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Phase 1 study of ibrutinib and the CXCR4 antagonist ulocuplumab in CXCR4-mutated Waldenström macroglobulinemia. | LitMetric

AI Article Synopsis

  • MYD88 and CXCR4 mutations are frequently found in Waldenström macroglobulinemia (WM) and the CXCR4 mutation can affect patient response to BTK inhibitors.
  • A phase 1 trial tested the CXCR4-antagonist ulocuplumab combined with ibrutinib, enrolling 13 symptomatic patients, which resulted in significant declines in median immunoglobulin M levels and bone marrow disease.
  • The study achieved high response rates, with a 2-year progression-free survival of 90%, while showing that combining the two treatments is feasible and well-tolerated, despite some adverse events.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8786275PMC
http://dx.doi.org/10.1182/blood.2021012953DOI Listing

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