CXCR4 mutation subtypes impact response and survival outcomes in patients with Waldenstrom macroglobulinaemia treated with ibrutinib

Ibrutinib is associated with response rate of 90% and median progression-free survival (PFS) in excess of 5 years in Waldenstrom macroglobulinaemia (WM) patients. CXCR4 mutations are detected in 30-40% of patients with WM and associate with lower rates of response and shorter PFS to ibrutinib therapy. Both frameshift (CXCR4(FS)) and nonsense (CXCR4(NS)) CXCR4 mutations have been described. The impact of these mutations on outcomes to ibrutinib have not been evaluated in WM patients. We studied consecutive patients with a diagnosis of WM, on ibrutinib therapy, for the presence of CXCR4(FS) and CXCR4(NS) mutations and evaluated the differences in response and PFS between groups. Of 180 patients, 68 patients (38%) had CXCR4 mutations; 49 (27%) had CXCR4(NS) and 19 (11%) had CXCR4(FS) mutations. In multivariate models, patients with CXCR4(NS) had lower odds of major response (Odds ratio 0 center dot 25, 95% confidence interval [CI] 0 center dot 12-0 center dot 53; P < 0 center dot 001) and worse PFS (Hazard ratio 4 center dot 02, 95% CI 1 center dot 95-8 center dot 26; P < 0 center dot 001) than patients without CXCR4 mutations. CXCR4(FS) was not associated with worse major response or PFS rates than patients without CXCR4 mutations. Our results suggest different response and PFS rates to ibrutinib for WM patients with CXCR4(NS) and CXCR4(FS), and advocate in favour of CXCR4 mutational testing as well as CXCR4-directed therapy.