CXCR4 mutation subtypes impact response and survival outcomes in patients with Waldenström macroglobulinaemia treated with ibrutinib. (3rd July 2019)

• Record Type: Journal Article
• Authors: Castillo, Jorge J.; Xu, Lian; Gustine, Joshua N.; Keezer, Andrew; Meid, Kirsten; Dubeau, Toni E.; Liu, Xia; Demos, Maria G.; Kofides, Amanda; Tsakmaklis, Nicholas; Chen, Jiaji G.; Munshi, Manit; Guerrera, Maria L.; Chan, Gloria G.; Patterson, Christopher J.; Yang, Guang; Hunter, Zachary R.; Treon, Steven P.
• Is Part Of: British journal of haematology. Volume 187:Number 3(2019)
• Page Start: 356
• Page End: 363
• Publication Date: 2019-07-03
• Subjects: Waldenström macroglobulinaemia -- ibrutinib -- CXCR4 -- response -- survival; Hematology -- Periodicals; Blood -- Diseases -- Periodicals; 616.15
• DOI: 10.1111/bjh.16088
• Languages: English
• ISSNs: 0007-1048

Abstract

Summary: Ibrutinib is associated with response rate of 90% and median progression‐free survival (PFS) in excess of 5 years in Waldenström 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 0·25, 95% confidence interval [CI] 0·12–0·53; P < 0·001) and worse PFS (Hazard ratio 4·02, 95% CI 1·95–8·26; P < 0·001) 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.