Immunoglobulin heavy chain variable region gene and prediction of time to first treatment in patients with chronic lymphocytic leukemia: Mutational load or mutational status? Analysis of 1003 cases

Morabito, Fortunato; Shanafelt, Tait D.; Gentile, Massimo; Reda, Gianluigi; Mauro, Francesca Romana; Rossi, Davide; Renzo, Nicola Di; Molica, Stefano; Angrilli, Francesco; Chiarenza, Annalisa; Cutrona, Giovanna; Chaffee, Kari G.; Tripepi, Giovanni; D’Arrigo, Graziella; Vigna, Ernesto; Recchia, Anna Grazia; Cortelezzi, Agostino; Gaïdano, Gianluca; Raimondo, Francesco Di; Fais, Franco; Foà, Robin; Neri, Antonino; Ferrarini, Manlio

doi:10.1002/ajh.25206

Cited by 15 publications

(9 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Jain et al have reported that in FCR (fludarabine–cyclophosphamide–rituximab)‐treated patients, the absolute level of IGHV percentage of identity rather than the 98% cut‐off is a better predictor of post‐treatment outcome, pointing to the potential relevance of the SHM as a continuous rather than a dichotomized variable to predict FCR efficacy (Jain et al , ). A subsequent study on 1003 CLL patients, including the newly diagnosed Binet stage A patients from protocol O‐CLL1, did not confirm the value of SHM as a continuous variable in the prognostic assessment of TFT (Morabito et al , ), reinforcing the 98% cut‐off as the best cut‐off to distinguish two groups with a different prognostic likelihood, without the need for a further subdivision.…”

Section: Resultsmentioning

confidence: 97%

Redefining the prognostic likelihood of chronic lymphocytic leukaemia patients with borderline percentage of immunoglobulin variable heavy chain region mutations

et al. 2020

Self Cite

View full text Add to dashboard Cite

Summary In chronic lymphocytic leukaemia (CLL), caution is warranted regarding the clinical implications of immunoglobulin variable heavy chain region (IGHV) rearrangements with a ‘borderline’ (BL) percentage of mutations (i.e. 97–97·9% IGHV identity). We analysed the IGHV mutational status in 759 untreated CLL patients (cohort 1). BL‐CLL (n = 36, 5%) showed a time to first treatment (TFT) similar to that of M‐CLL (n = 338) and significantly longer than that of UM‐CLL (n = 385), despite the enrichment in subset #2 cases. In fact, CLLs belonging to subset #2 (n = 15/759, 2%) were significantly more frequent among BL‐CLLs (n = 5/36, 14%), with a brief TFT. TFT of BL‐CLL remained comparable to that of M‐CLL also considering the 327 CLL patients evaluated at diagnosis. These findings were then validated in an independent cohort 2 of 759 newly diagnosed CLL patients (BL‐CLL: n = 11, 1·4%) and in all newly diagnosed patients from cohorts 1 and 2 (n = 1 086, 84% stage A; BL‐CLL: n = 47, 4·3%). BL‐CLL at diagnosis showed a biological profile comparable to that of M‐CLL with a low frequency of unfavourable prognostic markers, except for a significant enrichment in subset #2. Our data suggest that the prognosis of BL‐CLL is good and similar to that of M‐CLL, with the exception of subset #2 cases.

show abstract

Section: Resultsmentioning

confidence: 97%

Redefining the prognostic likelihood of chronic lymphocytic leukaemia patients with borderline percentage of immunoglobulin variable heavy chain region mutations

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Jain et al, from the MD Anderson Cancer Center demonstrated a significant association with PFS and OS in 203 treatment naïve patients treated with frontline FCR when IGHV % was treated as a continuous variable with higher percentages incrementally associated with favorable PFS and OS (p < 0.001) [66]. A subsequent study by Morabito et al investigating the impact of IGHV % as a continuous variable on TTFT in a large cohort of 467 newly diagnosed Binet stage A patients failed to recapture the results demonstrated by the MDACC group, instead further strengthening the use of a 2% cutoff for prognostication [67].…”

Section: Immunoglobulin Mutational Statusmentioning

confidence: 97%

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

View full text Add to dashboard Cite

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.

show abstract

“…Defining the IGHV gene mutation status of a patient's leukemic B cell clone is a cornerstone of prognosis in CLL (3,47). Although several studies have addressed the best cutoff to be used in this analysis (46,(48)(49)(50)(51)(52), there has not been a detailed investigation aimed at determining if a loss of (auto) antigen -BCR interaction, which could obviate or reduce transmission of ongoing survival signals to the leukemic B cell, is the feature that is most responsible for defining M-CLL patients with better clinical outcomes. Here, we have tried to address this issue.…”

Section: Discussionmentioning

confidence: 99%

Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia

Kaufman

Yan

et al. 2022

Front. Oncol.

View full text Add to dashboard Cite

Patients with CLL with mutated IGHV genes (M-CLL) have better outcomes than patients with unmutated IGHVs (U-CLL). Since U-CLL usually express immunoglobulins (IGs) that are more autoreactive and more effectively transduce signals to leukemic B cells, B-cell receptor (BCR) signaling is likely at the heart of the worse outcomes of CLL cases without/few IGHV mutations. A corollary of this conclusion is that M-CLL follow less aggressive clinical courses because somatic IGHV mutations have altered BCR structures and no longer bind stimulatory (auto)antigens and so cannot deliver trophic signals to leukemic B cells. However, the latter assumption has not been confirmed in a large patient cohort. We tried to address the latter by measuring the relative numbers of replacement (R) mutations that lead to non-conservative amino acid changes (Rnc) to the combined numbers of conservative (Rc) and silent (S) amino acid R mutations that likely do not or cannot change amino acids, “(S+Rc) to Rnc IGHV mutation ratio”. When comparing time-to-first-treatment (TTFT) of patients with (S+Rc)/Rnc ≤ 1 and >1, TTFTs were similar, even after matching groups for equal numbers of samples and identical numbers of mutations per sample. Thus, BCR structural change might not be the main reason for better outcomes for M-CLL. Since the total number of IGHV mutations associated better with longer TTFT, better clinical courses appear due to the biologic state of a B cell having undergone many stimulatory events leading to IGHV mutations. Analyses of larger patient cohorts will be needed to definitively answer this question.

show abstract

Immunoglobulin heavy chain variable region gene and prediction of time to first treatment in patients with chronic lymphocytic leukemia: Mutational load or mutational status? Analysis of 1003 cases

Cited by 15 publications

References 13 publications

Redefining the prognostic likelihood of chronic lymphocytic leukaemia patients with borderline percentage of immunoglobulin variable heavy chain region mutations

Redefining the prognostic likelihood of chronic lymphocytic leukaemia patients with borderline percentage of immunoglobulin variable heavy chain region mutations

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

Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia

Contact Info

Product

Resources

About