Single-Cell Transcriptomic Analysis of Myeloid Lineage Evolution from CD19 CAR-T Cell Therapy.

Abstract

Introduction: We report a case of relapse and refractory acute B-lymphoblastic leukemia (r/r B-ALL) apparently turned into acute myeloid leukemia, which is occasional and fatal during CAR-T treatment. There are still limited data to clarify the molecular mechanism of myeloid blast populations proliferation during CAR-T treatment.

Case presentation: A 21-year-old man with an established history of r/r B-ALL with a complex chromosome karyotype and renal extramedullary infiltration presented to our institution. He exhibited a rapid relapse with acute monocytic leukemia 19 days after CD19 CAR-T cell infusion with extensive infiltration of skin and brain. Salvage chemotherapy was ineffective, and he subsequently succumbed to the uncontrolled invasion and infiltration of leukemia cells and hemorrhage. RNA velocity analysis predicted that HSCs differentiated into GMPs and then GMPs differentiated into myeloid lineage cells. The ANXA1-FPR1/2 axis expression was significantly increased post-treatment, which promotes tumor cell proliferation, invasion, and angiogenesis. 6q deletion (6q-) was the common genetic abnormality across all cell populations, indicating that 6q- conferred a survival ability to HSCs during CAR-T cell therapy.

Conclusions: This case demonstrates potential mechanisms of clone evolution molecular events that CD19 CAR-T cell infusion accelerated the existing myeloid lineage evolution via ANXA1-FPR1/2 axis expression from HSCs with 6q-. (Cyto-)genetic aberrations and/or pathways previously not included in the risk stratification of B-ALL might well be predictive for response and outcome in the era of immunotherapy.