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

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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Copyright © 2022 Kaufman, Yan, Li, Ghia, Langerak, Rassenti, Belessi, Kay, Davi, Byrd, Pospisilova, Brown, Catherwood, Davis, Oscier, Montillo, Trentin, Rosenquist, Ghia, Barrientos, Kolitz, Allen, Rai, Stamatopoulos, Kipps, Neuberg and Chiorazzi.

Déclaration de conflit d'intérêts

The following authors received funding from other sources as listed. However, these funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. MK is Chief Executive Officer, StationMD; AL has received unrestricted research grants and/or speaker fees from Roche-Genentech, AbbVie, and Janssen. NK serves on Advisory Boards for AbbVie, Astra Zeneca, Beigene, Behring, Cytomx Therapy, Dava Oncology, Janssen, Juno Therapeutics, Onco tracker, Pharmacyclics and Targeted Oncology, is a member of Data Safety Monitoring Committees for Agios Pharm, AstraZeneca, BMS–Celgene, Cytomx Therapeutics, Janssen, Morpho-sys, Rigel, and received research funding from AbbVie, Acerta Pharma, Bristol Meyer Squib, Celgene, Genentech, MEI Pharma, Pharmacyclics, Sunesis, TG Therapeutics, Tolero Pharmaceuticals. JRB has served as a consultant for Abbvie, Acerta/Astra-Zeneca, BeiGene, Bristol-Myers Squibb/ Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Hutchmed, Janssen, MEI Pharma, Morphosys AG, Novartis, Pfizer, Pharmacyclics, Rigel; received research funding from Beigene, Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics. MM has received research funding from Roche-Genentech, has had advisory roles for Abbvie, Astra Zeneca, Gilead, Janssen Pharmaceuticals, and Verastem Oncology. RR has received honoraria from AbbVie, AstraZeneca, Janssen, Illumina, and Roche. PG has served on advisory boards or as a consultant for AbbVie, AstraZenenca, BeIgene, BMS, Janssen, Lilly/Loxo Merck, Roche Sanofy, and received research support from AbbVie, AstraZenenca, and Janssen. JoCB has received research support from Pharmacyclics/Abbvie and AstraZeneca, Oncternal, and Velosbio, and has served on advisory boards for Pharmacyclics/Abbvie, Beigene, AstraZeneca, TG Therapeutics, and MEI. SA owns stock in Bristol Myers Squibb and C4 Therapeutics and has served on the Advisory Boards of Stemline Therapeutics and Sanofi Genzyme. KS has received support from the Hellenic Precision Medicine Network in Oncology and the project ODYSSEAS funded by the Operational Programme “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014–2020) and co financed by Greece and the European Union, with grant agreement no: MIS 5002462. TK has had consultancy/advisory roles for AbbVie, Genentech-Roche, Gilead, Pharmacyclics LLC, an AbbVie Company, and Celgene; and research funding from AbbVie, Genentech-Roche, Pharmacyclics LLC, an AbbVie Company, and Oncternal. DN has stock in Madrigal Pharmaceuticals and receives research funding from Pharmacyclics LLC, an AbbVie Company. NC has received research funding from Verastem Oncology, argenx, Janssen Pharmaceuticals, and AVA Lifesciences GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.