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

Expert Rev Hematol. 2019 Oct;12(10):873-881. doi: 10.1080/17474086.2019.1649132. Epub 2019 Jul 30.


Introduction: The genomic landscape of Waldenström macroglobulinemia (WM) is characterized by recurrent MYD88 (MYD88L265P) and CXCR4 mutations (CXCR4MUT), detected in 90% and 30% of cases, respectively. The role of CXCR4MUT 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 CXCR4MUT in WM patients, and at assessing differences in clinical features and outcomes to therapy between WM patients with and without CXCR4MUT. Seventeen studies were included in our analysis. The pooled prevalence of CXCR4MUT in WM patients was 31%; 34% in MYD88L265P and 5% in MYD88WT patients. CXCR4MUT were associated with higher serum IgM levels and higher risk of hyperviscosity than CXCR4WT patients. Very good partial response (VGPR) and progression-free survival (PFS) rates to ibrutinib, with and without rituximab, appeared lower in CXCR4MUT than in CXCR4WT patients. Response and PFS rates were not affected by CXCR4MUT status on patients treated with proteasome inhibitors. Expert opinion: Our systematic review shows that WM patients with CXCR4MUT 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.

Keywords: Waldenstrom macroglobulinemia; cxcr4; ibrutinib; outcomes; rituximab.

Publication types

  • Systematic Review

MeSH terms

  • Adenine / analogs & derivatives
  • Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors
  • Agammaglobulinaemia Tyrosine Kinase / genetics
  • Agammaglobulinaemia Tyrosine Kinase / immunology
  • Antineoplastic Agents / therapeutic use*
  • Blood Viscosity / drug effects
  • Gene Expression
  • Humans
  • Immunoglobulin M / blood*
  • Mutation
  • Myeloid Differentiation Factor 88 / genetics*
  • Myeloid Differentiation Factor 88 / immunology
  • Piperidines
  • Progression-Free Survival
  • Proteasome Inhibitors / therapeutic use
  • Pyrazoles / therapeutic use
  • Pyrimidines / therapeutic use
  • Receptors, CXCR4 / genetics*
  • Receptors, CXCR4 / immunology
  • Rituximab / therapeutic use
  • Treatment Outcome
  • Waldenstrom Macroglobulinemia / drug therapy
  • Waldenstrom Macroglobulinemia / genetics*
  • Waldenstrom Macroglobulinemia / immunology
  • Waldenstrom Macroglobulinemia / mortality


  • Antineoplastic Agents
  • CXCR4 protein, human
  • Immunoglobulin M
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • Piperidines
  • Proteasome Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Receptors, CXCR4
  • ibrutinib
  • Rituximab
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • Adenine