Nikiforow, Sarah

Objective Identifying eligible patients for precision oncology clinical trials is challenging, particularly for rare molecular subpopulations. To address this challenge, A2 Biotherapeutics developed BASECAMP-1 ( NCT04981119 ), a non-interventional master screening study to identify patients eligible for interventional studies of logic-gated Tmod chimeric antigen receptor T-cell therapies. Eligible patients for these interventional trials have an advanced solid malignancy and are germline human leucocyte antigen (HLA)-A*02 heterozygous, with tumour-associated HLA-A loss of heterozygosity (LOH). HLA-A LOH occurs in ~16% of advanced solid malignancies; therefore, an efficient screening strategy is required. This report describes BASECAMP-1; compares the efficiency of two screening methods; and discusses the broader advantages of BASECAMP-1 beyond efficient enrolment. Methods and analysis Patients are identified for BASECAMP-1 using two approaches. In the traditional approach, common for clinical trials, investigators consent and screen all patients who might be good candidates for cell therapy trials, with no prior knowledge of patient HLA-A type or LOH status. To further optimise our approach, we co-developed with Tempus AI (Tempus) the bioinformatic programme Aware, which identifies potentially eligible patients with tumour-associated HLA-A*02 LOH within a clinico-genomic database that includes linked genomic and transcriptomic sequencing and clinical data collected during routine care. Results Over 42 months of using a traditional approach to identify eligible patients, 1918 patients at 13 study sites were consented and screened for BASECAMP-1; of these, 30 patients with tumour-associated HLA-A*02 LOH were enrolled (~0.7 participants per month). Over the last 30 months of that same period, Tempus Aware screening was implemented and 55 patients with tumour-associated HLA-A*02 LOH were enrolled (~1.8 participants per month). The bioinformatic approach identified more patients than the traditional approach and used sequencing results produced as part of the standard clinical tumour sequencing workflow, reducing resource use and study staff burden. Additional advantages of using a screening study, such as BASECAMP-1, include manufacturing efficiencies and collection of a large dataset of molecular and clinical parameters that can be used to supplement trial analyses. Conclusions The BASECAMP-1 study demonstrates a clinico-genomic screening approach can more efficiently identify patients for precision oncology trials. Furthermore, precision oncology can be enhanced through collaborative data-sharing. Trial registration number NCT04981119 .

Abstract Chimeric antigen receptor (CAR) T-cell products axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel) are approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Emerging evidence indicates that delayed CAR T-cell infusion, including prolonged time from leukapheresis to infusion, known as vein-to-vein time (V2Vt), may adversely impact clinical outcomes. We conducted a systematic literature review (SLR) and meta-analysis to identify differences in V2Vt in patients with R/R LBCL treated with axi-cel, tisa-cel, or liso-cel. The impact of V2Vt (<28 days vs ≥28 to <40 days vs ≥40 days) on effectiveness and safety outcomes was evaluated in patients treated with axi-cel enrolled in a post-authorization safety study using the Center for International Blood and Marrow Transplant Research data. SLR and meta-analysis showed that patients treated with axi-cel had the shortest median V2Vt (30.6 days) compared with tisa-cel (48.4 days) or liso-cel (35.9 days). Real-world analysis of patients treated with axi-cel demonstrated that V2Vt ≥40 days was associated with significantly lower complete response rate than V2Vt <28 days (odds ratio [OR], 0.61) or ≥28 to <40 days (OR, 0.66) and significantly worse overall survival than V2Vt <28 days (hazard ratio [HR], 1.33) or ≥28 to <40 days (HR, 1.36). Higher prolonged thrombocytopenia rates were observed in patients with axi-cel V2Vt ≥28 to <40 days or ≥40 days compared with <28 days (OR, 1.44 or 1.95, respectively). Together, these results show the impact of V2Vt on patient outcomes with axi-cel therapy and that earlier infusion with CD19-CAR therapies may be beneficial.

Abstract Background and Rationale: Axi-cel is a standard-of-care treatment for relapsed or refractory LBCL after 2 or more lines of systemic therapy. Some patients who would have been ineligible for ZUMA-1 criteria due to comorbidities have been treated with axi-cel in the real-world setting. We interrogated a large registry of patients treated with standard-of-care axi-cel for a definitive report on the impact of age or certain comorbidities on safety and efficacy outcomes after axi-cel infusion. Methods: From October 2017 to August 2020, 1500 patients were enrolled in the postapproval safety observational study of axi-cel treated at 79 centers. Patients eligible for the protocol and followed up for at least 6 months with complete data entry by the time of analyses were included. One patient rescinded consent and 1 was deemed ineligible. Patients previously treated with immune effector cell therapy (n=31), with incomplete follow-up reporting (n=92), or alive but last contacted <180 days postinfusion (n=32) were excluded from analysis. Main efficacy outcomes included complete and objective response rates (CR and ORR), duration of response (DOR), progression-free and overall survival (PFS and OS). Safety endpoints of interest included cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Outcomes were assessed and compared by age and preselected coexisting disease or organ impairment within 3 months prior to the infusion included in the hematopoietic cell transplantation comorbidity index. Multivariate logistic and Cox regression models were used to assess the impact of age or coexistent organ dysfunction on outcomes via odds ratio (OR) or hazard ratio (HR) and their 95% CIs. Results A total of 1343 patients were included in the analysis with a median 25.1 months (range, 10.3-42.7 months) for potential follow-up, defined from infusion to data cutoff date, and a median 11.8 months (range, 0.1-38.8 months) for actual follow-up time, defined from infusion to date of death or last contact. Of these, 38% were 65 years or older (median 62 years), 4% had a performance score ≥2, 13% had cardiac comorbidities, 16% had a prior cancer, 9% were obese, 2% had moderate to severe hepatic comorbidities, and 2% had renal comorbidities. Transformed lymphoma, double or triple-hit by fluorescence in situ hybridization, prior autologous transplant and refractory disease were present in 28%, 15%, 27% and 66%, respectively. Bridging therapy was administered in 21% of patients. Overall, ORR was 74%, (CR 56%), and probabilities of DOR, PFS, and OS at 18 months were 61% (95% CI, 57-65%), 42% (95% CI, 39-45%) and 52% (95% CI, 49-55%), respectively. Overall rates of CRS and ICANS were 83% and 55%, respectively. ORR was 78% (CR 62%, median OS 17.5 [95% CI, 16.0-not evaluated (NE)] months) for patients ≥65 years, ORR 57% (CR 29%; median OS 4.3 [95% CI, 2.5-8.3] months) for patients with hepatic dysfunction, ORR 70% (CR 43%; median OS 8.9 [95% CI, 3.8-NE] months) for patients with renal dysfunction; and ORR 47% (CR 20%, median OS 4 [95% CI, 2.6-6.9] months) for patients with Eastern Cooperative Oncology Group (ECOG) 2 or 3. Multivariate analyses indicated that advanced age (≥65 years vs <65 years; OR 1.38; 95% CI, 1.05-1.83), moderate to severe pulmonary disease (yes vs no; OR 0.74; 95% CI, 0.55-0.98), and ECOG (2-3 vs 0-1; OR 0.31, 95% CI, 0.18-0.53) impacted ORR (Table). Age ≥65 years did not have an impact on survival (HR 1.05, 95% CI, 0.88-1.26), although it was associated with CRS (OR 1.42, 95% CI, 1.03-1.96) and ICANS (OR 1.78, 95% CI, 1.39-2.28). Coexistent cardiac disease (HR 1.44, 95% CI, 1.12-1.83), renal disease (HR 2.13, 95% CI, 1.32-3.46) and hepatic dysfunction (HR 2.65, 95% CI, 1.69-4.14) had an impact on OS, but not on response, CRS, and ICANS. ECOG significantly impacted all efficacy outcomes. None of the other comorbidities tested significantly impacted outcomes. Conclusion: Advanced age (≥65 years) was not associated with worse efficacy outcomes after axi-cel, despite higher rates of CRS and ICANS, which require closer monitoring. Performance status rather than age should be accounted for in patient selection and treatment decisions with axi-cel. Most coexistent organ dysfunctions have no clinically significant impact on axi-cel objective response and safety outcomes. Figure 1 Figure 1. Disclosures Locke: Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; Amgen: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; EcoR1: Consultancy; Emerging Therapy Solutions: Consultancy; Gerson Lehrman Group: Consultancy; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; Takeda: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Wugen: Consultancy, Other; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Umoja: Consultancy, Other; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; Cowen: Consultancy; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Legend Biotech: Consultancy, Other; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Janssen: Consultancy, Other: Scientific Advisory Role. Jacobson: Axis: Speakers Bureau; Nkarta: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel support; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Clinical Care Options: Speakers Bureau. Ma: Kite, a Gilead Company: Current Employment. Dong: Kite, a Gilead Company: Current Employment. Hu: Kite, a Gilead Company: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Siddiqi: BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Oncternal: Research Funding; Janssen: Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: 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; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; TG Therapeutics: Research Funding. Ahmed: Seagen: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Xencor: Research Funding. Ghobadi: Atara: Consultancy; Wugen: Consultancy; Amgen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Consultancy. Miklos: Pharmacyclics: Patents & Royalties; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy; Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees. Lin: Kite, a Gilead Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Legend: Consultancy; Vineti: Consultancy; Sorrento: Consultancy; Gamida Cell: Consultancy; Janssen: Consultancy, Research Funding; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Novartis: Consultancy; Merck: Research Funding; Takeda: Research Funding. Perales: Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Nektar Therapeutics: Honoraria, Other; Miltenyi Biotec: Honoraria, Other; MorphoSys: Honoraria; NexImmune: Honoraria; Sellas Life Sciences: Honoraria; Cidara: Honoraria; Merck: Honoraria; Omeros: Honoraria; Servier: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Other; Kite/Gilead: Honoraria, Other; Incyte: Honoraria, Other; Medigene: Honoraria; Karyopharm: Honoraria; Equilium: Honoraria. Lunning: Daiichi-Sankyo: Consultancy; TG Therapeutics: Consultancy; Kite, a Gilead Company: Consultancy; ADC Therapeutics: Consultancy; Spectrum: Consultancy; Beigene: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; Legend: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy; Morphosys: Consultancy; Verastem: Consultancy; Novartis: Consultancy; Myeloid Therapeutics: Consultancy; Janssen: Consultancy; Acrotech: Consultancy; Kyowa Kirin: Consultancy; Karyopharm: Consultancy. Hill: Gentenech: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Celgene (BMS): Consultancy, Honoraria, Research Funding. Nikiforow: Kite/Gilead: Other: ad HOC Advisory Boards; Novartis: Other: ad Hoc Advisory Boards; Iovance: Other: ad Hoc Advisory Boards; Glaxo Smith Kline (GSK): Other: ad Hoc Advisory Boards. Xu: Gilead Sciences: Other: stock or other ownership ; Kite, A Gilead Company: Current Employment. Pasquini: Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; Kite Pharma: Research Funding; GlaxoSmithKline: Research Funding.

Abstract Background: CD19 CAR T cell therapies have demonstrated high initial complete remission (CR) rates of 70-80% in relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) with durable remissions observed in a subset of patients. Despite the remarkable initial CR rate, relapses occur in 20-45% of patients and with increasing use of CD19 CAR T cell therapies in ALL, a key remaining clinical question is the role of post-CAR HCT. Methods: Patients up to 26 years treated with the commercial (i.e., tisagenlecleucel) or investigational CD19 CAR T cell products from 2014 to 2019 in the United States were included. The objectives were to examine the impact of post-CAR HCT on mortality, disease-free survival (DFS), leukemia relapse, GVHD and transplant related mortality among HCT recipients. The intent of HCT was analyzed as consolidation when there was no evidence of post-CAR T cell relapse prior to HCT. Cox regression multivariable analysis used HCT as time-dependent variable along with age, performance status and time from diagnosis to CAR-T cell infusion to evaluate its impact on outcomes. Results: We identified 347 patients who received CD19 CAR T cells from 86 centers. Median age was 13 (range, 0.4-26 years) with 39% of patients from Hispanic or Latino ethnic origin. Patients were high risk and heavily pretreated; 56% had poor cytogenetics, 51% had ≥3 line of prior therapies and 34% had prior HCT. Most of the patients (74%) received tisagenlecleucel. Disease burden at the time of CAR T cell infusion included morphologic disease (≥5% bone marrow blasts) (65%), measurable residual disease (MRD) positive (16%) and negative CR (18%). CRS of all grades was observed in 57.6% and grade 3-4 CRS in 13%; neurotoxicity of all grades was observed in 25% and grade 3-4 in 8%. With a median follow-up of 12.7 months (range, 2.2-60.3), DFS at 3, 6 and 12 months following CAR T cell infusion was 80.9% % (95% CI: 76.6%-84.9%), 71.2% (95% CI: 66.1%-76.0%) and 57.6% (95% CI: 51.8%-63.3%), respectively. OS at 3, 6 and 12 months was 93.6% (95% CI: 90.8%-96.0%), 89.8% (95% CI: 86.4%-92.8%) and 79.4% (95% CI: 74.7%-83.6%), respectively. Incidences of relapse without censoring at subsequent HCT at month 3, 6 and 12 were 18.5% (95% CI: 14.5%-22.8%), 28.2% (95% CI: 23.5%-33.3%), and 40.6% (95% CI: 35.0%-46.3%), respectively. Of the 347 patients who received CD19 CAR therapy, 62 patients (18%) had subsequent HCT in CR as a consolidation post-CAR with a median time from CAR T to HCT of 4.7 months (range, 1.1-18.6). 36% had a prior HCT (i.e., pre-CAR), 87% received myeloablative regimen and among the 57 patients with MRD evaluation 56 were negative (98%). Frequencies of post-CAR HCT did not change during the 5-year study period. Overall, transplant related mortality (TRM) at month 6 was 8.9% (95% CI: 3.6-16.1), and grade 2-4 acute GvHD was observed in 38.0% (95% CI: 28.4-48.2) of patients at month 6. Post-CAR HCT used as a consolidation was associated with lower relapse (hazard ratio (HR) 0.37; p=0.037) but no significant impact on mortality (HR 0.75, p=0.51) or DFS (HR=0.46, p=0.057). When accounting for any HCT performed after CAR T cell, HCT was associated with higher mortality (Figure). Conclusions: This is the largest clinical series to date examining the impact of post-CAR HCT on clinical outcome of R/R B-ALL patients. We found that 18% of the patients had post-CAR HCT as a consolidation therapy with a favorable safety profile of 8.9% TRM rate despite a prior transplant rate of 36%. Consolidation HCT after CAR T cell resulted in significant reduction in leukemia relapse with a trend towards better DFS. Consolidation HCT seem safe and incurred a benefit by reducing disease relapse. Further studies in understanding the role of consolidation HCT as planned, or post-CAR T cell response-based strategy or treatment for early B-cell recovery are needed to further define the best candidates for HCT after tisagenlecleucel . Figure 1 Figure 1. Disclosures Park: BMS: Consultancy; Affyimmune: Consultancy; Kite Pharma: Consultancy; Curocel: Consultancy; Novartis: Consultancy; Minerva: Consultancy; Innate Pharma: Consultancy; PrecisionBio: Consultancy; Intellia: Consultancy; Amgen: Consultancy; Autolus: Consultancy; Servier: Consultancy; Artiva: Consultancy; Kura Oncology: Consultancy. Nikiforow: Kite/Gilead: Other: ad HOC Advisory Boards; Novartis: Other: ad Hoc Advisory Boards; Iovance: Other: ad Hoc Advisory Boards; Glaxo Smith Kline (GSK): Other: ad Hoc Advisory Boards. Hu: Kite/Gilead: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Ahmed: Merck: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seagen: Research Funding; Xencor: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Cairo: Servier: Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees; Nektar: Membership on an entity's Board of Directors or advisory committees. Dholaria: Janssen: Research Funding; Takeda: Research Funding; Jazz: Speakers Bureau; MEI: Research Funding; Pfizer: Research Funding; Angiocrine: Research Funding; Poseida: Research Funding; Celgene: Speakers Bureau. Grover: Kite: Other: Advisory Board; Genentech: Research Funding; ADC: Other: Advisory Board; Tessa: Consultancy; Novartis: Consultancy. Locke: Gerson Lehrman Group: Consultancy; Emerging Therapy Solutions: Consultancy; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy; Calibr: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Wugen: Consultancy, Other; Legend Biotech: Consultancy, Other; Janssen: Consultancy, Other: Scientific Advisory Role; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; Novartis: Consultancy, Other, Research Funding; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Takeda: Consultancy, Other; EcoR1: Consultancy; Cowen: Consultancy; Umoja: Consultancy, Other; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding. Murthy: CRISPR Therapeutics: Research Funding. Mussetti: GILEAD: Other: Clinical trials participation, Research Funding; TAKEDA: Honoraria; NOVARTIS: Honoraria, Other: Clinical trials participation. Pulsipher: Jasper Therapeutics: Honoraria; Adaptive: Research Funding; Equillium: Membership on an entity's Board of Directors or advisory committees. Qayed: Novartis: Membership on an entity's Board of Directors or advisory committees; Medexus: Membership on an entity's Board of Directors or advisory committees; Mesoblast: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; BMS: Other. Reshef: Gilead, BMS, Precision, Immatics, Atara, Takeda, Shire, Pharmacyclics, Incyte: Research Funding; Gilead and Novartis: Honoraria; Bayer, BMS, Regeneron, TScan, Synthekine, Atara, Jasper: Consultancy. Rizzieri: Kite: Honoraria, Speakers Bureau; Incyte: 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; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acrotech: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; AbbVie: 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; 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; 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. Sharma: Vertex Pharmaceuticals/CRISPR Therapeutics: Other: Salary support paid to institution; Medexus Inc: Consultancy; CRISPR Therapeutics: Other, Research Funding; Vindico Medical Education: Honoraria; Spotlight Therapeutics: Consultancy; Novartis: Other: Salary support paid to institution. Schultz: BMS DSMB: Other: payment; Sobi: Membership on an entity's Board of Directors or advisory committees. Turtle: Century Therapeutics Ad hoc advisory boards (last 12 months): Nektar Therapeutics, Allogene, PACT Pharma, Astra Zeneca, Amgen: Membership on an entity's Board of Directors or advisory committees; Precision Biosciences: Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Membership on an entity's Board of Directors or advisory committees; T-CURX: Membership on an entity's Board of Directors or advisory committees; Myeloid Therapeutics: Membership on an entity's Board of Directors or advisory committees; ArsenalBio: Membership on an entity's Board of Directors or advisory committees; Minerva: Other; Nektar Therapeutics: Other; Juno Therapeutics/BMS: Other: Payments, Patents & Royalties: Patent licensed to Juno Therapeutics.; Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Myeloid Therapeutics, ArsenalBio: Current holder of stock options in a privately-held company. Pasquini: Kite Pharma: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; GlaxoSmithKline: Research Funding. Perales: MorphoSys: Honoraria; Cidara: Honoraria; Bristol-Myers Squibb: Honoraria; Miltenyi Biotec: Honoraria, Other; Sellas Life Sciences: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Omeros: Honoraria; Nektar Therapeutics: Honoraria, Other; Equilium: Honoraria; Novartis: Honoraria, Other; NexImmune: Honoraria; Incyte: Honoraria, Other; Kite/Gilead: Honoraria, Other; Merck: Honoraria; Servier: Honoraria; Medigene: Honoraria.

7552 Background: Axi-cel is approved in the US for the treatment of adult patients with relapsed or refractory LBCL after 2 or more lines of systemic therapy. Post-market long term follow up study of commercial Axi-cel recipients using the Center for International Blood and Marrow Transplant Research was recently completed. Methods: From October 2017 to August 2020, 1,500 Axi-cel recipients from 79 centers were enrolled. Of these, 1001 patients with at least 6 months of follow-up were included in this analysis. Outcomes include complete and overall responses rates (CR and ORR), duration of response (DOR), progression-free and overall survival (PFS and OS), cytokine release syndrome (CRS) (Lee D 2014 and American Society for Transplantation and Cellular Therapy [ASTCT]), immune effector cell associated neurotoxicity syndrome (ICANS), hematologic recovery and subsequent neoplasm (SN). Subgroup analysis by sensitivity to therapy, defined as responsive to the last line of therapy prior to Axi-cel. Median follow-up was 12 months (range, 6-28 months). Results: The median age overall was 62 years, 37% were ≥ 65 years, 83% with Eastern Cooperative Oncology Group (ECOG) performance score 0-1, 28% with transformed lymphoma, 14% with high grade lymphoma, 29% with prior autologous transplant, and 66% with chemotherapy-resistant disease prior to Axi-cel. The median time from diagnosis to Axi-cel infusion was 15 months. Best ORR was 70% (CR 53%). Landmark analysis of patients in CR at 6 months post Axi-cel demonstrates a low number of subsequent progression/death events. With respect to outcomes for chemotherapy-sensitive disease versus resistant disease, the ORR, CR, 12-month PFS and OS were 78% vs. 66%, 60% vs. 48%, 55% (95% CI, 48-62%) vs. 40% (95% CI, 37-44%), and 70% (95% CI, 63-76%) vs. 54% (95% CI, 50-58%), respectively. CRS of any grade was reported in 83% of patients. Incidence of Grades ≥ 3 CRS was 10% according to Lee et al 2014, and 13% according to ASTCT Consensus Grading. Median time to any grade CRS was 4 days (range, 1-28 days), and 93% of CRS cases resolved with a median duration of 7 days (range, 1-121 days). ICANS were reported in 576 (57%) patients, grade >3 was 26%. The median time to onset of ICANS was 7 days (range, 1-82 days), and 86% resolved with a median duration of 9 days (range, 1 to 115 days). Twenty-nine patients (2.9%) reported SN: hematologic (N = 17), solid tumors (N = 12). Conclusions: This is the largest report on Axi-cel in the real-world setting and demonstrates consistent efficacy outcomes and further characterizes safety outcomes. Patients in CR at 6 months have sustained disease control with low number of relapse events. Although patients with therapy-sensitive disease experience better outcomes than patients with therapy-resistant, the overall outcomes on both groups of patients are favorable.

Abstract Introduction: Relapse is the primary cause of death after reduced intensity conditioning (RIC) hematopoietic cell transplantation (HCT). Documented responses have been reported after combination chemotherapy, hypomethylating agents, donor lymphocyte infusions, and second transplants. For patients with early relapse after RIC HCT while still on immunosuppression (IS), IS taper alone may induce significant graft-versus-tumor (GVT) activity. We describe the clinical characteristics and subsequent course of 48 patients with disease recurrence that responsed to IS taper alone without any additional chemotherapy, radiation, or donor lymphocyte infusion. Methods: We reviewed medical records of all patients with frank histologic or radiographic evidence of relapse (n=477) and those with impending relapse defined by development of cytopenias with a fall in donor derived hematopoietic cell chimerism (n=87) within one year of allogeneic RIC HCT who were on IS at time of relapse between January 1, 2004 and December 31, 2013 at Dana Farber Cancer Institute/Brigham and Women's Hospital. Complete response after IS taper was defined as complete recovery of peripheral blood counts, bone marrow biopsy with absence of disease, negative radiologic imaging, or chimerism recovery to above 90 percent. Partial response was defined as improvement in disease burden in bone marrow or by imaging. Survival probabilities were calculated using the Kaplan Meier method. Results: Forty-eight patients (37 male, 11 female) who relapsed within one year of HCT responded to IS taper alone. Of these, 14 had impending relapse and 34 had frank relapse at time of IS taper. The median age of patients was 62 years at time of transplant. The most frequent indication for transplant was MDS (n=14) followed by AML (n=11), non-Hodgkin's lymphoma (n=8), CLL (n=6), Hodgkin's disease (n=4), CML (n=3) and multiple myeloma (n= 2). At time of transplant, 9 patients had standard risk disease and 39 had high risk disease. All patients except one underwent conditioning with busulfan (≤ 6.4 mg/kg) and fludarabine. Five patients had graft versus host disease (GVHD) prior to relapse. The median time to frank or impending relapse was 105 days (range 57-360) after HCT. The median interval between starting and completing IS taper was 30 days (range 0-251), but 13 patients could not come off IS completely due to GVHD. The median time to documented response after initiation of IS taper was 77 days (range 14-189). Thirty-five patients had a complete response and the remaining 13 patients had a partial response. Nine patients subsequently relapsed late after initial response to IS taper at a median time of 2.38 years (range 0.88-3.95). Forty-five of the 48 patients developed or had a flare of previous GVHD as a consequence of IS taper. Of these, 26 patients had grade II-IV acute GVHD and 19 had chronic GVHD. The median time to developing GVHD after starting IS taper was 39 days (range 7-261 days). Twenty-five patients died during follow-up (10 from GVHD, 6 from disease, 7 from infection, 1 from congestive heart failure and 1 unknown). The median follow-up time among survivors was 4 years (range 1.6, 9.4). The median overall survival (OS) time from IS taper was 4.78 years (95% CI 2.93-7.35, see figure). The 4 year overall survival was 56%. There was no difference in survival for those with frank or impending relapse. Conclusion: Immunosuppression taper alone in patients who relapse early after RIC HCT can produce durable remissions but is almost always associated with development of GVHD. Understanding the clinical, molecular and immunologic characteristics of underlying disease will allow us to better predict who will respond to this manipulation. When feasible, this strategy should be given sufficient time to allow for a GVT response to develop in order to possibly avoid the adverse effects of more aggressive therapies. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.