Working Toward a Genomic Prognostic Classification of Waldenström Macroglobulinemia

Magierowicz, Marion; Tomowiak, Cécile; Leleu, Xavier; Poulain, Stéphanie

doi:10.1016/j.hoc.2018.05.007

Cited by 5 publications

(6 citation statements)

References 48 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: 59%

“…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. 21,36 Only AEs with rates $ 5% are reported.…”

Section: Inclusion N=50contrasting

confidence: 59%

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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: 59%

Section: Inclusion N=50contrasting

confidence: 59%

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

Tomowiak

Poulain

Herbaux³

et al. 2021

Blood Advances

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“…Genes of canonical and noncanonical NF-κB pathways, CXCR4, Toll-like receptors (TLR), and B cell receptor (BCR) may be activated deregulation of survival, apoptosis and proliferation, which may lead to WM clone expansion and tumor progression. Reprinted from Magierowicz et al [8], with permission from Elsevier in this latest report (1.8 versus 2.9 years without reaching statistical significance). In summary, more prospective studies are needed to conclude.…”

Section: Introductionmentioning

confidence: 89%

“…Preclinical studies with the most common CXCR4 S338X mutation in WM have shown sustained signaling of AKT, ERK, and BTK following CXCL12 binding in comparison with wildtype CXCR4, as well as increased cell growth and survival of WM cells. CXCR4 mutations are associated with complex genomic aberrations [8,32]. Patients with CXCR4 mutations demonstrate lower adenopathies, delineating differences in disease tropism, and nonsense mutations are associated with higher IgM production and hyperviscosity [12].…”

Section: Cxcr4 Mutation: a Prognostic Factor?mentioning

confidence: 99%

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

et al. 2019

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Purpose of Review Waldenström macroglobulinemia (WM) is a rare lymphoproliferative disorder. Up to now, therapeutic choice was not influenced by the biological characteristics of the disease. Here, we will review how recent advances in biology in WM may affect therapy strategy. Recent Findings Recently, WM has been described as a new oncogenic model. MyD88 mutation has been described as a key driver mutation and has functional consequences which could be targeted. Other mutations, such as CXCR4 or TP53, have been reported. These mutations are associated with different clinical presentation, prognosis, and treatment response. Summary Mutational status may influence therapeutic choice in some patients but additional data are required. New targeted therapies are on development.

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“…It has been associated with prognosis in some studies [85] but not confirmed in others [123], and it has been considered as predictive for response to ibrutinib [157,158]. However, additional follow up is needed to confirm the prognostic impact, especially in non-ibrutinib-treated patients [159].…”

Section: Cxcr4 Whim-like Mutations In Lpl/wmmentioning

confidence: 99%

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

et al. 2020

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Deciphering the molecular alterations leading to disease initiation and progression is currently crucial to identify the most relevant targets for precision therapy in cancer patients. Cancers express a complex chemokine network influencing leucocyte infiltration and angiogenesis. Moreover, malignant cells also express a selective repertoire of chemokine receptors that sustain their growth and spread. At present, different cancer types have been shown to overexpress C-X-C chemokine receptor type 4 (CXCR4) and to respond to its ligand C-X-C motif chemokine 12 (CXCL12). The CXCL12/CXCR4 axis influences cancer biology, promoting survival, proliferation, and angiogenesis, and plays a pivotal role in directing migration of cancer cells to sites of metastases, making it a prognostic marker and a therapeutic target. More recently, mutations in the C-terminus of CXCR4 have been identified in the genomic landscape of patients affected by Waldenstrom’s macroglobulinemia, a rare B cell neoplasm. These mutations closely resemble those occurring in Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis (WHIM) syndrome, an immunodeficiency associated with CXCR4 aberrant expression and activity and with chemotherapy resistance in clinical trials. In this review, we summarize the current knowledge on the relevance of CXCR4 mutations in cancer biology, focusing on its importance as predictors of clinical presentation and response to therapy.

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Working Toward a Genomic Prognostic Classification of Waldenström Macroglobulinemia

Cited by 5 publications

References 48 publications

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

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

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

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

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