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The FDA in combination with chemotherapy for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in previously untreated adults, the agency announced this week.

Support for the approval came from PhALLCON, an open-label phase III trial involving 245 adults with newly diagnosed Ph+ ALL, a rare form of the leukemia that affects about a fourth of ALL patients.

With its new indication, the tyrosine kinase inhibitor (TKI) becomes the first targeted agent to be approved in combination with chemotherapy for previously untreated Ph+ cases, according to drugmaker Takeda.

"Ph+ ALL is an extremely aggressive cancer and patients with this disease suffer from poor outcomes. There has long been a need for a potent TKI that can suppress mutation development and elicit deep responses in the frontline," said PhALLCON investigator Elias Jabbour, MD, of the University of Texas MD Anderson Cancer Center in Houston, in a from the company. "Ponatinib may help address these factors and impact long-term outcomes."

Patients in the study were randomized to receive either oral ponatinib or imatinib in a 2:1 fashion along with reduced-intensity chemotherapy: three induction cycles of vincristine and dexamethasone; six alternating consolidation cycles of methotrexate and cytarabine; and 11 maintenance cycles of vincristine and prednisone.

The multicenter study met its primary endpoint: at the end of induction, patients assigned to ponatinib had a significantly greater minimal residual disease (MRD)-negative complete remission (CR) rate (30% vs 12% with imatinib, P=0.0004), an endpoint that "reflects deep molecular and clinical responses and is an important prognostic indicator for long-term outcomes" in this patient population, said Takeda. Data on the key secondary endpoint of event-free survival are not yet mature.

As a condition of the accelerated approval, confirmatory data may be required to demonstrate the drug's clinical benefit in this setting.

According to the , adverse events that occurred in 20% or more patients treated with ponatinib included liver dysfunction, arthralgia, rash, headache, pyrexia, abdominal pain, constipation, fatigue, oral mucositis, hypertension, pancreatitis/elevated lipase, peripheral neuropathy, hemorrhage, febrile neutropenia, fluid retention and edema, nausea and vomiting, paresthesia, and arrhythmias.

Ponatinib in frontline Ph+ ALL is meant to be continued with chemotherapy for up to 20 cycles until either loss of response or unacceptable toxicity.

The drug is also approved in Ph+ ALL as monotherapy for T315I-positive cases and for patients where no other TKIs are indicated, and also carries indications in chronic myeloid leukemia.

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