Mutations in CXCR4 are common in patients with Waldenström macroglobulinemia (WM), and have implications with respect to the clinical presentation of disease and patient response to treatment. The findings from this study were published in Expert Reviews in Hematology.1
The prevalence of somatic alterations in the MYD88 gene has been estimated at more than 90% in bone marrow specimens of patients with WM, a low-grade B-cell lymphoma characterized by an accumulation of lymphoplasmacytic cells that infiltrate the bone marrow and secrete a monoclonal IgM immunoglobulin.
Of MYD88 alterations, the MYD88 L265P mutation is by far the most common in this setting, and has been associated with suppression of apoptosis via mutated MYD88 receptor activation of the JAK/STAT and nuclear factor κB signaling pathways.2 It has also been identified as a prognostic marker of worse clinical outcomes that may influence patient response to treatment.1,3
Continue Reading
Because somatic alterations in CXCR4 have also been reported to commonly occur in patients with WM, the aim of this systematic review was to evaluate the mechanisms of action of these alterations and their prevalence in this disease, as well as their potential impact on clinical presentation, treatment response, and prognosis in patients with WM.
This systematic review included 85 publications, the majority of which were wee divided between preclinical studies, clinical studies, and review articles in approximately equal numbers.
Regarding the mechanisms of action of the unmutated, activated form of the CXCR4 receptor, evidence was found in the literature for its involvement in cell migration and adhesion through G-coupled activation of phosphatidylinositol-3-kinase via activation of the Src family of tyrosine kinases. In addition, activation of the CXCR4 receptor was also implicated in JAK/STAT pathway activation through regulation of gene expression. Alterations in CXCR4 were associated with prolongation of these signaling processes.
Of the 17 studies evaluating the prevalence of CXCR4 mutations in WM, the prevalence of CXCR4 alterations was 34% and 5% in patients with disease characterized by MYD88 L265P and wild-type MYD88, respectively.
Regarding the association of mutated CXCR4 with clinical presentation in WM, there was some evidence that these patients were more likely to develop symptomatic hyperviscosity due to higher serum IgM levels compared with patients with CXCR4 wild-type disease. With respect to extramedullary disease, such as lymphadenopathy and/or splenomegaly, rates of lymphadenopathy were lower in patients with disease characterized by mutated CXCR4 compared with the wild-type CXCR4 gene. However, the frequencies of splenomegaly were similar when these 2 groups were compared.
Furthermore, a relationship between a lower serum beta-2-microglobulin, and disease characterized by a CXCR4 mutation, was also observed.
With respect to the association between the status of the CXCR4 gene and response to specific therapies in WM, there was evidence that patients with disease characterized by mutated CXCR4 were less likely to respond to single-agent ibrutinib, a Bruton tyrosine kinase inhibitor, or ibrutinib/rituximab combination therapy than patients with CXCR4 wild-type disease. However, no significant differences in progression-free survival were observed between these 2 groups when they were treated with a proteasome inhibitor in combination with dexamethasone and rituximab.
Finally, 2 studies evaluating the prognostic impact of a mutated CXCR4 gene did not find an association between CXCR4 gene status and overall survival in patients with WM.
In their concluding remarks, the authors of this systematic review stated that “additional research is needed to further understand the biology of CXCR4 mutations in WM and how to overcome its adverse effect on outcomes of WM patients treated with ibrutinib.”
They also noted that there is a need for the development of standardized testing for CXCR4 mutations in the setting of WM, and encouraged the design and implementation of clinical trials of patients with CXCR4-mutated disease across hematologic and solid cancers. In particular, they cited an ongoing phase 1/2 clinical trial evaluating the combination of ibrutinib and ulocuplumab, an anti-CXCR4 monoclonal antibody, in patients with WM characterized by CXCR4 mutations (ClinicalTrials.gov Identifier: NCT03225716).
Disclosure: Some of the authors of the original study cited potential conflicts of interest with AbbVie, BeiGene, Janssen, Millenium Pharmaceuticals, TG Therapeutics, Bristol-Myers Squibb, and Pharmacyclics. For a full list of disclosures, please refer to the primary study.
References
- Castillo JJ, Moreno DF, Arbelaez MI, et al. CXCR4 mutations affect presentation and outcomes in patients with Waldenström macroglobulinemia: A systematic review [published online July 25, 2019]. Expert Rev Hematol. doi: 10.1080/17474086.2019.1649132
- Nagao T, Oshikawa G, Ishida S, et al. A novel MYD88 mutation, L265RPP, in Waldenström macroglobulinemia activates the NF-κB pathway to upregulate Bcl-xL expression and enhances cell survival. Blood Cancer J. 2015;5:e314.
- Castillo JJ, Ghobrial IM, Treon SP. Response to ibrutinib in a patient with IgG lymphoplasmacytic lymphoma carrying the MYD88L265P gene mutation. Leuk Lymphoma. 2016;57:2699-2701.