VENETOCLAX IN RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) WITH 17P DELETION: OUTCOME AND MINIMAL RESIDUAL DISEASE FROM THE FULL POPULATION OF THE PIVOTAL M13-982 TRIAL
Author(s): ,
Stephan Stilgenbauer
Affiliations:
University of Ulm,Ulm,Germany
,
Brenda Chyla
Affiliations:
AbbVie Inc,North Chicago, IL,United States
,
Barbara Eichhorst
Affiliations:
Universitätsklinikum Köln,Cologne, Germany,Germany
,
Johannes Schetelig
Affiliations:
University Hospital, Technische Universität Dresden,Dresden,Germany
,
Talha Munir
Affiliations:
St James's University Hospital,Leeds,United Kingdom
,
Peter Hillmen
Affiliations:
St James's University Hospital,Leeds,United Kingdom
,
John F. Seymour
Affiliations:
Peter MacCallum Cancer Centre,Melbourne,Australia
,
Andrew W. Roberts
Affiliations:
Royal Melbourne Hospital,Melbourne,Australia
,
Steven Coutre
Affiliations:
Stanford University Medical Center,Stanford, CA,United States
,
Wojciech Jurczak
Affiliations:
Jagiellonian University,Kraków,Poland
,
Stephen P Mulligan
Affiliations:
Royal North Shore Hospital,Sydney,Australia
,
Soham Puvvada
Affiliations:
University of Arizona,Tucson, AZ,United States
,
Clemens-Martin Wendtner
Affiliations:
Klinikum Schwabing,Munich,Germany
,
Matthew Davids
Affiliations:
Dana-Farber Cancer Institute,Boston, MA,United States
,
Sebastian Böettcher
Affiliations:
University Hospital of Schleswig-Holstein,Kiel,Germany
,
Elisa Cerri
Affiliations:
AbbVie Inc,North Chicago, IL,United States
,
Lang Zhou
Affiliations:
AbbVie Inc,North Chicago, IL,United States
,
Relja Popovic
Affiliations:
AbbVie Inc,North Chicago, IL,United States
,
Mia Poteracki
Affiliations:
AbbVie Inc,North Chicago, IL,United States
,
Jennifer Arzt
Affiliations:
AbbVie Inc,North Chicago, IL,United States
,
Su Young Kim
Affiliations:
AbbVie Inc,North Chicago, IL,United States
,
Maria Verdugo
Affiliations:
AbbVie Inc,North Chicago, IL,United States
,
Anahita Bhathena
Affiliations:
AbbVie Inc,North Chicago, IL,United States
,
William Wierda
Affiliations:
UT MD Anderson Cancer Center,Houston, TX,United States
Michael Hallek
Affiliations:
Universitätsklinikum Köln,Cologne, Germany,Germany
EHA Library. Stilgenbauer S. Jun 25, 2017; 182058; S771
Prof. Dr. Stephan Stilgenbauer
Prof. Dr. Stephan Stilgenbauer
Contributions
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Abstract

Abstract: S771

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 08:30 - 08:45

Location: Hall A

Background
Venetoclax monotherapy in patients (pts) with relapsed/refractory CLL harboring deletion 17p (del17p) resulted in an ORR of 79% with a CR rate of 7% as determined by an independent review committee at the initial analysis of the pivotal M13-982 trial (n=107). Subsequently, 51 additional pts were enrolled in a safety expansion cohort. 

Aims
To present results from the full trial, including minimal residual disease (MRD) status by both flow cytometry and next generation sequencing (NGS). 

Methods
Pts received venetoclax 400 mg daily after initial standard ramp-up until PD or discontinuation due to other reasons. CT scan was mandatory at week 36, after which disease assessment was by clinical evaluation. MRD assessment was performed beginning with the first clinical assessment of CR or PR with nodes <2 cm and then every 12 weeks until MRD negativity (defined at 10−4 sensitivity). MRD was assessed by NGS and multicolor flow cytometry and the best response was reported. Data cutoff date was 10 June 2016.

Results
Pts (N=158) had a median age of 67 (range, 29–85) years; a median of 2 prior therapies (range, 0–10); 32% were fludarabine refractory; 11% had previously received a B-cell receptor signaling inhibitor (BCRi); 48% had nodes ≥5 cm; and 78% had unmutated IGHV. The median duration of venetoclax therapy was 16.7 (range 0–34.4) months. Primary reasons for discontinuation (50.6% of pts) were PD (31.0%), adverse events (AEs) (12.6%), withdrawal of consent (2.5%), stem cell transplant (2.5%), and other (1.9%).

For all 158 pts, the investigator-assessed ORR was 77% and CR rate was 18%. The 24-month estimates for progression-free survival (PFS) and overall survival (OS) were 52% and 72%, respectively. The safety expansion cohort included 5 pts with previously untreated del(17p) CLL. These pts had an ORR of 80%, CR rate of 40%, and all 5 were alive and progression-free 1 year after the start of study treatment. Among the 18 pts with prior BCRi treatment, ORR was 61% and CR was 11%, with 12-month PFS and OS estimates of 50% and 72%, respectively.
The most commonly reported AEs were neutropenia (42%), nausea (37%), diarrhea (37%), anemia (24%), and fatigue (22%). The most common grade 3–4 AEs were neutropenia (39%), thrombocytopenia (15%), and anemia (14%). Infection rate (77% all grades, 22% grade 3–4) and spectrum were consistent with the underlying disease. The rate of laboratory tumor lysis syndrome (TLS) was 5%, with no cases of clinical TLS.
Of 101 pts with evaluable blood MRD by flow cytometry, 76 also had MRD data by NGS. From the full trial cohort of 158 pts, 42 (27%) demonstrated blood MRD negativity at 10-4 by flow cytometry, and 28 had a contemporaneous NGS sample. MRD negativity (10−4 sensitivity) was confirmed by NGS in 20 pts (71%), and 8 pts (29%) were MRD-positive by NGS. MRD negativity by NGS (≤10−4) was observed in 22 pts in blood; 9 pts were also negative in the marrow although not necessarily at the same time. One pt negative by NGS did not have a matching flow cytometry assessment and 1 pt was positive by flow cytometry (0.008% vs 0.02%). Pts who achieved blood MRD-negative CR by flow cytometry (n=19) had a 24-month PFS estimate of 100%, compared with 78.5% pts who had blood MRD-negative PR (n=23). Similar results were obtained when assessed by NGS.

Conclusion
Venetoclax monotherapy resulted in a high response rate that was durable in this high-risk population, including among pts who had previously received a BCR inhibitor. MRD negativity by either flow cytometry or NGS correlated with outstanding outcomes. 

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

Keyword(s): Relapse, Refractory, Minimal residual disease (MRD), Chronic Lymphocytic Leukemia

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