PACE: ponatinib in Philadelphia chromosome-positive leukaemias resistant to earlier tyrosine kinase inhibitors
Ponatinib produced deep responses in patients with chronic myeloid leukaemia or Philadelphia-positive acute lymphoblastic leukaemia whose disease had resisted other kinase inhibitors, including the T315I mutation that no other drug could reach.
Overview
Phase 2 study of 449 heavily pretreated patients with chronic, accelerated or blast-phase CML or Ph-positive ALL, including 128 with the T315I gatekeeper mutation, treated with ponatinib 45 mg daily.
In chronic phase, 56 percent achieved a major cytogenetic response (70 percent of those with T315I); responses in accelerated and blast phase were lower and shorter. Arterial occlusive events emerged as the defining toxicity, later prompting dose reduction strategies.
- Major cytogenetic response in 56 percent of chronic-phase patients and 70 percent of those with T315I.
- Major haematological response in 55 percent of accelerated-phase and 31 percent of blast-phase or Ph-positive ALL patients.
Ponatinib is the drug for T315I-mutated disease and for patients who have failed several inhibitors, including in accelerated and blast phase as a bridge to transplant. Cardiovascular risk must be managed actively.
- Serious arterial thrombotic events in a substantial minority, increasing with time on treatment.
- Single-arm design; response-based dose reduction (OPTIC) came later.
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