Impact of clonal hematopoiesis on clinical outcomes to BCMA CAR-T in multiple myeloma Open Access

TO THE EDITOR:

Chimeric antigen receptor (CAR) T-cell (CAR-T) therapy targeting B-cell maturation antigen (BCMA) is a novel treatment for multiple myeloma (MM). Currently, idecabtagene vicleucel and ciltacabtagene autoleucel are approved for patients with MM.^1-5 Although both agents are highly active, treatment-related toxicities frequently occur, including cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS), and prolonged cytopenias.^1-5 In preclinical studies, clonal hematopoiesis of indeterminate potential (CHIP) has been shown to confer a hyperinflammatory phenotype and modulate interactions between immune cells, including CAR-T.^6-11 CHIP commonly occurs in patients with MM,^12,13 but the clinical implications of CHIP with BCMA CAR-T therapy are unknown. This prompted us to evaluate the impact of CHIP on both the efficacy and safety of BCMA CAR-T therapy in patients with MM.

We identified consecutive patients with MM treated with BCMA CAR-T therapy from 2017 to 2023. Patients underwent targeted exome sequencing (ie, Heme SNaPshot) on whole bone marrow (BM) aspirate immediately before CAR-T. CHIP was defined by a leukemia-associated somatic mutation with a variant allele fraction of ≥2%, without morphological evidence of a myeloid neoplasm.^14,15 TP53 mutations were not considered to be CHIP defining because they can be present in either MM or CHIP clones. Treatment responses were assessed per the International Myeloma Working Group.¹⁶ CRS and ICANS were graded according to the American Society for Transplantation and Cellular Therapy guidelines,¹⁷ and cytopenias were graded according to the Common Terminology Criteria for Adverse Events version 5. Time-to-event analyses were performed with the Kaplan-Meier method and log-rank test. The Cox-proportional hazard regression method was used to fit multivariate models. Cumulative incidence estimates for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) were made with the Fine-Gray method, accounting for death as a competing risk. All patients underwent informed consent per institutional guidelines and in accordance with the Declaration of Helsinki.

A total of 104 patients with MM were included, of whom 57 (55%) had CHIP (supplemental Table 1). Among patients with CHIP, the median number of CHIP-related mutations was 1 (range, 1-6), and 20 patients (35%) had >1 mutation. Ten patients with CHIP (18%) had a TP53 mutation. There were no significant differences in clinical characteristics between patients with and without CHIP (supplemental Table 2). The median follow-up for patients with and without CHIP was 12 months (95% confidence interval, 10-17) and 14 months (95% confidence interval, 10-23), respectively (P = .52).

Table 1 summarizes treatment responses, survival, and safety outcomes for immune-mediated toxicities after CAR-T therapy. There were no significant differences in categorial responses, progression-free survival, or overall survival between patients with and without CHIP (supplemental Figure 1). There were also no significant differences in the incidence, severity, onset time, or management of CRS and ICANS.

We next evaluated the impact of CHIP on cytopenias after CAR-T therapy. Patients with CHIP had a significantly higher risk of prolonged transfusion dependence for both packed red blood cells (pRBCs) and granulocyte colony-stimulating factor (G-CSF), as well as higher thrombopoietin receptor agonist use (Table 2; supplemental Figure 2). There was also a trend for higher transfusion dependence for platelets with CHIP. On multivariate modeling, CHIP was independently associated with delayed time to transfusion independence for pRBCs (hazard ratio [HR], 0.56; P = .008) and G-CSF (HR, 0.45; P < .001), and there was also a trend for platelets (HR, 0.72; P = .12; supplemental Table 3). The number of CHIP mutations also positively correlated with the risk of prolonged cytopenias. At day +100, transfusion dependence for patients with 0, 1, and >1 CHIP mutations were as follows: for pRBCs, 0%, 11%, and 23%, respectively (P = .02); platelets, 0%, 7%, and 26%, respectively (P = .01); and G-CSF, 9%, 28%, and 35%, respectively (P < .001; supplemental Figure 3). The specific CAR-T product was not associated with transfusion dependence (P >.05 for all comparisons).

Two patients (1.9%) developed MDS/AML after receiving CAR-T therapy and both had CHIP. Patient 1 received ciltacabtagene autoleucel and had U2AF1 and TP53 mutations. Patient 2 received idecabtagene vicleucel and had a PPM1D mutation. Both patients were penta-exposed before CAR-T, whereas only patient 1 had received ASCT. The estimated 3-year risk of MDS/AML after CAR-T was 2.8%, and it did not statistically differ between patients with and without CHIP (4.9% vs 0%; P = .22). No patients developed a T-cell malignancy.

Overall, we present to our knowledge, the first study evaluating the impact of CHIP on outcomes to BCMA CAR-T therapy in patients with MM. Our data show that CHIP is not associated with response rates, survival outcomes, or immune-mediated toxicities (ie, CRS and ICANS). Similar data have been reported in non-Hodgkin lymphoma with CD19 CAR-T.^18-20 A notable finding was the association between CHIP and delayed hematopoietic recovery after BCMA CAR-T therapy. Indeed, nearly 1 in 7 patients with CHIP were still receiving growth factor and/or transfusion support 1 year after CAR-T therapy. These findings are important because prolonged neutropenia predisposes patients with MM to infection, which represents the most frequent cause of nonrelapse mortality after CAR-T therapy.^21-23 Despite a higher risk of prolonged cytopenias, CHIP did not appear to increase the risk of MDS/AML after CAR-T therapy, expanding upon similar data with ASCT in patients with MM.^12,24 

The mechanism underlying the delayed hematopoietic recovery after BCMA CAR-T therapy with CHIP is unknown. Prolonged cytopenias have been described in patients with MM with elevated inflammatory markers and CRS after CAR-T therapy, suggesting that inflammation contributes to cytopenia development.^22,25 Consistent with these findings, a recent study demonstrated that inflammatory cytokines secreted by BCMA CAR-T in patients with MM induce hematopoietic cell maturation arrest via a paracrine effect.²⁵ CHIP-mutated myeloid cells can also induce a hyperinflammatory phenotype with cytokine secretion.^6-9 The presence of CHIP may therefore exacerbate local inflammation in the BM microenvironment, thereby impairing hematopoiesis and causing prolonged cytopenias. Longitudinal studies comparing the cytokine profile after BCMA CAR-T therapy in patients with MM with and without CHIP would provide mechanistic insights into this hypothesis.

This study is not without limitations. Because the genetic sequencing was performed in a clinical laboratory, BM aspirate was used without any paired tissue. As such, we were unable to confirm whether the CHIP mutations were somatic or not present in the MM tumor cells. Because TP53 mutations can be present in both MM and CHIP, we did not consider TP53 mutations to be CHIP defining. However, this did not alter any of our results because all patients with a TP53 mutation had at least 1 additional CHIP mutation (data not shown). We also performed a sensitivity analysis in which CHIP was determined only with driver genes of almost certain myeloid origin (ie, DNMT3A, ASXL1, TET2, PPM1D, and BCOR). Our findings were unchanged in the sensitivity analysis: CHIP did not affect response rates, progression-free survival, overall survival, CRS, or ICANS (P > .05 for all comparisons), but it was associated with delayed transfusion independence for G-CSF (HR, 0.52; P = .005), pRBCs (HR, 0.66; P = .06), and platelets (HR, 0.66; P = .06). The prevalence of CHIP was also higher in our cohort of heavily treated patients with MM than what has been described in newly diagnosed patients,^12,24 although prior MM-directed treatment may account for this finding. Indeed, in a cohort of patients with longitudinal sequencing (n = 52), the prevalence of CHIP increased from 5.8% at MM diagnosis to 25% after treatment, consistent with a fourfold increase in CHIP after a median follow-up of 3 years.²⁴ Another potential explanation is that we defined CHIP based on the variant allele fraction identified in BM as opposed to peripheral blood or apheresis products before ASCT,^12,14 which may have increased the prevalence of CHIP.

In summary, the presence of CHIP in patients with MM did not affect the treatment efficacy or the risk of immune-mediated toxicities (ie, CRS and ICANS) to BCMA CAR-T therapy, but was associated with prolonged transfusion-dependent cytopenias.

Acknowledgments: The authors acknowledge the multidisciplinary care teams, the patients, and their families.

J.N.G. was awarded a Young Investigator Award for this research at the 21st International Myeloma Society Annual Meeting (Rio de Janeiro, Brazil, September 2024).

Contribution: All authors contributed to the study design, data analysis, manuscript preparation, and patient care, and critically reviewed and approved the manuscript.

Conflict-of-interest disclosure: A.J.Y. has been a consultant for AbbVie, Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Johnson & Johnson (Janssen), Karyopharm, Oncopeptides, Pfizer, Prothena, Regeneron, Sanofi, Sebia, and Takeda; and has received research funding to the institution from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Johnson & Johnson (Janssen), and Sanofi. M.V.M. is an inventor on patents related to adoptive cell therapies, held by Massachusetts General Hospital (some licensed to ProMab and Luminary) and University of Pennsylvania (some licensed to Novartis); receives grant/research support from Kite Pharma, Moderna, and Sobi; holds equity in 2Seventy Bio, A2 Bio, AffyImmune, BendBio, Cargo, GBM newco, Model T bio, Neximmune, and Oncternal; serves on the board of directors for 2Seventy Bio; and is or has been a consultant for A2 Bio, Adaptimmune, AffyImmune, Bristol Myers Squibb, Cabaletta, Cargo, In8bio, GlaxoSmithKline, Kite Pharma, Neximmune, Novartis, Oncternal, and Sobi. M.J.F. has been a consultant for Kite, Bristol Myers Squibb, Johnson & Johnson/Legend, and Novartis. N.S.R. received research funding and/or consulting fees from AbbVie, Bristol Myers Squibb, Caribou, GlaxoSmithKline, Immuneel, Janssen, K36 Therapeutics, Pfizer, and Sanofi. The remaining authors declare no competing financial interests.

Correspondence: Noopur S. Raje, Center for Multiple Myeloma, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114; email: nraje@mgh.harvard.edu.