Application of Stem Cell Boost for Immune Effector Cell Associated Hematotoxicity (ICAHT) Following BCMA Directed Chimeric Antigen Receptor (CAR) T-Cell Therapy for Multiple Myeloma (MM)

Introduction: Persistent ICAHT is increasingly recognized as an adverse effect following BCMA CAR T-cell therapy. Alongside supportive care measures, we previously reported that stem cell boost helps ameliorate ICAHT. In addition, stem cell boost may minimize long-term complications such as infections while enabling therapeutic options in the post CAR T-cell therapy relapse setting. Herein, we report our follow-up of a multi-institutional experience with ICAHT in patients who received autologous BCMA CAR T-cell therapy both in commercial and clinical trial settings.

Methods: We included recipients of autologous BCMA CAR T-cell therapy at 2 large academic centers between 2020 and 2024. For this study, neutropenia was defined as an absolute neutrophil count (ANC) of ≤ 1000, thrombocytopenia as platelet counts ≤ 50,000 and anemia as hemoglobin ≤9 g/dL. ICAHT was characterized by the presence of any of these hematological abnormalities. The variables were assessed at 21 days, 3 months, and 6 months post CAR T-cell infusion. Application of stem cell boost was at the discretion of treating physician. Median follow up time for patients still under observation was 16.5 months.

Results: A total of 159 patients received BCMA CAR T-cell therapy, 69 were treated on a clinical trial, 65 received commercial idecabtagene vicleucel and 25 commercial ciltacabtagene autoleucel. The median age was 65 (IQR59-70) years, with 96/159 (60%) being male. 139/159 (87%) received at least one prior ASCT and the median prior lines of therapy was 5 (IQR 4-6). At D+21, ICAHT was observed in 58% (n=89/154) of patients, which reduced to 28% (n=39/137) and 17% (n=21/122) at the 3-month and 6-month assessments, respectively. Risk factors for ICAHT at D+21 were as follows: high risk disease by FISH or PET CT, use of tocilizumab therapy, prior ASCT, higher median prior lines of therapy, and ICANS. Among patients with ICAHT at D+21, 43% had persistent ICAHT at 3 months and 27% at 6 months. About 92% (n=82/89) of patients with ICAHT at D+21 had stem cells in storage and 27% of those (n=22/82) received a stem cell boost. The median time to stem cell boost following CAR T-cell infusion was 52 (IQR 30-143) days. The median dose of stem cell infused was 4 (IQR 2.46-5.60) x10⁶ CD34/kg cells. As expected, patients with ICAHT at D+21 who received a stem cell boost had significantly worse cytopenia prior to the boost compared to those without stem cell infusions: hemoglobin levels were 8.5 g/dL vs. 9.5 g/dL, p < 0.002 and median platelet counts were 21 x 10⁹/L vs. 48 x 10⁹/L, p < 0.001, respectively. ANC levels were not significantly different between the groups (800/μL vs. 290/μL, p < 0.119). Stem cell infusion significantly improved hemoglobin levels at 3 and 6 months to 10.9 g/dL, p < 0.001, and 12.2 g/dL, p = 0.002, respectively. Platelet counts at 3- and 6-months post stem cell boost also significantly improved to 127 x 10^9/L, p < 0.001, and 152 x 10^9/L, p < 0.001, respectively. ANC levels showed a statistically significant increase to 3000/μL at both 3 months (p = 0.003) and 6 months (p = 0.021).Overall blood counts were similar between the group with ICAHT at D+21 with or without a stem cell boost at 6 months, despite the statistically significant and profound cytopenia noted prior to stem cell boost in patients with ICAHT at D+21 who received a boost, compared to those who did not, suggesting a clinically meaningful effect of stem cell boost in patients with ICAHT.

We further investigated whether the occurrence MDS/AML, post CAR T cell therapy correlated with ICAHT and/or stem cell boost. There were 4 cases of MDS and 1 case of AML post CAR T cell therapy. All 5 cases of MDS/AML occurred in patients who did not have ICAHT and/or a stem cell boost. The 12-month PFS was 66.6% (95% CI 59.2-74.9) and OS was 88.3% (95% CI 83.3-93.5). On multivariate analysis the presence of ICAHT at D+21 and use of stem cell boost were not associated with inferior PFS or OS, the presence of high-risk FISH and EMD on PET CT conferred inferior outcomes.

Conclusion: About 58% of patients had ICAHT at D+21 post BCMA CAR T- cell therapy for MM. Nearly a third of these patients with ICAHT at D+21 had severe cytopenias and received a stem cell boost with clinically and statistically significant improvement in the cell counts at 3 and 6 months. The improvement in counts could help to prevent infections, reduce transfusion requirements and allow patients to undergo further therapy after progression from CAR T-cell therapy.

Al Hadidi:Pfizer: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Zangari:Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Shah:Gilead-Kite, BMS-Juno, Miltenyi, Lilly Onclogy, Novartis, Seattle Genetics, Janssen, Abbvie, Cargo, Beigene, Galapagos, AstraZeneca: Honoraria; Tundra Therapeutics: Current holder of stock options in a privately-held company; Miltenyi Biomedicine, Lilly Oncology: Research Funding. van Rhee:Takeda: Consultancy; Secura Bio: Membership on an entity's Board of Directors or advisory committees; Adicet Bio: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Castleman Disease Collaborative Network: Membership on an entity's Board of Directors or advisory committees. Hamadani:Kite Pharma: Consultancy, Speakers Bureau; Spectrum Pharmaceuticals: Research Funding; Allovir: Consultancy; Autolus: Consultancy; Caribou: Consultancy; Genmab: Consultancy; AbbVie: Consultancy; Sanofi Genzyme: Speakers Bureau; Forte Biosciences: Consultancy; ADC Therapeutics: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy; CRISPR: Consultancy; Byondis: Consultancy; BeiGene: Speakers Bureau; AstraZeneca: Speakers Bureau; Astellas Pharma: Research Funding; Omeros: Consultancy; Myeloid Therapeutics: Speakers Bureau; Genentech: Speakers Bureau; DMC, Inc: Speakers Bureau; CRISPR: Speakers Bureau; Takeda: Research Funding. Dhakal:Genentech: Consultancy, Honoraria; Karyopharm: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Carsgen: Research Funding; C4 therapeutics: Research Funding; Medical College of Wisconsin: Current Employment; Bristol Myers Squibb: Honoraria, Research Funding; Acrellx: Research Funding; Sanofi: Research Funding. D'Souza:Novartis: Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Caelum: Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Prothena: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Research Funding; Takeda: Research Funding. Mohan:Pfizer: Consultancy; Legend biotech: Consultancy; Janssen: Consultancy; Sanofi: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy. Schinke:Janssen: Consultancy, Honoraria, Speakers Bureau; Arcellx: Consultancy; OncLive: Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau; Cancer Network: Honoraria.