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. 2020 Feb 11;4(3):530-538.
doi: 10.1182/bloodadvances.2019000268.

Side-effects profile and outcomes of ponatinib in the treatment of chronic myeloid leukemia

Onyee Chan  1   2 , Chetasi Talati  2 , Leidy Isenalumhe  2 , Samantha Shams  1   2 , Lisa Nodzon  2 , Michael Fradley  3 , Kendra Sweet  2 , Javier Pinilla-Ibarz  2
Affiliations

Side-effects profile and outcomes of ponatinib in the treatment of chronic myeloid leukemia

Onyee Chan et al. Blood Adv. .

Abstract

Ponatinib is associated with cardiovascular adverse events (CAEs), and its frequency in the real world is limited. In this retrospective study, we examined the survival outcomes and associated toxicities in 78 consecutive ponatinib-treated patients with chronic myeloid leukemia (CML) at the Moffitt Cancer Center from January 2011 through December 2017. The most common non-CAE was thrombocytopenia (39.7%), occurring in a dose-dependent fashion. Eighteen patients (23.1%) experienced some form of CAE, with the most common being arrhythmia (9%) and hypertension (7.7%), whereas 3 patients experienced myocardial infarction (3.8%). Before 2014, most patients were started on ponatinib 45 mg daily. There was an inverse correlation between cardio-oncology referral and the number of CAEs (P = .0440); however, a lower ponatinib starting dose, more frequent dose reduction, and increased cardio-oncology referral all were likely to have contributed to the observed decrease in CAEs after 2014. The response rate and 5-year overall survival (OS) were higher than those observed in the Ponatinib Ph+ ALL and CML Evaluation (PACE) trial (major molecular response, 58.7% vs 40% and OS, 76% vs 73%; median follow-up of 32.5 months). Ponatinib-treated patients with chronic phase-CML did not show a significant improvement with allogeneic stem cell transplantation, whereas those with accelerated phase/blast phase-CML had a much better outcome (median OS of 32.9 months vs 9.2 months; P = .01). These results demonstrate that ponatinib is highly effective. Dose adjustments and increased awareness of the cardiotoxicities associated with ponatinib may help maximize its benefits.

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Conflict of interest statement

Conflict-of-interest disclosure: J.P.-I. has received honoraria for consulting from Novartis and Bristol-Myers Squibb and is on the speakers bureau of Takeda. K.S. has received honoraria from Novartis for consulting and is on its speakers bureau. L.N. is on the speakers bureau of Novartis and has received a consulting fee from Pfizer. M.F. has received honoraria from Novartis for consulting. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Frequency of adverse events in ponatinib-treated patients. (A) New-onset non-CAEs increased in a ponatinib dose-dependent fashion. (B) New-onset CAEs were fewer in comparison with non-CAEs. The most common CAEs were arrhythmia and hypertension.
Figure 2.
Figure 2.
Cardiac safety profile of ponatinib with its associated dosing and frequency of cardio-oncology referral over time. The reason for the decrease in incidence of CAEs since 2014 is multifactorial, including heightened awareness of cardiovascular risks, with ponatinib treatment leading to increased cardio-oncology referrals, shorter time to ponatinib dose reduction when clinically indicated, and lower starting dose. Pre-2014 patients with CAE(s): 10 of 37 (28.0%); post-2014 CAE(s): 8 of 14 (19.5%).
Figure 3.
Figure 3.
Outcomes of CML patients treated with ponatinib. (A) OS since ponatinib initiation was significantly better for CP-CML patients compared with AP patients, with a 5-year OS of 76.8% and median OS of 20.8 months, respectively. (B) Overall survival since ponatinib initiation, by SCT status. allo-SCT conferred a significant benefit in AP patients, but the response was not found in CP-CML patients.
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Comment in

  • Poor tolerability to ponatinib in Indian CML patients.
    Singh C, Jain A, Lad D, Prakash G, Khadwal A, Bhurani D, Ahmed R, Agrawal N, Easow J, Varma N, Malhotra P. Singh C, et al. Blood Adv. 2020 May 12;4(9):1927-1929. doi: 10.1182/bloodadvances.2020001944. Blood Adv. 2020. PMID: 32380534 Free PMC article. No abstract available.

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