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.
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. 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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. 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Swaminathan:Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees. 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