Lenalidomide-associated B-cell ALL: clinical and pathologic correlates and sensitivity to lenalidomide withdrawal.

Lenalidomide is an effective component of induction and maintenance therapy for multiple myeloma, though with risk of secondary malignancies, including acute lymphoblastic leukemia (ALL). In contrast to therapy-related myeloid neoplasia, lenalidomide-associated lymphoblastic neoplasia remains poorly characterized. We conducted a dual institution retrospective study of 32 ALL cases that arose following lenalidomide maintenance (all B-lineage, 31/32 BCR::ABL-negative). B-ALL was diagnosed at median 54 months (range 5-119) following first exposure to lenalidomide and following median 42 months of cumulative lenalidomide exposure (range 2-114). High incidence of TP53 mutations (9/19 evaluable cases) and low hypodiploidy (8/26) were identified. Despite older age of many patients and poor-risk features of B-ALL cases observed, rates of complete response (CR) or CR with incomplete hematologic recovery were high following B-ALL therapy (25/28 patients receiving treatment). Median event-free survival was 35.4 months among treated patients (not reached among those undergoing allogeneic hematopoietic cell transplantation [HCT]), and 16 patients remain alive without evidence of B-ALL following HCT or extended maintenance therapy. Additionally, we describe regression of B-ALL or immature B-cell populations with B-ALL immunophenotype following discontinuation of lenalidomide in 5 patients, suggesting that lenalidomide may drive leukemic progression even after initiation of lymphoblastic neoplasia and that lenalidomide withdrawal alone may be an appropriate first-line intervention in selected patients. Monitoring for early B-ALL-like proliferations may offer opportunities for lenalidomide withdrawal to prevent progression. Established combination chemotherapy regimens, newer surface antigen-targeted approaches, and allogeneic HCT are effective in many patients with lenalidomide-associated B-ALL and should be offered to medically fit patients.