Tausch, Eugen, Schneider, Christof, Robrecht, Sandra, Zhang, Can, Dolnik, Anna, Bloehdorn, Johannes, Bahlo, Jasmin, Al-Sawaf, Othman, Ritgen, Matthias, Fink, Anna-Maria, Eichhorst, Barbara, Kreuzer, Karl-Anton, Tandon, Maneesh, Humphrey, Kathryn, Jiang, Yanwen, Schary, William, Bullinger, Lars, Mertens, Daniel, Lura, Michele Porro, Kneba, Michael, Doehner, Hartmut, Fischer, Kirsten, Hallek, Michael and Stilgenbauer, Stephan (2020). Prognostic and predictive impact of genetic markers in patients with CLL treated with obinutuzumab and venetoclax. Blood, 135 (26). S. 2402 - 2413. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 1528-0020

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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 obinutuzumab1chlorambucil (GClb) vs obinutuzumab1venetoclax (VenG). The incidences of genomic aberrations considering the hierarchical modelwere del(17p) 7%, del(11q) 18%, 112 18%, and del(13q) 35%, whereas IGHV was unmutated in 60% of patients. NOTCH1 mutations weremost 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, andBIRC3, 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Tausch, EugenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, ChristofUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Robrecht, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhang, CanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dolnik, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bloehdorn, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bahlo, JasminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Al-Sawaf, OthmanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ritgen, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fink, Anna-MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eichhorst, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kreuzer, Karl-AntonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tandon, ManeeshUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Humphrey, KathrynUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jiang, YanwenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schary, WilliamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bullinger, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mertens, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lura, Michele PorroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kneba, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doehner, HartmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, KirstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stilgenbauer, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-329144
DOI: 10.1182/blood.2019004492
Journal or Publication Title: Blood
Volume: 135
Number: 26
Page Range: S. 2402 - 2413
Date: 2020
Publisher: AMER SOC HEMATOLOGY
Place of Publication: WASHINGTON
ISSN: 1528-0020
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CHRONIC LYMPHOCYTIC-LEUKEMIA; INDEPENDENT PREDICTOR; CLINICAL IMPACT; MUTATIONS; SURVIVAL; NOTCH1; PROGRESSION; IBRUTINIB; SF3B1; BIRC3Multiple languages
HematologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/32914

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