Prognostic and predictive impact of genetic markers in patients with CLL treated with obinutuzumab and venetoclax
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- 25 June 2020
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 135 (26), 2402-2412
- https://doi.org/10.1182/blood.2019004492
Abstract
Genetic parameters are established prognostic factors in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy but less well studied with novel compounds. We assessed IGHV mutation status, common genomic aberrations and gene mutations in 421 untreated patients within the CLL14 trial (NCT02242942) comparing obinutuzumab+chlorambucil (GClb) vs. obinutuzumab+venetoclax (VenG). The incidences of genomic aberrations considering the hierarchical model were del(17p) 7%, del(11q) 18%, +(12) 18% and del(13q) 35%, while IGHV was unmutated in 60% of patients. NOTCH1 mutations were most common (23%), followed by SF3B1 (16%), ATM (13%) and TP53 (10%). While the overall response rate (ORR) for GClb was lower in patients with del(17p), del(11q), mutated TP53, ATM and BIRC3, none of these parameters reduced complete remission (CR) and ORR with VenG. At a median follow-up of 28 months, del(17p) and mutated TP53 were the only abnormalities with impact on PFS for both treatment arms, GClb (HR 4.6, p<0.01, HR 2.7, p<0.01) and VenG (HR 4.4, p<0.01, HR 3.1 p<0.01). No other factors affected outcome with VenG, while for GClb del(11q), BIRC3, NOTCH1 and unmutated IGHV associated with shorter PFS. Multivariable analysis identified del(17p), del(11q), unmutated IGHV and mutated TP53, BIRC3 and SF3B1 as independent prognostic factors for PFS with GClb, while for VenG only del(17p) was significant. VenG was superior to GClb across most genetic subgroups. Especially patients with adverse genetic markers had the strongest benefit from VenG, particularly subjects with unmutated IGHV, which was identified as a predictive factor in a multivariable treatment-interaction analysis.Keywords
This publication has 46 references indexed in Scilit:
- From Biology to Therapy: The CLL Success StoryHemaSphere, 2019
- iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLLBlood, 2018
- Mutations driving CLL and their evolution in progression and relapseNature, 2015
- Non-coding recurrent mutations in chronic lymphocytic leukaemiaNature, 2015
- Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trialBlood, 2014
- Cancer Genome LandscapesScience, 2013
- Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemiaBlood, 2012
- TP53 Mutation and Survival in Chronic Lymphocytic LeukemiaJournal of Clinical Oncology, 2010
- Genomic Aberrations and Survival in Chronic Lymphocytic LeukemiaThe New England Journal of Medicine, 2000
- Unmutated Ig VH Genes Are Associated With a More Aggressive Form of Chronic Lymphocytic LeukemiaBlood, 1999