Phase 1 study of ibrutinib and the CXCR4 antagonist ulocuplumab in CXCR4-mutated Waldenström macroglobulinemia
Steven P Treon, Kirsten Meid, Zachary R Hunter, Catherine A Flynn, Shayna R Sarosiek, Carly R Leventoff, Timothy P White, Yang Cao, Aldo M Roccaro, Antonio Sacco, Maria G Demos, Maria Luisa Guerrera, Amanda Kofides, Xia Liu, Lian Xu, Christopher J Patterson, Manit Munshi, Nicholas Tsakmaklis, Guang Yang, Irene M Ghobrial, Andrew R Branagan, Jorge J Castillo, Steven P Treon, Kirsten Meid, Zachary R Hunter, Catherine A Flynn, Shayna R Sarosiek, Carly R Leventoff, Timothy P White, Yang Cao, Aldo M Roccaro, Antonio Sacco, Maria G Demos, Maria Luisa Guerrera, Amanda Kofides, Xia Liu, Lian Xu, Christopher J Patterson, Manit Munshi, Nicholas Tsakmaklis, Guang Yang, Irene M Ghobrial, Andrew R Branagan, Jorge J Castillo
Abstract
MYD88 and CXCR4 mutations are common in Waldenström macroglobulinemia (WM). Mutated CXCR4 (CXCR4Mut) impacts BTK-inhibitor response. We conducted a phase 1 trial of the CXCR4-antagonist ulocuplumab with ibrutinib in this first-ever study to target CXCR4Mut in WM. Ibrutinib was initiated at 420 mg/d with cycle 1 and continued until intolerance or progression; ulocuplumab was given cycles 1 to 6, with a 3 + 3 dose-escalation design. Each cycle was 4 weeks. Thirteen symptomatic patients, of whom 9 were treatment-naive patients were enrolled. Twelve were evaluable for response. At best response, their median serum immunoglobulin M declined from 5574 to 1114 mg/dL; bone marrow disease decreased from 65% to 10%, and hemoglobin increased from 10.1 to 14.2 g/dL (P < .001). The major and VGPR response rates were 100% and 33%, respectively, with VGPRs observed at lower ulocuplumab dose cohorts. Median times to minor and major responses were 0.9 and 1.2 months, respectively. With a median follow-up of 22.4 months, the estimated 2-year progression-free survival was 90%. The most frequent recurring grade ≥2 adverse events included reversible thrombocytopenia, rash, and skin infections. Ulocuplumab dose-escalation did not impact adverse events. The study demonstrates the feasibility of combining a CXCR4-antagonist with ibrutinib and provides support for the development of CXCR4-antagonists for CXCR4Mut WM. This trial was registered at www.clinicaltrials.gov as #NCT03225716.
© 2021 by The American Society of Hematology.
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Source: PubMed