98% IGHV gene identity is the optimal cutoff to dichotomize the prognosis of Chinese patients with chronic lymphocytic leukemia

Shi, Ke; Sun, Qiang; Qiao, Chun; Zhu, Huayuan; Wang, Li; Wu, Jia‐Zhu; Wang, Lili; Fu, Jianxin; Young, Ken H.; Fan, Lei; Xia, Yi; Xu, Wei; Li, Jianyong

doi:10.1002/cam4.2788

Cited by 5 publications

(6 citation statements)

References 34 publications

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“…MYD88 variants were associated with a distinctive grouping status in the CLL/SLL cohort. The incidence of MYD88 variants has been discordant according to previous research, with variant frequencies ranging from 3 to 20% in different studies [ 15 , 17 , 18 ]. In our cohort, MYD88 variants showed significant differences in the incidence of immunophenotype grouping.…”

Section: Discussionmentioning

confidence: 90%

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MYD88-Mutated Chronic Lymphocytic Leukaemia/Small Lymphocytic Lymphoma as a Distinctive Molecular Subgroup Is Associated with Atypical Immunophenotypes in Chinese Patients

Fan²,

Chen

et al. 2023

JCM

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Chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) is a heterogeneous disease in Western and Chinese populations, and it is still not well characterized in Chinese patients. Based on a large cohort of newly diagnosed CLL/SLL patients from China, we investigated immunophenotypes, genetic abnormalities, and their correlations. Eighty-four percent of the CLL/SLL patients showed typical immunophenotypes with scores of 4 or 5 points in the Royal Marsden Hospital (RMH) scoring system (classic group), and the remaining 16% of patients were atypical with scores lower than 4 points (atypical group). Trisomy 12 and variants of TP53, NOTCH1, SF3B1, ATM, and MYD88 were the most recurrent genetic aberrations. Additionally, unsupervised genomic analysis based on molecular genetics revealed distinctive characteristics of MYD88 variants in CLL/SLL. By overlapping different correlation grouping analysis from genetics to immunophenotypes, the results showed MYD88 variants to be highly related to atypical CLL/SLL immunophenotypes. Furthermore, compared with mantle cell lymphoma (MCL), the genetic landscape showed potential value in clinical differential diagnosis of atypical CLL/SLL and MCL patients. These results reveal immunophenotypic and genetic features, and may provide insights into the tumorigenesis and clinical management of Chinese CLL/SLL patients.

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Section: Discussionmentioning

confidence: 90%

“…IGHV1-69 is a significant geographical distribution-related V gene segment recurrently selected in the West (~15%) but rare in Asian and Chinese CLL/SLL patients (1~10%) [ 5 , 18 , 28 ]. Due to the fact that the presence of IGHV1-69 is associated with non-hypermutated IGHV status, IGHV1-69 is related to unfavourable prognosis.…”

Section: Discussionmentioning

confidence: 99%

MYD88-Mutated Chronic Lymphocytic Leukaemia/Small Lymphocytic Lymphoma as a Distinctive Molecular Subgroup Is Associated with Atypical Immunophenotypes in Chinese Patients

Fan²,

Chen

et al. 2023

JCM

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“…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.

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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.

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“…It is worth noting how these two studies used different cutoffs of IGHV identity in the germline sequence to define the BL-IGHV group, underscoring how IGHV mutational status is still defined based on arbitrary cutoffs. Indeed, different groups also tried to re-explore the optimal cutoffs to discern between M-IGHV and U-IGHV patients or analyzing IGHV mutational status as a continuous variable, but without establishing new cutoffs in clinical practice [ 37 , 38 ].…”

Section: Introductionmentioning

confidence: 99%

Chronic Lymphocytic Leukemia (CLL) with Borderline Immunoglobulin Heavy Chain Mutational Status, a Rare Subgroup of CLL with Variable Disease Course

Angotzi,

Cellini,

Ruocco

et al. 2024

Cancers

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Chronic lymphocytic leukemia (CLL) exhibits substantial variability in disease course. The mutational status of the B-cell receptor immunoglobulin heavy variable (IGHV) chain is a critical prognostic factor, categorizing patients into mutated (M-IGHV) and unmutated (U-IGHV) groups. Recently, a third subgroup with borderline mutational status (BL-IGHV) has been identified, comprising approximately 5% of CLL cases. This study retrospectively analyzes the outcomes of 30 BL-IGHV mutated patients among a cohort of 653 CLL patients, focusing on time to first treatment (TTFT) and overall survival (OS). BL-IGHV patients had a short TTFT similar to U-IGHV patients (median 30.2 vs. 34 months; p = 0.9). Conversely, the OS of BL-IGHV patients resembled M-IGHV patients (median NR vs. 258 months; p = 1). Despite a similar incidence in unfavorable prognostic factors, the TTFT was shorter compared to other published cohorts. However, striking similarities with other experiences suggest that BL-IGHV mutated patients share common biological characteristics, biased IGHV gene usage and BCR subset frequency. These findings also underscore the need for multicentric efforts aggregating data on BL-IGHV CLL in order to elucidate its disease course and optimize therapeutic approaches for this rare subgroup. Until then, predicting outcomes and optimal management of BL-IGHV CLL will remain challenging.

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98% IGHV gene identity is the optimal cutoff to dichotomize the prognosis of Chinese patients with chronic lymphocytic leukemia

Cited by 5 publications

References 34 publications

MYD88-Mutated Chronic Lymphocytic Leukaemia/Small Lymphocytic Lymphoma as a Distinctive Molecular Subgroup Is Associated with Atypical Immunophenotypes in Chinese Patients

MYD88-Mutated Chronic Lymphocytic Leukaemia/Small Lymphocytic Lymphoma as a Distinctive Molecular Subgroup Is Associated with Atypical Immunophenotypes in Chinese Patients

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

Chronic Lymphocytic Leukemia (CLL) with Borderline Immunoglobulin Heavy Chain Mutational Status, a Rare Subgroup of CLL with Variable Disease Course

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