapy in HL pts with previously chemorefractory disease. We hypothesized that PD-(L)1 mAb-based salvage therapy may therefore also improve ASCT outcomes for HL pts who had failed salvage therapy. Methods: Medical records were reviewed at 13 US transplant centers to identify pts with a diagnosis of classic HL who failed at least 2 systemic therapies, were treated with a PD-1 or PD-L1 mAb (either alone or in combination) as 3rd line or later therapy, and subsequently underwent ASCT. Results: 44 eligible pts were identified. The median age was 33 (range 19-68). Pts received ABVD (39), AVD (2), brentuximab vedotin (BV) + AVD (1), Stanford V (1), or eBEACOPP (1) as 1st line therapy. 26 pts (59%) were refractory to 1st line treatment and 8 additional pts (18%) relapsed within 12 months. High-risk clinical features were observed frequently at 1st relapse including extranodal involvement (47%), B symptoms (27%), and advanced stage (64%). Pts received PD-(L)1 based treatment after failing 2 lines (32%), 3 lines (57%), or ≥4 lines (11%) of therapy. 32 pts (73%) were refractory to the line of therapy before PD-(L)1, 25 pts (57%) to 2 consecutive lines before PD-(L)1, and 10 pts (22%) to 3 consecutive lines before PD-(L)1. 16 pts (36%) were refractory to ≥2 salvage therapies immediately before PD-(L)1 therapy and 17 (39%) were refractory to all prior treatments. 39 pts (89%) received BV or a BV-based combination before ASCT. 67% were BV-refractory, including 86% of those receiving BV monotherapy. Pts received a median of 6 doses of a PD-(L)1 mAb (range 2-26) either as monotherapy (75%) or as part of a PD-1 based combination (25%). The median time from last dose of PD-(L)1 mAb to ASCT was 54 days (range 12-386). Best response to PD-(L)1-based therapy was CR (53%), PR (33%), SD (12%), or PD (2%). The median number of systemic therapies (including PD-(L)1) before ASCT was 4 (range 3-7) and 12 pts (27%) received intervening salvage therapy between PD-(L)1 treatment and ASCT. Pre-ASCT PET status was CR in 31 pts (70%), PR in 9 (18%), SD in 4 (9%), and PD in 1 (2%). There were no ASCT-related deaths. 2 pts developed BCNU pneumonitis and 1 developed engraftment syndrome. All 3 pts responded to steroids. 14 pts (32%) have received maintenance therapy with BV (4), a PD-1 mAb (8), or BV + PD-1 mAb (2). 4 pts (9%) received consolidative radiation. With a median post-ASCT follow-up of 12.2 months, progression-free survival (PFS) at 1 yr was 91% [95CI 75-97]. Notably, resistance to chemotherapy before PD-(L)1 therapy did not predict worse post-ASCT outcomes (see Table). 1-yr PFS was 90% for pts who were refractory to the 3 lines of therapy before PD-(L)1, 93% for pts refractory to ≥2 salvage therapies immediately before PD-(L)1, and 90% for pts refractory to all prior treatments. Favorable 1-yr PFS was also seen among pts who received PD-(L)1 as 4th or later line therapy (88% vs 100% for pts receiving PD-[L] 1 as 3rd line, p=0.17) and among pts who failed to achieve a CMR on pre-ASCT PET (1-yr PFS 81% vs 96% for CMR pts, p=0.34). Lack of response to PD-(L)1 therapy (1-yr PFS 67% vs 96%, p=0.04), receipt of intervening salvage therapy (1-yr PFS 72% vs 100%, p=0.026), and increasing age (HR 1.11, p=0.015) were all significant predictors of inferior PFS. 1-yr overall survival was 100%. Conclusions: This high-risk cohort is heterogenous in terms of number of prior therapies and degree of chemoresistance, but excellent post-ASCT outcomes were observed among even the most heavily pre-treated, chemorefractory subgroups. Outcomes for PD-(L)1 responders were particularly favorable with a 1-yr PFS of 96%, suggesting that response to PD-(L)1 rather than prior chemotherapy may be the more important predictor of post-ASCT outcomes in this pt population. While longer follow-up is required to confirm the durability of these remissions, ASCT can be considered for HL pts responding to PD-(L)1 based salvage therapy, even if they have previously demonstrated a high degree of chemoresistance. Table Disclosures Nieto: Novartis: Research Funding; Astra-Zeneca: Research Funding; Affimed: Research Funding; Affimed: Consultancy. Byrne:Karyopharm: Research Funding. Maddocks:BMS: Research Funding; Novartis: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Merck: Research Funding. Svoboda:BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy; Celgene: Research Funding; Kyowa: Consultancy; Kite: Consultancy. McGuirk:Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding; Fresenius Biotech: Research Funding; Astellas: Research Funding; Bellicum Pharmaceuticals: Research Funding. Advani:Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Millennium: Research Funding; Janssen: Research Funding; Cell Medica, Ltd: Consultancy; Regeneron: Research Funding; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stanford University: Employment, Equity Ownership; Agensys: Research Funding; Kura: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Seattle Genetics: Consultancy, Research Funding; Infinity Pharma: Research Funding; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cohen:Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; ASH: Research Funding; Lymphoma Research Foundation: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy. Frigault:Xenetic: Consultancy; Foundation Medicine: Consultancy; Novartis: Consultancy; Nkarta: Consultancy; Juno/Celgene: Consultancy; Kite/Gilead: Honoraria; Incyte: Consultancy. Chen:Magenta: Consultancy; Takeda: Consultancy; Incyte: Consultancy; Kiadis: Consultancy; Abbvie: Consultancy. Lynch:Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Rhizen Pharmaceuticals S.A: Research Funding; Juno Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; T.G. Therapeutics: Research Funding. Smith:Seattle Genetics: Research Funding; Denovo Biopharma: Research Funding; Ayala (spouse): Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Acerta Pharma BV: Research Funding; Incyte Corporation: Research Funding; Ignyta (spouse): Research Funding; Genentech: Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ho:Jazz Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Consultancy; Omeros Corporation: Membership on an entity's Board of Directors or advisory committees. Armand:Affimed: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sigma Tau: Research Funding; Infinity: Consultancy; Otsuka: Research Funding; Genentech: Research Funding; Pfizer: Consultancy; ADC Therapeutics: Consultancy; Tensha: Research Funding; Roche: Research Funding; Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Herrera:Merck: Consultancy; BMS: Consultancy; Genentech: Research Funding; Adaptive Biotechnologies: Consultancy; Gilead Sciences: Research Funding; KiTE/Gilead: Consultancy; Genentech: Consultancy; Merck: Research Funding; Astra-Zeneca: Research Funding; Seattle Genetics: Consultancy; BMS: Research Funding; Seattle Genetics: Research Funding.