How Recent Advances in Biology of Waldenström’s Macroglobulinemia May Affect Therapy Strategy

Baron, Marine; Simon, Laurence; Poulain, Stéphanie; Leblond, Véronique

doi:10.1007/s11912-019-0768-4

Cited by 4 publications

(4 citation statements)

References 47 publications

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“…9 The frequency of CXCR4 MUT patients in our trial was higher than previously described (56%), likely as a result of the sensitivity of the deep NGS strategy and digital PCR, as well as the relapse setting. 34,35 We did not find any difference in time to response, quality of response, or PFS according to CXCR4 mutation profile or type of mutation (frameshift [FS] vs nonsense [NS]), in contrast to previously described patients treated with ibrutinib. 35 TP53 mutations were observed in 24% of the patients in our R/R cohort, which is also higher than previously described at diagnosis.…”

Section: Inclusion N=50contrasting

confidence: 66%

Obinutuzumab and idelalisib in symptomatic patients with relapsed/refractory Waldenström macroglobulinemia

Tomowiak

Poulain

Herbaux³

et al. 2021

Blood Advances

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We present the results of a phase 2 study evaluating the combination of obinutuzumab + idelalisib in relapsed/refractory (R/R) Waldenström macroglobulinemia (WM). The goal was to determine the safety and efficacy of a fixed-duration chemotherapy-free treatment. During the induction phase, patients received idelalisib + obinutuzumab for 6 cycles, followed by a maintenance phase with idelalisib alone for ≤2 years. Forty-eight patients with R/R WM were treated with the induction combination, and 27 patients participated in the maintenance phase. The best responses, reached after a median of 6.5 months (interquartile range, 3.4-7.1; range, 2.6-22.1 months), were very good partial response in 5 patients, partial response in 27 patients, and minor response in 3 patients, leading to overall response rate and major response rate estimates of 71.4% (95% confidence interval [CI], 56.7-83.4) and 65.3% (95% CI, 50.4-78.3), respectively. With a median follow-up of 25.9 months, median progression-free survival was 25.4 months (95% CI, 15.7-29.0). Univariate analysis focusing on molecular screening found no significant impact of CXCR4 genotypes on responses and survivals but a deleterious impact of TP53 mutations on survival. Although there was no grade 5 toxicity, 26 patients were removed from the study because of side effects; the most frequent were neutropenia (9.4%), diarrhea (8.6%), and liver toxicity (9.3%). The combination of idelalisib + obinutuzumab is effective in R/R WM. Nonetheless, the apparent lack of impact of genotype on outcome could give new meaning to targeting of the phosphatidylinositol 3-kinase pathway in WM. This trial was registered at www.clinicaltrials.gov as #NCT02962401.

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Section: Inclusion N=50contrasting

confidence: 66%

Obinutuzumab and idelalisib in symptomatic patients with relapsed/refractory Waldenström macroglobulinemia

Tomowiak

Poulain

Herbaux³

et al. 2021

Blood Advances

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“…Considered as secondary genetic events, activating mutations of CXCR4 (CXCR4 S338X or CXCR4 WHIM ), a receptor implicated in migration and bone marrow (BM) homing of leucocytes, are found in 30% of WM cases ( 6 ). Additional mutations of CD79b , ARID1A or TP53 have been reported ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

“…Despite these advances, WM pathophysiology is incompletely understood. Its treatment remains challenging and the exact role of MYD88 mutations in the emergence of lymphoplasmacytic B-cell clones is not known ( 7 , 8 ). Indeed, MYD88 mutations are also found in 30% of activated B-cell type diffuse large B-cell lymphomas (ABC-DLBCL), more than half of primary cutaneous DLBCLs, leg type, and many DLBCLs at immune-privileged sites but not in plasma cell myelomas, even IgM types ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Continuous MYD88 Activation Is Associated With Expansion and Then Transformation of IgM Differentiating Plasma Cells

et al. 2021

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Activating mutations of MYD88 (MYD88L265P being the far most frequent) are found in most cases of Waldenström macroglobulinemia (WM) as well as in various aggressive B-cell lymphoma entities with features of plasma cell (PC) differentiation, such as activated B-cell type diffuse large B-cell lymphoma (DLBCL). To understand how MYD88 activation exerts its transformation potential, we developed a new mouse model in which the MYD88L252P protein, the murine ortholog of human MYD88L265P, is continuously expressed in CD19 positive B-cells together with the Yellow Fluorescent Protein (Myd88L252P mice). In bone marrow, IgM B and plasma cells were expanded with a CD138 expression continuum from IgMhigh CD138low to IgMlow CD138high cells and the progressive loss of the B220 marker. Serum protein electrophoresis (SPE) longitudinal analysis of 40 Myd88L252P mice (16 to 56 weeks old) demonstrated that ageing was first associated with serum polyclonal hyper gammaglobulinemia (hyper Ig) and followed by a monoclonal immunoglobulin (Ig) peak related to a progressive increase in IgM serum levels. All Myd88L252P mice exhibited spleen enlargement which was directly correlated with the SPE profile and was maximal for monoclonal Ig peaks. Myd88L252P mice exhibited very early increased IgM PC differentiation. Most likely due to an early increase in the Ki67 proliferation index, IgM lymphoplasmacytic (LP) and plasma cells continuously expanded with age being first associated with hyper Ig and then with monoclonal Ig peak. This peak was consistently associated with a spleen LP-like B-cell lymphoma. Clonal expression of both membrane and secreted µ chain isoforms was demonstrated at the mRNA level by high throughput sequencing. The Myd88L252P tumor transcriptomic signature identified both proliferation and canonical NF-κB p65/RelA activation. Comparison with MYD88L265P WM showed that Myd88L252P tumors also shared the typical lymphoplasmacytic transcriptomic signature of WM bone marrow purified tumor B-cells. Altogether these results demonstrate for the first time that continuous MYD88 activation is specifically associated with clonal transformation of differentiating IgM B-cells. Since MYD88L252P targets the IgM PC differentiation continuum, it provides an interesting preclinical model for development of new therapeutic approaches to both WM and aggressive MYD88 associated DLBCLs.

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“…The significant degree of clinical and genetic heterogeneity can be attributed mostly to WM tumoral clone compartment which consists of clonal B-cells, clonal plasma cells and a lymphoplasmacytic population [7,20]. Whole-genome sequencing studies have shown recurrent somatic mutations in WM and IgM MGUS as the most important prognostic markers defining prognosis, risk of progression, and treatment decisions [21]. Previous GEP profiling studies have identified several pathways and gene expression alterations in WM and IgM MGUS patients [15,16].…”

Section: Discussionmentioning

confidence: 99%

Identification of a Candidate Gene Set Signature for the Risk of Progression in IgM MGUS to Smoldering/Symptomatic Waldenström Macroglobulinemia (WM) by a Comparative Transcriptome Analysis of B Cells and Plasma Cells

Trojani

Camillo

Bossi

et al. 2021

Cancers

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Waldenström Macroglobulinemia (WM) is a B-cell lymphoma characterized by the precursor condition IgM monoclonal gammopathies of undetermined significance (IgM MGUS). We performed a gene expression profiling study to compare the transcriptome signatures of bone marrow (BM) B-cells and plasma cells of 36 WM patients, 13 IgM MGUS cases, and 7 healthy subjects used as controls (CTRLs) by Affymetrix microarray. We determined 2038 differentially expressed genes (DEGs) in CD19+ cells and 29 DEGs genes in CD138+ cells, respectively. The DEGs identified in B-cells were associated with KEGG pathways, mainly involved in hematopoietic cell lineage antigens, cell adhesion/focal adhesion/transmembrane proteins, adherens junctions, Wnt-signaling pathway, BCR-signaling pathway, calcium signaling pathway, complement/coagulation cascade, platelet activation, cytokine-cytokine receptor interactions, and signaling pathways responsible for cell cycle, apoptosis, proliferation and survival. In conclusion, we showed the deregulation of groups of genes belonging to KEGG pathways in the comparison among WM vs. IgM MGUS vs. CTRLs in B-cells. Interestingly, a small set of genes in B-cells displayed a common transcriptome expression profile between WM and IgM MGUS compared to CTRLs, suggesting its possible role in the risk of transformation of IgM MGUS to WM.

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How Recent Advances in Biology of Waldenström’s Macroglobulinemia May Affect Therapy Strategy

Cited by 4 publications

References 47 publications

Obinutuzumab and idelalisib in symptomatic patients with relapsed/refractory Waldenström macroglobulinemia

Obinutuzumab and idelalisib in symptomatic patients with relapsed/refractory Waldenström macroglobulinemia

Continuous MYD88 Activation Is Associated With Expansion and Then Transformation of IgM Differentiating Plasma Cells

Identification of a Candidate Gene Set Signature for the Risk of Progression in IgM MGUS to Smoldering/Symptomatic Waldenström Macroglobulinemia (WM) by a Comparative Transcriptome Analysis of B Cells and Plasma Cells

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