Ponatinib with fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor chemotherapy for patients with blast-phase chronic myeloid leukaemia (MATCHPOINT): a single-arm, multicentre, phase 1/2 trial

Mhairi Copland, Daniel Slade, Graham McIlroy, Gillian Horne, Jenny L. Byrne, Kate Rothwell, Kristian Brock, Hugues De Lavallade, Charles Craddock, Richard E. Clark, Matthew L. Smith, Rachel Fletcher, Rebecca Bishop, Dragana Milojkovic, Christina Yap

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Abstract

Background: Outcomes for patients with blast-phase chronic myeloid leukaemia are poor. Long-term survival depends on reaching a second chronic phase, followed by allogeneic haematopoietic stem-cell transplantation (HSCT). We investigated whether the novel combination of the tyrosine-kinase inhibitor ponatinib with fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) could improve response and optimise allogeneic HSCT outcomes in patients with blast-phase chronic myeloid leukaemia. The aim was to identify a dose of ponatinib, which combined with FLAG-IDA, showed clinically meaningful activity and tolerability. Methods: MATCHPOINT was a seamless, phase 1/2, multicentre trial done in eight UK Trials Acceleration Programme-funded centres. Eligible participants were adults (aged ≥16 years) with Philadelphia chromosome-positive or BCR-ABL1-positive blast-phase chronic myeloid leukaemia, suitable for intensive chemotherapy. Participants received up to two cycles of ponatinib with FLAG-IDA. Experimental doses of oral ponatinib (given from day 1 to day 28 of FLAG-IDA) were between 15 mg alternate days and 45 mg once daily and the starting dose was 30 mg once daily. Intravenous fludarabine (30 mg/m2 for 5 days), cytarabine (2 g/m2 for 5 days), and idarubicin (8 mg/m2 for 3 days), and subcutaneous granulocyte colony-stimulating factor (if used), were delivered according to local protocols. We used an innovative EffTox design to investigate the activity and tolerability of ponatinib–FLAG-IDA; the primary endpoints were the optimal ponatinib dose meeting prespecified thresholds of activity (inducement of second chronic phase defined as either haematological or minor cytogenetic response) and tolerability (dose-limiting toxicties). Analyses were planned on an intention-to-treat basis. MATCHPOINT was registered as an International Standard Randomised Controlled Trial, ISRCTN98986889, and has completed recruitment; the final results are presented. Findings: Between March 19, 2015, and April 26, 2018, 17 patients (12 men, five women) were recruited, 16 of whom were evaluable for the coprimary outcomes. Median follow-up was 41 months (IQR 36–48). The EffTox model simultaneously considered clinical responses and dose-limiting toxicities, and determined the optimal ponatinib dose as 30 mg daily, combined with FLAG-IDA. 11 (69%) of 16 patients were in the second chronic phase after one cycle of treatment. Four (25%) patients had a dose-limiting toxicity (comprising cardiomyopathy and grade 4 increased alanine aminotransferase, cerebral venous sinus thrombosis, grade 3 increased amylase, and grade 4 increased alanine aminotransferase), fulfilling the criteria for clinically relevant activity and toxicity. 12 (71%) of 17 patients proceeded to allogeneic HSCT. The most common grade 3–4 non-haematological adverse events were lung infection (n=4 [24%]), fever (n=3 [18%]), and hypocalcaemia (n=3 [18%]). There were 12 serious adverse events in 11 (65%) patients. Three (18%) patients died due to treatment-related events (due to cardiomyopathy, pulmonary haemorrhage, and bone marrow aplasia). Interpretation: Ponatinib–FLAG-IDA can induce second chronic phase in patients with blast-phase chronic myeloid leukaemia, representing an active salvage therapy to bridge to allogeneic HSCT. The number of treatment-related deaths is not in excess of what would be expected in this very high-risk group of patients receiving intensive chemotherapy. The efficient EffTox method is a model for investigating novel therapies in ultra-orphan cancers. Funding: Blood Cancer UK and Incyte.

Original languageEnglish
Pages (from-to)e121-e132
Number of pages12
JournalThe Lancet Haematology
Volume9
Issue number2
Early online date11 Dec 2021
DOIs
Publication statusPublished - Feb 2022

Bibliographical note

Funding Information:
MC has received research funding from Novartis, Bristol Myers Squibb, Cyclacel, and Takeda/Incyte; is an advisory board member for Bristol Myers Squibb, Novartis, Incyte, Daiichi Sankyo, and Pfizer; has received honoraria from Astellas, Bristol Myers Squibb, Novartis, Incyte, Pfizer, and Gilead. JLB is on the advisory board for and has received honoraria from Incyte. KR is on the advisory board for Novartis; and has received honoraria from Novartis, Incyte, Pfizer, and Daiichi Sankyo. KB is employed by UCB; has received personal fees from Eli Lilly and Invex Therapeutics; has received reimbursement from Merck and Roche; and holds shares in AstraZeneca and GlaxoSmithKline. HDL has received research funding from Incyte and Bristol Myers Squibb; and has received speaker fees from Incyte, Bristol Myers Squibb, and Pfizer. REC has received research support and honoraria from Novartis and Bristol Myers Squibb; and has received honoraria from Pfizer in the past 3 years. MLS is on the advisory board for Daiichi Sankyo and Pfizer; and has received honoraria from ARIAD. DM has received honoraria and been part of the speakers bureau for Novartis, Incyte, Bristol Myers Squibb, and Pfizer. CY has received personal fees from Celgene and Faron Pharmaceuticals, outside the submitted work. All other authors declare no competing interests.

MATCHPOINT was funded by Blood Cancer UK, through the Trials Acceleration Programme, and by Incyte Biosciences International. Ponatinib was provided free of charge by Incyte. The trial has been supported by the facilities funded through Birmingham Science City Translational Medicine Clinical Research Infrastructure and Trials Platform, an Advantage West Midlands funded project that forms part of the Science City University of Warwick and University of Birmingham Research Alliance. We are grateful to David Marin for helpful discussions and advice during protocol development. This use of ponatinib was outside of the approved label.

Publisher Copyright:
© 2022 Elsevier Ltd

ASJC Scopus subject areas

  • Hematology

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