Tumor mutational load predicts time to first treatment in chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis beyond the CLL international prognostic index

Geffen Kleinstern; Daniel R O'Brien; Xing Li; Shulan Tian; Brian F Kabat; Kari G Rabe; Aaron D Norman; Huihuang Yan; Celine M Vachon; Nicholas J Boddicker; Timothy G Call; Sameer A Parikh; Laura Bruins; Cecilia Bonolo de Campos; Jose F Leis; Tait D Shanafelt; Wei Ding; James R Cerhan; Neil E Kay; Susan L Slager; Esteban Braggio

doi:10.1002/ajh.25831

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Tumor mutational load predicts time to first treatment in chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis beyond the CLL international prognostic index

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Tumor mutational load predicts time to first treatment in chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis beyond the CLL international prognostic index

Geffen Kleinstern, Daniel R O'Brien, Xing Li, Shulan Tian, Brian F Kabat, Kari G Rabe, Aaron D Norman, Huihuang Yan, Celine M Vachon, Nicholas J Boddicker, …

American journal of hematology, Vol.95(8), pp.906-917

08/2020

DOI: 10.1002/ajh.25831

PMCID: PMC7409825

PMID: 32279347

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Abstract

Next-generation sequencing identified about 60 genes recurrently mutated in chronic lymphocytic leukemia (CLL). We examined the additive prognostic value of the total number of recurrently mutated CLL genes (i.e., tumor mutational load [TML]) or the individually mutated genes beyond the CLL international prognostic index (CLL-IPI) in newly diagnosed CLL and high-count monoclonal B-cell lymphocytosis (HC MBL). We sequenced 59 genes among 557 individuals (112 HC MBL/445 CLL) in a multi-stage design, to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time-to-first treatment (TTT), adjusted for CLL-IPI and sex. TML was associated with shorter TTT in the discovery and validation cohorts, with a combined estimate of continuous HR = 1.27 (CI:1.17-1.39, P = 2.6 × 10 ; c-statistic = 0.76). When stratified by CLL-IPI, the association of TML with TTT was stronger and validated within low/intermediate risk (combined HR = 1.54, CI:1.37-1.72, P = 7.0 × 10 ). Overall, 80% of low/intermediate CLL-IPI cases with two or more mutated genes progressed to require therapy within 5 years, compared to 24% among those without mutations. TML was also associated with shorter TTT in the HC MBL cohort (HR = 1.53, CI:1.12-2.07, P = .007; c-statistic = 0.71). TML is a strong prognostic factor for TTT independent of CLL-IPI, especially among low/intermediate CLL-IPI risk, and a better predictor than any single gene. Mutational screening at early stages may improve risk stratification and better predict TTT.

Adult

Aged

Aged, 80 and over

Female

High-Throughput Nucleotide Sequencing - methods

Humans

Leukemia, Lymphocytic, Chronic, B-Cell - genetics

Leukemia, Lymphocytic, Chronic, B-Cell - pathology

Lymphocytosis - metabolism

Male

Middle Aged

Prognosis

Details

Title: Subtitle: Tumor mutational load predicts time to first treatment in chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis beyond the CLL international prognostic index
Creators: Geffen Kleinstern - Mayo Clinic
Daniel R O'Brien - Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
Xing Li - Mayo Clinic
Shulan Tian - Mayo Clinic
Brian F Kabat - Mayo Clinic
Kari G Rabe - Mayo Clinic
Aaron D Norman - Mayo Clinic
Huihuang Yan - Mayo Clinic
Celine M Vachon - Mayo Clinic
Nicholas J Boddicker - Mayo Clinic
Timothy G Call - Mayo Clinic
Sameer A Parikh - Mayo Clinic
Laura Bruins - Division of Hematology /Oncology Mayo Clinic Scottsdale Arizona USA
Cecilia Bonolo de Campos - Division of Hematology /Oncology, Mayo Clinic, Scottsdale, Arizona, USA
Jose F Leis - Mayo Clinic
Tait D Shanafelt - Stanford University
Wei Ding - Mayo Clinic
James R Cerhan - Mayo Clinic
Neil E Kay - Mayo Clinic
Susan L Slager - Mayo Clinic
Esteban Braggio - Mayo Clinic
Resource Type: Journal article
Publication Details: American journal of hematology, Vol.95(8), pp.906-917
DOI: 10.1002/ajh.25831
PMID: 32279347
PMCID: PMC7409825
NLM abbreviation: Am J Hematol
ISSN: 0361-8609
eISSN: 1096-8652
Grant note: R25 CA092049 / NCI NIH HHS R01 CA197120 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01 CA235026 / NCI NIH HHS P50 CA097274 / NCI NIH HHS
Language: English
Date published: 08/2020
Academic Unit: Epidemiology
Record Identifier: 9984368086202771

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