scholarly journals Connect ® Lymphoma Disease Registry: A US-Based, Prospective, Observational Cohort Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1460-1460
Author(s):  
Christopher R. Flowers ◽  
David Andorsky ◽  
John M. Burke ◽  
James R. Cerhan ◽  
David L. Grinblatt ◽  
...  
Keyword(s):  
Patient Outcomes ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Disease Registry ◽  
Free Survival ◽  
Large B Cell Lymphoma ◽  
Emerging Therapies ◽  
Car T ◽  
Observational Cohort ◽  
Grade 3

Abstract Introduction: Non-Hodgkin lymphoma (NHL) constitutes ~40% of hematologic malignancies and, in 2020, resulted in 19,940 deaths in the USA. The most common NHL subtypes are diffuse large B-cell lymphoma (DLBCL), including primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma (FL). Although a majority of patients respond to standard-of-care therapy, many patients with NHL eventually relapse, highlighting the need for additional treatments. Real-world data regarding the safety and efficacy of emerging therapies in the relapsed/refractory (R/R) population, and the association between treatment patterns and patient outcomes, are limited. These data could provide unique insights to clinical and health-related quality of life (HRQoL) outcomes in patients with DLBCL, FL, or PMBCL treated with emerging therapies, especially novel options such as chimeric antigen receptor (CAR) T cell therapies. Methods: The Connect ® Lymphoma Disease Registry (NCT04982471) is a US-based, multicenter, prospective observational cohort study of patients with R/R NHL (DLBCL, FL, and PMBCL). Approximately 2100 patients ≥ 18 years of age from ~200 community oncology (~80%) or academic (~20%) sites will be enrolled over a ~3-year period. Patients with histologically confirmed NHL subtypes will be enrolled into 1 of 4 cohorts: first R/R DLBCL, second R/R DLBCL, first R/R FL, or first R/R PMBCL (Figure). Patients will be required to have begun second- (first R/R) or third- (second R/R) line systemic treatment within 60 days prior to enrollment. Patients receiving treatment for any active malignancy other than DLBCL, FL, or PMBCL at the time of enrollment, or who are diagnosed with any other malignancy in the 6 months prior to enrollment, will be excluded. All treatment and management decisions will be determined by the practicing clinicians. Patients may undergo hematopoietic stem cell transplantation, CAR T cell therapy, or other treatments at other sites while participating in this study. Patients will be followed from enrollment for up to 5 years or until death, withdrawal of consent, loss to follow-up, or study termination, whichever occurs first. Data collection will occur at enrollment (baseline) and then every ~3 months. The main objectives of the Connect ® Registry are to describe patient characteristics, practice patterns, and factors associated with treatment choice, sequencing, and effectiveness in NHL subtypes. Secondary objectives include describing treatment regimen safety, patient-reported outcomes (PROs) including HRQoL, and healthcare resource utilization outcomes. Exploratory objectives include tumor and blood biomarker evaluation and understanding the availability of social support and its impact on long-term treatment decision-making. Case report forms will be used to collect clinical and treatment data, including baseline demographics, clinical characteristics, treatment details and response, and socioeconomic factors. Outcome measures for efficacy will be progression-free survival, event-free survival, objective response rate, time to next treatment, and overall survival. The availability of social support will be assessed via a specific questionnaire administered at baseline. General (EQ-5D-5L) and disease-specific (FACT-Lym) questionnaires will also be administered. Patients may also optionally agree to release tumor biopsies and blood samples for biomarker analysis. Clinicians will be required to report serious adverse events (AEs), secondary primary malignancies, and confirmed COVID-19 infections within 24 hours. Non-serious AEs of interest include grade 1-3 cytokine release syndrome, grade 1-3 neurotoxicity, grade 3 colitis, grade 3 arrhythmia, grade 3 hemorrhage. Other AEs of interest to be collected include grade 3 hypogammaglobulinemia, prolonged grade 3 cytopenia, and grade 3 infections. Data collected in the Connect ® Registry will increase understanding of the association between emerging therapies and patient outcomes for R/R DLBCL, FL, and PMBCL. Study support: Bristol Myers Squibb Figure 1 Figure 1. Disclosures Flowers: Amgen: Research Funding; Janssen: Research Funding; Biopharma: Consultancy; Ziopharm: Research Funding; Burroughs Wellcome Fund: Research Funding; Nektar: Research Funding; Karyopharm: Consultancy; Iovance: Research Funding; Allogene: Research Funding; AbbVie: Consultancy, Research Funding; Cellectis: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; BeiGene: Consultancy; Kite: Research Funding; EMD: Research Funding; Genentech/Roche: Consultancy, Research Funding; Morphosys: Research Funding; Adaptimmune: Research Funding; Novartis: Research Funding; Epizyme, Inc.: Consultancy; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Acerta: Research Funding; 4D: Research Funding; Denovo: Consultancy; Celgene: Consultancy, Research Funding; Guardant: Research Funding; Genmab: Consultancy; Gilead: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; SeaGen: Consultancy; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Takeda: Research Funding; National Cancer Institute: Research Funding; TG Therapeutics: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Xencor: Research Funding; Pharmacyclics: Research Funding. Andorsky: Celgene/Bristol Myers Squibb: Research Funding; AbbVie: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; AstraZeneca: Other: served on steering committees; Epizyme: Research Funding; AbbVie: Research Funding. Burke: SeaGen: Consultancy, Speakers Bureau; X4 Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Verastem: Consultancy; AstraZeneca: Consultancy; MorphoSys: Consultancy; Adaptive Biotechnologies: Consultancy; Roche/Genentech: Consultancy; Epizyme: Consultancy; Kura: Consultancy; AbbVie: Consultancy; Beigene: Consultancy, Speakers Bureau; Kymera: Consultancy. Cerhan: Genentech: Research Funding; NanoString: Research Funding; Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; Regeneron Genetics Center: Other: Research Collaboration. Grinblatt: Astellas Pharma, Inc.: Consultancy; Bristol Myers Squibb: Consultancy; Astra Zeneca: Consultancy; AbbVie: Consultancy. Toomey: Bristol Myers Squibb: Consultancy. Zelenetz: Gilead: Honoraria, Research Funding; Verastem: Honoraria; Novartis: Honoraria; MEI Pharma: Honoraria, Research Funding; SecuraBio: Honoraria; Abbvie: Honoraria, Research Funding; MorphoSys: Honoraria; Pharmacyclics: Honoraria; AstraZeneca: Honoraria; LFR: Other; Genentech/Roche: Honoraria, Research Funding; NCCN: Other; MethylGene: Research Funding; Beigene: Honoraria, Other, Research Funding; BMS/Celgene/JUNO: Honoraria, Other; Amgen: Honoraria; Gilead: Honoraria; Janssen: Honoraria. Sullivan: Bristol Myers Squibb: Current Employment, Current holder of individual stocks in a privately-held company. Flick: Bristol Myers Squibb: Current Employment. Kiselev: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Kaplan: Bristol Myers Squibb: Current Employment. Ahn: Bristol Myers Squibb: Current Employment.

scholarly journals MSKCC Early Experience Using Radiotherapy As a Bridging Strategy for Relapsed Diffuse Large B Cell Lymphoma before CD19 CAR T Therapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3238-3238 ◽  
Author(s):  
Brandon Imber ◽  
M. Lia Palomba ◽  
Carl DeSelm ◽  
Connie Lee Batlevi ◽  
Parastoo B. Dahi ◽  
...  
Keyword(s):  
Family Member ◽  
Board Of Directors ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Equity Ownership ◽  
Grade 3 ◽  
Bridging Strategy

Background: CD19-targeted chimeric antigen receptor T cell (CAR T) therapies have remarkable overall response rates (ORR) for relapsed diffuse large B cell lymphoma (DLBCL). There is strong rationale to use a radiotherapy (RT) bridge during the cell manufacturing process including palliation, local control and cytoreduction with limited count impact. Recent data from our institution suggests RT may augment an immune response and sensitize antigen negative cells to CAR-mediated death. This series details our early experience using RT conditioning. Methods: 13 patients (median age 64 years) with DLBCL (n=9) or transformed follicular lymphoma (n=4) were analyzed. Overall, patients had a median of 2 prior therapies (range 1-8) including 3 with autologous transplant, 3 with distant RT and 1 with CAR T infusion. Several CAR products were used, including axicabtagene ciloleucel (n=8), JCAR017 (n=3, per NCT02631044), tisagenlecleucel (n=1) and EGFRt/19-28z/4-1BBL "armored" CAR (n=1, per NCT03085173). Most patients (n=10) began RT post apheresis with median duration between RT and CAR infusion of 20d (range 13-80, Figure 2). The most common RT regimen (n=8) was 20 Gy in 5 fractions (range 20-47 Gy) but 2 received our pre-transplant regimen of 30 Gy in 20 BID fractions. None received concurrent chemotherapy with RT but one had a cycle post RT and pre CAR. All had cyclophosphamide and fludarabine lymphodepletion. PET response was evaluated by Lugano criteria. Results: Three patients had limited stage PET avid disease at RT and were treated comprehensively pre-CAR. The remaining 10 were advanced stage and were treated palliatively to limited sites. Irradiated sites included the pelvis/groin (n=4), neck (n=3), intraabdominal (n=2) and extremity (n=2). Most (n=10) had intensity modulated radiotherapy. RT fields were large (median planning treatment volume of 887 cc, range 163-1641). Post RT PET interpretation was challenging given a short interval since RT ended (median 11d) but of 11 evaluable patients, many (n=8, 73%) had partial response (PR). Though locally controlled, most (n=10, 91%) had out of field progressive disease (PD) pre-CAR. Post CAR T, no severe adverse events in the RT field were noted, 9/13 had cytokine release syndrome (n=1 grade 3, n=2 grade 2) and 4 had neurotoxicity (n=3 grade 3). At day 30, ORR was 90%; of 10 evaluable patients, 7 had complete response (CR) and 2 had partial response (PR). Of the 7 evaluable patients at day 90, 4 (57%) had continued CR and the other 3 (43%) had PD and subsequently died from DLBCL. One relapsed at 95d post armored CAR both in and out of the RT field, and the other relapsed at 64d post JCAR017 primarily out of field. Conclusions: Use of RT as a CAR T bridging strategy is feasible and associated with excellent pre-CAR local control and initial post CAR ORR in a cohort of heavily pre-treated DLBCL patients. We observed moderate serious CAR toxicity that did not appear to be augmented by RT. Future efforts should clarify the optimal RT timing/dose and assess the potential for incremental immunogenicity with combined therapy. Disclosures Palomba: Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights . Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Giralt:Celgene: Consultancy, Research Funding; Takeda: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Noy:Medscape: Honoraria; Prime Oncology: Honoraria; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding; NIH: Research Funding; Janssen: Consultancy. Park:Amgen: Consultancy; Autolus: Consultancy; AstraZeneca: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Allogene: Consultancy. Sauter:Juno Therapeutics: Consultancy, Research Funding; Genmab: Consultancy; GSK: Consultancy; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Kite/Gilead: Consultancy; Precision Biosciences: Consultancy; Sanofi-Genzyme: Consultancy, Research Funding. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Shah:Janssen: Research Funding; Amgen: Research Funding. Sadelain:Memorial Sloan Kettering Cancer Center: Employment; Juno Therapeutics: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics: Consultancy, Patents & Royalties. Perales:Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; MolMed: Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding.

scholarly journals End of Phase 1 Results from Zuma-6: Axicabtagene Ciloleucel (Axi-Cel) in Combination with Atezolizumab for the Treatment of Patients with Refractory Diffuse Large B Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4192-4192 ◽  
Author(s):  
Caron A. Jacobson ◽  
Frederick L. Locke ◽  
David B. Miklos ◽  
Alex F. Herrera ◽  
Jason R. Westin ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Grade 3

Abstract Background: Axi-cel is a US FDA-approved autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for treatment of adult patients (pts) with relapsed or refractory large B cell lymphoma after ≥ 2 prior lines of therapy. In ZUMA-1, the pivotal study of pts with refractory large B cell lymphoma, the objective response rate (ORR) was 82%, including a 58% complete response (CR) rate (Neepalu and Locke, et al. N Engl J Med. 2017). Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events were observed in 12% and 31% of pts, respectively, and were generally reversible. Checkpoint proteins, such as PD-1 and PD-L1, have been shown to be expressed on both CAR T cells and in the tumor microenvironment and subsequently upregulated after CAR T cell infusion (Vranic, et al. PLoS One. 2017; Cherkassky, et al. J Clin Invest. 2016; Galon, et al. ASCO 2017. #3025). This suggests that axi-cel activity could be augmented by incorporating PD-L1 blockade. This end of Phase 1 analysis of ZUMA-6 examines the safety and preliminary efficacy of axi-cel in combination with the anti-PD-L1 antibody atezolizumab (atezo) in pts with refractory diffuse large B cell lymphoma (DLBCL; NCT02926833). Methods: Eligible pts (≥ 18 years) with refractory DLBCL, defined as stable or progressive disease to last line of therapy or relapse within 12 months after autologous stem cell transplant, must have recieved prior CD20-targeting and anthracycline-containing regimen and had ECOG ≤ 1 and adequate bone marrow and organ function. Pts received low-dose conditioning with fludarabine 30 mg/m2/day and cyclophosphamide 500 mg/m2/day × 3 days followed by axi-cel infusion at a target dose of 2 × 106 cells/kg. Atezo was administered at 1200 mg every 21 days for 4 doses starting on Day 21, 14, and 1 post-axi-cel infusion for Cohorts 1, 2, and 3, respectively. This report describes Phase 1 results from all 3 cohorts. Incidence of dose-limiting toxicities (DLTs) was the primary endpoint. Secondary endpoints included the frequency of adverse events (AEs), disease response, pharmacokinetics, and biomarkers. Results: As of January 19, 2018, 12 pts have received axi-cel and at least 1 dose of atezo (3 in Cohort 1; 3 in Cohort 2, 6 in Cohort 3). Median age was 55 years (range, 30 - 66). Most pts (9/12, 75%) had received ≥ 3 prior therapies, and 4 pts (33%) had an International Prognostic Index score of 3 or 4. The median follow-up from axi-cel infusion was 4.4 months (range, 0.8 - 12.6), with 50% of pts having ≥ 6 months of follow-up. Eight pts (67%) have received all 4 doses of atezo, and 11/12 pts have received all scheduled doses of atezo. One pt in Cohort 3 experienced a DLT of Grade 4 thrombocytopenia and neutropenia lasting longer than 30 days. All pts experienced at least 1 AE (92% Grade ≥ 3), with no apparent exacerbation or recurrence of axi-cel-related toxicity following atezo infusion. Only 1 Grade ≥ 3 AE was attributed solely to atezo. Overall, the most common grade ≥ 3 AEs were anemia (9/12, 75%), encephalopathy (5/12, 42%), and neutropenia (5/12, 42%). Grade ≥ 3 CRS and neurologic events occurred in 3 (25%) and 6 (50%) pts, respectively. The ORR in evaluable pts was 9/10 (90%), with 6 pts (60%) in CR and 3 (30%) in partial response (PR); 2/6 pts (33%) had converted to CR at month 6 and month 9 after initially achieving a PR. CAR T cell expansion as measured by area under the curve in the first 28 days (AUC0-28) was over 2-fold higher in ZUMA-6 than the median observed in pts with DLBCL in ZUMA-1 (ZUMA-6: median, 823 cells/µL × days, range, 99 - 2301; ZUMA-1: median, 357 cells/µL × days, range, 5 - 11,507; Figure). Median CAR T cell levels remained higher than ZUMA-1 beyond 28 days. However, initial peak CAR T cell levels were similar (ZUMA-6: median, 68 cells/µL, range, 9 - 274; ZUMA-1: median, 32 cells/µL, range, 1 - 1513). Interferon-γ (IFNγ) levels peaked within the first week after axi-cel infusion and reached a median of 730.5 pg/mL (range, 212 - 1876). The median peak IFNγ level in pts from ZUMA-6 was 1.5-fold higher than that from pts enrolled in Cohort 1 of ZUMA-1 (493.8 pg/mL, range, 32.4 - 1876). Conclusions: PD-L1 blockade with atezo following axi-cel infusion has a manageable safety profile, with a low incidence of DLTs and no clinically significant evidence of increased incidence of AEs. Encouraging efficacy results support the opening of Phase 2 of ZUMA-6 in which 22 pts will be treated according to the Cohort 3 schedule. Pharmacokinetic data suggest the potential for enhanced CAR T cell expansion. Figure. Figure. Disclosures Locke: Kite Pharma: Other: Scientific Advisor; Novartis Pharmaceuticals: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy. Miklos:Kite - Gilead: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Pharmacyclics - Abbot: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Genentech: Research Funding; Janssen: Consultancy, Research Funding. Herrera:Merck, Inc.: Consultancy, Research Funding; Immune Design: Research Funding; Pharmacyclics: Consultancy, Research Funding; KiTE Pharma: Consultancy, Research Funding; Seattle Genetics: Research Funding; Gilead Sciences: Research Funding; AstraZeneca: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Westin:Apotex: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Lee:Kite Pharma, Caladrius Biosciences: Employment; Kite Pharma, Caladrius Biosciences: Equity Ownership; Kite Pharma: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Rossi:KITE: Employment. Zheng:Kite Pharma: Employment. Avanzi:Kite Pharma: Employment. Roberts:KITE: Employment. Sun:Kite, a Gilead Company: Employment.

scholarly journals Lenalidomide/RCHOP (R2CHOP) Produces High Response Rates and Overall Survival in New, Untreated Diffuse Large B Cell Lymphoma Transformed from Follicular Lymphoma- Results from MC078E

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 47-48
Author(s):  
Sanjal H Desai ◽  
Betsy Laplant ◽  
William R. Macon ◽  
Rebecca L. King ◽  
Yucai Wang ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Free Survival ◽  
Large B Cell Lymphoma ◽  
Pet Ct ◽  
Grade 3 ◽  
Large B Cell

Introduction: Transformation of low grade follicular lymphoma (FL) to diffuse large B cell lymphoma (DLBCL) carries a poor prognosis. In retrospective studies, 5-year survival of transformed DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) without autologous stem cell transplant is 40-60%, underscoring need to improve frontline treatment of transformed DLBCL beyond R-CHOP. The overall response rate (ORR) to lenalidomide used as a single agent for relapsed transformed non Hodgkin lymphoma was 45% with 21% complete response (CR) rate and a median duration of response of 12 months (Witzig et al, Ann Onc 2011). These data provided the rationale to include patients with transformed DLBCL (with historical and concurrent FL) in MC078E, a phase II clinical trial testing lenalidomide plus R-CHOP (R2CHOP) for patients with new and untreated de novo and transformed DLBCL (NCT00670358). Here we present analysis of the subset of transformed DLBCL patients. Methods: Adult patients with transformed DLBCL and either historical or concurrent FL, stage >=2, measurable disease by Positron Emission Tomography/computed tomography (PET/CT) and adequate organ function were included. Patients with Central Nervous System (CNS) involvement, significant comorbidities, active non-lymphomatous malignancy, life-threatening thromboembolism (TE) and contraindication to aspirin prophylaxis were excluded. Study participants received up to 6 cycles of rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and vincristine (1.4 mg /m2) on day 1, prednisone (100 mg) on day 1-5, pegfilgrastim on day 2, and Lenalidomide 25 mg day 1-10 of 21 day cycle. Tumor lysis prophylaxis was per local practice; patients also received TE prophylaxis with aspirin. Primary outcome was event free survival (EFS) at 12 months, where an event was defined as death, progression or subsequent anti-lymphoma therapy. Secondary outcomes included ORR, CR, progression free survival (PFS), and overall survival (OS). Response was evaluated by PET/CT after cycle 2 and cycle 6 with revised response criteria (Cheson et al, 2007). Adverse events were recorded according to CTCAE version 3.0. The Kaplan-Meier method was used to estimate time to event endpoints. Results: Thirty-nine patients were accrued from August 5, 2013 to July 28, 2020 and 33 were eligible by central pathology review. Median age was 64 (range 24-80) years and 18 (54%) were >60 years old. Eighteen (54%) were male, and 32 (97%) had ECOG performance status <2. Twenty-three (70%) had historical FL and 10 (30%) had concurrent FL. Twenty-six (79%) had advanced stage (III-IV). Median number of extra nodal sites were 1 (0-4). Thirteen (39%) had high international prognostic index (IPI) (4-5). Thirty-two (97%) completed at least 2 cycles (30 completed all 6 cycles) and were evaluable for response. ORR was 97% (32/33), 29 (88%) had CR and 3 had PR. EFS at 12 months was 87.9% (95% CI: 71.8, 96.6). Two-year PFS and OS were 84.5% (95% CI: 72.8%-98%) and 96.9% (95% CI: 91-100%) (Figure 1). Twenty nine completed study protocol, 4 discontinued protocol early for disease progression (1), adverse event (AE) (1), refusal (1) and noncompliance (1). Thirty (91%) had hematologic AE of grade 3 or above, 27 (82%) had neutropenia, 16 (48%) had thrombocytopenia, and 7 (21%) had anemia. Sixteen (48%) had grade 3 or above non-hematologic AE. Eight (24%) had febrile neutropenia. There were 3 deaths on this study, 1 due to progressive DLBCL, 1 due to AML and 1 due to malignant melanoma. Conclusion: R2CHOP appears effective in transformed DLBCL with high response rates, event free, progression free and overall survival seen in current study. This study supports the inclusion of anthracycline naive patients with transformed DLBCL in future randomized studies of lenalidomide or other novel immunomodulatory (IMiD) analogues. Disclosures Wang: Novartis: Research Funding; Innocare: Research Funding; Incyte: Research Funding. Ansell:Bristol Myers Squibb: Research Funding; Takeda: Research Funding; AI Therapeutics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; ADC Therapeutics: Research Funding. Witzig:Spectrum: Consultancy; Immune Design: Research Funding; Karyopharm Therapeutics: Research Funding; Acerta: Research Funding; Incyte: Consultancy; AbbVie: Consultancy; MorphSys: Consultancy; Celgene: Consultancy, Research Funding. Nowakowski:Celgene/BMS: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy; Kymera: Consultancy; Curis: Consultancy; Seattle Genetics: Consultancy; NanoString: Research Funding.

R-CHOEP-14 × 6 Followed by Systemic CNS Prophylaxis for Diffuse Large B-Cell Lymphoma/Follicular Lymphoma Grade 3 with Age Adjusted IPI Score 2–3: Final Results of a Nordic Lymphoma Group Phase 2 Study Including 156 Patients Aged 18–65 Years.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2805-2805 ◽  
Author(s):  
Harald Holte ◽  
Sirpa Leppä ◽  
Magnus Bjorkholm ◽  
Øystein Fluge ◽  
Sirkku Jyrkkiö ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Cns Prophylaxis ◽  
Large B Cell Lymphoma ◽  
Residual Masses ◽  
Grade 3 ◽  
Large B Cell

Abstract Abstract 2805 CHOP – based chemotherapy for aggressive lymphomas in patients with age-adjusted International Prognostic Index (IPI) score of 2–3 resulted in a historical 3-year progression free survival of approximately 30% in a previous Nordic phase III study. The aim of the present study is to determine whether an intensified regimen with chemoimmunotherapy and CNS prophylaxis improves outcome. Methods: From October 2004 to June 2008 patients were included in a phase II study. Inclusion criteria: 1) Age 18–65 years. 2) Newly diagnosed de novo diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) grade III. 3) No clinical sign of CNS disease and negative CSF cytology/flow cytometry by lumbar puncture. 4) No HIV infection. 5) WHO performance score 0–3. 6) Adequate organ functions. Schedule: Six courses of R-CHOEP14. Pegfilgrastim 6 mg sc. day four of each cycle. One course of high dose cytarabine 12 g/m2 (6 g/m2 for patients 60–65 years). One course of high dose methtrexate 3 g/m2 (1 g/m2 for patients 60–65 years). Biopsy and/or 18FDG PET/CT imaging of residual masses after fulfilled therapy was recommended, but not mandatory. Radiotherapy was given to residual masses of uncertain significance. Results. Demographic data:.156 eligible patients were included (97 males). Median age: 54 years (range 20–64). Histology: DLBCL: 145, FL grade 3: 12 (three patients no data). Age adjusted IPI score: 2: 117; 3: 39. Stage III-IV: 150 patients. LDH elevated: 151 patients. Performance status 2–3: 51 patients. B-symptoms were registered in 97 patients, more than one extranodal site in 42 and bulky lesions (≥ 10 cm) in 68. Median observation time for patients alive at last follow up was 36 months. Toxicity: Three toxic deaths are registered, one large bowel perforation, one fulminant hepatic necrosis and one septic shock. Hematological toxicity grade 4 was seen in 78% of the patients, infection grade 4 in 8%. Radiotherapy was given to 16% of the patients. Response: Response rates at end of therapy: CR/CRu: 69%, PR: 22%, SD: 1%, PD: 4.5%. Seventeen patients (7%) were not treated according to protocol, either due to lack of response (6 patients) or due to toxicity (eleven patients). The majority of the PR patients were considered to have residual masses and not viable tumour tissue. Survival: Three year overall survival was 80% (95% CI +/− 6.5%) and three year treatment failure free time 67% (95% CI +/−8.0%). CNS events: Seven patients had a CNS relapse, all but one were isolated (4 intracerebral, 3 meningeal). All CNS relapses occurred within 6 months after inclusion. Conclusions: The results are promising with a low three year treatment failure rate, a low toxic death rate and fewer CNS events than expected. The CNS events might be further reduced by earlier CNS prophylaxis. The study was supported by an unrestricted grant from Amgen Disclosures: Holte: Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. LeppÃ: Roche: Honoraria. Bjorkholm:Roche: Research Funding. Jyrkkiö:Roche: Honoraria. Kolstad:Roche: Honoraria; Amgen: Honoraria. Fosså:Roche: Honoraria. φstenstad:Roche: Honoraria; Amgen: Honoraria. Eriksson:Amgen: Research Funding.

Rituximab and CODOX-M / IVAC Without Stem Cell Transplantation For Poor Risk Diffuse Large B Cell Lymphoma (IPI3-5) and Burkitts Lymphoma Is Feasible and Gives a High Response Rate: Preliminary Results Of a Phase 2 UK National Cancer Research Institute Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4348-4348 ◽  
Author(s):  
Andrew McMillan ◽  
Kirit M Ardeshna ◽  
Jo Gambell ◽  
Andrew Jack ◽  
Amy Kirkwood ◽  
...  
Keyword(s):  
Research Funding ◽  
Response Rate ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Poor Risk ◽  
Large B Cell Lymphoma ◽  
Pet Scanning ◽  
Burkitts Lymphoma ◽  
Grade 3 ◽  
Large B Cell

Abstract Introduction R-CHOP is the standard of care for patients with diffuse large B cell lymphoma (DLBCL) however poor risk patients (IPI 3-5) still have an inadequate outcome. Neither first remission high dose chemotherapy and peripheral blood stem cell transplantation (HDC+PBSCT) nor selection of cases for intensification by interim PET scanning have demonstrated a proven benefit. In the case of Burkitts lymphoma (BL) there is a paucity of data on the addition of Rituximab to the CODOX-M and IVAC regimen. Patients and Methods 113 patients with DLBCL and 37 with BL were recruited from 53 UK sites between May 2008 and April 2013. Median age was 49 years (18-65). For DLBCL patients IPI scores were 3 – 72 ( 64%), 4 -40 (35%) and 5 – 1 (1%). All patients received the modified CODOX-M and IVAC regimen including all CNS directed therapy( Mead et al Ann Oncol. 2002 Aug;13(8):1264-74) and 8 doses of rituximab. The primary end point of the study was Progression Free survival (PFS) and secondary endpoints included toxicity and CR rate. Results The main toxicities reported were neutropenia ( 89% grade 3 or 4), thrombocytopenia (84.2% grade 3 or 4), infection 61.6% grade 3 or 4 and mucositis (30.1% grade 3 or 4). 4 patients were excluded from toxicity assessment as they did not start therapy after registration. There were 8 treatment related deaths observed (infection with neutropenia (5), GI haemorrhage (1), acute cerebral haemorrhage (1) and bowel perforation (1) ). 78 patients with DLBCL and 31 with BL have completed all therapy ( 78.5 % of patients with available data) with an overall response rate of 92 % for DLBCl and 94% for BL. In patients who completed all therapy CR was achieved in 34 (44%), CR (u) in 8 (10%) and PR in 30 (38%) for DLBCL patients and CR was achieved in 21 (68%), CR (u) in 6 (19%) and PR in 2 (6%) in BL patients. 3 patients ( 2 DLBCL and 1 BL) who progressed during therapy have been included in the response analysis. End of treatment PET scanning was not obligatory. 80 patients with DLBCL and 30 patients with BL remain alive and without progression at a median follow up of 18.6 and 19.3 months respectively. Conclusion The R-CODOX-M -R-IVAC regimen can be delivered to patients with poor risk DLBCL in a multicentre setting. High rates of haematological toxicity and consequent infection are inevitable with treatment of this intensity but appear acceptable when compared with other treatments such as HDC+PBSCT. Response rates are encouraging in view of the very poor risk IPI profile of the patients included in this study. Burkitts lymphoma patients also achieved an excellent response rate with no apparent additional toxicity attributable to the addition of rituximab to the regimen. We currently plan the first analysis for the primary endpoint of PFS in 2015. The Trial was supported by Leukaemia and Lymphoma Research (LLR). Disclosures: McMillan: Roche: Consultancy, Honoraria; Amgen: Research Funding. Off Label Use: Rituximab usage in Burkitts Lymphoma. Ardeshna:Roche: Honoraria, Research Funding. Jack:Roche/Genentech: Research Funding. Patmore:Roche: Consultancy, Honoraria. Pettengell:Roche: Honoraria; Amgen: Honoraria. Linch:Roche: Honoraria, Research Funding.

Phase II Study Of Anti-CD19 Antibody Drug Conjugate (SAR3419) In Combination With Rituximab: Clinical Activity and Safety In Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (NCT01470456)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4395-4395 ◽  
Author(s):  
Bertrand Coiffier ◽  
Catherine Thieblemont ◽  
Sophie de Guibert ◽  
Jehan Dupuis ◽  
Vincent Ribrag ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Duration Of Response ◽  
Grade 3

Abstract Background SAR3419 is a humanized anti-CD19 antibody conjugated to maytansin DM4, a potent cytotoxic agent. SAR3419 targets CD19, an antigen expressed in the majority of B cell non-Hodgkin lymphomas (NHL). The recommended dose for single agent SAR3419 was previously determined to be 55 mg/m2 administered IV every week for 4 weeks, then bi-weekly. In phase I, clinical activity was shown mainly in patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). (Trial funded by Sanofi). Methods Patients (pts) with a CD20+ and CD19+ DLBCL relapsing or refractory (R/R) after at least 1 standard treatment including rituximab and not candidate for or who already underwent transplantation, were eligible. Refractory disease was defined as unresponsive to or progressing within 6 months of regimen completion. Fresh (or recent formalin-fixed, paraffin-embedded) biopsy was required before SAR3419 start. Pts received 375 mg/m2 of rituximab (R) IV and 55 mg/m² of SAR3419 on day 1, 8, 15, 22 (35-day cycle 1), followed by bi-weekly R and SAR3419 at the same doses for 2 additional 28-day cycles, provided there was no disease progression or other study discontinuation criteria met. The primary objective was the overall response rate (ORR) following Cheson 2007 criteria, with the first tumor assessment being done 42 days after the last study treatment administration. Secondary objectives were: safety, pharmacokinetics (PK), duration of response (DOR), progression free survival (PFS), overall survival (OS) and correlation of the antitumor and biological activity of the combination with tumor biomarker status. Results Fifty-three pts were enrolled, 52 treated. Median age was 66.5 years (range 38-85), 50% were male; 23%, 33% and 40% of patients had received 1, 2 or ≥3 prior chemo/immunotherapy regimens for DLBCL, respectively. Of the enrolled patients, 3.8% had received no prior regimen for DLBCL and therefore were excluded from primary analysis for efficacy. Seventy-three percent had stage III/IV disease, 59% had elevated lactate dehydrogenase (LDH), and 63% had bulky disease. Sixty percent were refractory to first regimen (primary refractory), 16% were refractory to last regimen and 24% were relapsed pts. The ORR in the per-protocol population (n=45) was 31.1% (80% confidence interval (CI): 22.0% to 41.6%). Among the 14 responders, 5 had progressed at the time of analysis, with duration of response beyond 6 months for 3 of them. The ORR was 58.3% (80% CI: 36.2% to 78.1%) for patients with relapsed DLBCL (n=12), 42.9% (80% CI: 17.0% to 72.1%) for pts refractory to last regimen (n=7) and 15.4% (80% CI: 6.9% to 28.4%) for primary refractory pts (n=26). Overall survival and PFS data are not yet mature. Biomarkers and PK data will be presented at the meeting. The most common (≥10%) all grades non-hematologic treatment-emergent adverse events (TEAEs) were asthenia (25.0%), nausea (21.2%), cough (19.2%), diarrhea (17.3%), weight decrease (17.3%), vomiting (15.4%), dyspnea (15.4%), abdominal pain (13.5%), back pain (13.5%), pyrexia (13.5%) and constipation (11.5%). Related grade 3-4 TEAEs were: 1 syncope, 1 bronchospasm, 2 neutropenia and 1 anemia. No TEAEs led to treatment discontinuation, no grade 3-4 peripheral neuropathy or grade 3-4 ocular events were observed. Two pts experienced grade 2 keratitis, both rapidly recovered with local treatment. Hematological toxicity was moderate, with grade 3-4 neutropenia and thrombocytopenia in 15.7% and 9.8% pts, respectively. No complications related to neutropenia were reported. Grade 3 transaminase increase was observed in 1 patient. Conclusions The combination of SAR3419 plus R showed moderate ORR in R/R DLBCL; however the study population was of poor prognosis (60% refractory to first line therapy). In the relapsed DLBCL patients a higher ORR was observed. SAR3419 plus R presented with a favorable safety profile. Further investigations on biomarker expression are ongoing to identify a sub-group of pts who could have better benefited from this combination. Disclosures: Coiffier: Sanofi: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Phase II of SAR3419. Ribrag:Johnson & Johnson: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Servier: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cartron:LFB: Honoraria; GSK: Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau. Casasnovas:Roche: Consultancy, Honoraria, Research Funding. Hatteville:Sanofi: Employment. Zilocchi:Sanofi: Employment. Oprea:Sanofi: Employment. Tilly:Amgen: Research Funding; Janssen: Honoraria; Pfizer: Honoraria; Takeda: Membership on an entity’s Board of Directors or advisory committees; Roche: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

scholarly journals Genomic Drivers of Large B-Cell Lymphoma Resistance to CD19 CAR-T Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 42-42
Author(s):  
Michael D. Jain ◽  
Bachisio Ziccheddu ◽  
Caroline A. Coughlin ◽  
Rawan Faramand ◽  
Anthony J. Griswold ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Newly Diagnosed ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Scientific Advisory ◽  
Heavily Pretreated ◽  
Advisory Role

Abstract Introduction: Anti-CD-19 chimeric antigen receptor-reprogrammed autologous T cells are breakthrough immunotherapies for heavily pretreated patients with aggressive B-cell lymphomas; however, across CAR-19 products, ~60% of patients do not achieve remission or relapse and unfortunately typically progress and rapidly die. Factors associated with impaired response to CAR-19 include inflammatory markers such as interferon signaling and clinical factors such as the need for bridging therapy and high pre-CAR-19 tumor burden, but cell-intrinsic driver of CAR-19 resistance remain largely undefined. Methods: To characterize the genomic mechanisms involved in diffuse large B cell lymphoma (DLBCL) resistance to CAR-19, we interrogated whole genome sequencing (WGS) from 28 relapsed/refractory (r/r) aggressive lymphoma patients treated with axicabtagene ciloleucel (axi-cel). The median coverage was 44.8X. To increase statistical power of analyses, we included also 50 newly diagnosed DLBCL patients from the Pan-Cancer Analysis of Whole Genomes (PCAWG). Results: As reported in other series, neither double hit cytogenetics nor MYC-BCL2 double expression associated with CAR-19 resistance, despite their negative predictive power for newly diagnosed DLBCL patients. Chapuy and LymphGen classification algorithms also demonstrated no prognostic significance. Among known mutated driver genes, only TP53 was significantly enriched in our cohort in comparison to the PCAWG cohort (p=0.002), but it did not predict poor CAR-19 outcome. Among other genes known to be involved in DLBCL pathogenesis, only mutations in NFKBIA or MYC, associated with worse PFS (p=0.04, p=0.025 respectively). Next, we identified 12 single base substitution (SBS) mutational signatures detected in our cohort of r/r lymphomas, four of which are caused by exposure to distinct chemotherapies (Landau et al., 2020, Nat Comm). The melphalan-related signature (SBS-MM1) was identified in 4 out 5 patients who received high dose melphalan followed by autologous stem cell transplant, and 75% of patients exposed to platinum had evidence of one of the three known platinum signatures. Across different SBS signatures, only presence of APOBEC (SBS2 and SBS13) associated with worse PFS with 4/5 patients progressing (p=0.03). We compared newly diagnosed and r/r DLBCL by GISTIC2.0 copy number variation (CNV) analysis, revealing three gene deletions significantly enriched in our r/r cohort: TP53, RHOA and RB1. Interestingly, the deletions involving RHOA and RB1 both independently predicted poor outcome (p=0.0007 and p=0.05 respectively) with 5/5 and 6/8 patients progressing respectively. The third, involving TP53 (46.4% of patients), had no prognostic impact but reflected the high-risk nature of the heavily pretreated tumors. WGS allows detailed identification of structural variants and complex events. Indeed, we found evidence of chromothripsis, a catastrophic event in which one or more chromosomes are shattered and aberrantly reassembles generating multiple aneuploidies, in 39.3% of r/r DLBCL. This strongly associated with poor CAR-19 outcome, with 9/11 affected cases experiencing early progression (p=0.041). Finally, reduced expression (n=3) or genomic alteration (n=3) of CD19 did not associate with poor outcome. We found one case, with durable response, containing a sub-clonal mutation in CD19 (L174V) at baseline, previously reported as associated with CAR-19 resistance. In line with recent evidence, these findings indicate that antigen-mediated tumor killing is not the only mechanism of tumor eradication, and CD19-independent resistance mechanisms predominate. Conclusions: Leveraging the high resolution of WGS, we observed that markers of genomic complexity (chromothripsis and APOBEC) and specific genomic alterations (RHOA and RB1 deletion) associate with resistance to CAR-19 immunotherapy for aggressive B-cell lymphomas. Fifteen out of sixteen patients (93.8%) who relapsed on CAR-19 contained at least one of the described genomic alterations. Recent data demonstrate that an immunosuppressed TME leads to CAR-19 failure in patients, and animal studies show activation of host T cells by CAR-T cells. Combining these findings with these genomics findings, successful CAR-19 therapy must overcome the immune-exhausted tumor microenvironment to mobilize the host immune system and eliminate the tumor. Figure 1 Figure 1. Disclosures Jain: Takeda: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria. Faramand: Novartis: Research Funding; Kite/Gilead: Research Funding. Landgren: Amgen: Research Funding; Janssen: Research Funding; Amgen: Honoraria; Celgene: Research Funding; Janssen: Other: IDMC; Janssen: Honoraria; Takeda: Other: IDMC; GSK: Honoraria. Locke: Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; Gerson Lehrman Group: Consultancy; Calibr: Consultancy, Other: Scientific Advisory Role; Janssen: Consultancy, Other: Scientific Advisory Role; Umoja: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Takeda: Consultancy, Other; Emerging Therapy Solutions: Consultancy; EcoR1: Consultancy; Cowen: Consultancy; Wugen: Consultancy, Other; Legend Biotech: Consultancy, Other; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy. Maura: Medscape: Consultancy, Honoraria; OncLive: Honoraria. Davila: Precigen: Research Funding.

scholarly journals Safety of Anti-CD-19 Chimeric Antigen Receptor T-Cell Therapy in the Older Population with Diffuse Large B Cell Lymphoma: A Meta-Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4814-4814
Author(s):  
Anosha Tariq ◽  
Vatsala Katiyar ◽  
Talha Aijaz
Keyword(s):  
Elderly Population ◽  
Meta Analysis ◽  
B Cell Lymphoma ◽  
The Elderly ◽  
Pooled Analysis ◽  
Younger Patients ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
The Mean ◽  
Grade 3

Abstract Introduction Patients with refractory or relapsed diffuse large B cell lymphoma (DLBCL) have very limited treatment options. Axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel are the Anti-CD-19 chimeric antigen receptor T-cell (CAR-T) therapy have been recently approved for refractory or relapsed DLBCL patients who have failed at least two lines of treatment. CAR-T therapy has significant adverse effects, most notably cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), limiting its use, particularly in the elderly population. In this meta-analysis, we analyzed the safety of CAR-T therapy in the elderly population compared to the younger patients with DLBCL. Methods Randomized controlled trials and observational studies in adult patients with DLBCL treated with anti-CD-19 CAR-T therapy were included in the meta-analysis. Case reports, case series, and review articles were excluded. We searched PubMed for studies published before 1st July 2021 using keywords "tisagenlecleucel," "axicabtagene ciloleucel," and "lisocabtagene maraleucel." The study selection process is shown in figure 1. Statistical analysis was performed with Comprehensive meta-analysis version 3. The fixed-effect model was used for pooled analysis. Heterogeneity across studies was analyzed using I2 statistics. Results Three studies, comprising of 616 patients, were included in the analysis. Characteristics of the study population and the number of events in each study are shown in figure 2. Two studies used a cut-off of 65 years, while one study used a cut-off of 70 years for the older population. The mean age in the younger population was 55, while the mean age in the elderly population ranged from 69 to 76. Mean follow-up ranged widely in the three studies ranging from 7 months to 27.1 months. Incidence of CRS ranged from 36% to 84% in the elderly population compared to 34% to 83% in younger patients. Grade 3 or 4 CRS ranged from 1 to 14% in the elder compared to 2 to 14% in younger patients. The pooled analysis shown in figure 3 revealed an odd ratio of 1.11 with a confidence interval ranging from 0.76 to 1.63 (p=0.58), implying there is no statistical difference between the two groups. The incidence of ICANS ranged from 27% to 65% in elderly patients compared to 8.5% to 47% in younger patients. Grade 3 or 4 ICANS ranging from 2 to 47% in elderly patients compared to 2% to 18% in younger patients. The pooled analysis shown in figure 4 showed an odd ratio of 1.59 with a confidence interval ranging from 1.09 to 2.34 (p=0.02), suggesting the risk of ICANS is higher in older patients. Conclusion CRS and ICANS are the most common adverse effects limiting the use of CAR-T therapy in the elderly. Our analysis showed that age does not impact the risk of CRS in DLBCL patients treated with anti-CD19 CAR-T treatment. However, older patients are at a higher risk of ICANS as compared to younger, suggesting CAR-T therapy should be used with caution in patients older than 65 years of age, especially if they have baseline neurological impairment. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Safety of Axicabtagene Ciloleucel CD19 CAR T-Cell Therapy in Elderly Patients with Relapsed or Refractory Large B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 96-96 ◽  
Author(s):  
Dahlia Sano ◽  
Loretta J. Nastoupil ◽  
Nathan H. Fowler ◽  
Luis Fayad ◽  
F. B. Hagemeister ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Age Groups ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Large B Cell

Abstract Background Axicabtagene ciloleucel (axi-cel) is an autologous CD19-specific CAR T-cell therapy product that was FDA approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after at least two lines of systemic therapy. In the pivotal ZUMA-1 study, the best overall response (ORR) and complete response (CR) rates observed in 108 patients treated with axi-cel were 82% and 58%, respectively. At a median follow-up of 15.4 months, 42% of the patients remain in ongoing response (Neelapu et al. N Eng J Med 2017). Analysis of efficacy outcomes in patients <65 years (N=81) and ³65 years (N=27) showed that the ORR and ongoing response at 12 months were comparable between the two subgroups (Neelapu et al. N Eng J Med 2017). Whether the safety is also comparable between the two subgroups is unknown. Here, we report safety outcomes in elderly patients (³65 years) with large B-cell lymphoma treated with axi-cel at our institution. Methods We retrospectively analyzed and reviewed the data from patients treated with axi-cel at our institution. Patients had a diagnosis of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma (HGBCL), and transformed follicular lymphoma (TFL). Patients were treated with conditioning chemotherapy with cyclophosphamide and fludarabine for 3 days followed by axi-cel infusion after 2 days of rest at a dose of 2 x 106 CAR+ T cells/kg body weight. Patients were monitored for toxicities for at least 7 days in the hospital after CAR T infusion and those who had at least 30 days of follow-up after axi-cel were considered to be evaluable for safety. Cytokine release syndrome (CRS) and neurological toxicity termed as CAR-related encephalopathy syndrome (CRES) were graded according to the CARTOX grading system (Neelapu et al. Nat Rev Clin Oncol 2018). Results A total of 61 patients with relapsed or refractory large B-cell lymphoma who received axi-cel at our institution were included. Of these, 44 (72%) patients were <65 years of age and 17 (28%) patients were ³65 years of age. The baseline characteristics of the patients are summarized in Table 1. ORR and CR rates at Day 30 were comparable between the two groups. CRS was common in both groups and was observed in 83% and 91% of the patients in the older and younger age groups, respectively. But most CRS events were grade 1-2. Grade 3 or higher CRS was observed in 18% vs. 11% in the older vs. younger age groups (P=0.67). One patient with a history of autoimmune disease in the elderly group died of hemophagocytic lymphohistiocytosis (HLH). CRES was observed in 58% and 71% of the patients in the older and younger age groups, respectively. Grade 3 or higher CRES was observed in 29% vs. 39% in the older vs. younger age groups (P=0.58). Median hospitalization period for axi-cel CAR T-cell therapy was comparable between the two groups. Conclusions Our results suggest that response rates are comparable between the elderly and younger age groups at day 30 after axi-cel therapy. Importantly, toxicities due to CRS and/or CRES after axi-cel CD19 CAR T cell therapy are comparable between the elderly (³65 years) and younger (<65 years) patients with relapsed or refractory large B-cell lymphoma. Table 1 Table 1. Disclosures Nastoupil: Merck: Honoraria, Research Funding; Janssen: Research Funding; Juno: Honoraria; Novartis: Honoraria; Genentech: Honoraria, Research Funding; TG Therappeutics: Research Funding; Karus: Research Funding; Celgene: Honoraria, Research Funding; Spectrum: Honoraria; Gilead: Honoraria. Fowler:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Samaniego:ADC Therapeutics: Research Funding. Wang:Kite Pharma: Research Funding; Acerta Pharma: Honoraria, Research Funding; Novartis: Research Funding; Juno: Research Funding; Pharmacyclics: Honoraria, Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MoreHealth: Consultancy; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Westin:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees.

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