Spotlight on ponatinib in the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia: patient selection and perspectives

Abstract

Ponatinib, a third-generation tyrosine kinase inhibitor that inhibits BCR/ABL independent of the mutation status, is currently approved for the treatment of patients with chronic myeloid leukemia or acute lymphoblastic leukemia that are either resistant or unable to tolerate another tyrosine kinase inhibitor. Its US Food and Drug Administration approval was based on results from long-term follow-up of the pivotal Phase II PACE trial, which demonstrated deep and durable molecular responses in the treated patients. Despite the remarkable responses, ponatinib has been associated with high frequency of severe vascular events, which led to its withdrawal from the market in 2013. Following analysis of the risk factors of patients who developed vascular side effects, ponatinib was reintroduced in the market 1 year later with specific dose-reduction recommendations and carrying a black box warning. Thus, careful patient selection with identification of patients whose potential benefit from ponatinib exceeds the potential risks associated with its use is crucial. Ongoing and future studies are focusing on earlier detection of mutations, strategies to minimize side effects, and potential expansion of the treatment indications. Clinical trials testing the safety and efficacy of ponatinib as frontline therapy are ongoing.

Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1

“…Inhibiting the kinase activity of BCR-ABL1 by targeting its ATP-binding site with drugs such as imatinib (Gleevec), dasatinib (Sprycel), nilotinib (Tasigna), and bosutinib (Bosulif) greatly reduces leukemic tumor burden and increases the overall survival rate of CML patients, thereby validating ABL1 as a target for therapeutic intervention for this disease. − With such targeted tyrosine kinase inhibitors (TKIs), the majority of chronic phase CML patients continuously treated according to current guidelines have a normal life expectancy . However, despite the success of these drugs in transforming the prognosis of a fatal malignancy, some patients suffer from either poor initial response, loss of response, or tolerability issues. , Loss of response is frequently associated with drug resistance, which can emerge when clones harboring mutations in the BCR-ABL1 kinase (BCR-ABL1 mut ) that hinder TKI binding expand to further drive the disease. , Of these mutations the one harboring a substitution of the threonine T315 to isoleucine (BCR-ABL1 T315I ) is only inhibited by ponatinib (Iclusig), the dosing of which is limited by adverse events . Many of the adverse events recorded for TKIs that lead to tolerability issues in CML patients result from off-target activities, and consequently a drug that specifically targeted ABL kinase activity would probably have fewer side effects.…”

“…10,11 Of these mutations the one harboring a substitution of the threonine T315 to isoleucine (BCR-ABL1 T315I ) is only inhibited by ponatinib (Iclusig), the dosing of which is limited by adverse events. 18 Many of the adverse events recorded for TKIs that lead to tolerability issues in CML patients result from off-target activities, and consequently a drug that specifically targeted ABL kinase activity would probably have fewer side effects.…”

Differentiation of imatinib -resistant chronic myeloid leukemia cells with BCR-ABL-T315I mutation induced by Jiyuan Oridonin A

“…Ponatinib was clinically effective against the T315I mutation [16]. However, ponatinib treatment accompanied by adverse side effects limited its clinical utility [17]. Fortunately, asciminib was approved by the US FDA to treat CML patients who treated with two prior TKIs or with BCR-ABL-T315I mutation in 2021.…”

A review of the therapeutic role of the new third-generation TKI olverembatinib in chronic myeloid leukemia

“…If disease progresses to AP or BP during TKI treatment, we recommend choosing third-generation TKIs, bone marrow transplantation or experimental treatment ( 44 ). In CML patients with the BCR-ABL1 T315I mutation, the third-generation TKIs ponatinib and asciminib are preferentially recommended ( 45 ). Nevertheless, there is no consensus about the choice of treatment strategy.…”