PREVALENCE AND PROGNOSTIC IMPACT OF THE IGLV3-21 G110R MUTATION IN CLL – A PATHOBIOLOGICAL REDEFINITION OF THE UNFAVORABLE CLL SUBTYPE II
Author(s): ,
Rob S. Barendse
Affiliations:
Hematology,Leiden University Medical Center,Leiden,Netherlands
,
Wajiha Ismailzada
Affiliations:
Hematology,Leiden University Medical Center,Leiden,Netherlands
,
Marvyn T. Koning
Affiliations:
Hematology,Leiden University Medical Center,Leiden,Netherlands
,
Edwin Quinten
Affiliations:
Hematology,Leiden University Medical Center,Leiden,Netherlands
,
Hassan Jumaa
Affiliations:
Immunology,University of Ulm,Ulm,Germany
,
Cornelis A.M. van Bergen
Affiliations:
Hematology,Leiden University Medical Center,Leiden,Netherlands
Hendrik Veelken
Affiliations:
Hematology,Leiden University Medical Center,Leiden,Netherlands
EHA Library. Veelken H. Jun 15, 2018; 214801; PF326
Prof. Dr. Hendrik Veelken
Prof. Dr. Hendrik Veelken
Contributions
Abstract

Abstract: PF326

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background
One-third of CLL cases can be classified into stereotypes by sequence similarities of their B-cell receptors (BCR). CLL stereotypy has been interpreted as consequence of selection for antigen binding. Since antigen-independent, autonomous BCR signaling has been discovered as an indispensable, dominant oncogenic CLL driver, stereotypy likely reflects BCR sequences that structurally facilitate autonomous BCR signaling. CLL subtype II has a relatively poor prognosis and is conventionally defined by expression of a mutated IGHV3-21/IGHJ06-containing BCR heavy chain (HC) with a CDR3 of 9 amino acids and a D or E residue at position 3, and coexpression of an IGLV3-21-containing BCR light chain (LC). A recurrent G110R mutation of the IGLV3-21 allele causes autonomous BCR signaling in subtype II.

Aims

  1. To determine the prevalence of the IGLV3-21G110R mutation in CLL.
  2. To assess its impact on the natural CLL history, irrespective of its occurrence in conventionally defined subtype II.

Methods

BCR HC and LC sequences were determined by ARTISAN PCR on 132 cases of biobanked CLL (diagnosis confirmed by immunophenotyping). Time from diagnosis to first treatment (TTFT) and overall survival (OS) were obtained from patients’ records and compared by log-rank test.

Results

Six CLL cases (4.5%) were conventional subtype II, all indeed expressing the mutated IGLV3-21G110R allele. Four CLL (3.0%) expressed a LC containing wild-type IGLV3-21. Twenty-six CLL expressed IGLV3-21 that carried the G110R mutation (19.7%; 95% CI: 12.9-26.5%). In 122 CLL with sufficient clinical information, age, Rai stage, and chromosomal aberrations were not significantly different between IGLV3-21G110R-expressing and remaining mutated CLL. Conventional subtype II cases had a nonsignificantly different TTFT (median: 22 months) from unmutated CLL (n=65; median 13 months; p=0.91) and an inferior TTFT compared to the remaining mutated CLL (n=51, median 121 months; p=0.016). TTFT of IGLV3-21G110R-expressing CLL (median: 28 months) was similar to unmutated CLL (p=0.23) and strikingly inferior to the remaining mutated CLL (median: 147 months; p<0.0001). TTFT of IGLV3-21G110R-expressing CLL not belonging to conventional subtype II (i.e. expressing a HC chain not containing IGHV3-21; n=20) likewise had an inferior TTFT (median: 28 months; p=0.001) than mutated CLL not expressing IGLV3-21G110R. The median OS of patients with conventionally defined subtype II CLL (146 months) was not statistically different from the remaining mutated CLL (211 months) or unmutated CLL (102 months). Patients with a IGLV3-21G110R-expressing CLL had inferior median OS (143 months) compared to mutated CLL (247 months; p=0.03); their survival was not significantly different form unmutated CLL (101 months; p=0.08). When conventional subtype II cases were excluded, OS of IGLV3-21G110R-expressing CLL (132 months) remained inferior to mutated CLL (p=0.04) but was not significantly different from unmutated CLL (p=0.12).

Conclusion
The IGLV3-21G110R mutation has an unfavorable prognostic impact in accordance with its role in causing antigen-independent, autonomously active BCR signaling. The IGLV3-21G110R mutation rather than BCR HC criteria should serve as a new definition of the prognostically unfavorable CLL subtype II, thereby creating  the largest (app. 20%) immunologically defined subgroup of CLL.

Session topic: 5. Chronic lymphocytic leukemia and related disorders – Biology & Translational Research

Keyword(s): Chronic Lymphocytic Leukemia, Immunoglobulin gene, prognosis

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