We report a female in her late 80s with high-risk pleomorphic mantle cell lymphoma (MCL) harboring germline ATM mutation and 17p deletion who achieved complete metabolic response with zanubrutinib plus rituximab. Serial peripheral blood next-generation sequencing (NGS) during remission revealed emergence of a molecularly distinct pre-leukemic clone characterized by DNMT3A, TET2, and a TP53 point mutation (p.Tyr220Cys)—distinct from the original 17p deletion. Approximately 20 months after MCL diagnosis, she developed acute myeloid leukemia (AML) with FLT3-TKD and NPM1 mutations, confirming transformation of the pre-leukemic clone. Longitudinal VAF tracking demonstrated complete eradication of MCL-associated mutations (ID3, BIRC3) while the myeloid clone expanded. This case provides direct molecular evidence that AML arose from clonal evolution of a pre-existing hematopoietic clone rather than direct MCL transformation, with implications for understanding second malignancies in BTK inhibitor-treated patients.
Mohamed et al. (Mon,) studied this question.