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883 Novel Agents May be Preferable to Chemotherapy for Large B-Cell Lymphoma Progressing after CD19-CAR-T: A Multicenter Observational Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 627. Aggressive Lymphomas: Clinical and Epidemiological: Real World evidence for CAR-T Management II
Hematology Disease Topics & Pathways:
Biological, Adults, Lymphomas, Clinical Research, Health Outcomes Research, B Cell Lymphoma, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Clinically Relevant, Patient-Reported Outcomes, Diseases, Real World Evidence, Aggressive Lymphoma, Therapies, Lymphoid Malignancies, Study Population
Monday, December 13, 2021: 6:15 PM

Ana Alarcon Tomas1*, Joshua A Fein, MD2, Shalev Fried, BSc3,4*, Warren Fingrut, MD5,6, Theodora Anagnostou, MD1*, Anna Alperovich, MD7, Nishi Shah, MD7, Ellen Fraint, MD8, Richard J Lin, MD, PhD9, Michael Scordo, MD10, Aishat Olaide Afuye, BA11*, Connie Lee Batlevi, MD, PhD1,12, Michal Besser, PhD13,14*, Parastoo B Dahi, MD9*, Ivetta Danylesko15*, Sergio Giralt, MD9,16*, Brandon S. Imber, MD17, Elad Jacobi, MD4,18*, Arnon Nagler, M.D.19,20,21,22, M. Lia Palomba, MD23,24, Gilles Salles, MD, PhD25, Craig S. Sauter, MD1,16, Gunjan L Shah, MD11,16*, Noga Shem-Tov, MD4,26*, Avichai Shimoni, MD4,22*, Joachim Yahalom, MD1, Ronit Yerushalmi, MD4,26, Abraham Avigdor, MD26,27, Miguel-Angel Perales, MD1,28 and Roni Shouval, MD, PhD1,4,26

1Memorial Sloan Kettering Cancer Center, New York, NY
2University of Connecticut Medical Center, Farmington, CT
3Chaim Sheba Medical Center, Ramat Gan, Israel
4Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
5Stem Cell Club, Toronto, ON, Canada
6Department of Medicine, Adult Bone Marrow Transplantation Service, New York, NY
7Adult BMT Service, Memorial Sloan Kettering Cancer Center, New York, NY
8Children's Hospital at Montefiore, Stratford, CT
9Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY
10Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center/New York, New York, NY
11Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
12Weill Cornell Medicine, New York, NY
13Sackler School of Medicine, Department of Clinical Microbiology and Immunology, Tel-Aviv University, Tel-Aviv, Israel
14Chaim Sheba Medical Center, Ella Lemelbaum Institute for Immuno Oncology, Tel Hashomer, Israel
15Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
16Department of Medicine, Weill Cornell Medical College, New York, NY
17Department of Radiation Oncology, David H. Koch Center For Cancer Care At Memorial Sloan Kettering Cancer Center, New York, NY
18Department of Pediatric Hematology-Oncology, Safra Children's Hospital, Chaim Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
19EBMT, Acute Leukemia Working Party, Paris, France
20Hematology Division, Chaim Sheba Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Hashomer, Israel
21Division of Hematology, Chaim Sheba Medical Center, Tel Hashomer, Israel
22Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Ramat-Gan, Israel
23Deparment of Medicine, University Weill Cornell Medicine, New York, NY
24Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
25Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY
26Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer, Israel
27Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
28Weill Cornell Medical College, Cornell University, New York, NY

Up to 70% of large B-cell lymphoma (LBCL) patients will eventually experience relapse or progress following CD19-CAR-T therapy. Data guiding management of this challenging population are lacking. Therefore, we aimed to study the relationship between treatment strategies and outcomes following CD19-CAR-T failure.

We included 273 adults, from two centers, treated with CD19-CAR-T (axicabtagene-ciloleucel [98, 36%], tisagenlecleucel [76, 28%], lisocabtagene-maraleucel [28, 10%], and an academic CD28-product [71, 26%]) for relapsed/refractory LBCL Cumulative incidence of relapse or progression was 40% (95% CI: 34%, 46%). Of 176 patients with residual or relapsed disease post-CAR-T (Fig. A), 133 received subsequent first-line anti-cancer therapy for active or residual disease (primary cohort) at a median of 79 days (interquartile range 49-124) after CAR-T infusion.

Within the primary cohort, 65% of patients had stage III-IV disease at time of subsequent therapy. Most lymphomas remained CD19-positive after CAR-T therapy (45 biopsies, 91% positive by flow cytometry [58% normal, 33% dim expression]). At time of first treatment post-CAR-T, nearly all patients had either relapsed disease or stable/progressive disease (SD/PD), with eight patients in ongoing partial response (PR).

With a median follow-up of 14.5 months (95% CI: 11.5-21.4), the median overall survival (OS) from time of first subsequent therapy was 8.6 months (IQR 6.9-12.0). We sought to identify determinants of survival among patients receiving initial post-CAR-T treatment. Variables measured pre- and post-CAR-T therapy and significantly associated (p < 0.1) with OS in univariable Cox regression were introduced into a multivariable model. Age ≥ 65y (HR 2.01 [95% CI: 1.23-3.29], p 0.005), bulky disease at apheresis (HR 2.05 [1.07-3.95], p 0.031), and disease refractory to CAR-T therapy (HR 1.89 [1.19-2.98], p 0.007) were associated with inferior OS in the multivariable analysis. Based on the cumulative burden of OS determinants, we propose a prognostic tool allowing risk stratification of patients receiving treatment post-CAR-T. Increasing number of these three risk factors was associated with greater mortality (HR 1.86 [1.32-2.62], p<0.001; Fig. B). Six-month OS ranged from 30% (95% CI: [16-57]) with ≥ 2 factors to 76% (64-91) with none.

Therapy strategies post-CAR-T varied. Polatuzumab (n=25), anthracycline or platinum (“chemotherapy”; n=17), BTK inhibitors (n=13) and lenalidomide (n=12) based treatment were most frequently administered for non-localized disease (stage ≥2). Involved site radiation therapy (ISRT; n=20) was primarily given for stage I disease (Fig. C). Overall response rate (ORR) in the entire cohort was 47% (25% CR; 22% PR). Fig. D shows response rates by treatment. Remarkably, novel agents, including polatuzumab and lenalidomide-based therapies, had ORR of 52% (CR 35%) and 33% (CR 33%), respectively. In contrast, traditional chemotherapy-based approaches did not result in CR, and only 50% achieved PR. Survival was poorest with chemotherapy (6 month OS: 25% [95% CI: [11-59]), while rates with lenalidomide and polatuzumab-based therapies were 65% (42-100) and 67% (50-89). Patients and disease characteristics across treatment groups were unbalanced. However, the three prognostic factors comprising the OS prognostic tool: age ≥ 65y, bulky disease at apheresis and disease refractoriness to CAR-T, were similar across lenalidomide, polatuzumab, checkpoint inhibitors, and chemotherapy-based treatment groups. Patients who underwent alloHCT were significantly younger but achieved high rates of response.

In conclusion, we present the most extensive and detailed experience of treatment outcomes post-CAR-T therapy. Our data suggest that novel agents may be preferable to traditional chemotherapies as the first post-CAR-T treatment. However, survival is still poor, and investigation of curative approaches is needed. We provide a tool to inform mortality risk in this difficult-to-treat population.

Disclosures: Scordo: i3 Health: Other: Speaker; Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; McKinsey & Company: Consultancy; Omeros Corporation: Consultancy; Angiocrine Bioscience: Consultancy, Research Funding. Batlevi: Kite Pharma: Consultancy; Moderna: Current holder of individual stocks in a privately-held company; Karyopharm: Consultancy; Dava Oncology: Honoraria; Regeneron: Current holder of individual stocks in a privately-held company; Life Sciences: Consultancy; Seattle Genetics: Consultancy; TouchIME: Honoraria; Juno/Celgene: Consultancy; GLG Pharma: Consultancy; ADC Therapeutics: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; TG Therapeutics: Consultancy; BMS: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; Bayer: Research Funding; Medscape: Honoraria; Xynomic: Research Funding; Roche/Genentech: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Autolus: Research Funding; Epizyme: Research Funding. Dahi: Gilead sciences: Membership on an entity's Board of Directors or advisory committees; Kite pharma: Membership on an entity's Board of Directors or advisory committees. Giralt: PFIZER: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees; JANSENN: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees. Palomba: Pluto: Honoraria; Lygenesis: Honoraria; Magenta: Honoraria; Juno: Patents & Royalties; Wolters Kluwer: Patents & Royalties; WindMIL: Honoraria; Priothera: Honoraria; Nektar: Honoraria; Rheos: Honoraria; BeiGene: Consultancy; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Kite: Consultancy; Ceramedix: Honoraria; Notch: Honoraria, Other: Stock; Novartis: Consultancy; PCYC: Consultancy. Salles: Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Consultancy; AbbVie: Consultancy, Honoraria; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Loxo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ipsen: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Debiopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rapt: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Velosbio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allogene: Consultancy. Sauter: Genmab: Consultancy; Celgene: Consultancy, Research Funding; Gamida Cell: Consultancy; GSK: Consultancy; Bristol-Myers Squibb: Research Funding; Kite/Gilead: Consultancy; Precision Biosciences: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. Shah: Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Avigdor: Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Research Funding; Janssen: Research Funding; Takeda: Consultancy, Honoraria. Perales: Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Equilium: Honoraria; Cidara: Honoraria; MorphoSys: Honoraria; Incyte: Honoraria, Other; Servier: Honoraria; Celgene: Honoraria; Medigene: Honoraria; Kite/Gilead: Honoraria, Other; Karyopharm: Honoraria; Nektar Therapeutics: Honoraria, Other; Merck: Honoraria; Novartis: Honoraria, Other; NexImmune: Honoraria; Miltenyi Biotec: Honoraria, Other; Omeros: Honoraria; Sellas Life Sciences: Honoraria. Shouval: Medexus: Consultancy.

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