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Fund

The results for patients with chronic myeloid leukemia in the blast phase are poor. Long-term survival depends on achieving a second chronic phase, followed by allogeneic hematopoietic 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 the response and optimize the results of the Allogeneic HSCT in patients with chronic myeloid leukemia in the blast phase. The objective was to identify a dose of ponatinib which, in combination with FLAG-IDA, showed clinically significant activity and safety.

Methods

MATCHPOINT was a continuous phase 1/2 multicenter trial carried out at eight centers funded by the UK’s Trials Acceleration Program. Eligible participants were adults (aged ≥16 years) with a positive Philadelphia chromosome or BCR-ABL1-Chronic myeloid leukemia in positive blast phase, suitable for intensive chemotherapy. Participants received up to two cycles of ponatinib with FLAG-IDA. The experimental oral ponatinib doses (administered from day 1 to day 28 of FLAG-IDA) ranged from 15 mg every other day to 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 applicable), were delivered according to local protocols. We used an innovative EffTox design to study the activity and tolerability of ponatinib-FLAG-IDA; the primary endpoints were the optimal dose of ponatinib meeting predefined activity thresholds (induction of a chronic second phase defined as a minor hematologic or cytogenetic response) and tolerability (dose-limiting toxicities). Analyzes were planned by intention to treat. MATCHPOINT was registered as an international standard randomized controlled trial, ISRCTN98986889, and has completed enrollment; the final results are presented.

Results

Between March 19, 2015 and April 26, 2018, 17 patients (12 men, five women) were recruited, of which 16 were evaluable for the co-primary outcomes. The median follow-up was 41 months (IQR 36–48). The EffTox model simultaneously considered clinical responses and dose-limiting toxicities, and determined the optimal dose of ponatinib at 30 mg per day, in combination with FLAG-IDA. 11 (69%) of 16 patients were in the second chronic phase after a treatment cycle. Four (25%) patients experienced dose-limiting toxicity (including cardiomyopathy and grade 4 alanine aminotransferase elevation, cerebral venous sinus thrombosis, grade 3 amylase elevation, and elevation of grade 4 alanine aminotransferase. grade 4 alanine aminotransferase), meeting the clinically relevant activity and toxicity criteria. 12 (71%) of 17 patients underwent allogeneic HSCT. The most common Grade 3 to 4 non-haematologic adverse events were pulmonary infections (n ​​= 4 [24%]), fever (n = 3 [18%]), and hypocalcemia (n = 3 [18%]). There were 12 serious adverse events in 11 (65%) patients. Three (18%) patients died from treatment-related events (due to cardiomyopathy, pulmonary hemorrhage and bone marrow aplasia).

Interpretation

Ponatinib-FLAG-IDA can induce a chronic second phase in patients with chronic blast phase myeloid leukemia, which represents an active lifesaving therapy to bridge allogeneic HSCT. The number of treatment-related deaths does not exceed what would be expected in this very high-risk group of patients receiving intensive chemotherapy. The effective EffTox method is a model for studying new therapies in ultra-orphan cancers.

Funding

Blood Cancer UK and Incyte.