Subtype of CXCR4 Mutation Correlated With Inferior Response to Ibrutinib in Waldenström Macroglobulinemia

Patients with Waldenström macroglobulinemia (WM) who harbor a certain kind of genetic mutation in CXCR4 and receive ibrutinib are less likely to experience a major response to therapy and are more likely to have worse progression-free survival (PFS) compared with patients with no mutations in CXCR4, according to a study published in the British Journal of Haematology.

Approximately 30% to 40% of patients with WM harbor mutations in CXCR4, and presence of these mutations correlates with decreased response rates and inferior PFS with treatment with ibrutinib. These mutations in CXCR4 can occur as frameshift mutations (CXCR4^FS), in which an insertion or deletion in the DNA sequence results in a shift in how the DNA is read, or as nonsense mutations (CXCR4^NS), in which a mutation in a codon results in early termination of a protein.

To assess whether CXCR4^FS and CXCR4^NS were associated separately with different clinical outcomes in patients with WM treated with ibrutinib, researchers at the Bing Center for Waldenström Macroglobulinemia at the Dana-Farber Cancer Institute in Boston, Massachusetts, identified 180 consecutive patients who received ibrutinib between May 2012 and December 2017. A total of 38% of patients (68/180) had CXCR4 mutations, with 27% (49/180) having CXCR4^NS and 11% (19/180) having CXCR4^FS. Two patients with more than 1 CXCR4 mutation were excluded from the analysis.

Harboring CXCR4^NS was correlated with reduced odds of a major response to treatment with ibrutinib (odds ratio, 0.25; 95% CI, 0.12-0.53; P <.001) and inferior PFS (hazard ratio, 4.02; 95% CI, 1.95-8.26; P <.001) compared with patients with WM with no CXCR4 mutation. Major response was defined as a partial response or better.

Although presence of the nonsense mutation was associated with lower odds of responding to ibrutinib and a worse clinical outcome compared with patients with no mutation, the presence of CXCR4^FS was not associated with any difference in odds of major response to therapy or in PFS rates compared with patients with no mutation.

The authors suggested there is a need for independent validation of these results and encouraged the development of therapies specifically targeting CXCR4.

Disclosures: Some authors have declared affiliations with the pharmaceutical industry. Please refer to the original study for a full list of disclosures.

Reference

1.     Castillo JJ, Xu L, Gustine JN, et al. CXCR4 mutation subtypes impact response and survival outcomes in patients with Waldenström macroglobulinaemia treated with ibrutinib [published online July 3, 2019]. Br J Haematol. doi:10.1111/bjh.16088