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
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.
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