Persistent Thrombocytopenia and Neutropenia Are Associated with Increased Mortality in Patients Treated with Anti-BCMA CAR T Cells for Relapsed/Refractory Multiple Myeloma

Background:

CAR T cell therapy has transformed the treatment landscape for relapsed/refractory multiple myeloma (RRMM). However, some patients experience significant hematologic toxicities, potentially restricting their wider use. In this study, we investigated the occurrence of thrombocytopenia and neutropenia in patients receiving anti-BCMA CAR T cell therapy and examined their associations with in vivo CAR T cell expansion and clinical outcomes.

Methods:

We conducted a retrospective analysis of 61 patients treated with anti-BCMA CAR T cell therapies. All patients received bridging therapy (BT), and type of BT was classified as bispecific antibodies, anti-CD38-based, anti-SLAMF7-based or conventional chemotherapy. Responders were defined as patients achieving PR or better according to IMWG criteria by month 6 after CAR T cell infusion. Flow cytometry was utilized to monitor CAR+ and non-transduced T cell subsets on days 0, 7, 14, 30, and 100 post-infusion. Neutropenia was defined as absolute neutrophile count <1.5 G/L. Immune effector cell-associated hematotoxicity grading (ICAHT) and phenotypes of neutrophil recovery (quick vs intermittent vs aplastic/ no neutrophil recovery) were used to determine severity of neutropenia. Thrombocytopenia was defined as platelet count <150 G/L and severe thrombocytopenia as any grade 4 event. Persistent cytopenia was defined as any cytopenia ≥90 days. Survival analyses were performed using time from CAR T cell infusion to death from any cause (overall survival, OS), or to MM progression (progression-free survival, PFS).

Results:

Thirty-four patients received idecabtagene vicleucel (ide-cel, 56%) and 27 patients ciltacabtagene autoleucel (cilta-cel, 44%). Persistent cytopenia was observed in 25 (41%) patients, with 22 (18%) showing persistent and 13 (21%) severe thrombocytopenia. Persistent neutropenia was detected in 8 patients (13%), ICAHT grade ≥ 3 in 6 (10%) and 7 (11%) had aplastic kinetics or no neutrophil recovery. Persistent cytopenia was more frequent in ide-cel recipients (52%) compared to cilta-cel (25%, p=0.04). Penta refractoriness, extramedullary disease, and remission status prior to CAR T cell infusion did not affect the length and severity of cytopenia. Anti-SLAMF7 based BT was associated with higher grade thrombocytopenia (p=0.02), delayed platelet regeneration (p=0.02) and aplastic neutropenia (p<0.01).

Persistent cytopenia was detected in 37% of non-responders vs 43% of responders (p=0,79). Severe and persistent thrombocytopenia were associated with delayed recovery of CD4+ T cells on day 14 (severe vs mild: 132 vs 70 x10⁶/mL, p=0.02; <90 days vs ≥90 days 132 vs 70 x10⁶/mL, p=0.02). Patients with severe thrombocytopenia also showed delayed recovery of Treg (26 vs 14 x10⁶/mL, p=0.03) and CD8+ T cells (378 vs 154 x10⁶/mL, p=0.03) on day 14. At the same time, expansion of total CAR T cells was delayed in patients with severe (204 vs 18 x10⁶/mL, p<0.01) and persistent (204 vs 20 x10⁶/mL, p<0.01) thrombocytopenia, as well as for severe (117 vs 14 x10⁶/mL, p<0.01) and persistent (114 vs 14 x10⁶/mL, p=0,04) CD8+CAR+ cells. There was no association of neutropenia and expansion of CAR+ and non-transduced T cells.

In univariate analysis, OS was significantly lower in patients with severe thrombocytopenia (HR: 15,7 [95%CI, 3,5-69,3], p<0.001), severe neutropenia with aplastic kinetics or lack of neutrophil recovery (HR: 26.8 [3.4-209.8], p<0.01), and ICAHT grade ≥ 3 (HR: 7.9 [1.1-59.1], p=0.04). OS was also reduced in patients with persistent thrombocytopenia (HR: 3,9 [1,2-13,2], p=0,03) and persistent neutropenia (HR: 16,6 [2,4-117,1], p<0.01). However, no severe or persistent cytopenia was associated with PFS. Notably, 3 out of 4 patients who died within the first year after CAR-T cell infusion due to severe infections presented persistent and severe cytopenia.

Conclusion:

This study highlights the impact of cytopenia on mortality in RRMM patients receiving CAR T cell therapy. Delayed T cell recovery and CAR T cell expansion linked to thrombocytopenia potentially increase infection risk and reduce therapeutic efficacy. Severe and persistent neutropenia may also exacerbate infection rates, contributing to increased mortality. The associations with reduced OS underscore their prognostic importance and the need to implement effective strategies for clinical management of cytopenia following CAR T cell therapy.

Metzeler:Servier: Honoraria; AstraZeneca: Honoraria; Abbvie: Honoraria, Research Funding; Astellas: Honoraria; Janssen: Consultancy, Honoraria; Menarini Stem Line: Honoraria; Otsuka: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Sysmex: Honoraria. Jentzsch:Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria; Delbert Laboratories: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Platzbecker:Amgen: Consultancy, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; MDS Foundation: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Research Funding; Curis: Consultancy, Honoraria, Research Funding; Geron: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Novartis: Consultancy, Research Funding. Vucinic:Gilead/Kite, Janssen, BMS Celgene, Novartis: Consultancy, Honoraria; Amgen: Honoraria, Other: Travel grant. Merz:Amgen, BMS, Celgene, Gilead, Jannsen, Stemline, SpringWorks and Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.