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Year : 2020  |  Volume : 3  |  Issue : 1  |  Page : 138-139

Ponatinib: Harnessing the elixir potential

Department of Haemato-Oncology, Kingston Hospital NHS Foundation Trust; Lead for Commercial Education and Training, Haematology Institute, King's College Health Partners; King's College, London, UK

Date of Submission13-Jan-2020
Date of Acceptance13-Jan-2020
Date of Web Publication24-Feb-2020

Correspondence Address:
Vishal Jayakar
Kingston Hospital, Kingston upon the Thames, London
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_20_20

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How to cite this article:
Jayakar V. Ponatinib: Harnessing the elixir potential. Cancer Res Stat Treat 2020;3:138-9

How to cite this URL:
Jayakar V. Ponatinib: Harnessing the elixir potential. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Jul 12];3:138-9. Available from: http://www.crstonline.com/text.asp?2020/3/1/138/279098

In this painstakingly thorough and meticulous drug review,[1] the authors provide an up-to-date evidence-based monograph on ponatinib.

The mechanism of its action could have been explained better and figuratively. The T315I mutation deposits a bulky isoleucine amino acid residue in the BCR-ABL oncogene pocket near-completely blocking it, making it challenging and impossible for the first- and second-generation tyrosine kinase inhibitors (TKIs) to navigate through this tight pocket. Ponatinib, with its gracile neck-like structure, is the only TKI that can circumnavigate this gridlock displacing the isoleucine residue;, therefore, breaking the T315I impasse.[2]

Although the authors describe the phase II trial involving the combination of ponatinib with hyper CVAD in Philadelphia-positive (Ph pos) acute lymphoblastic leukemia (ALL)[3] in detail, I want to register the growing enthusiasm and promise surrounding chemotherapy-free regimens in combination with ponatinib in the treatment of de novo Ph pos ALL– TKI. The D-ALBA study utilizing dasatinib with blinatumomab in Ph pos ALL with promising results was presented as a late-breaking abstract at the ASH 2019 congress.[4] The results of ponatinib with blinatumomab in a similar disease cohort are eagerly awaited.

Learning to personalize the ponatinib doses (15–45 mg/day) to the patient narratives with pragmatic reductions and de-escalation commensurate to their cardiovascular/atherosclerotic risk status, rather than a “one size fits all”-blanket approach, seems to be the sensible way forward to mitigate toxicity.

The future truly lies in its judicious dosing and combination with chemo-free constructs in this historically “difficult to treat” cohort of Ph pos ALL.

Ponatinib's most exciting indication is likely to find its niche in these chemo-free combinations (immune checkpoint inhibitors and chimeric antigen receptor T-cells) rather than its single-agent use.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Jain H, Thorat J, Sengar M, Dubey A. Ponatinib: A drug review. Cancer Res Stat Treat 2019;2:190-6.  Back to cited text no. 1
  [Full text]  
Wehrle J, von Bubnoff N. Ponatinib: A third-generation inhibitor for the treatment of CML. Recent Results Cancer Res 2018;212:109-18.  Back to cited text no. 2
Jabbour E, Short NJ, Ravandi F, Huang X, Daver N, DiNardo CD, et al. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: Long-term follow-up of a single-centre, phase 2 study. Lancet Haematol 2018;5:e618-27.  Back to cited text no. 3
Bassan R, Vitale A, Elia L, Piciocchi A, Puzzolo C, Canichella M, et al. Dasatinib-Blinatumomab Combination for the Front-Line Treatment of Adult Ph+ ALL Patients. Updated Results of the Gimema LAL2116 D-Alba Trial. Blood 2019;134 (Supplement_1):740.  Back to cited text no. 4


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