Guideline for the treatment of chronic lymphocytic leukaemia

Schuh, Anna; Parry‐Jones, Nilima; Appleby, Niamh; Bloor, Adrian; Dearden, Claire; Fegan, Chris; Follows, George; Fox, Christopher P.; Iyengar, Sunil; Kennedy, Ben; McCarthy, Helen; Parry, Helen; Patten, Piers; Pettitt, Andrew R.; Ringshausen, Ingo; Walewska, Renata; Hillmen, Peter

doi:10.1111/bjh.15460

Cited by 30 publications

(30 citation statements)

References 106 publications

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“…According to most practice guidelines today, TP53 disruption remains the lone predictive biomarker in CLL [38][39][40][41] and should be analyzed prior to treatment initiation in all patients owing to the large body of evidence demonstrating that patients either do not respond to initial chemoimmunotherapy (CIT) or experience relapse soon after remission [42] (Table 2). The most comprehensive data addressing the predictive capacity of TP53 disruption comes from an analysis of the CLL-8 trial [43], a phase 3, randomized (1:1) study comparing treatment with fl a phase and cyclophosphamide (FC) or FC with rituximab (FCR) in 817 previously untreated patients in which Stilgenbauer et al, showed that patients with TP53 disruption experienced poorer clinical responses, minimal residual disease (MRD) negativity, progression-free survival (PFS) and OS after treatment with FC and FCR [44] and that anti-CD20 therapy added no OS benefit.…”

Section: Tp53 Disruptionmentioning

confidence: 99%

“…We support the use of FCR in younger, fit patients with M IGHV given its potential for long-term remission and we recommend targeted therapy with a novel pathway inhibitor in patients with UM IGHV with case-by-case determinations being made in the setting of older and less fit CLL patients. Society guideline recommendations for the analysis of IGHV gene mutational status can be found in Table 2 [38][39][40][41].…”

Section: Immunoglobulin Mutational Statusmentioning

confidence: 99%

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An Updated Perspective on Current Prognostic and Predictive Biomarkers in Chronic Lymphocytic Leukemia in the Context of Chemoimmunotherapy and Novel Targeted Therapy

Cohen

Bomben

Pozzo

et al. 2020

Cancers

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Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course. Novel biomarkers discovered over the past 20 years have revolutionized the way clinicians approach prognostication and treatment especially in the chemotherapy-free era. Herein, we review the best established prognostic and predictive biomarkers in the setting of chemoimmunotherapy (CIT) and novel targeted therapy. We propose that TP53 disruption (defined as either TP53 mutation or chromosome 17p deletion), unmutated immunoglobulin heavy chain variable region gene status (UM IGHV), NOTCH1 mutation, and CD49d expression are the strongest prognosticators of disease progression and overall survival in the field of novel biomarkers including recurrent gene mutations. We also highlight the predictive role of TP53 disruption, UM IGHV, and NOTCH1 mutation in the setting of CIT and TP53 disruption and CD49d expression in the setting of novel targeted therapy employing B-cell receptor (BCR) and B-cell lymphoma-2 (BCL2) inhibition. Finally, we discuss future directions in the field of biomarker development to identify those with relapsed/refractory disease at risk for progression despite treatment with novel therapies.

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Section: Tp53 Disruptionmentioning

confidence: 99%

Section: Immunoglobulin Mutational Statusmentioning

confidence: 99%

An Updated Perspective on Current Prognostic and Predictive Biomarkers in Chronic Lymphocytic Leukemia in the Context of Chemoimmunotherapy and Novel Targeted Therapy

Cohen

Bomben

Pozzo

et al. 2020

Cancers

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“…Reassessment at each pretreatment time point should be undertaken as clonal evolution can occur 24. As already stated, the assessment of del(17 p) by FISH is routinely performed.…”

Section: Current Testing Regimens In Routine Practicementioning

confidence: 99%

Relevance of TP53 for CLL diagnostics

et al. 2019

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TP53 disruption in chronic lymphocytic leukaemia (CLL) is a well-established prognostic marker and informs on the appropriate course of treatment for patients. TP53 status is commonly assessed by fluorescence in situ hybridisation for del(17 p) and Sanger sequencing for TP53 mutations. At present, current screening methods for TP53 mutations fail to detect diagnostically relevant mutations potentially leading to inappropriate treatment decisions. In addition, low levels of mutations that are proving to be clinically relevant may not be discovered with current less sensitive techniques. This review describes the structure, function and regulation of the TP53 protein, the mutations found in cancer and CLL, the relevance of TP53 disruption in CLL and the current screening methods for TP53 mutations including next-generation sequencing.

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“…Disruption of TP53 either via deletion, mutation or both has also been shown to be a poor prognostic factor in CLL associated with primary refractoriness to chemo-immunotherapy, even if the aberration is in a small subclone [127,128]. In such cases, small molecular inhibitors targeting BTK, PI3K or BCL2 are preferred [129]. Deep sequencing using NGS panels can detect subclonal mutations, which may ultimately confer resistance to these inhibitors, many months before relapse, e.g.…”

Section: Chronic Lymphocytic Leukaemiamentioning

confidence: 99%

Application of Genomics to Clinical Practice in Haematological Malignancy

et al. 2019

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Purpose of Review The usual abundance of fresh cells and high-quality DNA derived from bone marrow aspirate and peripheral blood mean haematological malignancies are at the forefront of the application of genomics to malignancy. This review evaluates where genomics is routinely used in clinical care and where opportunities for further application exist. Recent Findings The 2016 revision of the WHO classification of tumours of haematopoietic and lymphoid tissues increased the number of disease entities defined by, or whose diagnosis was strongly supported by, a specific genetic change. Increasingly combinations of mutations rather than individual lesions are being used to genomically classify heterogeneous disorders to inform prognosis and direct treatment. Furthermore, the role of different genetic aberrations as markers of measurable residual disease is being evaluated in clinical trials to allow intensification/de-intensification of treatment as appropriate and early detection of relapse. Summary Implementation of broader sequencing technologies such as whole exome/genome sequencing coupled with continuing developments in genomic technology to improve turnaround times are likely to further reinforce the centrality of genomics in the management of haematological malignancies.

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Guideline for the treatment of chronic lymphocytic leukaemia

Cited by 30 publications

References 106 publications

An Updated Perspective on Current Prognostic and Predictive Biomarkers in Chronic Lymphocytic Leukemia in the Context of Chemoimmunotherapy and Novel Targeted Therapy

An Updated Perspective on Current Prognostic and Predictive Biomarkers in Chronic Lymphocytic Leukemia in the Context of Chemoimmunotherapy and Novel Targeted Therapy

Relevance of TP53 for CLL diagnostics

Application of Genomics to Clinical Practice in Haematological Malignancy

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