With respect to side effects, bosutinib is known for its gastrointestinal adverse events, and patients on ponatinib are at a risk for arterial occlusive events. Regardless of this, the analysis notes that the rate of discontinuation due to adverse events was not higher for patients on ponatinib even though patients were on therapy for a longer period of time. 

The authors noted that the MAIC (adjusted) data seen with ponatinib were similar to those reported in the initial PACE study (unadjusted) and both sets of data were qualitatively higher than those seen with bosutinib and suggested that the higher responses with ponatinib were not due to baseline differences in the patient populations across the studies.  


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“ … the unprecedented efficacy demonstrated by ponatinib in this difficult-to-treat patient population [in the third-line setting] makes it a therapeutic option to be considered despite its associated increased risk of vascular occlusion,” the authors concluded. They suggested that more patients given third-line ponatinib are likely to have better outcomes with allogeneic hematopoietic stem cell transplantation (alloHSCT) due to better responses seen with this therapy prior to transplant.  

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Clinical Implications 

Until recently, patients with CP CML had 3 first-line treatment options with tyrosine kinase inhibitors (TKIs) — imatinib, dasatinib, and nilotinib. In December 2017, the US Food and Drug Administration (FDA) included bosutinib for first-line treatment based on a major molecular response and major cytogenetic response from the BFORE study.4 

Corresponding author Moshe Yair Levy, MD, the Baylor University Medical Center in Dallas, Texas, explained that this study compares the latter use of ponatinib with bosutinib, and ponatinib is not approved as a first-line therapy in patients with CML. 

Dr Levy explained that CML is a disease that is uniformly deadly in the absence of effective therapy. “For progression on a second-generation TKI, it makes sense to use a drug that offers disease control and [does] not allow for further mutations — and  it is preferable not [to] cycle through all the TKIs,” he said.

“Despite the toxicity challenges associated with the drug, ponatinib offers the best chance of durable responses, and therefore gives the most favorable benefit/risk ratio in this select population,” Dr Levy asserted.

At Baylor, Dr Levy indicated that younger patients or high-risk patients with CML are initially started on a second-generation TKI (nilotinib, dasatinib, or bosutinib). He explained that patients can switch after intolerance or progression and if patients are intolerant to a [previous] TKI, bosutinib may be more appropriate (if they have not received bosutinib first line). However, if patients progress on a previous TKI, then ponatinib may be a better choice. 

“I advocate for changing to ponatinib after progression on a second-generation TKI,” he said. Currently, there are no head-to-head trials between the currently approved TKIs, Dr Levy noted.

Disclosure: Some of the authors of this study have received various fees from pharmaceutical companies. Please refer to the original study for a full list of disclosures.

References

  1. Levy MY, McGarry LJ, Huang H, Lustgarten S, Chiroli S, Iannazzo S. Benefits and risks of ponatinib versus bosutinib following treatment failure of two prior tyrosine kinase inhibitors in patients with chronic phase chronic myeloid leukemia: a matching-adjusted indirect comparison[article published online August 24, 2018:1-9]. Curr Med Res Opin.doi: 10.1080/03007995.2018.1510225
  2. Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failureBlood. 2012;119(15):3403-3412.
  3. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al; PACE Investigators. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemiasN Engl J Med. 2013;369(19):1783-1796.
  4. US Food & Drug Administration. FDA grants accelerated approval to bosutinib for treatment of newly-diagnosed PH+ CML. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm589856.htm. Updated December 19, 2017. Accessed September 9, 2018.