FLAG-IDA and Ponatinib in Patients with Blast Phase Chronic Myeloid Leukaemia: Results from the Phase I/II UK Trials Acceleration Programme Matchpoint Trial
Authors: Copland Mhairi , Slade Daniel , Byrne Jenny , Brock Kristian , De Lavallade Hugues , Craddock Charles , Clark Richard , Smith Matthew , Bishop Rebecca , Milojkovic Dragana , Yap Christina 
Published: February 2020

Background: The outcome of patients with blast phase chronic myeloid leukaemia (CML) remains extremely poor despite the advent of tyrosine kinase inhibitors (TKIs), and the majority of blast phase patients have already failed the currently licensed TKIs during the chronic phase. Currently there is no standard therapy for patients with blast phase CML, but most will receive 2 or 3 courses of chemotherapy or a TKI, followed by stem cell transplantation (alloSCT). In the PACE clinical trial of ponatinib, 23% of patients with blast phase CML achieved major cytogenetic response, with overall survival of 20% at 12 months. To date, there has been no prospective evaluation of salvage chemotherapy in combination with ponatinib.

Methods: MATCHPOINT is a seamless Phase I/II trial to determine the optimal dose of ponatinib in combination with conventional chemotherapy (fludarabine, cytarabine, idarubicin and G-CSF; FLAG-IDA) for the treatment of CML in blast phase. An efficient Bayesian design, EffTox, which utilises both efficacy and toxicity to select desirable doses for subsequent patient cohorts, was used. Given the observed patient outcomes and the investigators' prior beliefs, the next cohort's dose is chosen adaptively to optimize the risk-benefit trade-off between efficacy and toxicity. The initial ponatinib dose was 30mg daily, commenced on day 1 of FLAG-IDA chemotherapy. Where possible, ponatinib was given continuously during the remission-induction phase, but ponatinib therapy was interrupted from day 28 of each cycle if haematologic recovery had not occurred. Patients received one or two cycles of FLAG-IDA chemotherapy plus ponatinib at the allocated dose level, and then proceeded to alloSCT followed by ponatinib maintenance. The co-primary outcome measured toxicity (dose-limiting toxicity; DLT) during the first therapy cycle and efficacy (clinical response; haematologic or cytogenetic) after the first cycle.

Results: A total of 17 patients were recruited between March 2015 and May 2018. Eight presented with de-novo blast phase CML and 9 had progressed on TKI. Eight patients had additional cytogenetic abnormalities and 3 had BCR-ABL kinase domain mutations (E255K x2 and T315I x1) at study entry. Nine and 8 patients commenced 1 or 2 cycles of FLAG-IDA + ponatinib, respectively. Of these, 16 patients were evaluable for the primary analysis. Treatment-related mortality (TRM) occurred in 3 patients during remission-induction (cardiomyopathy x1, pulmonary haemorrhage x1 and marrow aplasia x1). During cycle 1, 4/16 patients experienced a DLT (raised ALT x1, fulminant cardiomyopathy x1, cerebral sinus vein thrombosis x1, elevated amylase x1). Eleven of 16 (69%) patients achieved a clinical response, defined as either complete haematologic (3 patients) or cytogenetic response (1 minor and 9 major [2 partial and 7 complete]). Five patients achieved major molecular remission after cycle 1. All patients were recommended to be dosed at the 30mg dose, which was defined as the optimal dose for ponatinib with FLAG-IDA. Nine patients proceeded to alloSCT (7 myeloablative and 2 reduced intensity). Four patients developed acute GvHD (grades 2-4) and 3 had CMV reactivation. Four patients re-started ponatinib maintenance post alloSCT, and de-escalated to 15mg if major molecular remission was maintained. Overall 1-year survival was 45.8% (95% CI 26.9-77.7%), estimated using Kaplan Meier.

Summary/Conclusion: We report the first prospective trial of ponatinib and conventional chemotherapy for blast phase CML. The EffTox model combined Phase I and II, and delivered efficiency in determining the trial's optimal dose. This innovative statistical model has the potential to be applied in other rare malignancies. We confirm that FLAG-IDA + ponatinib 30mg, is a tolerable combination in blast phase CML, with promising response and survival. Post-transplant ponatinib was well tolerated and no excess toxicity was observed when ponatinib was used both pre- and post alloSCT. The combination of ponatinib and FLAG-IDA represents a potentially important advance in the treatment of blast phase CML, a rare complication which currently has a very poor outcome.

Disclosures

Copland: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; Cyclacel: Research Funding. Byrne:Ariad/Incyte: Honoraria, Speakers Bureau. Brock:Astrazeneca: Equity Ownership, Honoraria. De Lavallade:Incyte biosciences: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Clark:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ariad/Incyte: Honoraria; Jazz Pharmaceuticals: Honoraria; AbbVie: Honoraria. Milojkovic:Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Yap:Celgene: Honoraria; Faron Pharmaceuticals: Other: Consultancy.

OffLabel Disclosure:

Ponatinib is a tyrosine kinase inhibitor (TKI). It is licensed to treat: - chronic myeloid leukaemia where the leukaemic cells have gene change (mutation) called T315I - acute lymphoblastic leukaemia that has an abnormal chromosome called the Philadelphia chromosome, or has the T315I mutation