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
Mené sur 17 patients atteints d'une leucémie myéloïde chronique en phase blastique (durée médiane de suivi : 41 mois), cet essai de phase I/II évalue la dose maximale tolérée du ponatinib en combinaison avec une chimiothérapie de type FLAG-IDA (fludarabine, cytarabine, facteur de stimulation des colonies de granulocytes et idarubicine)
Background : Outcomes for patients with blast-phase chronic myeloid leukaemia are poor. Long-termsurvival depends on reaching a second chronic phase, followed by allogeneic haematopoieticstem-cell transplantation (HSCT). We investigated whether the novel combination of the tyrosine-kinase inhibitor ponatinib with fludarabine, cytarabine, granulocytecolony-stimulating factor, and idarubicin (FLAG-IDA) could improve response and optimiseallogeneic HSCT outcomes in patients with blast-phase chronic myeloid leukaemia. Theaim 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 AccelerationProgramme-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 dosesof oral ponatinib (given from day 1 to day 28 of FLAG-IDA) were between 15 mg alternatedays and 45 mg once daily and the starting dose was 30 mg once daily. Intravenousfludarabine (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 ofsecond chronic phase defined as either haematological or minor cytogenetic response)and tolerability (dose-limiting toxicties). Analyses were planned on an intention-to-treatbasis. MATCHPOINT was registered as an International Standard Randomised ControlledTrial, 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 afterone cycle of treatment. Four (25%) patients had a dose-limiting toxicity (comprising cardiomyopathy and grade 4 increased alanine aminotransferase, cerebral venous sinusthrombosis, grade 3 increased amylase, and grade 4 increased alanine aminotransferase),fulfilling the criteria for clinically relevant activity and toxicity. 12 (71%) of17 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 chronicmyeloid leukaemia, representing an active salvage therapy to bridge to allogeneicHSCT. The number of treatment-related deaths is not in excess of what would be expectedin this very high-risk group of patients receiving intensive chemotherapy. The efficientEffTox method is a model for investigating novel therapies in ultra-orphan cancers.
The Lancet Haematology , résumé, 2020