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

Abstract

Lenalidomide is an effective component of induction and maintenance therapy for multiple myeloma, though with a 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 after lenalidomide maintenance (all B-lineage, 31/32 BCR::ABL-negative). B-cell ALL (B-ALL) was diagnosed at median 54 months (range, 5-119) after first exposure to lenalidomide and after median 42 months of cumulative lenalidomide exposure (range, 2-114). High incidence of TP53 mutations (9/19 evaluable cases) and low hypodiploidy (8/26 patients) were identified. Despite median age of 65 years and poor-risk B-ALL features observed in the cohort, rates of complete response (CR) or CR with incomplete hematologic recovery were high (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]). Sixteen patients remain alive without evidence of B-ALL after HCT or extended maintenance therapy. We also describe regression of B-ALL or immature B-cell populations with B-ALL immunophenotype after lenalidomide discontinuation in 5 patients, suggesting 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.

Graphical abstract

Figure 1.

Cytogenetic and molecular features of lenalidomide-associated ALL. Oncoprint depicting somatic alterations and rearrangements/fusions identified by one of several NGS panels and targeted RNA-seq panels (eg, FoundationOne Heme and Archer FusionPlex) identified in evaluable patients developing B-ALL after lenalidomide therapy, including single-nucleotide variations (SNVs), insertions, copy number loss, deletions, and splicing variants. Dark grey boxes indicate the target gene/fusion was not evaluated in that patient; ∗, FoundationOne Heme panel includes RNA-seq.

Figure 2.

Clinical course of lenalidomide-associated ALL in one patient. (A) Clinical course of patient #9, who was found to have an immature B-cell population with B-ALL immunophenotype at 48 months into lenalidomide maintenance for MM, with regression of B-ALL after lenalidomide withdrawal and subsequent progression to overt B-ALL at 284 days from the initial finding of abnormal B lymphoblasts. He received B-ALL therapy consisting of hyper-CVAD followed by blinatumomab and achieved CR with MRD negativity, followed by haploidentical allogeneic HCT and remains in continuous, ongoing MRD⁻ CR. Flow cytometry plots from BMAs and TdT immunostains on core biopsies depict evolution in B-lymphoblast population from initial finding 48 months into lenalidomide maintenance (B,E) to regression after lenalidomide withdrawal (C,F) to overt progression to B-ALL (D,G). All blast percentages are from BMAs.

Figure 3.

Flow cytometric features of B-ALL-like cell populations arising during lenalidomide therapy. BM flow cytometry dot plots depicting abnormal immature B-cell populations arising during lenalidomide therapy, which ultimately resolved with holding lenalidomide. Plots reflect normal case (blue dots) with abnormal immature B cells (A) (red, emphasized) in patient #15 showing abnormally increased CD20 and CD34 with abnormally decreased CD38 and abnormal immature B cells (B) (red dots) in patient #10 with similar abnormal phenotype.

Figure 4.

Survival outcomes in patients with lenalidomide-associated ALL. (A) EFS among patients in cohort actively treated for B-ALL. (B) OS in the entire cohort. EFS (C) and OS (D) from time of transplant in subgroup of patients undergoing allogenic HCT.