A small, retrospective study of young patients with chronic myeloid leukemia (CML) showed a high overall response rate for the third-generation tyrosine kinase inhibitor (TKI) ponatinib when used in populations outside of clinical trials.1                              

Adi Shacham-Abulafia, MD, of the Davidoff Cancer Center in Israel, and colleagues conducted a small retrospective study to examine the safety and efficacy of ponatinib in a real-world population. They found that 85% of patients responded, with almost half achieving a major molecular response.

Based on these results, the researchers concluded that ponatinib is a “niche drug” that should be “reserved for a unique population of exceptionally young patients with CML with or without the T315I mutation.”

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Ponatinib History

According to the study, widespread adoption of ponatinib has been slow because of safety concerns associated with the drug.

Ponatinib was originally approved by the US Food and Drug Administration (FDA) in December 2012 in its accelerated approval program, but development was halted by the FDA in October 2013 in order to investigate adverse events associated with the drug.2

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“Ponatinib was put on hold by FDA for the increased risk of cardiovascular events,” Massimo Breccia, MD, of Sapienza University of Rome in Italy, told Cancer Therapy Advisor.

In 2016, ponatinib received full FDA approval for adults with chronic-phase, accelerated-phase, or blast-phase CML for whom no other TKI therapy is indicated and in patients with T315I-positive CML.3 The full approval was based on 48-month follow-up results of the phase 2 PACE trial, which showed that 55% of the patients with chronic-phase CML had a major cytogenetic response. In the study, serious arterial thrombotic events occurred in 9% of patients and were considered related to drug treatment in only 3%.4

Real-World Experience

According to Dr Shacham-Abulafia and colleagues, there are limited data about the use of ponatinib outside of clinical trials. To characterize patients treated with the drug and information about dosage, efficacy, and safety, they looked at data from 37 patients with CML who received ponatinib at one of 7 medical centers in Israel between 2011 and 2016. Twenty-one patients had chronic-phase disease and 16 were in the advanced phase; 26% of patients were T315I-positive.

All patients had received at least one prior TKI. The median age of patients in the study was 43, which the researchers said was significantly younger than would be expected for patients with relapsed or refractory disease, and younger than the median age of patients in the phase 2 PACE study.

According to Dr Breccia, younger patients may have been preferred by clinicians in these real-world settings because of the cardiovascular profile of ponatinib.

“The cohort of patients enrolled in clinical sponsored trials usually were selected for specific inclusion criteria based on [the] specific safety profile of the drug,” Dr Breccia said. “Usually, for example, the elderly category did not receive the drug. Real-life cohorts represent what we treated in clinical practice without selection.”

In the retrospective study, after a median follow-up of 14 months, the overall response rate was 85% with 47% of patients achieving a deep molecular response. A little less than half (43%) of patients discontinued treatment because of disease progression. Only one patient discontinued treatment due to vascular complications.

Dr Breccia said he disagreed, however, with the statement that ponatinib is a “niche drug.” In a similar retrospective study, Dr Breccia and colleagues looked at ponatinib as a second-line treatment in 29 patients with chronic-phase CML with resistance or intolerance to prior TKIs.5 The median age of these patients was 54. Here, 85% of patients improved their level of response compared with baseline, and about one-third of patients achieved a deep molecular response. No thrombotic events were recorded.

Dr Breccia and colleagues concluded in that paper that “ponatinib seems a valid second-line treatment option for chronic-phase CML, in particular for patients who failed a front-line second-generation TKI due to BCR-ABL-independent mechanisms of resistance.”


  1. Shacham-Abulafia A, Raanani P, Lavie D, et al. Real-life experience with ponatinib in chronic myeloid leukemia: a multicenter observational study. Clin Lymphoma Myeloma Leuk. 2018;18(7):e295-e301.
  2. Roth AJ. Reversing Halt, FDA Reauthorizes Sale of Ponatinib. https://www.ajmc.com/journals/evidence-based-oncology/2014/february-2014/reversing-halt-fda-reauthorizes-sale-of-ponatinib. Updated February 12, 2014. Accessed August 6, 2018.
  3. Ariad Announces FDA Full Approval and Label Update for Iclusig® (ponatinib) Based on Long-Term Efficacy and Safety Data from Phase 2 PACE Clinical Trial [press release]. https://www.businesswire.com/news/home/20161129005510/en/ARIAD-Announces-FDA-Full-Approval-Label-Update. Updated November 29, 2016. Accessed August 6, 2018.
  4. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome–positive leukemias. N Engl J Med. 2013;369:1783-1796.
  5. Breccia M, Abruzzese E, Castagnetti F, et al. Ponatinib as second-line treatment in chronic phase chronic myeloid leukemia patients in real-life practice. Ann Hematol. 2018;97(9):1577-1580. doi: 10.1007/s00277-018-3337-2