Diagnostically challenging Pro-B ALL followed by emergence of monocytic AML after successful CAR-T treatment

Introduction: Therapy-related acute myeloid leukemia (t-AML) is a recognized complication of leukemia-directed cytotoxic therapy. However, the emergence of therapy-related monocytic AML shortly after successful CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy for relapsed Pro-B acute lymphoblastic leukemia (B-ALL) raises important questions regarding clonal evolution, lineage plasticity, and treatment-related leukemogenesis. Case Description: We describe a 73-year-old man diagnosed with Philadelphia chromosome-negative Pro-B ALL with hyperdiploidy/tetraploidy, whose initial presentation posed a diagnostic challenge due to expression of immature and partial myeloid-associated markers, initially suggesting minimally differentiated AML. Repeat immunophenotyping clarified the diagnosis as Pro-B ALL. The patient achieved complete remission with the GMALL Elderly protocol despite severe infectious and treatment-related complications. Following relapse during maintenance therapy, he received salvage treatment with inotuzumab ozogamicin followed by CD19-directed CAR-T therapy, achieving marrow remission. Five months later, he developed secondary monocytic AML with no immunophenotypic evidence of residual B-ALL. Conclusion: This case underscores the importance of precise immunophenotypic characterization in diagnostically ambiguous acute leukemias and illustrates the complex biologic evolution that may follow sequential chemotherapy and modern immunotherapeutic approaches, including the emergence of secondary myeloid neoplasms after CAR-T therapy.