Introduction: The immunomodulatory agent lenalidomide (Len) has improved overall survival (OS) in patients (pts) with multiple myeloma (MM). Pts receiving Len for MM exhibit increased risk of second primary hematologic malignancies, particularly those with melphalan (Mel) exposure, with a high incidence of acute lymphoblastic leukemia (ALL) observed in some series (Palumbo et al., Lancet Oncol, 2014; Tan et al., Hematol Oncol, 2015). Len degrades or down-regulates known B-cell ALL (B-ALL) tumor suppressors (e.g. IZKF1, IZKF3, IRF4); Len-associated ALL remains relatively uncharacterized.
Methods: We identified 9 pts at MSKCC diagnosed with ALL from 2008-2016 during or within 4 months of therapy with Len for MM. Diagnostic molecular studies from bone marrow (BM) to characterize B-ALL included Archer FusionPlex (n=4), FoundationOne Heme (n=3) to assess for Philadelphia chromosome (Ph)-like ALL, other hematologic cancer-targeted mutation analyses (n=2), and NGS based clonality testing (Lymphotrack) for characterization and monitoring of clonal IGH rearrangements (n=3).
Results: Of the 9 pts (5M, 4F), median ages at MM and B-ALL diagnoses were 59 years (range, 46-77) and 64 years (range, 50-81), respectively. MM was standard-risk by cytogenetic studies in all pts but 1 who had excess 1q. Pts received Len during first induction (n=5) and/or subsequent salvage (n=2) and/or maintenance (n=9). Median length of Len exposure was 57.3 months (range 23.0-69.2). MM therapy included Mel 200 mg/m2 and autologous stem cell rescue (ASCR, n=6) and radiation therapy to sites of osseous disease (n=4). 3 pts did not receive Mel/ASCR. Median time from MM diagnosis to B-ALL diagnosis was 5.6 years (range 3.0-7.7). Len was discontinued between 109 days before B-ALL diagnosis (largely due to cytopenias) and 42 days after B-ALL recognition in BM (median, day of diagnosis).
ALL was B-lineage, Ph-negative, and CD10+ in all 9 pts. Biologic characteristics of B-ALL and treatment are noted in Table 1. In pt #6, LymphoTrack studies confirmed B-ALL and MM clones did not share common IgH rearrangement. In 1 pt with CRLF2 rearrangement, withdrawal of Len alone led to resolution of cytopenias and regression of BM blasts, with only residual MRD detectable. He remains in remission w/o further therapy for 7 months.
Of 7 pts receiving B-ALL therapy at MSKCC, 6 achieved CR following first induction (PR in 1 pt, who achieved CR following consolidation). 5 of 6 pts w/ MRD assessment achieved MRD-negative CR after induction ± post-remission chemotherapy. 5 of 7 pts treated at MSKCC then underwent allogeneic hematopoietic cell transplantation (AlloHCT). Conditioning was reduced-intensity (fludarabine + busulfan or Mel) in 4 pts and TBI + cyclophosphamide (Cy) in 1 pt. GVHD prophylaxis was tacrolimus + methotrexate (n=3), post-AlloHCT Cy (n=1), or CD34-selection w/o pharmacologic prophylaxis (n=1). One pt died 41 days post-AlloHCT in CR w/o GVHD. 4 remain in continuous MRD-negative CR post-AlloHCT (median f/u 19.0 months, range 4.6-36.5) w/o IBMTR grade 3-4 acute GVHD; 1 developed mild chronic GVHD based on 2015 Consensus criteria. One pt diagnosed with B-ALL at age 81 did not undergo alloHCT and died 27 months post-diagnosis w/o evidence of B-ALL.
None of the 9 pts have experienced relapse of B-ALL or yet required further therapy for MM. Median time from B-ALL diagnosis to last f/u is 10.8 months (range 4.1-41.1).
Conclusions: B-ALL following maintenance therapy with Len for MM is uncommon but increasingly recognized, even in the absence of prior Mel/ASCR. Activating CRLF2 fusions were observed in 2 of 4 pts undergoing detailed molecular profiling. Despite advanced age and poor risk features in several pts (MLL rearrangement, Ph-like ALL, complex karyotype, loss of TP53), all pts treated at MSKCC achieved CR, largely MRD-negative. None developed relapse of B-ALL. Withdrawal of Len alone was associated with B-ALL regression in 1 pt and may have facilitated the responses observed in others. AlloHCT may be effective for long-term control of B-ALL and MM in such pts as well.
Next-generation sequencing-based assays may be considered as a tool to characterize development of clonal lymphoid populations during Len therapy. Further investigation of Len-associated leukemogenesis warrants further consideration, particularly as extended Len therapy is increasingly used in pts with MM and other malignancies.
Landau: Spectrum Pharmaceuticals: Other: Advisory Board, Research Funding; Karyopharm: Consultancy; Pfizer: Honoraria; Janssen: Honoraria; Takeda: Research Funding; Celgene: Other: Advisory Board; Amgen: Research Funding. Hassoun: Oncopeptides AB: Research Funding. Dogan: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Peer Review Institute: Consultancy; Roche Pharmaceuticals: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Arcila: Archer: Honoraria; Raindance Tecnologies: Honoraria; Invivoscribe: Honoraria. Park: Amgen: Consultancy.
Asterisk with author names denotes non-ASH members.