Prognostic and predictive impact of genetic markers in patients with CLL treated with obinutuzumab and venetoclax

Item Type:	Article
Title:	Prognostic and predictive impact of genetic markers in patients with CLL treated with obinutuzumab and venetoclax
Creators Name:	Tausch, E. and Schneider, C. and Robrecht, S. and Zhang, C. and Dolnik, A. and Bloehdorn, J. and Bahlo, J. and Al-Sawaf, O. and Ritgen, M. and Fink, A.M. and Eichhorst, B. and Kreuzer, K.A. and Tandon, M. and Humphrey, K. and Jiang, Y. and Schary, W. and Bullinger, L. and Mertens, D. and Lurà, M.P. and Kneba, M. and Döhner, H. and Fischer, K. and Hallek, M. and Stilgenbauer, S.
Abstract:	Genetic parameters are established prognostic factors in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy, but are less well studied with novel compounds. We assessed immunoglobulin heavy variable chain (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%, whereas IGHV was unmutated in 60% of patients. NOTCH1 mutations were most common (23%), followed by SF3B1 (16%), ATM (13%), and TP53 (10%). Although 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) rate and ORR with VenG. At a median follow-up of 28 months, del(17p) and mutated TP53 were the only abnormalities with an effect on progression-free survival (PFS) for both treatment groups: GClb (hazard ratio [HR], 4.6 [P < .01]; HR, 2.7 [P < .01], respectively) and VenG (HR, 4.4 [P < .01]; HR, 3.1 [P < .01], respectively). No other factors affected outcome with VenG, whereas for GClb del(11q), BIRC3, NOTCH1, and unmutated IGHV were 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, whereas for VenG, only del(17p) was significant. VenG was superior to GClb across most genetic subgroups. 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:	Antineoplastic Combined Chemotherapy Protocols, B-Cell Chronic Lymphocytic Leukemia, Chlorambucil, Chromosome Aberrations, Follow-Up Studies, Genetic Markers, Heterocyclic Bridged Bicyclo Compounds, Humanized Monoclonal Antibodies, Immunoglobulin Heavy Chains, Immunoglobulin Variable Region, Kaplan-Meier Estimate, Multicenter Studies as Topic, Mutation, Neoplasm Genes, Phase III as Topic Clinical Trials, Prognosis, Progression-Free Survival, Remission Induction, Residual Neoplasm, Sulfonamides
Source:	Blood
ISSN:	0006-4971
Publisher:	American Society of Hematology
Volume:	135
Number:	26
Page Range:	2402-2412
Date:	25 June 2020
Official Publication:	https://doi.org/10.1182/blood.2019004492
PubMed:	View item in PubMed

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