VENETOCLAX (ABT-199 / GDC-0199) COMBINED WITH RITUXIMAB INDUCES DEEP RESPONSES IN PATIENTS WITH RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA
Author(s): ,
Andrew W. Roberts
Affiliations:
Royal Melbourne Hospital and Walter and Eliza Hall Institute of Medical Research,Parkville,Australia
,
Shuo Ma
Affiliations:
Northwestern University,Chicago,United States
,
Danielle Brander
Affiliations:
Duke University Medical Center,Durham,United States
,
Thomas J. Kipps
Affiliations:
University of California San Diego,La Jolla,United States
,
Jacqueline C. Barrientos
Affiliations:
Hofstra North Shore-LIJ School of Medicine,Lake Success,United States
,
Matthew S. Davids
Affiliations:
Dana-Farber Cancer Institute,Boston,United States
,
Mary Ann Anderson
Affiliations:
Royal Melbourne Hospital and Walter and Eliza Hall Institute of Medical Research,Parkville,Australia
,
Michael Choi
Affiliations:
University of California San Diego,La Jolla,United States
,
Constantine Tam
Affiliations:
Peter MacCallum Cancer Centre,Melbourne,Australia
,
Lisa Magee
Affiliations:
Royal Melbourne Hospital and Walter and Eliza Hall Institute of Medical Research,Parkville,Australia
,
Jennifer Kreutzer
Affiliations:
Northwestern University,Chicago,United States
,
Ranju Singh
Affiliations:
Duke University Medical Center,Durham,United States
,
Jennifer Kim
Affiliations:
University of California San Diego,La Jolla,United States
,
Belinda Dimovski
Affiliations:
Peter MacCallum Cancer Centre,Melbourne,Australia
,
Tanita Mason-Bright
Affiliations:
AbbVie,North Chicago,United States
,
Betty Prine
Affiliations:
AbbVie,North Chicago,United States
,
Ming Zhu
Affiliations:
AbbVie,North Chicago,United States
,
Rod A. Humerickhouse
Affiliations:
AbbVie,North Chicago,United States
John F. Seymour
Affiliations:
Peter MacCallum Cancer Centre,Melbourne,Australia
EHA Learning Center. W Roberts A. Jun 13, 2015; 103125
Andrew W Roberts
Andrew W Roberts

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Abstract
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Abstract: S431

Type: Oral Presentation

Presentation during EHA20: From 13.06.2015 11:30 to 13.06.2015 11:45

Location: Room A7

Background
Venetoclax is a selective, orally bioavailable BCL-2 inhibitor. Single agent venetoclax induces responses in ~80% of pts with relapsed/refractory chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL). Pts were enrolled in a phase 1b, open-label, dose-escalation, multicenter study of venetoclax plus rituximab (R), to determine safety, PK and efficacy. We have previously reported the recommended phase 2 dose for venetoclax in this combination to be 400 mg/day. 

Aims
The goal of this analysis was to determine the response rate and minimal residual disease status and to update the safety profile for the combination.

Methods
Eligible pts began treatment with 20 or 50 mg venetoclax daily, increasing weekly to final cohort doses of 200–600 mg. After the weekly lead-in phase, monthly R was added (at 375 mg/m2 and then 500 mg/m2) for 6 doses. Responses were assessed using iwCLL criteria, including CT scan and bone marrow (BM) biopsy at the end of combination therapy (7 months). MRD was assessed in local laboratories using ≥4 color flow cytometry on cells in BM and blood (minimum sensitivity of 0.01%).

Results
Accrual is complete with 49 pts (48 CLL / 1 SLL) of median age 68 (50–88) years enrolled in 5 dose escalation cohorts (n=41) and a safety expansion cohort at 400 mg/day (n=8). The median number of prior regimens was 2 (1–5). Forty-five (92%) had prior R; 14/49 (29%) were R-refractory. Twenty-eight (57%) had prior fludarabine (F); 9/49 (30%) were F-refractory. Of 46 pts with available data, 9 (20%) had del17p; 19/27 (70%) with available data had unmutated IGVH. Eleven pts have discontinued the study: 6 due to PD, 2 due to AEs (neuropathy, TLS), and 3 withdrew consent. The median time on study as of Jan 21, 2015 was 13 (0.03–28) months. The overall response rate (ORR) was 84% (41/49), with 20 (41%) achieving either a complete response (CR) or CR with incomplete marrow recovery (CRi). MRD was evaluable in 40 pts. MRD-negativity in BM was achieved in 13/20 (65%) pts with CR/CRi and in 24/49 (49%) pts overall. Responses are summarized in the table. Only 3/41 (7%) responders have progressed (at 5, 8 and 12 months). Six pts stopped daily venetoclax after achieving CR/CRi. These pts continue in follow up and all have maintained a response after a median time of 12 months (0–21) off venetoclax. Treatment-emergent AEs in >25% were neutropenia (53%), diarrhea and nausea (each 47%), upper respiratory tract infection (41%), pyrexia (37%) and fatigue, headache and cough (each 33%). Grade 3/4 AEs in >10% were neutropenia (51%), thrombocytopenia (16%) and anemia (14%). There was 1 treatment-emergent AE that led to death (TLS) and there were 2 deaths after PD. 

Summary
The combination of venetoclax and R has a tolerable safety profile and induces deep and durable responses, with 41% of pts achieving CR/CRi and 49% of pts achieving MRD negativity in BM. A phase 3 trial comparing venetoclax and R versus bendamustine and R in pts with previously treated CLL is underway.

Keyword(s): BCL2, Chronic lymphocytic leukemia, Phase I, Rituximab

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