Abstract
The treatment of chronic myeloid leukemia (CML) has been advanced by the development of small-molecule tyrosine kinase inhibitors (TKIs), which target the fusion protein BCR-ABL1 expressed by the Philadelphia chromosome. Ponatinib is a 3rd generation TKI that binds BCR-ABL1 with high affinity and inhibits most BCR-ABL1 mutants, including the T315I mutation. The approved starting dose of ponatinib is 45 mg once daily (full dose), however, the need for a full dose, especially in patients with dose adjustments due to tolerability problems, remains undemonstrated. Lower starting doses of ponatinib (30 mg or 15 mg once daily) for patients “with lesser degrees of resistance or multiple intolerances, especially those with an increased cardiovascular risk profile” has been recommended by the 2020 European LeukemiaNet. However, the available literature and guidance on the use of ponatinib at low dosage are limited. The objective of this paper is to describe how we select ponatinib dosage for CML patients in chronic phase in our clinical practice based on the available evidence and our clinical experience. We propose dosing regimens for the optimal starting dose for six generic cases of CML patients in chronic phase eligible for the switch to ponatinib and provide an algorithm to guide ponatinib dosing during treatment.
Highlights
The development, over the past two decades, of small-molecule tyrosine kinase inhibitors (TKIs) targeting the fusion protein BCR-ABL1 expressed by the Philadelphia chromosome (Ph) has considerably advanced the treatment of chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL)
Based on the initial efficacy results of the pivotal phase 2 PACE (Ponatinib Ph+ ALL and CML Evaluation) trial [2], ponatinib was approved in December 2012 by the United States Food and Drug Administration (FDA) via an accelerated approval program [4]
Our experience in the treatment of CML, in the following practice-oriented section we propose dosing regimens for initiating ponatinib in eligible patients and provide an algorithm for guiding ponatinib dosing during treatment
Summary
The development, over the past two decades, of small-molecule tyrosine kinase inhibitors (TKIs) targeting the fusion protein BCR-ABL1 expressed by the Philadelphia chromosome (Ph) has considerably advanced the treatment of chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL). An indirect comparison between the PACE trial (n=257) and the 45 mg starting dose of the OPTIC IA (n=93), recently presented at the 2020 ASH Meeting, confirmed that a prompt dose reduction to 15 mg after achievement of MR2 does not jeopardize the efficacy of ponatinib and remarkably reduced the incidence of treatment-emergence arterial occlusive events [15] Both PACE and the OPTIC IA showed an increase over time in the ≤1% BCR-ABL1 response rate (from 42.0% to 47.1%, respectively, at 12 and 60 months for PACE, and from 47.3% to 51.6%, respectively, at 12 and 24 months in the OPTIC IA). Recent recommendations from a German expert consensus panel on ponatinib proposed the following criteria supporting a ponatinib starting dose of 30 mg/day in CML patients: chronic phase, good response status, no mutations, resistance to only one TKI, intolerance despite good response, and increased cardiovascular risk [35]. The strategy to start ponatinib at doses lower than 45 mg/day should be guided by a thorough evaluation of risk factors, as well as the depth and stability of molecular response, and total exposure to ponatinib; continued monitoring of response is highly recommended [26]
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