Genomic Determinants and Clinical Outcomes of Second Primary Hematological Malignancies in Patients with B-cell Cancers

Patients with lymphoid malignancies are at increased risk for second primary hematological malignancies (SPHM) due to reduced immune surveillance, genetic predispositions, and previous cancer therapies, including chemotherapy. SPHMs can substantially increase morbidity and mortality. In this study, we aim to characterize the clinical and genomic features, risk factors, and outcomes of patients who developed SPHMs following therapy for hematological malignancies, including multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and lymphoma. We conducted a retrospective analysis of the incidence, clinical features, genomic determinants, and outcomes of SPHMs in patients with MM and compared them with patients who had prior CLL or lymphoma to explore differences in leukemogenesis. We also analyzed pre-SPHM samples to detect clonal myeloid (M-CHIP) and lymphoid (L-CHIP) somatic mutations that may promote SPHM development. Twenty-six patients with MM developed SPHMs, including 14 patients with therapy-related acute lymphoblastic leukemia (t-ALL) and 12 patients with therapy-related acute myeloid leukemia (t-AML). Median overall survival (OS) was markedly shorter for patients with MM and t-AML (0.28 years) than for those with t-ALL (2.54 years). TP53 mutations, complex karyotypes, and other high-risk prognostic features were common. In a comparator cohort of 25 patients with prior CLL or lymphoma who developed t-AML, TP53 alterations and adverse cytogenetics were also frequent, and outcomes were uniformly poor, with median OS under 1 year across cohorts. Pretransplant sequencing identified low-VAF (variant allele frequency) TP53 and DNMT3A clones in several patients that expanded at transformation; 1 patient carried a germline DDX41 loss-of-function variant. In conclusion, our study adds to the growing body of literature characterizing the features and burden of therapy‑related hematological malignancies and highlights the potential value of early detection of pre‑malignant clonal populations.