Up to 6.5 years (median 4 years) of follow-up of first-line ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and high-risk genomic features: integrated analysis of two phase 3 studies

Abstract

Genomic abnormalities, including del(17p)/TP53 mutation, del(11q), unmutated IGHV, and mutations in BIRC3, NOTCH1, SF3B1, and XPO1 predict poor outcomes with chemoimmunotherapy in chronic lymphocytic leukemia. To better understand the impact of these high-risk genomic features on outcomes with first-line ibrutinib-based therapy, we performed pooled analysis of two phase 3 studies with 498 patients randomized to receive ibrutinib- or chlorambucil-based therapy with median follow-up of 49.1 months. Ibrutinib-based therapy improved overall response rates (ORRs), complete response rates, and progression-free survival (PFS) versus chlorambucil-based therapy across all subgroups. In ibrutinib-randomized patients with versus without specified genomic features, ORR and PFS were comparable across subgroups. PFS hazard ratio (95% CI) for del(17p)/TP53 mutated/BIRC3 mutated: 1.05 (0.54–2.04); del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV: 1.11 (0.69–1.77); unmutated IGHV: 1.79 (0.99–3.24); and NOTCH1 mutated 1.05 (0.65–1.69). This integrated analysis demonstrated efficacy of first-line ibrutinib-based treatment irrespective of cytogenetic and mutational risk features.

Registered at ClinicalTrials.gov (NCT01722487 and NCT02264574).

Keywords:

• Chronic lymphocytic leukemia
• ibrutinib
• chlorambucil
• obinutuzumab
• pooled analysis

Acknowledgments

The authors thank all the patients who participated in the RESONATE-2 and iLLUMINATE studies and their families. We also thank Jennifer Lin, MA, MS, for biometrics support and Melanie Sweetlove, MSc, for medical writing support, funded by Pharmacyclics LLC, an AbbVie Company.

Author contributions

JAB, TJK, and AT designed the analyses in collaboration with representatives of the sponsor; JAB, TR, FD, OB, CM, DSi, TM, DAS, TJK, and AT contributed to data collection; SD, LWKC, and KK performed the data analyses; SD, LWKC, KK, IL, and EH confirmed the accuracy of the data and compiled it for analysis; all authors had access to the data and were involved in the interpretation of data, contributed to the manuscript review and revisions, and approved the final version for submission.

Disclosure statement

JAB: honoraria from and consulting/advisory role for Janssen; research funding from AstraZeneca, BeiGene, and Pharmacyclics LLC, an AbbVie Company; and speakers bureau for and travel/accommodations/expenses from Gilead, Janssen, Novartis, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company. TR: honoraria from AstraZeneca and Janssen; and consulting/advisory role for and research funding from Acerta, AstraZeneca, and Janssen. FD: consulting/advisory role for AbbVie, Amgen, AstraZeneca, and Roche; research funding from AbbVie, AstraZeneca, Janssen, and Pharmacyclics LLC, an AbbVie Company; speakers bureau for AbbVie, Amgen, and Janssen; and travel/accommodations/expenses from AbbVie, Amgen, Janssen, and Pfizer. OB: consulting/advisory role for AbbVie, AstraZeneca, and Janssen; and research funding from Janssen. CM: consulting/advisory role for AbbVie, AstraZeneca, BeiGene, and Janssen; research funding from AbbVie and Janssen; and speakers bureau for Janssen. DSi: employment and stock or other ownership with BeiGene; honoraria and travel/accommodations/expenses from AbbVie and Janssen; research funding from AbbVie, Acerta, Amgen, BeiGene, Celgene, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Roche, Sanofi, and Pharmacyclics LLC, an AbbVie Company. TM: honoraria from AbbVie, AstraZeneca, Gilead, Janssen, and Novartis; consulting/advisory role for MorphoSys and Sunesis; and travel/accommodations/expenses from AbbVie, Gilead, and Janssen. DAS: consulting/advisory role for Amgen and MorphoSys. SD: current employment with Horizon Therapeutics and previously employed with Pharmacyclics LLC, an AbbVie Company; and stock or other ownership with AbbVie, Bristol Myers Squibb, Exelixis, Gilead, GlaxoSmithKline, Horizon Therapeutics, Myovant Sciences, and Revance Therapeutics. LWKC: employment with Pharmacyclics LLC, an AbbVie Company; stock or other ownership with AbbVie; and other relationships with Pfizer and Tizona Therapeutics. KK: current employment with BioSplice Therapeutics and previously employed with Pharmacyclics LLC, an AbbVie Company; and stock or other ownership with AbbVie, BioSplice Therapeutics, and Gilead. IL: current employment with Gilead Sciences and previously employed with Pharmacyclics LLC, an AbbVie Company; spouse employment with The Permanente Medical Group; and stock or other ownership with AbbVie, Clovis, Gilead Sciences, Infinity, Reviva Pharmaceuticals, and The Permanente Medical Group. EH: employment with Pharmacyclics LLC, an AbbVie Company; and stock or other ownership with AbbVie. TJK: employment with Moores Cancer Center; stock or other ownership with Oncternal; honoraria from AbbVie, Celgene, DAVA Oncology, Genentech, Gilead, Janssen, Roche, and Pharmacyclics LLC, an AbbVie Company; consulting/advisory role with AbbVie, Celgene, DAVA Oncology, Genentech-Roche, Gilead, Janssen, and Pharmacyclics LLC, an AbbVie Company; research funding from Celgene, CIRM, MD Anderson Cancer Center, Oncternal, Velos, and Pharmacyclics LLC, an AbbVie Company; speakers bureau for AbbVie, DAVA Pharmaceuticals, Genentech, Gilead, Janssen, Verastem, and Pharmacyclics LLC, an AbbVie Company; patents/royalties/other intellectual property for development of cirmtuzumab, which is licensed by Oncternal from the University of California; and travel/accommodations/expenses from AbbVie, Bionest Partners, Celgene, DAVA Oncology, G-Therapeutics Genentech, Gilead, Indy Hematology Review, Janssen, OncLive, Roche, Verastem, and Pharmacyclics LLC, an AbbVie Company. AT: consulting/advisory role and speakers bureau for AbbVie, AstraZeneca, BeiGene, and Janssen.

Data availability statement

Requests for access to individual participant data from clinical studies conducted by Pharmacyclics LLC, an AbbVie Company, can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu

Additional information

Funding

The RESONATE-2 and iLLUMINATE studies were sponsored by Pharmacyclics LLC, an AbbVie Company.