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1837 Comprehensive Characteristics and Outcomes of Myeloid Neoplasms Following Chimeric Antigen Receptor T-Cell Therapy for Other Hematologic Malignancies

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Acute Myeloid Malignancies, AML, MDS, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Chronic Myeloid Malignancies, CMML, Diseases, Therapy sequence, Treatment Considerations, Biological therapies, Myeloid Malignancies
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Danielle Hammond, MD1, Koji Sasaki, MD1, Koichi Takahashi, MD, PhD1, Elizabeth J. Shpall, MD2, Uday Popat, MD2, Betul Oran, MD, MS2, Gheath Al-Atrash, MD, PhD2*, Krina K. Patel, MD, MSc3, Jason R. Westin, MD4, Sattva S. Neelapu, MD5, Yesid Alvarado Valero, MD1, Kelly S. Chien, MD6, Naval Daver, MD7, Guillermo Montalban-Bravo, MD1, Abhishek Maiti, MBBS1, Musa Yilmaz, MD1*, Elias Jabbour, MD8, Naveen Pemmaraju, MD1, Mahesh Swaminathan, MD1, Jo Ishizawa, MD, PhD9, Nitin Jain, MD1, Alessandra Ferrajoli, MD1, Farhad Ravandi, MBBS10, Steven M. Kornblau, MD1, Gautam Borthakur, MD9, Guillermo Garcia-Manero, MD1, Hagop M. Kantarjian, MD1, Patrick K. Reville, MD, MPH1 and Hussein A. Abbas, MD, PhD1

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
3M.D. Anderson Cancer Center, MD Anderson Cancer Center, Houston, TX
4The University of Texas M D Anderson Cancer Center, Houston, TX
5Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
6Department of Leukemia, MD Anderson, Houston, TX
7MD Anderson Cancer Center, Houston, TX
8Department of Leukemia, University of Texas M.D. Anderson Cancer Ctr., Houston, TX
9Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
10Department of Leukemia, University of Texas- MD Anderson Cancer Center, Houston, TX

Introduction: Secondary myeloid neoplasms (MN) are a recognized risk following chimeric antigen receptor (CAR) T-cell therapy. Prior studies are limited to low-resolution adverse event reporting or small case series. We provide a comprehensive account of MN characteristics and outcomes following CAR T.

Methods: We reviewed our institutional experience with consecutive MN cases diagnosed after CAR T therapy for other hematologic malignancies since 2015. All preceding lines of therapy (LoT), including those administered before histologic transformation, were documented. Autologous stem cell transplant (autoSCT) was counted as a unique LoT. We compared available bone marrow samples from the immediate pre-CAR T period with those from MN diagnosis to identify clonal expansion.

Results: Of 1,484 patients treated with immune effector cells at our center, 37 (2.5%) received a subsequent MN diagnosis. Patients primarily received CD19- (81%) or BCMA- (16%) targeting CAR T products, all with fludarabine and cyclophosphamide lymphodepletion, at a median of 65 years of age (IQR 60-69) after a median of 5 (range 1-11) prior LoT for non-Hodgkin B-cell lymphoma or multiple myeloma (MM). Forty-three percent had undergone prior autoSCT with BEAM or melphalan conditioning. All patients had prior exposure to alkylating agents, and 41% had previous exposure to lenalidomide (len). Complete response rate post initial CAR T was 87%. Of the 11 patients who required additional therapy for the primary malignancy, 2 received a second CAR T infusion.

Among the patients (28 with MDS, 1 with CMML, 8 with AML) who developed a MN, 70% were male. At the time of MN diagnosis, 95% of patients had their primary malignancy in remission. Median baseline bone marrow blast percentage was 6% (IQR 2-11) and 46% of cases had ≥ 2% ring sideroblasts. Cytogenetic risk was chiefly adverse: 46% complex karyotype, 62% deletion 7/7q, 14% MECOM rearranged and 3% KMT2A rearranged. While no patients had pure erythroid leukemia, 18 had a multi-hit TP53 status per International Consensus Classification 2022 criteria. The MN was diagnosed a median of 16.1 months (IQR 8.8-24.4) following CAR T infusion, and a median of 5.5 years, 5.1 years, and 5.7 years after first autoSCT, alkylating agent, and len exposures, respectively. One third of patients received only supportive care and 65% were treated with hypomethylating agents. Most (80%) patients had no response to initial therapy. Of the 6 patients who underwent allogeneic stem cell transplant (alloSCT), 3 died from infection or graft-versus-host disease. Of the 3 patients who experienced a durable remission post alloSCT, 2 had a wild-type TP53 status.

Median overall survival (mOS) after MN diagnosis was 9.0 months (95% CI 6.1, 16.2). The majority (89%) of deaths were from MN-related complications. No statistically significant associations were identified between post MN survival and sex, age ≥ 65 years at CAR T infusion, prior autoSCT, ≥ 3 LoT pre-CAR T or TP53 status. There was an observed survival benefit with len exposure: mOS 14.3 months (95% CI 9.0, NE) with versus (vs) 5.1 months (95% CI 2.3, 16.1) without prior len exposure (p = 0.029). This association persisted when MM cases were excluded (p = 0.005). A trend towards improved survival was observed in alloSCT recipients: median OS 14.3 months with vs 7.5 months without transplant, although it did not reach statistical significance.

All 4 patients with documented TP53 mutation(s) (variant allele frequency [VAF] detection limit 0.3 to 2%) within 12 months prior to CAR T, and without active marrow involvement from the primary malignancy, demonstrated clonal expansion (relative VAF increase ≥ 50%), often accompanied by a second TP53 hit. Retrospective TP53 sequencing and T-cell profiling in available marrow samples are being explored.

Conclusions: Our incidence of MN following CAR T is reassuringly rare and comparable to an incidence of 1.4% from publicly available FDA data. The 5-year latency from pre–CAR T therapies to MN diagnosis aligns with historical therapy-related MN latencies, underscoring their role in malignant transformation. The shorter latency after CAR T therapy is confounded by lead-time bias but raises the question of whether CAR T-induced immune dysregulation amplifies clonal selection. Screening for TP53 mutations before CAR T administration may inform MN risk in a patient population now often cured of their primary malignancy.

Disclosures: Sasaki: Daiichi-Sankyo: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Enliven: Research Funding; Chugai: Other: Lecture fees; Otsuka: Other: Lecture fees. Shpall: Adaptimmune Limited: Other: Scientific Advisor; Zelluna Immunotherapy: Other: Scientific Advisor; FibroBiologics: Other: Scientific Advisor; Axio Research: Current Employment, Other: Scientific Advisor; National Marrow Donor Program: Other: Board of Directors/Management. Popat: Bayer: Research Funding; T Scan: Research Funding; Incyte: Research Funding; Abbvie: Research Funding. Patel: AstraZeneca: Consultancy; Johnson & Johnson (Janssen): Consultancy; Pfizer: Consultancy; Merck: Consultancy; Takeda: Consultancy; Genentech: Consultancy; Kite, A Gilead company: Consultancy, Other: scientific advisory board; BMS: Consultancy, Other: chair of scientific advisory board ; Poseida: Consultancy; Abbvie: Consultancy; Sanofi: Consultancy; Caribou Sciences: Consultancy; Oricel: Consultancy, Other: Chair of scientific board. Westin: Allogene: Consultancy, Research Funding; AbbVie/GenMab: Consultancy; Regeneron: Consultancy; Janssen: Consultancy, Research Funding; Kite/Gilead: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy; AstraZeneca: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Morphosys/Incyte: Consultancy, Research Funding; Nurix: Consultancy, Research Funding. Neelapu: Allogene: Consultancy, Research Funding; Merck: Consultancy; Orna Therapeutics: Consultancy; Sana Biotechnology: Consultancy, Research Funding; Carsgen: Consultancy; ImmunoACT: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Caribou Biosciences: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Athenex: Consultancy; Astellas Pharma: Consultancy; Longbow Immunotherapy: Current holder of stock options in a privately-held company; Appia Bio: Consultancy; Chimagen: Consultancy; MorphoSys: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy; Fosun Kite: Consultancy; bluebird bio: Consultancy; Sellas Life Sciences: Consultancy; Anthenex: Consultancy; Adicet Bio: Consultancy, Research Funding; Synthekine: Consultancy; Takeda: Consultancy; Precision Biosciences: Research Funding; Cargo Therapeutics: Research Funding. Alvarado Valero: FibroGen: Research Funding; Daiichi-Sankyo: Research Funding; Sun Pharma: Consultancy, Research Funding; Astex: Research Funding; Jazz: Research Funding; CytomX Therapeutics: Consultancy. Chien: AbbVie: Consultancy; Rigel Pharmaceuticals: Consultancy. Daver: Novimmune: Research Funding; Servier: Consultancy, Research Funding; Celgene: Consultancy; Syndax: Consultancy; Genentech: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Agios: Consultancy; Shattuck Labs: Consultancy; Astellas: Consultancy, Research Funding; Novartis: Consultancy; Trillium: Consultancy, Research Funding; Trovagene: Research Funding; FATE Therapeutics: Other: Consulting Fees, Research Funding; Jazz: Consultancy; Menarini Group: Consultancy; KITE: Research Funding; Hanmi: Research Funding; Pfizer: Consultancy, Research Funding; Arog: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Glycomimetics: Research Funding. Montalban-Bravo: Rigel: Research Funding; Takeda: Research Funding. Maiti: CytoMed Therapeutics: Research Funding; Inspirna: Research Funding; Indapta Therapeutics: Research Funding; Hibercell Inc.: Research Funding; Lin Biosciences: Research Funding; Chimeric Therapeutics: Research Funding. Yilmaz: daiichi sankyo: Honoraria, Research Funding. Jabbour: AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Pfizer, Takeda: Research Funding; AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, Genentech, Incyte, Pfizer, Takeda: Consultancy. Pemmaraju: Stemline Therapeutics: Honoraria, Other: Travel Expenses, Research Funding; Roche Molecular Diagnostics: Honoraria; Mustang Bio: Honoraria, Other: Travel Expenses, Research Funding; Springer Science + Business Media: Honoraria; Triptych Health Partners: Consultancy; Affymetrix/Thermo Fisher Scientific: Research Funding; LFB Biotechnologies: Honoraria; ClearView Healthcare Partners: Consultancy; Incyte: Honoraria; Celgene: Honoraria, Other: Travel Expenses; Protagonist Therapeutics: Consultancy; Neopharm: Honoraria; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Plexxikon: Research Funding; Samus Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy; Aptitude Health: Honoraria; Novartis: Honoraria, Research Funding; DAVA Oncology: Honoraria, Other: Travel Expenses; Pacylex: Consultancy; CareDx: Honoraria; Blueprint Medicines: Consultancy, Honoraria; Immunogen: Consultancy; CTI BioPharma: Consultancy; Astellas: Consultancy; AbbVie: Honoraria, Other: Travel Expenses, Research Funding; Blueprint Medicines OncLive PeerView Institute for Medical Education: Consultancy, Other: advisory board; ASH Committee on Communications ASCO Cancer.NET Editorial Board: Other: Leadership; Karger Publishers: Other: Licenses; National Institute of Health/National Cancer Institute (NIH/NCI): Research Funding; HemOnc Times/Oncology Times: Other: uncompensated. Swaminathan: Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jain: Aprea Therapeutics: Research Funding; MingSight: Honoraria, Research Funding; Takeda: Research Funding; Cellectis: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pfizer: Research Funding; Fate Therapeutics: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; NovalGen: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel Support; Medisix: Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; TransThera Sciences: Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support, Research Funding; Genentech: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel Support, Research Funding; ADC Therapeutics: Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel Support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; BeiGene: Consultancy, Honoraria, Other: Travel Support; CareDx: Consultancy, Honoraria, Other: Travel Support; Servier: Research Funding; Loxo Oncology: Research Funding; Incyte: Research Funding; Newave: Research Funding; Dialectic Therapeutics: Research Funding; Ipsen: Consultancy, Honoraria, Other: Travel Support; MEI Pharma: Consultancy, Honoraria, Other: Travel Support; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding. Ravandi: Syros: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Research Funding; Xencor: Research Funding; Prelude: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Syndax: Honoraria; Astyex/Taiho: Research Funding. Borthakur: Catamaran Bio, AbbVie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees. Garcia-Manero: Helsinn: Other: Personal fees; Novartis: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; AbbVie: Research Funding; Aprea: Research Funding; Astex: Other: Personal fees; H3 Biomedicine: Research Funding; Onconova: Research Funding; Astex: Research Funding; Merck: Research Funding; Curis: Research Funding; Helsinn: Research Funding; Amphivena: Research Funding; Genentech: Other: Personal fees. Kantarjian: AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria. Abbas: Blueprint Medicines Corporation: Research Funding; GlaxoSmithKline: Research Funding; Enzyme By Design: Research Funding; Alamar Biosciences: Honoraria; Molecular Partners: Consultancy; Genentech: Research Funding; Ascentage: Research Funding; Illumina: Honoraria, Other: Inkind Support, Research Funding.

*signifies non-member of ASH