Diagnostic Tools of Waldenström’s Macroglobulinemia – Best Possibilities for Non-invasive and Long-term Disease Monitoring

Abstract

Waldenströms macroglobulinemia (WM) is a B-cell malignancy characterized by high level of monoclonal immunoglobulin M (IgM) paraprotein in blood serum and associated with the bone marrow infiltration by malignant cells with lymphoplasmacytic differentiation. WM remains incurable advances in therapy. Most of WM cases are associated with a somatic point mutation L265P in MYD88. Significantly higher risk of progression from the IgM monoclonal gammopathy of undetermined significance (IgM MGUS) to WM for patients with mutated MYD88 gene suggests that this mutation is an early oncogenic event and plays a central role in development of malignant clones. The second, most prevalent mutation in WM is found in the CXCR4 gene and is often associated with drug resistance and aggressive disease presentation. Therefore, detection of these mutations (MYD88L265P and CXCR4S338X) could be useful diagnostic and prognostic tool for the patients with WM. While detection of these mutations in bone marrow sample is common, the aim of our study was to compare sensitivity of detection of mutation from different cell fraction from peripheral blood and bone marrow. The results show possibility to describe MYD88 and CXCR4 mutation status even from peripheral blood sample (sensitivity for MYD88L265P was 100%, for CXCR4S338X 91%), which significantly facilitate material collection. Moreover, comparable detection sensitivity of these mutations in bone marrow and peripheral blood samples examined before and during the therapy offers a promising tool for more routine diagnostic and monitoring of disease progression.Key words: Waldenström macroglobulinemia - hematology - neoplasms - lymphoma - mutation - MYD88 - CXCR4.

Detection of MYD88 and CXCR4 mutations in cell-free DNA of patients with IgM monoclonal gammopathies

“…The prevalence of MYD88 L265P (82%) in our cohort is comparable to the rates observed in other studies [ 5 , 29 , 33 , 34 ]. The prevalence rates are also comparable to those achieved using CD19-selected cells from PB [ 20 , 21 ]. Although previous studies using unselected PB cells from untreated WM patients have shown that the MYD88 L265P mutation can be detected, the detection sensitivity was so low (39.5%) that they were prompted to examine the mutation in CD19-selected PB cells using magnetic bead isolation for AS-PCR [ 20 ].…”

“…Studies have shown the relevance of specific CXCR4 mutations to enhanced WM cell dissemination leading to in vivo disease progression as well as increased resistance to ibrutinib treatment [ 17 – 19 ]. Both MYD88 and CXCR4 mutations are detected in the bone marrow (BM), although there have been attempts to detect them in CD19 + -selected cells in the peripheral blood (PB) of patients with IgM monoclonal gammopathies [ 20 , 21 ].…”

Cell‐free DNA analysis for detection of MYD88L265P and CXCR4S338X mutations in Waldenström macroglobulinemia

“…[1][2][3]5,6 Although MYD88 and CXCR4 mutations can also be identified in peripheral blood (PB), the diagnostic yield in PB is inferior to BM, particularly for previously treated patients. 7,8 Tumor enrichment with B-cell selection can significantly improve testing sensitivity, but pre-sorting B cells is time-consuming and not feasible in most clinical laboratories. 7,9 Recent studies have demonstrated the feasibility of identifying MYD88 and CXCR4 mutations by using cell-free DNA (cfDNA) from WM patients.…”

Exploratory Study of MYD88 L265P, Rare NLRP3 Variants, and Clonal Hematopoiesis Prevalence in Patients With Schnitzler Syndrome

“…Significantly, this variant was detected in PB from 9 of 30 SchS patients by ASO‐PCR, which has detection sensitivity down to 1% of the mutant allele and thus can detect mutations in circulating myeloid cells. This technique is highly utilized in laboratories worldwide for the diagnostic assessment of WM and other B cell chronic lymphoproliferative disorders .…”