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Ponatinib/Chemotherapy Granted Accelerated Approval for Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia.

The FDA has granted accelerated approval to ponatinib (Iclusig®, Takeda Pharmaceuticals USA, Inc.) with chemotherapy for adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).  

Why it matters: "Tyrosine kinase inhibitors (TKIs) are a critical component in the treatment of newly diagnosed Ph+ ALL; their use has dramatically improved outcomes among patients with this condition," said Dr. Tristan Knight, MD, FRCPC, an Oncology Data Advisor Editorial Board Member and Clinical Assistant Professor at Fred Hutchinson Cancer Center and Seattle Children's Hospital.

Tristan Knight, MD, FRCPC.

Why it matters (continued): "The BCR-ABL fusion gene characterizes Ph+ ALL and is also seen in chronic myeloid leukemia (CML)—albeit resulting in a slightly different fusion protein," continued Dr. Knight. "However, unlike CML, in which TKI resistance is relatively uncommon, TKI resistance readily develops in Ph+ ALL, resulting in a loss of therapeutic efficacy. In particular, the presence of a T315I mutation at diagnosis, or the development of a T315I mutation during treatment, is implicated in TKI resistance and occurs in up to three-quarters of patients who relapse after using first- or second-generation TKIs. Ponatinib, as a third-generation TKI, not only targets T315I, but also appears to be more effective than other TKIs at targeting and inhibiting the BCR-ABL fusion protein."

What they studied: Efficacy was studied in the PhALLCON trial (NCT03589326), a phase 3, active-controlled, multicenter, open-label trial which enrolled 245 adult patients with newly diagnosed Ph+ ALL. Patients were randomized 2:1 to receive either 30 mg of ponatinib orally, once daily or 600 mg of imatinib orally, once daily, followed by chemotherapy consisting of three cycles of induction with vincristine and dexamethasone, six cycles of consolidation alternating between methotrexate and cytarabine, and 11 cycles of vincristine and prednisone maintenance. After completion of the induction phase and achievement of minimal residual disease (MRD)–negative (BCR:ABL1 ≤0.01%) complete remission (CR), ponatinib was reduced to a dosage of 15 mg daily. Imatinib with chemotherapy is an unapproved regimen.

The primary efficacy measure was MRD-negative CR rate at the end of induction.

What they found: The MRD-negative CR rate at the end of induction was 30% in the ponatinib arm compared with 12% in the imatinib arm.

Adverse events: The most common adverse events were hepatic dysfunction, arthralgia, rash and related conditions, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/elevated lipase, peripheral neuropathy, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia, and cardiac arrhythmias.

Conclusion: "The PhALLCON trial—upon which this approval was based—highlights several key points related to ponatinib. Firstly: while the TKIs are, as a class, effective against Ph+ ALL, treatment with ponatinib is notably superior to imatinib at achieving MRD-negative status and demonstrates longer progression-free survival. Second: ponatinib is more cardiotoxic than other TKIs, and clinicians must therefore maintain vigilance for this particular toxicity. However, it is reassuring that the observed rates of serious adverse events and of treatment discontinuation were similar between the imatinib and ponatinib arms, implying that ponatinib's toxicity profile is tolerable in this population," concluded Dr. Knight.

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