Ponatinib Shows Promise in Pediatric/Adolescent ALL Patients


Ponatinib (Iclusig) induced a complete remission in one pediatric/adolescent patient with Philadelphia chromosome-positive acute lymphoblastic leukemia, and demonstrated promising clinical activity in another.

Stephanie E. Gruner, RN

Stephanie E. Gruner, RN

Stephanie E. Gruner, RN

Ponatinib (Iclusig) induced a complete remission (CR) in one pediatric/adolescent patient with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL), and demonstrated promising clinical activity in another, according to results from a case study presented at the 2018 American Society of Pediatric Hematology/Oncology (ASPHO) Conference.1

The third-generation tyrosine kinase inhibitor (TKI) ponatinib is not indicated for pediatric/adolescent patients, but the drug may have a role to play in children and young adults with mutations that have proven to be resistant to first- and second-generation TKIs.

“This drug has not been studied in the pediatric population but it has a huge clinical significance because…we’re seeing [more of these mutations] on these long-term TKI drugs for this specific diagnosis,” lead author Stephanie E. Gruner, RN, Texas Children’s Cancer & Hematology Centers, said in an interview with OncLive.

Ponatinib is FDA-approved for patients with chronic-phase, accelerated-phase, or blast-phase chronic myeloid leukemia (CML) or Ph-positive ALL for whom no other TKI is indicated, and for adults with T315I­positive CML or Ph-positive ALL. Gruner said it has not been extensively studied in a pediatric/adolescent population, likely due to a black box warning for arterial occlusion, venous thromboembolism, heart failure, and hepatotoxicity.2

Both patients in the analysis presented at ASPHO relapsed while on treatment with upfront chemotherapy and dasatinib (Sprycel) at Texas Children’s Cancer & Hematology Centers. Physicians performed mutation testing to investigate the reasons for the relapses.

The first patient, diagnosed at age 13 years, relapsed after 2 years of treatment with chemotherapy/dasatinib. In mutational testing, physicians identified a T315I mutation and subsequently initiated ponatinib treatment.

“To date, in the literature, this mutation has not been identified in a pediatric patient,” Gruner said. “With this case 1, we went back to the diagnostic sample and discovered she did not have the mutation at diagnosis—she developed it on the dasatinib.”

This patient went into CR while on ponatinib, but had to discontinue after only a week due to grade 3 peripheral edema, bilateral pleural effusion, and pericardial effusion.

“That just really highlights the fact this drug has clinical relevance, but we don’t know how to dose these patients or use it in conjunction with other chemotherapeutic agents,” Gruner said.

That patient underwent stem cell transplantation (SCT) at 5 months post-relapse and went into CR, but later died due to infection.

The second patient, now aged 21 years, was diagnosed with Ph-positive ALL at age 15. She relapsed while on chemotherapy/dasatinib after 9 months and underwent SCT because of high-risk disease features.

One-year posttransplant, physicians initiated treatment with imatinib (Gleevec) because of rising BCR-ABL polymerase chain reaction (PCR). She was switched to dasatinib 1.5 years later, again, due to rising BCR-ABL. Her BCR-ABL PCR kept rising and she underwent mutational testing 9 months later, at which point physicians discovered F359V and F317L mutations.

Physicians then initiated ponatinib treatment lasting 1.5 years. The only major side effect was a persistent rash that did not resolve with dose reduction.

Eventually, the patient discontinued ponatinib due to relapse. After reinduction chemotherapy, she underwent CD34-positive donor lymphocyte infusion and leukemia-directed cytotoxic T-lymphocytes, and received a year of bosutinib (Bosulif) therapy.

The patient remains alive and in TKI-free remission.

Gruner said that not every institution performs routine mutational testing on pediatric patients and most physicians would likely switch to a different TKI first. According to Gruner, broader adoption of mutational testing may help physicians make treatment decisions and spare relapsed/refractory patients exposure to side effects associated with drugs that will not have clinical value.

“It’s important to make it [clear] to clinicians that, when you do have a relapse or you’re seeing the BCR-ABL PCR is rising, consider mutational testing to identify these mutations and whether it’s clinically relevant to continue these drugs,” she said.


  1. Gruner SE, Sayeed H, Suarez-Ferguson L, et al. Ponatinib use in pediatric/adolescent and young adult patients with relapsed Ph+ ALL: a case series and review of the literature. Presented at: the 2018 ASPHO Conference; May 2-5, 2018; Pittsburgh, PA. Poster 079.
  2. Iclusic [package insert]. Cambridge, MA: ARIAD Pharmaceuticals Inc; 2017.
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