Low‐dose ponatinib is a good option in chronic myeloid leukemia patients intolerant to previous <scp>TKIs</scp>

Iurlo, Alessandra; Cattaneo, Daniele; Malato, Alessandra; Accurso, Vincenzo; Annunziata, Mario; Gozzini, Antonella; Scortechini, Anna Rita; Bucelli, Cristina; Scalzulli, Emilia; Attolico, Imma; Maggi, Alessandro; Martino, Bruno; Caocci, Giovanni; Abruzzese, Elisabetta; Pregno, Patrizia; Luciano, Luigiana; Breccia, Massimo

doi:10.1002/ajh.25908

Cited by 19 publications

(18 citation statements)

References 8 publications

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“…The efficacy and safety profile of low-dose ponatinib in CML patients in chronic phase emerging from real-life observations appears to confirm the results of clinical trials (Table 1) (16)(17)(18)(19)(20)(21)(22)(23)(24). A lower ponatinib starting dose appears to be a beneficial strategy in selected CML patients, such as those intolerant or with a low level of resistance to other TKIs, with reported lower incidences of adverse events, no unexpected adverse events, and efficacy data in line with those from clinical trials.…”

Section: Reported Outcomes With Low-dose Ponatinibsupporting

confidence: 61%

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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Section: Reported Outcomes With Low-dose Ponatinibsupporting

confidence: 61%

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 question of a direct relationship between the doses of TKIs and their efficacy/safety profile is of fundamental importance with regard to ponatinib: in fact, data from both clinical trials and real-life experiences led to the indication to reduce its daily dose in patients who have already achieved at least an MCyR ( 48 , 49 ). Furthermore, considering the high anti-leukemic potency expressed by ponatinib, it is conceivable that lower-dose regimens or full-dose induction followed by dose reduction may also be useful for intolerant patients ( 50 , 51 ).…”

Section: Discussionmentioning

confidence: 99%

Treatment-Free Remission in Chronic Myeloid Leukemia Patients Treated With Low-Dose TKIs: A Feasible Option Also in the Real-Life. A Campus CML Study

et al. 2022

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Treatment-free remission (TFR) has become a primary therapeutic goal in CML and is also considered feasible by international guidelines. TKIs dose reduction is often used in real-life practice to reduce adverse events, although its impact on TFR is still a matter of debate. This study aimed to explore the attitude of Italian hematologists towards prescribing TKIs at reduced doses and its impact on TFR. In September 2020, a questionnaire was sent to 54 hematology centers in Italy participating to the Campus CML network. For each patient, data on the main disease characteristics were collected. Most of the hematologists involved (64.4%) believed that low-dose TKIs should not influence TFR. Indeed, this approach was offered to 194 patients. At the time of TFR, all but 3 patients had already achieved a DMR, with a median duration of 61.0 months. After a median follow-up of 29.2 months, 138 (71.1%) patients were still in TFR. Interestingly, TFR outcome was not impaired by any of the variables examined, including sex, risk scores, BCR-ABL1 transcript types, previous interferon, type and number of TKIs used before treatment cessation, degree of DMR or median duration of TKIs therapy. On the contrary, TFR was significantly better after dose reduction due to AEs; furthermore, patients with a longer DMR duration showed a trend towards prolonged TFR. This survey indicates that low-dose TKI treatment is an important reality. While one third of Italian hematologists still had some uncertainties on TFR feasibility after using reduced doses of TKIs outside of clinical trials, TFR has often been considered a safe option even in patients treated with low-dose TKIs in the real-life setting. It should be noted that only 28.9% of our cases had a molecular recurrence, less than reported during standard dose treatment. Consequently, TFR is not impaired using low-dose TKIs.

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“…The rate of hypertension was higher, between 5 and 19%. On the contrary, the identified articles on ponatinib were mostly retrospective studies (Breccia et al, 2018;Heiblig et al, 2018;Caocci et al, 2019b;Devos et al, 2019;Fava et al, 2019;Binotto et al, 2020;Iurlo et al, 2020), and as expected, they collected data on treatment lines higher than the third. In the clinical trials evaluated, ponatinib was administered as the firstor second-line treatment (Jain et al, 2015;Sanford et al, 2015;Cortes et al, 2018b;clinicaltrials (2021clinicaltrials ( ).…”

Section: Qualitative Analysismentioning

confidence: 94%

Arterial Hypertension and Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A Systematic Review and Meta-Analysis

et al. 2021

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Background: Off-target effects in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs) are associated with cardiovascular toxicity. Hypertension represents an important cardiovascular complication and, if not appropriately managed, can contribute to developing thrombotic events. Third-generation TKI ponatinib is associated with hypertension development, and its use is more restricted than in the past. Few data are reported for second-generation TKI, nilotinib, dasatinib, and bosutinib. The aim of this article was to evaluate with a systematic review and meta-analysis the real incidence of hypertension in CML patients treated with second- or third-generation TKI.Methods: The PubMed database, Web of Science, Scopus, and ClinicalTrials.gov were systematically searched for studies published between January 1, 2000, and January 30, 2021; the following terms were entered in the database queries: Cardiovascular, Chronic Myeloid Leukemia, CML, Tyrosine kinases inhibitor, TKI, and Hypertension. The study was carried out according to the Preferred Reporting Items for Systematic and Meta-Analyses (PRISMA) statement.Results: A pooled analysis of hypertension incidence was 10% for all new-generation TKI, with an even higher prevalence with ponatinib (17%). The comparison with the first-generation imatinib confirmed that nilotinib was associated with a significantly increased risk of hypertension (RR 2; 95% CI; 1.39-2.88, I2=0%, z=3.73, p=0.0002). The greatest risk was found with ponatinib (RR 9.21; 95% CI; 2.86-29.66, z=3.72, p=0.0002).Conclusion: Hypertension is a common cardiovascular complication in CML patients treated with second- or third-generation TKI.

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Low‐dose ponatinib is a good option in chronic myeloid leukemia patients intolerant to previous TKIs

Cited by 19 publications

References 8 publications

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

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

Treatment-Free Remission in Chronic Myeloid Leukemia Patients Treated With Low-Dose TKIs: A Feasible Option Also in the Real-Life. A Campus CML Study

Arterial Hypertension and Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A Systematic Review and Meta-Analysis

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