Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials

Abstract

TP53 aberrations [del(17p) or TP53 mutation] predict poor survival with chemoimmunotherapy in patients with chronic lymphocytic leukaemia (CLL). We evaluated long-term efficacy and safety of first-line ibrutinib-based therapy in patients with CLL bearing TP53 aberrations in a pooled analysis across four studies: PCYC-1122e, RESONATE-2 (PCYC-1115/16), iLLUMINATE (PCYC-1130) and ECOG-ACRIN E1912. The pooled analysis included 89 patients with TP53 aberrations receiving first-line treatment with single-agent ibrutinib (n = 45) or ibrutinib in combination with an anti-CD20 antibody (n = 44). All 89 patients had del(17p) (53% of 89 patients) and/or TP53 mutation (91% of 58 patients with TP53 sequencing results available). With a median follow-up of 49·8 months (range, 0·1-95·9), median progression-free survival was not reached. Progression-free survival rate and overall survival rate estimates at four years were 79% and 88%, respectively. Overall response rate was 93%, including complete response in 39% of patients. No new safety signals were identified in this analysis. Forty-six percent of patients remained on ibrutinib treatment at last follow-up. With median follow-up of four years (up to eight years), results from this large, pooled, multi-study data set suggest promising long-term outcomes of first-line ibrutinib-based therapy in patients with TP53 aberrations. Registered at ClinicalTrials.gov (NCT01500733, NCT01722487, NCT02264574 and NCT02048813).

Keywords: TP53 mutation; chronic lymphocytic leukaemia; del(17p); first-line; ibrutinib.

Conflict of interest statement

JNA: honoraria from AstraZeneca, Janssen, and AbbVie; consulting/advisory role for AstraZeneca, Pharmacyclics LLC, an AbbVie Company, BeiGene, AbbVie, Genentech, TG Therapeutics, Ascentage, ADC Therapeutics and Epizyme; research funding from Celgene, Genentech, AstraZeneca, TG Therapeutics and Janssen; and speakers bureau for AbbVie, Janssen, Pharmacyclics LLC, an AbbVie Company, AstraZeneca and BeiGene. TS: honoraria from Vanderbilt University, Cornell University, Eastside Health Network, Emory University, University of Nebraska, Columbia University, Memorial Sloan Kettering, Coalition for Physician Well‐Being, Washington Hospital, Nevada Physician Wellness Coalition, St. Christopher’s Hospital for Children, American Society for Nephrology, Lankenau Medical Center, Physicians’ Education Resource, Adventist Health Care, Advocate Health Care, Vancouver Physician Staff Association, Advent Health Care and Hospital for Special Surgery; research funding from Genentech, Pharmacyclics LLC, an AbbVie Company and AbbVie; and patents/royalties/other intellectual property with Mayo Clinic. AW: research funding from Pharmacyclics LLC, an AbbVie Company, Acerta, Merck, Nurix, Verastem and Genmab; and patents/royalties/other intellectual property with National Institutes of Health. CM: consulting/advisory role for Janssen, AbbVie, BioGene and AstraZeneca; research funding from AbbVie and Janssen; and speakers bureau for AbbVie and Janssen. SMO: consulting or advisory role for Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen, Aptose Biosciences, Vaniam Group, AbbVie, Alexion, Verastem, Eisai, Juno Therapeutics, Vida Ventures, Autolus, Johnson & Johnson, Merck, Bristol Myers Squibb, Gilead, Pharmacyclics LLC, an AbbVie Company, TG Therapeutics, Pfizer, NOVA Research Company and Sunesis; and research funding from Kite, Regeneron, Acerta, Gilead, Pharmacyclics LLC, an AbbVie Company, TG Therapeutics, Pfizer, Caribou and Sunesis. JL: employment with AbbVie and Summit Therapeutics; and stock or other ownership with AbbVie, Summit Therapeutics, Gilead, Vertex Pharmaceuticals, ALX Oncology, I‐Mab Biopharma, Surface Oncology, Moderna, Trillium Therapeutics, Pfizer, Novavax, BioMarin, Oncternal Therapeutics, Iovance Biotherapeutics, Fate Therapeutics, BeiGene, TG Therapeutics and Arbutus Biopharma. GK: employment with Pharmacyclics LLC, an AbbVie Company, AbbVie and Bristol Myers Squibb; stock or other ownership with AbbVie, Bristol Myers Squibb, Moderna, Dynavax and Inovio; and travel/accommodations/expenses from Bristol Myers Squibb. JPD: employment with Pharmacyclics LLC, an AbbVie Company; and stock or other ownership with AbbVie. IEA: nothing to disclose.

© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

Figures

Fig 1

Kaplan–Meier estimates of (A) progression‐free survival and (B) overall survivala in patients with TP53 aberrations receiving first‐line ibrutinib‐based therapy. aThe patient who had the longest follow‐up died at 96 months, resulting in an artefact for estimating median OS; this patient’s data were suppressed from the plot to correctly represent the population for which the median OS is not estimable.

Fig 2

Prevalence of grade ≥3 adverse events of clinical interest by yearly interval. aCombined terms. Infection was identified using the Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class term for Infections and infestations. Bleeding was identified using the Standardised MedDRA Query for Haemorrhage, excluding laboratory terms. [Colour figure can be viewed at wileyonlinelibrary.com]