Key Points

  • The CXCR4 antagonist ulocuplumab with ibrutinib is tolerated in CXCR4Mut WM patients with thrombocytopenia as most frequent adverse event.

  • The combination was associated with short time to a major response, major response attainment in all patients, and 90% 2-year PFS.

MYD88 and CXCR4 mutations are common in Waldenström Macroglobulinemia (WM). Mutated CXCR4 (CXCR4Mut) impacts BTK-inhibitor response. We conducted a Phase I trial of the CXCR4-antagonist ulocuplumab with ibrutinib in this first-ever study to target CXCR4Mut in WM. Ibrutinib was initiated at 420 mg/day with Cycle 1 and continued until intolerance or progression; ulocuplumab was given cycles 1-6, with a 3+3 dose-escalation design.Each cycle was 4 weeks. Thirteen symptomatic patients, nine treatment-naive were enrolled. Twelve were evaluable for response. At best response, their median serum IgM declined from 5,574 to 1,114 mg/dL; bone marrow disease decreased from 65% to 10%; and hemoglobin increased from 10.1 to 14.2 g/dL (p<0.001). 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 PFS 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. www.clinicaltrials.gov (NCT03225716)

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