Therapies for adults patients diagnosed with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) are limited and generally associated with poor outcomes. However, with the introduction of tyrosine kinase inhibitors (TKIs) in the management of Ph+ ALL, the prognosis of patients has improved dramatically.
The randomized Phase 3 PhALLCON trial of ponatinib (Iclusig®; Takeda Oncology) for the treatment of adult patients with newly-diagnosed Ph+ ALL met its primary efficacy endpoint in the frontline setting.
Ponatinib is a kinase inhibitor targeting BCR::ABL1, an abnormal tyrosine kinase that is expressed in CML and Ph+ ALL. The drug, previously AP24534 and originally developed by ARIAD Pharmaceuticals (no part of Takeda Oncology), is a targeted cancer medicine created by using a computational and structure-based drug-design platform, specifically designed to inhibit the activity of BCR::ABL1 and its mutations.
The drug, which was approved by the U.S. Food and Drug Administration in November 2016, inhibits native BCR::ABL1, as well as all BCR::ABL1 treatment-resistant mutations, including the most resistant T315I mutation.
A rare form of ALL
Philadelphia chromosome-positive acute lymphoblastic leukemia or Ph+ ALL is a rare form of ALL that affects approximately 25% of adult ALL patients in the United States and is characterized by the presence of an abnormal gene, known as the Philadelphia chromosome. In patients who are Philadelphia chromosome-positive (Ph+), an abnormal chromosome is formed when pieces of chromosomes 9 and 22 switch with each other. This forms a longer chromosome 9 and a shorter chromosome 22, which leads to the development of BCR::ABL1 and is associated with Ph+ ALL.
The PhALLCON study is a Phase 3 randomized, international, open-label multicenter trial evaluating the efficacy and safety of ponatinib versus Imatinib mesylate (Gleevec®/Glivec®; Novartis) in combination with reduced-intensity chemotherapy as a frontline therapy for adult patients with newly diagnosed Ph+ ALL.
The results of the study confirm that adult patients treated with ponatinib in combination with reduced-intensity chemotherapy achieved higher rates of minimal residual disease (MRD)-negative complete remission (CR) compared to imatinib.
MRD-negativity is associated with improvement in long-term outcomes for patients, as reported in literature. Ponatinib is the only pan-mutational and third-generation tyrosine kinase inhibitor (TKI), targeting BCR::ABL1 and all known single, treatment-resistant mutations, including the most resistant T315I mutation.
“Ph+ ALL is a fast-progressing disease with no targeted treatments currently approved in the frontline for patients in the U.S. There is an urgent need for an effective treatment that can suppress the development of difficult-to-treat mutations, which are associated with poor long-term outcomes,” said Awny Farajallah, MD, Head of Global Medical Affairs Oncology at Takeda.
“We are excited to see how ICLUSIG may be able to address this gap in care for these patients and look forward to sharing the results,” Farajallah concluded.
A Study of Ponatinib Versus Imatinib in Adults With Acute Lymphoblastic Leukemia – NCT03589326.
 Abou Dalle I, Jabbour E, Short NJ, Ravandi F. Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Curr Treat Options Oncol. 2019 Jan 24;20(1):4. doi: 10.1007/s11864-019-0603-z. PMID: 30675645.
 Foà R, Chiaretti S. Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. N Engl J Med. 2022 Jun 23;386(25):2399-2411. doi: 10.1056/NEJMra2113347. PMID: 35731654.
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