Ponatinib in the Treatment of Chronic Myeloid Leukemia and Philadelphia Chromosome-Positive Acute Leukemia: Recommendations of a German Expert Consensus Panel with Focus on Cardiovascular Management

Saußele, Susanne; Haverkamp, Wilhelm; Lang, Fabian; Koschmieder, Steffen; Kiani, Alexander; Jentsch-Ullrich, Kathleen; Stegelmann, Frank; Pfeifer, Heike; Rosée, Paul La; Goekbuget, Nicola; Rieger, Christina; Waller, Christiane; Franke, Georg‐Nikolaus; Coutre, Philipp le; Kirchmair, Rudolf; Junghanß, Christian

doi:10.1159/000501927

Cited by 34 publications

(33 citation statements)

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“…Several mechanisms have been hypothesized to explain the ponatinib-induced toxicity profile, i.e., the simultaneous inhibition of cardiovascular-related kinases [ 11 ], but further studies are needed to fully characterize the ponatinib signaling pathway. It is of interest to understand why the extent of the ponatinib-induced cardiotoxicity observed among the patients is uneven [ 12 ], and whether it is sex-related.…”

Section: Introductionmentioning

confidence: 99%

“…The Notch1 signaling influences multiple cell processes including differentiation, proliferation, apoptosis, migration, and angiogenesis. Notch1 has been shown to have both tumor suppressive and tumorigenic functions in different contexts [ 12 ]. Interestingly, it has been recently shown that a selective blockade of Notch1 can prevent vascular toxicity induced by ponatinib in human aortic endothelial cells [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Connexin 43 and Connexin 26 Involvement in the Ponatinib-Induced Cardiomyopathy: Sex-Related Differences in a Murine Model

Madonna

Moscato

Polizzi

et al. 2021

IJMS

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Cardiac connexins (Cxs) are proteins responsible for proper heart function. They form gap junctions that mediate electrical and chemical signalling throughout the cardiac system, and thus enable a synchronized contraction. Connexins can also individually participate in many signal transduction pathways, interacting with intracellular proteins at various cellular compartments. Altered connexin expression and localization have been described in diseased myocardium and the aim of this study is to assess the involvement of Cx43, Cx26, and some related molecules in ponatinib-induced cardiac toxicity. Ponatinib is a new multi-tyrosine kinase inhibitor that has been successfully used against human malignancies, but its cardiotoxicity remains worrisome. Therefore, understanding its signaling mechanism is important to adopt potential anti cardiac damage strategies. Our experiments were performed on hearts from male and female mice treated with ponatinib and with ponatinib plus siRNA-Notch1 by using immunofluorescence, Western blotting, and proteomic analyses. The altered cardiac function and the change in Cxs expression observed in mice after ponatinib treatment, were results dependent on the Notch1 pathway and sex. Females showed a lower susceptibility to ponatinib than males. The downmodulation of cardiac Cx43, Cx26 and miR-122, high pS368-Cx43 phosphorylation, cell viability and survival activation could represent some of the female adaptative/compensatory reactions to ponatinib cardiotoxicity.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Connexin 43 and Connexin 26 Involvement in the Ponatinib-Induced Cardiomyopathy: Sex-Related Differences in a Murine Model

Madonna

Moscato

Polizzi

et al. 2021

IJMS

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“…The advent of TKIs in the 2000s radically changed the fate of CML, since imatinib (IM), before, and nilotinib (NIL), dasatinib (DAS) or bosutinib (BOS), after, showed to be able to prevent the disease blastic transformation and significantly prolong the survival [ 20 , 21 , 22 , 23 ]. Achieving such a goal in up to 90% of the patient population treated first line with TKIs could mean that cure of CML have been finally achieved, but this is not completely true.…”

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confidence: 99%

Chronic Myeloid Leukemia Prognosis and Therapy: Criticisms and Perspectives

Russo

Garcia-Gutierrez

Soverini

et al. 2020

JCM

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Ph+ chronic myeloid leukemia (CML) is a clonal myeloproliferative disease whose clinical course is characterized by progression disease from the early chronic phase (CP) to the fatal blastic phase (BP). This programmed course is closely related to the translocation t(9;22)(q22;q11) and the resulting BCR-ABL1 fusion protein (p210) that drives the leukemic transformation of hematopoietic stem cells. Therefore, the cure of CML can only pass through the abrogation of the Ph+ clone. Allogeneic stem cell transplantation (allo-SCT) and interferon-alpha (IFNα) have been proven to reduce the Ph+ clone in a limited proportion of CML population and this translated in a lower rate of progression to BP and in a significant prolongation of survival. Tyrosine-kinase inhibitors (TKIs), lastly introduced in 2000, by preventing the disease blastic transformation and significantly prolonging the survival in up to 90% of the patient population, radically changed the fate of CML. The current therapy with TKIs induces a chronicization of the disease but several criticisms still persist, and the most relevant one is the sustainability of long-term therapy with TKIs in terms of compliance, toxicity and costs. The perspectives concern the optimization of therapy according to the age, the risk of disease, the potency and the safety profiles of the TKIs. The prolongation of survival is the most important end point which should be guaranteed to all patients. The treatment free remission (TFR) is the new goal that we would like to give to an increasing number of patients. The cure remains the main objective of CML therapy.

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“…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 ).…”

Section: Suggested Strategies For Initiating Treatment With Ponatinibmentioning

confidence: 99%

Dosing Strategies for Improving the Risk-Benefit Profile of Ponatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase

et al. 2021

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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.

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Ponatinib in the Treatment of Chronic Myeloid Leukemia and Philadelphia Chromosome-Positive Acute Leukemia: Recommendations of a German Expert Consensus Panel with Focus on Cardiovascular Management

Cited by 34 publications

References 50 publications

Connexin 43 and Connexin 26 Involvement in the Ponatinib-Induced Cardiomyopathy: Sex-Related Differences in a Murine Model

Connexin 43 and Connexin 26 Involvement in the Ponatinib-Induced Cardiomyopathy: Sex-Related Differences in a Murine Model

Chronic Myeloid Leukemia Prognosis and Therapy: Criticisms and Perspectives

Dosing Strategies for Improving the Risk-Benefit Profile of Ponatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase

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