Importance of sequential analysis of <i><scp>TP</scp>53</i> variation in patients with Waldenström Macroglobulinaemia

Christian, Amy; Davis, Zadie; Walewska, Renata; McCarthy, Helen

doi:10.1111/bjh.15909

Cited by 4 publications

(7 citation statements)

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“…They also appear to predict shorter times to progression in patients with asymptomatic disease. TP53 mutations may also be acquired during the course of the disease 35,37 . Assessment of TP53 for both 17p deletion and gene mutation could potentially influence treatment decisions.…”

Section: Diagnosis and Investigationsmentioning

confidence: 99%

“…There is conflicting evidence from retrospective data sets as to whether patients with MYD88 WT have a shorter OS than those with MYD88 L295P 23,27,43 . As described above, TP53 mutation/ TP53 loss, although rare, is associated with an inferior survival 35,37 …”

Section: Diagnosis and Investigationsmentioning

confidence: 99%

“…Although the incidence of TP53 disruption is low in untreated WM patients (2%–10%), this can increase under selective pressure of chemotherapy resulting in chemo‐refractoriness. Analogous to CLL, non‐chemotherapeutic options should be considered for WM patients harbouring TP53 disruption at relapse 35–37 …”

Section: Treatmentmentioning

confidence: 99%

“…TP53 mutations may also be acquired during the course of the disease. 35,37 Assessment of TP53 for both 17p deletion and gene mutation could potentially influence treatment decisions. As above, B-cell selection and high-throughput sequencing approaches are considered optimal for detecting TP53 mutation or loss.…”

Section: Pathological Diagnosis and Genomic Assessmentmentioning

confidence: 99%

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Diagnosis and management of Waldenström macroglobulinaemia—A British Society for Haematology guideline

et al. 2022

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Scope The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with Waldenström macroglobulinaemia. In individual patients, circumstances may dictate an alternative approach. Methodology This guideline was compiled according to the British Society for Haematology (BSH) process at http://www.b-s-h.org.uk/guidelines/proposing-and-writing-a-new-bsh-guideline/. Recommendations are based on a review of the literature using Medline, Pubmed, Embase, Central, Web of Science searches from beginning of 2013 (since the publication of the previous guidelines) up to November 2021. The following search terms were used: Waldenström(’s) macroglobulin(a)emia OR lymphoplasmacytic lymphoma, IgM(‐related) neuropathy OR cold h(a)emagglutinin disease OR cold agglutinin disease OR cryoglobulin(a)emia AND (for group a only) cytogenetic OR molecular OR mutation OR MYD88 OR CXCR4, management OR treatment OR transfusion OR supportive care OR plasma exchange OR plasmapheresis OR chemotherapy OR bendamustine OR bortezomib OR ibrutinib OR fludarabine OR dexamethasone OR cyclophosphamide OR rituximab OR everolimus, bone marrow transplantation OR stem cell transplantation. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. Review of the manuscript was performed by the British Society for Haematology (BSH) Guidelines Committee Haemato‐Oncology Task Force, the BSH Guidelines Committee and the Haemato‐Oncology sounding board of BSH. It was also on the members section of the BSH website for comment. It has also been reviewed by UK Charity WMUK; these organisations do not necessarily approve or endorse the contents.

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Section: Diagnosis and Investigationsmentioning

confidence: 99%

Section: Diagnosis and Investigationsmentioning

confidence: 99%

Section: Treatmentmentioning

confidence: 99%

Section: Pathological Diagnosis and Genomic Assessmentmentioning

confidence: 99%

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Diagnosis and management of Waldenström macroglobulinaemia—A British Society for Haematology guideline

et al. 2022

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“…Compensatory PI3K/Akt signaling may contribute to ibrutinib resistance in the CXCR4 MUT WM model, as well as in the CXCR4 WT WM model, resulting in synthetic lethality toward the PI3K/Akt inhibitor. [38][39][40] Therefore, targeting of the PI3K/Akt pathway could be an option in BTK inhibitor-resistant WM patients and appears to be a proof of concept regarding the efficacy of this class of compound in WM patients. In addition, for the first time, we provide an estimate of the response rate or PFS achieved with a combination regimen including inhibitors of BCRassociated kinases in TP53 MUT WM patients; however, the number of patients was small, and a nonstatistically significant deleterious effect of TP53 mutation was observed.…”

Section: Inclusion N=50mentioning

confidence: 99%

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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In-depth molecular analysis of lymphomas with lymphoplasmacytic differentiation may provide more precise diagnosis and rational treatment allocation

Brunner,

Thalhammer-Thurner,

Willenbacher

et al. 2023

Ann Hematol

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We performed a molecular analysis of formalin-fixed paraffin embedded and decalcified bone marrow trephine biopsies of 41 patients with a B-cell disorder with lymphoplasmacytic differentiation to enable a more precise diagnosis and to describe potentially prognostic and therapeutic relevant mutations. Analysis was performed with a commercially available next-generation sequencing (NGS) lymphoma panel (Lymphoma Solution, SophiaGenetics). Results were correlated with clinical and pathological parameters. Our group covered a spectrum of B-cell disorders with plasmacytic differentiation ranging from Waldenstroem’s macroglobulinemia (WM), to small-B-cell lymphomas with plasmacytic differentiation (SBCL-PC) to IgM myeloma (MM). The most helpful diagnostic criteria included morphology and immuno-phenotype as a prerequisite for the interpretation of molecular analysis. MYD88 mutation was present in nearly all WM, but also in 50% of SBCL-PCs, while MM were consistently negative. Driver mutations, such as TP53, were already detectable early in the course of the respective diseases indicating a higher risk of progression, transformation, and reduced progression-free survival. In addition, we report on a novel BIRC3 frameshift mutation in one case of a progressive WM. Our data indicate that patients with LPL/WM might benefit from thorough pathological work-up and detailed molecular analysis in terms of precise diagnosis and targeted treatment allocation.

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Importance of sequential analysis of TP53 variation in patients with Waldenström Macroglobulinaemia

Cited by 4 publications

References 10 publications

Diagnosis and management of Waldenström macroglobulinaemia—A British Society for Haematology guideline

Diagnosis and management of Waldenström macroglobulinaemia—A British Society for Haematology guideline

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

In-depth molecular analysis of lymphomas with lymphoplasmacytic differentiation may provide more precise diagnosis and rational treatment allocation

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