IMPACT OF TP53-MUTATED CLONE SIZE ON OUTCOME OF RELAPSED/REFRACTORY (R/R) CLL PATIENTS TREATED WITH VENETOCLAX PLUS RITUXIMAB WITHIN THE PHASE 3 MURANO STUDY
Author(s): ,
Arnon P. Kater
Affiliations:
Department of Hematology,Academic Medical Center Amsterdam,Amsterdam,Netherlands
,
Elizabeth A. Punnoose
Affiliations:
Genentech, Inc.,South San Francisco,United States
,
Marc Andre
Affiliations:
CHU UCL Namur,Yvoir,Belgium
,
Guillaume Cartron
Affiliations:
Department of Hematology,Centre Hospitalier Universitaire Montpellier,Montpellier,France
,
Barbara Eichhorst
Affiliations:
University Hospital Cologne and the Center for Integrated Oncology Cologne-Bonn,Cologne,Germany
,
Sebastian Grosicki
Affiliations:
Community of Hospitals Chorzow,Katowice,Poland
,
Peter Hillmen
Affiliations:
St. James’s University Hospital,Leeds,United Kingdom
,
Arpad Illes
Affiliations:
University of Debrecen,Debrecen,Hungary
,
Ulrich Jaeger
Affiliations:
Dept. of Medicine I, Division of Hematology and Hemostaseology,Medical University of Vienna,Vienna,Austria
,
Thomas J. Kipps
Affiliations:
University of California School of Medicine,San Diego,United States
,
Heidi Mocikova
Affiliations:
Charles University,Prague,Czech Republic
,
Marco Montillo
Affiliations:
Niguarda Cancer Center,Niguarda Hospital ,Milan,Italy
,
Adrian Tempescul
Affiliations:
Centre Hospitalier Universitaire Brest,Brest,France
,
Brenda Chyla
Affiliations:
AbbVie,North Chicago,United States
,
Michelle Boyer
Affiliations:
F. Hoffmann–La Roche,Welwyn Garden City,United Kingdom
,
Kathryn Humphrey
Affiliations:
F. Hoffmann–La Roche,Welwyn Garden City,United Kingdom
,
Jue Wang
Affiliations:
Genentech, Inc.,South San Francisco,United States
,
Jenny Wu
Affiliations:
Genentech, Inc.,South San Francisco,United States
,
Mehrdad Mobasher
Affiliations:
Genentech, Inc.,South San Francisco,United States
John F. Seymour
Affiliations:
Peter MacCallum Cancer Centre,Royal Melbourne Hospital, and University of Melbourne,Melbourne,Australia
EHA Library. Kater A. Jun 15, 2018; 214818; PF344
Prof. Dr. Arnon Kater
Prof. Dr. Arnon Kater
Contributions
Abstract

Abstract: PF344

Type: Poster Presentation

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

Location: Poster area

Background
CLL pts with alterations in the TP53 pathway (including del(17p) and TP53 mutations) are a high-risk population in need of novel therapies. Retrospective studies suggest that pts with low clone size (subclones) of del(17p) and/or TP53 mutations have similar poor survival as pts with high clone size following immunochemotherapy, but remains to be confirmed. We recently reported on improved efficacy with venetoclax plus rituximab (VenR) vs bendamustine plus rituximab (BR) in R/R CLL for ORR, PFS and MRD negativity (MRD–) (MURANO phase 3 study).

Aims
Assess the impact of clone size of TP53 alterations on prognosis and MRD negativity with both regimens in MURANO.

Methods
TP53 mutation status assessed centrally by targeted next-generation sequencing spanning exons 2–11 (entire TP53 coding region). Cutoff was ≥5% allele frequencies (AF). del(17p) status was assessed centrally by Vysis CLL FISH probe kit, with cutoff of 7% del(17p) nuclei used to define abnormality. Low clone size vs high clone size was defined for del(17p) by 7%≤20% del(17p) nuclei vs >20%; and TP53 mutations by 5%≤20% mutant AF vs >20% AF; definitions enabled subsets of adequate sample size to assess correlation with outcome.

Results
By central assessment 27% of pts had only del(17p), 26% only TP53 mutations, and 13% del(17p) and TP53 mutations; equally balanced between treatment arms. Among 92 pts with del(17p), clone size was highly variable (median=15%; range, 7.5%–94% of del(17p) nuclei). Among del(17p) pts, high del(17p) clone size (n=36, 10.5%) was associated with higher incidence of TP53 mutations vs low clone size (69% vs 34%), and in pts treated with BR, high del(17p) clone size was also associated with inferior PFS. At median follow-up of 23.8 mo., median PFS for VenR vs BR was not reached (NR) vs 8 mo. (HR 0.1; 0.02–0.47) in high clone size del(17p) pts, NR vs 21 mo. (HR 0.14; 0.04–0.43) in low clone size, and NR vs 21 months (HR 0.19; 0.12–0.32) in non-deleted pts. MRD negativity in VenR vs BR was 60% vs 10% in high clone size del(17p) pts, 94% vs 28% in low clone size and 87% vs 26% in non-deleted pts. Similarly for TP53 mutations, high clone size was associated with worse PFS vs low clone size in pts treated with BR. Patients with both del(17p) and TP53 mutations, indicative of loss of TP53 on both alleles, had inferior outcomes to pts with either del(17p) or TP53 mutation alone, with BR. Importantly, PFS was superior for VenR vs BR across subgroups with del(17p) and/or TP53 mutations including high and low clone size (Table & Figure). 2-year PFS rates between subsets by treatment arm will be presented.

Conclusion
A clear prognostic difference was found between low and high clone size with respect to chemoimmunotherapy. High-risk prognostication based on TP53 alterations is minimized by treatment with VenR; VenR is superior to BR in these biological subsets.

Session topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical

Keyword(s): Chronic Lymphocytic Leukemia, High risk, Phase III, Targeted therapy

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