Cytogenetic and molecular abnormalities in Waldenström's macroglobulinemia patients: Correlations and prognostic impact

Abstract

While Waldenström macroglobulinemia (WM) is characterized by an almost unifying mutation in MYD88, clinical presentation at diagnosis and response to therapy can be widely different among WM patients. Current prognostic tools only partially address this clinical heterogeneity. Limited data compiling both molecular and cytogenetic information have been used in risk prognostication in WM. To investigate the clinical impact of genetic alterations in WM, we evaluated cytogenetic and molecular abnormalities by chromosome banding analyses, FISH and targeted NGS in a retrospective cohort of 239 WM patients, including 187 patients treated by first-line chemotherapy or immunochemotherapy. Most frequent mutations were identified in MYD88 (93%), CXCR4 (29%), MLL2 (11%), ARID1A (8%), TP53 (8%), CD79A/B (6%), TBL1XR1 (4%) and SPI1 (4%). The median number of cytogenetic abnormalities was two (range, 0-22). Main cytogenetic abnormalities were 6q deletion (del6q) (27%), trisomy 4 (tri4) (12%), tri18 (11%), del13q (11%), tri12 (7.5%) and del17p (7%). Complex karyotype (CK) was observed in 15% (n = 31) of cases, including 5% (n = 12) of highly CK (high-CK). TP53 abnormalities (TP53abn) were present in 15% of evaluable patients. TP53abn and del6q were associated with CK/high-CK (p < .05). Fifty-three percent of patients with hyperviscosity harbored CXCR4 mutations. Cytogenetic and molecular abnormalities did not significantly impact time to first treatment and response to therapy. Prognostic factors associated with shorter PFS were del6q (p = .01), TP53abn (p = .002) and high-CK (p = .01). These same factors as well as IPSSWM, tri4, CXCR4 frameshift and SPI1 mutations were significantly associated with lower OS (p < .05). These results argue for integration of both cytogenetic and molecular screening in evaluation of first-line WM patients.

Post‐relapse survival in Waldenstrom macroglobulinemia patients experiencing therapy failure following autologous transplantation

“…20 Factors that influenced the risk of relapse post-auto-HCT were complex karyotype and increased lines of prior therapy, however there were only two patients with complex karyotype in our data which limited our power to make definitive However, the prognostic factors that were associated with shorter PFS included highly complex karyotype (p = 0.01) and lower OS (p < 0.05). 21 Wang et al, also reported complex karyotype was associated with significantly shorter OS, PFS, and time to treatment. 22 Of the 48 patients transplanted in our cohort during the time period of 2007 and 2017, 22 relapsed after auto-HCT.…”

“…Others have also explored the impact of cytogenetic and molecular abnormalities on outcomes of newly diagnosed WM receiving frontline therapy and discovered that they did not significantly impact time to first treatment and response to therapy. However, the prognostic factors that were associated with shorter PFS included highly complex karyotype ( p = 0.01) and lower OS ( p < 0.05) 21 . Wang et al., also reported complex karyotype was associated with significantly shorter OS, PFS, and time to treatment 22 …”

Nucleic Acid Biomarkers in Waldenström Macroglobulinemia and IgM-MGUS: Current Insights and Clinical Relevance

“…In a cohort of 219 patients, Krzisch et al found that 35% of del(6q) cases harbored CXCR4 mutations, as detected by chromosomal banding analysis (CBA), FISH, and targeted MPS. Moreover, a significantly more complex karyotype was shown in patients with del(6q) [110].…”

“…Albeit at low frequency, other recurring somatic mutations have been reported, including ARID1A (17%), CD79B, KMT2D (or MLL2), MYBBP1A and TP53 (<15% of cases each) (Table 3, Figure 2C) [26][27][28]. [110] Using MPS in a large series of WM and IgM-MGUS patients, Varettoni et al (2017) demonstrated subclonal mutations in KMT2D (16%), TP53 (8%), NOTCH2 (7%), PRDM1 (4%), ARID1A (3%), CD79B (3%) and TRAF3 (1%), while no mutations were found in MYBBP1A and TNFAIP3 [10]. Of note, the median number of KMT2D mutations was significantly higher in WM compared to IgM-MGUS patients.…”

Determinants of Drug Resistance in B-Cell Non-Hodgkin Lymphomas: The Case of Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia

“…The mechanisms of resistance are, in general, common to other types of malignant tumors, involving the overexpression of efflux drug transporters, mutations in TP53 and overexpression of oncogenic pathways, such as the mitogen-activated protein kinase (MAPK) and the PI3K/AKT cascades ( 28 , 29 ). Despite several cytogenetic and molecular alterations have been recognized to possess a prognostic role in LPL/WM, their precise significance in the resistance to chemotherapeutic drugs is still unknown ( 30 ).…”