IBRUTINIB FOR FIRST-LINE TREATMENT OF OLDER PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA (CLL/SLL): A 4-YEAR EXPERIENCE FROM THE RESONATE-2 STUDY
Author(s): ,
Jan Burger
Affiliations:
University of Texas MD Anderson Cancer Center,Houston, TX,United States
,
Paul Barr
Affiliations:
University of Rochester,Rochester, NY,United States
,
Tadeusz Robak
Affiliations:
Medical University of Łódź,Łódź,Poland
,
Carolyn Owen
Affiliations:
Tom Baker Cancer Centre,Calgary, AB,Canada
,
Paolo Ghia
Affiliations:
Università Vita-Salute San Raffaele and IRCCS Istituto Scientifico San Raffaele,Milan,Italy
,
Alessandra Tedeschi
Affiliations:
ASST Grande Ospedale Metropolitano Niguarda,Milan,Italy
,
Osnat Bairey
Affiliations:
Rabin Medical Center, Beilinson Campus,Petah Tikva,Israel
,
Peter Hillmen
Affiliations:
The Leeds Teaching Hospitals, St. James Institute of Oncology,Leeds,United Kingdom
,
Steven Coutre
Affiliations:
Stanford University School of Medicine,Stanford, CA,United States
,
Stephen Devereux
Affiliations:
Kings College Hospital, NHS Foundation Trust,London,United Kingdom
,
Sebastian Grosicki
Affiliations:
School of Public Health, Silesian Medical University,Katowice,Poland
,
Helen McCarthy
Affiliations:
Royal Bournemouth Hospital,Bournemouth,United Kingdom
,
Jianyong Li
Affiliations:
Jiangsu Province Hospital,Nanjing,China
,
David Simpson
Affiliations:
North Shore Hospital,Auckland,New Zealand
,
Fritz Offner
Affiliations:
Universitair Ziekenhuis Gent,Gent,Belgium
,
Carol Moreno
Affiliations:
Hospital de la Santa Creu i Sant Pau,Barcelona,Spain
,
Sandra Dai
Affiliations:
Pharmacyclics LLC, an AbbVie Company,Sunnyvale, CA,United States
,
James Dean
Affiliations:
Pharmacyclics LLC, an AbbVie Company,Sunnyvale, CA,United States
,
Danelle James
Affiliations:
Pharmacyclics LLC, an AbbVie Company,Sunnyvale, CA,United States
Thomas Kipps
Affiliations:
University of California, San Diego, Moores Cancer Center,La Jolla, CA,United States
EHA Library. Burger J. Jun 15, 2018; 214817; PF343
Dr. Jan A Burger
Dr. Jan A Burger
Contributions
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Abstract

Abstract: PF343

Type: Poster Presentation

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

Location: Poster area

Background
Ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase, is approved in the EU and other regions for the initial treatment of CLL. RESONATE-2 is a phase 3 study designed to compare efficacy and safety of first-line ibr vs chlorambucil (clb) in patients (pts) with CLL/SLL. Primary results (assessed by independent review committee [IRC]) with a median follow-up of 18.4 mo demonstrated that ibr reduced the risk of progressive disease (PD) or death by 84% (P<0.001) (Burger, N Engl J Med 2015). 

Aims
This extension study updates long-term ibr efficacy and safety from RESONATE‑2.

Methods
Pts with treatment-naïve CLL/SLL aged ≥65 y (ITT n=269) were randomized 1:1 to receive 420 mg ibr once-daily continuously or clb for up to 12 cycles. Pt informed consent was obtained. The primary endpoint was PFS by IRC. Secondary endpoints included ORR, rate of hematologic improvement, and safety; long-term follow-up safety focused on ibr. Pt-reported outcomes included FACIT-Fatigue (F). Pts with PD on clb could crossover to ibr. IRC was discontinued after primary analysis. Long-term efficacy is reported per the investigator. Additional review for CR was undertaken by the sponsor to assure alignment with iwCLL criteria.

Results
With median follow-up of 4 yrs (max 55 mo), prolongation of PFS benefit for ibr vs clb was sustained (HR 0.137; 95% CI 0.090-0.210; Figure), including in high-risk subgroups (del11q: HR 0.034; 95% CI 0.011-0.110; unmutated (UM)-IGHV: HR 0.088; 95% CI 0.046-0.169). 48-mo PFS rates for ibr vs clb overall were 74% vs 16%, in pts with del11q were 79% vs 0% (72% with ibr in pts without del11q) and in UM-IGHV were 75% vs 4% (79% with ibr in pts with mutated IGHV). ORR was 91% with ibr vs 37% with clb; sponsor-confirmed CR with ibr was 18% (increased from 4% [IRC-confirmed] at primary analysis). Ibr led to sustained hematologic improvement in 80% of pts with baseline anemia vs 24% with clb (P<0.0001) and in 54% of pts with thrombocytopenia vs 25% with clb (P=0.0229). Ibr led to significantly greater improvements over time vs clb in FACIT-F (P=0.0014; repeated measure analysis). Grade (Gr) ≥3 adverse events (AEs) in ≥5% of pts over the 4-yr follow-up included neutropenia (13%), pneumonia (12%), anemia (7%), hypertension (HTN; 7%) and hyponatremia (5%) terms. Gr ≥3 hematologic and infectious toxicities were generally highest in the first yr and then decreased, while HTN remained stable. Of interest, Gr ≥3 atrial fibrillation occurred in 4% of ibr-treated pts and Gr ≥3 major hemorrhage in 7%. The most common reason for discontinuation in ibr-treated pts was AEs (19%, n=26), which decreased over time (yr 0-1, n=9; yr 1-2, n=7; yr 2-3, n=6; yr 3-4, n=4). AEs leading to discontinuation in >1 pt were atrial fibrillation (n=4), palpitations, and pneumonia (n=2 each). With a median ibr treatment duration of 46.9 mo (range 0.7-55.2), 89/136 (65%) pts remain on first-line ibr; 7/136 pts discontinued ibr due to PD. 11/136 pts received subsequent CLL therapy after stopping ibr (most commonly FCR [n=3], BR [n=2], acalabrutinib [n=2]).

Conclusion
With 4 yrs of follow-up, efficacy of single-agent ibr continues to endure with 86% risk reduction of PD or death. Ibr substantially improved PFS in pts with traditional high-risk features del11q or UM-IGHV (risk reduction 97% and 91% vs clb, respectively). PFS with ibr was preserved in pts with or without del11q or UM-IGHV. CR rates improved with prolonged follow-up. Discontinuation due to AEs decreased over time, with 65% of ibr pts continuing daily treatment.

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

Keyword(s): Chronic Lymphocytic Leukemia, Kinase Inhibitor, Long-term follow-up, Survival

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