High risk-myelodysplastic syndrome following CAR T-cell therapy in a patient with relapsed diffuse large B cell lymphoma: A case report and literature review

Abstract

BackgroundChimeric antigen receptor (CAR) T-cell therapy represents the most advanced immunotherapy against relapsed/refractory B cell malignancies. While cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome are distinctive, known CAR T-cell acute adverse events, hematological toxicity has been increasingly reported. Cytopenia following CAR T-cell treatment is attributed in most cases to lymphodepletion regimens, bridging chemotherapy, or radiotherapy. However, when cytopenia becomes prolonged, the development of myelodysplastic syndrome (MDS) should be considered.Case presentationWe report a case of high risk (HR)-MDS following CAR T-cell therapy in a patient with relapsed diffuse large B cell lymphoma. Eight months after CAR T-cell infusion, the blood count showed progressive, worsening cytopenia and the bone marrow biopsy revealed multilineage dysplasia without excess of blasts associated with chromosome 7 deletion and RUNX1 mutation. Next generation sequencing analysis, retrospectively performed on stored samples, showed a germ line CSF3R mutation, CEBPA clonal hematopoiesis, but no RUNX1 lesion.ConclusionWe describe a case of HR-MDS, with deletion of chromosome 7 and acquisition of RUNX1 mutation, developing after CAR T-cell therapy in a patient with clonal hematopoiesis (CH). Previous chemotherapy favored MDS onset; however, we could not exclude the fact that the impairment of immunosurveillance related to either lymphodepletion or CAR T-cell infusion may play a role in MDS development. Thus, we designed a multicenter prospective study (ClonHema-CAR-T-Study) to investigate if cytopenia after CAR T-cell treatment may be due to underling CH as well as the presence of secondary myeloid malignancies.

Prolonged haematologic toxicity in CAR‐T‐cell therapy: A review

“… 47 Accorsi Buttini et al also reported that one patient with R/R DLBCL based on sustained CSF3R and CEBPA mutations developed secondary MDS and acquired a new RUNX1 mutation after CAR‐T‐cell therapy. 48 These two cases suggest that CAR‐T‐cell treatment is similar to a double hit to promote development of MDS for those who already have clonal haematopoiesis prior to CAR‐T‐cell therapy. Conversely, Zhao et al reported an incidence of therapy‐related myeloid neoplasms after CAR‐T‐cell therapy of 3.2%, comparable to that in patients who received chemotherapy or HSCT; hence, they deemed that CAR‐T‐cell infusion did not significantly increase the risk of therapy‐related myeloid neoplasms according to the current data for incidence.…”

“…47 Accorsi Buttini et al also reported that one patient with R/R DLBCL based on sustained CSF3R and CEBPA mutations developed secondary MDS and acquired a new RUNX1 mutation after CAR-T-cell therapy. 48 These two cases suggest that TA B L E 1 Factors related to prolonged haematologic toxicity.…”

“…DNMT3A and PPM1D mutations already existed before treatment, but with newly acquired RUNX1 mutation 47 . Accorsi Buttini et al also reported that one patient with R/R DLBCL based on sustained CSF3R and CEBPA mutations developed secondary MDS and acquired a new RUNX1 mutation after CAR‐T‐cell therapy 48 . These two cases suggest that CAR‐T‐cell treatment is similar to a double hit to promote development of MDS for those who already have clonal haematopoiesis prior to CAR‐T‐cell therapy.…”

Contemporary Approaches to Immunotherapy of Solid Tumors

“…However, the downregulation of inhibitory molecules can lead to uncontrolled T-cell proliferation or increased risk of autoimmunity, and the use of exogenous cytokines can lead to the development of serious adverse effects. Thus, in late January 2024, the FDA recommended including new “black box” warnings for CAR-T-cell therapy after reviewing clinical trial reports describing the occurrence of mature CAR-positive T-cell malignancies following CAR-T-cell immunotherapy [ 179 , 180 ].…”

Car-T Cell Therapy in Large B Cell Lymphoma

“…42 Other studies have reported myeloid malignancies development in LBCL patients undergoing anti-CD19 CAR-T cell treatments. [43][44] The precise mechanism behind the increased risk of tMN has to be elucidated and remains subject to speculation. It remains unclear whether the particular immune dysregulation in patients after CAR-T plays an important role or whether the occurrence of tMN is simply the consequence of genetic damage induced by the precedent lines of therapy in these mostly heavily pretreated patients.…”