FIRST-LINE IBRUTINIB (IBR) + VENETOCLAX (VEN) FOR PATIENTS (PTS) WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)/SMALL LYMPHOCYTIC LYMPHOMA (SLL): EFFICACY AND SAFETY RESULTS FROM CAPTIVATE MRD COHORT
Author(s): ,
Tanya Siddiqi
Affiliations:
City of Hope National Medical Center,Duarte,United States
,
Constantine S. Tam
Affiliations:
Peter MacCallum Cancer Centre & St. Vincent's Hospital,Melbourne,Australia
,
John N. Allan
Affiliations:
Weill Cornell Medicine,New York,United States
,
Thomas J. Kipps
Affiliations:
UCSD Moores Cancer Center,La Jolla,United States
,
Stephen Opat
Affiliations:
Monash University,Clayton,Australia
,
Alessandra Tedeschi
Affiliations:
ASST Grande Ospedale Metropolitano Niguarda,Milano,Italy
,
Paul M. Barr
Affiliations:
Wilmot Cancer Institute, University of Rochester Medical Center,Rochester,United States
,
Ryan Jacobs
Affiliations:
Levine Cancer Institute,Charlotte,United States
,
Xavier C. Badoux
Affiliations:
Ministry of Health,Kogarah,Australia
,
Bryone J. Kuss
Affiliations:
Flinders University and Medical Centre,Bedford Park,Australia
,
Carol Moreno
Affiliations:
Hospital de la Santa Creu I Sant Pau, Autonomous University of Barcelona,Barcelona,Spain
,
Sharon Jackson
Affiliations:
Middlemore Hospital,Auckland,New Zealand
,
Livio Trentin
Affiliations:
Hematology and Clinical Immunology Unit, Department of Medicine,University of Padova,Padova,Italy
,
Paolo Ghia
Affiliations:
Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele,Milano,Italy
,
Edith Szafer-Glusman
Affiliations:
Pharmacyclics LLC, an AbbVie Company,Sunnyvale,United States
,
Cathy Zhou
Affiliations:
Pharmacyclics LLC, an AbbVie Company,Sunnyvale,United States
,
Joi Ninomoto
Affiliations:
Pharmacyclics LLC, an AbbVie Company,Sunnyvale,United States
,
James P. Dean
Affiliations:
Pharmacyclics LLC, an AbbVie Company,Sunnyvale,United States
,
Danelle F. James
Affiliations:
Pharmacyclics LLC, an AbbVie Company,Sunnyvale,United States
William G. Wierda
Affiliations:
Department of Leukemia,University of Texas MD Anderson Cancer Center,Houston,United States
EHA Library. Siddiqi T. 06/12/20; 294978; S158
Tanya Siddiqi
Tanya Siddiqi
Contributions
Abstract

Abstract: S158

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: CLL - Targeted therapy I

Background
Ibr is the only once-daily Bruton tyrosine kinase inhibitor with significant overall survival benefit shown in 2 randomized phase 3 studies in first-line CLL (RESONATE-2; ECOG1912). When combined, Ibr + Ven (oral inhibitor of BCL2) may have synergistic antitumor activity via mobilization and clearance of CLL cells from protective niches and disease compartments beyond peripheral blood (PB) and bone marrow (BM). An all-oral, once-daily, fixed duration option with Ibr + Ven combination may offer improved pt convenience and ease of administration with reduced risk of tumor lysis syndrome (TLS) and reduced need for hospitalization for Ven initiation. CAPTIVATE (PCYC-1142) is a multicenter phase 2 study (NCT02910583) evaluating Ibr + Ven to achieve deep response, including undetectable minimal residual disease (uMRD), in first-line treatment of CLL/SLL.

Aims
To report results from the CAPTIVATE MRD cohort with 3 cycles of Ibr lead-in and 12 cycles of Ibr + Ven combination.

Methods
Pts aged <70 y with previously untreated CLL/SLL requiring therapy received 3 cycles of Ibr lead-in followed by 12 cycles of Ibr + Ven (Ibr 420 mg/day PO; Ven with ramp-up to 400 mg/day PO). Key endpoints were rates of uMRD (<10-4 by 8-color flow cytometry), clinical response, TLS risk, and adverse events (AEs) evaluated at regular intervals (~every 3 cycles) on study (BM MRD after 12 cycles of Ibr + Ven combination). 

Results
164 pts were enrolled: median age 58 y; del(17p) in 16%; del(17p) or TP53 mutation in 20%; del(11q) in 16%; complex karyotype (CK) in 19%; unmutated IGHV in 59%; lymph nodes ≥5 cm in 32%. Overall, 148 pts (90%) completed Ibr lead-in and all 12 cycles of Ibr + Ven combination. uMRD was achieved as best MRD response in 75% of pts (123/163) in PB and 72% (111/155) in BM and were highly concordant (90%). Rates of uMRD in PB increased over time (Figure). In the all-treated population (N=164), uMRD was achieved in 75% of pts in PB and 68% in BM. High rates of uMRD in BM (evaluable pts) were observed independent of baseline subgroups, including in high-risk pts with del(17p) (75%), del(17p) or TP53 mutation (70%), del(11q) (83%), CK (83%), and unmutated IGHV (81%). With median follow-up of 14.8 mo (range 14.5-21.7) in all-treated pts, ORR was 97%, with 51% complete responses. At 15 mo, 98% were progression free with no deaths. Among pts with high TLS risk at baseline, 90% were downgraded to medium/low risk after 3 cycles of Ibr lead-in and 75% avoided hospitalization for Ven initiation. Laboratory TLS was reported as an AE in 3 pts, of whom only 1 met Howard criteria. No pts developed clinical TLS. Median treatment duration was 14.7 mo (range 0.5-20.1) with Ibr and 12.0 mo (range 0.8-12.7) with Ven. Most common AEs with Ibr + Ven were primarily grade 1/2 with no new safety signals. Most common grade 3/4 AEs were neutropenia (35%), hypertension (7%), thrombocytopenia (5%), and diarrhea (5%). There were no fatal AEs. AEs leading to discontinuation of all study treatment were infrequent (5%).

Conclusion
Ibr + Ven represents an all-oral, once-daily, chemotherapy-free regimen that confers high rates of uMRD in PB and BM in first-line treatment of CLL, with highly concordant uMRD results between PB and BM. Results from CAPTIVATE validate the preclinical synergism of this combination. Ibr lead-in substantially reduced Ven-related TLS risk and need for intensive monitoring/hospitalization. The safety profile of Ibr + Ven was favorable with a low rate of discontinuation due to AEs and 90% completing all planned treatment with 3 cycles of Ibr and 12 cycles of Ibr + Ven combination. 

Session topic: 06. Chronic lymphocytic leukemia and related disorders - Clinical

Keyword(s): Chronic lymphocytic leukemia, Ibrutinib, Minimal residual disease (MRD), Targeted therapy

Abstract: S158

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: CLL - Targeted therapy I

Background
Ibr is the only once-daily Bruton tyrosine kinase inhibitor with significant overall survival benefit shown in 2 randomized phase 3 studies in first-line CLL (RESONATE-2; ECOG1912). When combined, Ibr + Ven (oral inhibitor of BCL2) may have synergistic antitumor activity via mobilization and clearance of CLL cells from protective niches and disease compartments beyond peripheral blood (PB) and bone marrow (BM). An all-oral, once-daily, fixed duration option with Ibr + Ven combination may offer improved pt convenience and ease of administration with reduced risk of tumor lysis syndrome (TLS) and reduced need for hospitalization for Ven initiation. CAPTIVATE (PCYC-1142) is a multicenter phase 2 study (NCT02910583) evaluating Ibr + Ven to achieve deep response, including undetectable minimal residual disease (uMRD), in first-line treatment of CLL/SLL.

Aims
To report results from the CAPTIVATE MRD cohort with 3 cycles of Ibr lead-in and 12 cycles of Ibr + Ven combination.

Methods
Pts aged <70 y with previously untreated CLL/SLL requiring therapy received 3 cycles of Ibr lead-in followed by 12 cycles of Ibr + Ven (Ibr 420 mg/day PO; Ven with ramp-up to 400 mg/day PO). Key endpoints were rates of uMRD (<10-4 by 8-color flow cytometry), clinical response, TLS risk, and adverse events (AEs) evaluated at regular intervals (~every 3 cycles) on study (BM MRD after 12 cycles of Ibr + Ven combination). 

Results
164 pts were enrolled: median age 58 y; del(17p) in 16%; del(17p) or TP53 mutation in 20%; del(11q) in 16%; complex karyotype (CK) in 19%; unmutated IGHV in 59%; lymph nodes ≥5 cm in 32%. Overall, 148 pts (90%) completed Ibr lead-in and all 12 cycles of Ibr + Ven combination. uMRD was achieved as best MRD response in 75% of pts (123/163) in PB and 72% (111/155) in BM and were highly concordant (90%). Rates of uMRD in PB increased over time (Figure). In the all-treated population (N=164), uMRD was achieved in 75% of pts in PB and 68% in BM. High rates of uMRD in BM (evaluable pts) were observed independent of baseline subgroups, including in high-risk pts with del(17p) (75%), del(17p) or TP53 mutation (70%), del(11q) (83%), CK (83%), and unmutated IGHV (81%). With median follow-up of 14.8 mo (range 14.5-21.7) in all-treated pts, ORR was 97%, with 51% complete responses. At 15 mo, 98% were progression free with no deaths. Among pts with high TLS risk at baseline, 90% were downgraded to medium/low risk after 3 cycles of Ibr lead-in and 75% avoided hospitalization for Ven initiation. Laboratory TLS was reported as an AE in 3 pts, of whom only 1 met Howard criteria. No pts developed clinical TLS. Median treatment duration was 14.7 mo (range 0.5-20.1) with Ibr and 12.0 mo (range 0.8-12.7) with Ven. Most common AEs with Ibr + Ven were primarily grade 1/2 with no new safety signals. Most common grade 3/4 AEs were neutropenia (35%), hypertension (7%), thrombocytopenia (5%), and diarrhea (5%). There were no fatal AEs. AEs leading to discontinuation of all study treatment were infrequent (5%).

Conclusion
Ibr + Ven represents an all-oral, once-daily, chemotherapy-free regimen that confers high rates of uMRD in PB and BM in first-line treatment of CLL, with highly concordant uMRD results between PB and BM. Results from CAPTIVATE validate the preclinical synergism of this combination. Ibr lead-in substantially reduced Ven-related TLS risk and need for intensive monitoring/hospitalization. The safety profile of Ibr + Ven was favorable with a low rate of discontinuation due to AEs and 90% completing all planned treatment with 3 cycles of Ibr and 12 cycles of Ibr + Ven combination. 

Session topic: 06. Chronic lymphocytic leukemia and related disorders - Clinical

Keyword(s): Chronic lymphocytic leukemia, Ibrutinib, Minimal residual disease (MRD), Targeted therapy

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