Clonal Myeloid Dysplasia Following CAR T-Cell Therapy: Chicken or the Egg?

Abstract

Multiple myeloma (MM) is characterized by recurrent relapses. Consequently, patients receive multiple therapy lines, including alkylating agents and immune modulators, which have been associated with secondary malignancies such as myelodysplastic syndrome (MDS). Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T cell (CART) therapy is efficacious in patients with relapsed/refractory (R/R) MM. However, the long-term complications, particularly MDS, are not well understood. Whether CART therapy causes or promotes MDS has not been thoroughly investigated. In this study, we explored the causal relationship between MDS and CART therapy. We retrospectively examined the prevalence of MDS-related morphological and mutational changes before and after administration of CART therapy in five patients. Among them, four developed MDS after CART therapy, while one had pre-existing MDS prior to CART. None of the four patients who developed post-CART MDS showed morphological MDS changes prior to CART therapy. However, all four patients exhibited molecular alterations associated with MDS in their pre-CART as well as post-CART therapy bone marrow. No new mutations were observed. Our findings provide initial evidence suggesting that anti-BCMA CART therapy in MM may promote expansion of pre-existing MDS clones rather than causing development of new clones.

The Dutch CAR-T Tumorboard Experience: Population-Based Real-World Data on Patients with Relapsed or Refractory Large B-Cell Lymphoma Referred for CD19-Directed CAR T-Cell Therapy in The Netherlands

“…We observed that three patients in remission died due to myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), underscoring the importance of adequate surveillance for MDS/AML after CAR-T. If post-CAR-T MDS/AML can be attributed to the CAR-T treatment itself, to the lymphodepleting chemotherapy or for example is merely a consequence of the cumulative exposure to prior DNA-damaging therapy still needs to be elucidated [32,33]. In line with other real-world cohorts, the main cause of NRM was infection.…”

Autologous hematopoietic stem cell transplantation for multiple myeloma in the age of CAR T cell therapy

“…However, it is unclear whether this a result of the CAR T or lymphodepleting chemotherapy. To that effect, a recent analysis of 4 patients who developed MDS after treatment with an investigational anti-BCMA CAR T showed that while none of the patients had morphologic changes consistent with MDS prior to CAR T infusion, all four patients exhibited molecular alterations associated with MDS in their pre-CAR T as well as post-CAR T therapy bone marrow with no new mutations observed after CAR T ( 56 ). Clearly further follow-up is warranted.…”

Immune Therapies in AL Amyloidosis—A Glimpse to the Future

“…Late toxicities include the development of prolonged cytopenias and hypogammaglobulinemia, with a resulting increased risk of infections [68]. Less commonly, secondary cancers have been reported, including 22 cases of T-cell lymphoma arising directly from the CART product [69] and the occurrence of myeloid neoplasms (myelodysplastic syndrome or acute leukemia) in as many as 10% of patients in some studies [70,71]. The mechanism underlying the latter toxicity remains unclear.…”