PRIMARY ANALYSIS OF THE FIXED-DURATION COHORT FROM THE PHASE 2 CAPTIVATE STUDY OF FIRST-LINE IBRUTINIB + VENETOCLAX FOR CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA
Author(s): ,
John N. Allan
Affiliations:
Weill Cornell Medicine,New York, NY,United States
,
William G. Wierda
Affiliations:
Department of Leukemia,University of Texas MD Anderson Cancer Center,Houston, TX,United States
,
Tanya Siddiqi
Affiliations:
City of Hope National Medical Center,Duarte, CA,United States
,
Thomas J. Kipps
Affiliations:
UCSD Moores Cancer Center,San Diego, CA,United States
,
Ryan Jacobs
Affiliations:
Levine Cancer Institute,Charlotte, NC,United States
,
Stephen Opat
Affiliations:
Monash University,Clayton, VIC,Australia
,
Paul M. Barr
Affiliations:
Wilmot Cancer Institute, University of Rochester Medical Center,Rochester, NY,United States
,
Alessandra Tedeschi
Affiliations:
ASST Grande Ospedale Metropolitano Niguarda,Milan,Italy
,
Livio Trentin
Affiliations:
Hematology and Clinical Immunology Unit, Department of Medicine, University of Padova,Padova,Italy
,
Rajat Bannerji
Affiliations:
Rutgers Cancer Institute of New Jersey,New Brunswick, NJ,United States
,
Sharon Jackson
Affiliations:
Middlemore Hospital,Auckland,New Zealand
,
Bryone Kuss
Affiliations:
Flinders University and Medical Centre,Bedford Park, SA,Australia
,
Carol Moreno
Affiliations:
Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona,Barcelona,Spain
,
Edith Szafer-Glusman
Affiliations:
Pharmacyclics LLC, an AbbVie Company,Sunnyvale, CA,United States
,
Kristin Russell
Affiliations:
Pharmacyclics LLC, an AbbVie Company,Sunnyvale, CA,United States
,
Cathy Zhou
Affiliations:
Pharmacyclics LLC, an AbbVie Company,Sunnyvale, CA,United States
,
Joi Ninomoto
Affiliations:
Pharmacyclics LLC, an AbbVie Company,Sunnyvale, CA,United States
,
James P. Dean
Affiliations:
Pharmacyclics LLC, an AbbVie Company,Sunnyvale, CA,United States
,
Constantine Tam
Affiliations:
Peter MacCallum Cancer Center & St. Vincent's Hospital and the University of Melbourne,Melbourne, VIC,Australia
Paolo Ghia
Affiliations:
Division of Experimental Oncology, Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele,Milan,Italy
EHA Library. N. Allan J. 06/09/21; 324555; S147
John N. Allan
John N. Allan
Contributions
Abstract
Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: S147

Type: Oral Presentation

Session title: Clinical trials with targeted therapies in CLL

Background
Ibrutinib (Ibr) + venetoclax (Ven) have synergistic and complementary antitumor activity that mobilizes and clears chronic lymphocytic leukemia (CLL) cells from multiple disease compartments, providing a rationale to evaluate time-limited treatment. We previously reported results from the Minimal Residual Disease (MRD) cohort of the multicenter phase 2 CAPTIVATE study of first-line Ibr + Ven in patients with CLL/small lymphocytic lymphoma (SLL). In that cohort, undetectable MRD (uMRD) was achieved in over two-thirds of patients (pts) with 12 cycles of Ibr + Ven; 30-month progression-free survival (PFS) rates were ≥95% irrespective of subsequent randomized treatment (Wierda, ASH 2020).

Aims
Here we present results from the fixed-duration (FD) cohort, evaluating fixed-duration treatment with Ibr + Ven.

Methods
Eligible patients were aged ≤70 y with previously untreated CLL/SLL. Patients received 3 cycles of Ibr lead-in followed by 12 cycles of Ibr + Ven (Ibr 420 mg/d orally; Ven ramp-up to 400 mg/d orally). The primary endpoint was complete response (CR) rate, including CR with incomplete recovery (CRi); secondary endpoints were overall response rate (ORR), duration of response, uMRD rate (<10–4 by 8-color flow cytometry), PFS, overall survival (OS), tumor lysis syndrome (TLS) risk reduction, and adverse events (AEs).

Results
Overall,159 patients were enrolled; median age was 60 y. High-risk features included del(17p)/TP53 mutation (17%), del(11q) (18%), complex karyotype (19%), and unmutated IGHV (56%). 147/159 (92%) patients completed planned treatment with Ibr, and 149/159 (94%) patients completed planned treatment with Ven. Median time on study was 27.9 months (range 0.8–33.2). With fixed-duration Ibr + Ven, 55% of patients in the overall population achieved a CR; the CR rate was consistent across high-risk subgroups. Of 88 patients who achieved CR, durable CR (duration ≥1 y from initial documentation of response) was confirmed in 78 patients (89%); an additional 9 patients (10%) were not yet evaluable with <1 y of post-CR follow-up and 1 pt died 7 months after achieving a CR. ORR was 96%. Best MRD response of uMRD was achieved in peripheral blood (PB) of 77% of patients and in bone marrow (BM) of 60% of patients. 24-month PFS and OS rates were 95% and 98%, respectively. Similar results were achieved in patients without del(17p) (n=136) (Table). In patients with del(17p)/TP53 mutation (n=27), the CR rate was 56%, uMRD rates were 81% (PB) and 41% (BM), and the 24-month PFS rate was 84% (95% CI 63%–94%). Of 34 patients with high baseline TLS risk based on tumor burden, 32 (94%) shifted to medium or low risk after Ibr lead-in; no TLS occurred. AEs were primarily grade 1/2. The most common grade 3/4 AEs were neutropenia (33%), hypertension (6%), and decreased neutrophil count (5%). AEs led to discontinuation of Ibr in 4% of patients and to discontinuation of Ven in 2% of patients.

Conclusion
First-line Ibr + Ven is an all-oral, once-daily, chemotherapy-free fixed-duration regimen that provides deep, durable responses in patients with CLL/SLL. Overall, CR, uMRD rates, PFS, and OS appear favorable, and benefit was observed regardless of genomic high-risk features. No new safety signals were identified, and the safety profile of Ibr + Ven was consistent with known safety profiles of each agent.

Keyword(s): BCL2, Chronic lymphocytic leukemia, Ibrutinib, Phase II

Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: S147

Type: Oral Presentation

Session title: Clinical trials with targeted therapies in CLL

Background
Ibrutinib (Ibr) + venetoclax (Ven) have synergistic and complementary antitumor activity that mobilizes and clears chronic lymphocytic leukemia (CLL) cells from multiple disease compartments, providing a rationale to evaluate time-limited treatment. We previously reported results from the Minimal Residual Disease (MRD) cohort of the multicenter phase 2 CAPTIVATE study of first-line Ibr + Ven in patients with CLL/small lymphocytic lymphoma (SLL). In that cohort, undetectable MRD (uMRD) was achieved in over two-thirds of patients (pts) with 12 cycles of Ibr + Ven; 30-month progression-free survival (PFS) rates were ≥95% irrespective of subsequent randomized treatment (Wierda, ASH 2020).

Aims
Here we present results from the fixed-duration (FD) cohort, evaluating fixed-duration treatment with Ibr + Ven.

Methods
Eligible patients were aged ≤70 y with previously untreated CLL/SLL. Patients received 3 cycles of Ibr lead-in followed by 12 cycles of Ibr + Ven (Ibr 420 mg/d orally; Ven ramp-up to 400 mg/d orally). The primary endpoint was complete response (CR) rate, including CR with incomplete recovery (CRi); secondary endpoints were overall response rate (ORR), duration of response, uMRD rate (<10–4 by 8-color flow cytometry), PFS, overall survival (OS), tumor lysis syndrome (TLS) risk reduction, and adverse events (AEs).

Results
Overall,159 patients were enrolled; median age was 60 y. High-risk features included del(17p)/TP53 mutation (17%), del(11q) (18%), complex karyotype (19%), and unmutated IGHV (56%). 147/159 (92%) patients completed planned treatment with Ibr, and 149/159 (94%) patients completed planned treatment with Ven. Median time on study was 27.9 months (range 0.8–33.2). With fixed-duration Ibr + Ven, 55% of patients in the overall population achieved a CR; the CR rate was consistent across high-risk subgroups. Of 88 patients who achieved CR, durable CR (duration ≥1 y from initial documentation of response) was confirmed in 78 patients (89%); an additional 9 patients (10%) were not yet evaluable with <1 y of post-CR follow-up and 1 pt died 7 months after achieving a CR. ORR was 96%. Best MRD response of uMRD was achieved in peripheral blood (PB) of 77% of patients and in bone marrow (BM) of 60% of patients. 24-month PFS and OS rates were 95% and 98%, respectively. Similar results were achieved in patients without del(17p) (n=136) (Table). In patients with del(17p)/TP53 mutation (n=27), the CR rate was 56%, uMRD rates were 81% (PB) and 41% (BM), and the 24-month PFS rate was 84% (95% CI 63%–94%). Of 34 patients with high baseline TLS risk based on tumor burden, 32 (94%) shifted to medium or low risk after Ibr lead-in; no TLS occurred. AEs were primarily grade 1/2. The most common grade 3/4 AEs were neutropenia (33%), hypertension (6%), and decreased neutrophil count (5%). AEs led to discontinuation of Ibr in 4% of patients and to discontinuation of Ven in 2% of patients.

Conclusion
First-line Ibr + Ven is an all-oral, once-daily, chemotherapy-free fixed-duration regimen that provides deep, durable responses in patients with CLL/SLL. Overall, CR, uMRD rates, PFS, and OS appear favorable, and benefit was observed regardless of genomic high-risk features. No new safety signals were identified, and the safety profile of Ibr + Ven was consistent with known safety profiles of each agent.

Keyword(s): BCL2, Chronic lymphocytic leukemia, Ibrutinib, Phase II

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