CXCR4 mutations affect presentation and outcomes in patients with Waldenström macroglobulinemia: A systematic review

Introduction: The genomic landscape of Waldenström macroglobulinemia (WM) is characterized by recurrent MYD88 (MYD88) and CXCR4 mutations (CXCR4), detected in 90% and 30% of cases, respectively. The role of CXCR4 in clinical features and outcomes to therapy in WM patients is evolving. Areas covered: We performed a systematic review aimed at evaluating the prevalence of CXCR4 in WM patients, and at assessing differences in clinical features and outcomes to therapy between WM patients with and without CXCR4. Seventeen studies were included in our analysis. The pooled prevalence of CXCR4 in WM patients was 31%; 34% in MYD88 and 5% in MYD88 patients. CXCR4 were associated with higher serum IgM levels and higher risk of hyperviscosity than CXCR4 patients. Very good partial response (VGPR) and progression-free survival (PFS) rates to ibrutinib, with and without rituximab, appeared lower in CXCR4 than in CXCR4 patients. Response and PFS rates were not affected by CXCR4 status on patients treated with proteasome inhibitors. Expert opinion: Our systematic review shows that WM patients with CXCR4 have specific clinical features and have lower response and PFS rates to BTK inhibitors. Our findings support standardization of CXCR4 testing and development of CXCR4-directed therapy.