Κυριακή, 14 Φεβρουαρίου 2016

NEXT GENERATION TKIs FOR CML INCREASE CARDIOVASCULAR RISK

NEW YORK (Reuters Health) - Some new-generation BCR-ABL tyrosine kinase inhibitors (TKIs) may improve major molecular response (MMR) in patients with chronic myeloid leukemia (CML) at one year, but not overall survival, according to a new systematic review and meta-analysis.
The main result of the analysis "is that dasatinib, nilotinib, and ponatinib are associated with a higher rate of vascular occlusive events than imatinib. A trend was observed with bosutinib. Therefore, we suggest that treatment with these TKIs should be associated with frequent cardiovascular monitoring and an intensive support of comorbidities," lead author Dr. Jonathan Douxfils, of the University of Namur in Belgium, told Reuters Health by email.
Dr. Douxfils and colleagues assessed the risk of vascular occlusive events in patients with CML treated with newer TKIs compared with imatinib, as reported in 10 randomized clinical trials involving more than 3,000 patients.
Vascular occlusive events occurred in 5.88% of the patients treated with newer TKIs, compared with 1.04% of patients treated with imatinib. Overall new generation TKIs were associated with a significantly higher risk of events (odds ratio, 3.45).
The researchers found significantly increased risks of vascular occlusive events for dasatinib (OR, 3.86), nilotinib (OR, 3.42), ponatinib (OR, 3.47), but not bosutinib, compared with imatinib, the standard of care.
They found that newer TKIs overall increased the rate of MMR at one year with a significant OR of 2.22, but did not lead to significant improvement in overall survival.
"We did not have access to individual data," Dr. Douxfils said. "It was therefore impossible to identify categories of patients for whom the risk of cardiovascular occlusive events is predominant. We suggest that specific cardiovascular monitoring should be applied to all patients treated with these molecules.
"The physician should certainly consider the goals of the treatment," he explained. "For elderly patients, improving survival is the main objective and in this context, imatinib remains an excellent choice. For patients with a life expectancy greater than 10 years in whom we aim to achieve a molecular response to potentially reach a point of treatment cessation, dasatinib and nilotinib could be preferred."
"However, the choice of dasatinib or nilotinib as first-line treatments should also involve a screening for potential risk factors and other underlying conditions such as diabetes, prior vascular occlusive events or any risk that could increase these adverse events," Dr. Douxfils added.
The new analysis builds on a previous study in which researchers looked into events reported to the Food and Drug Administration adverse event reporting system regarding BCR-ABL inhibitor-treated patients (http://bit.ly/1PaZMPO).
"I would say the most important message is to emphasize the need to report serious adverse events encountered during clinical use of these drugs so that we can have a better understanding of the type and frequency of different adverse events in standard practice," lead author of that study Dr. Jorge Cortes, of the University of Texas M.D. Anderson Cancer Center, Houston, told Reuters Health by email.
"This is important because what is reported in clinical trials may not fully reflect what is seen in standard practice because of patient selection, length of follow-up, and other factors," he said.
Another coauthor of the FDA-reporting study, Dr. Michael A. Mauro, of Memorial Sloan Kettering Cancer Center in New York, told Reuters Health by email, "As we study and gather reporting on adverse events for the most commonly used TKIs for chronic myeloid leukemia and other diseases, patterns have developed and categories of more serious complications such as cardiovascular and cardiopulmonary toxicity are linked to these medications. Physicians need to be aware of the type of complications, which medication is more likely to cause such effects, and how to manage them given that continued treatment for patients' leukemia is necessary."
"We need mechanism-based preclinical and clinical studies to unravel the reasons why these highly effective and relatively safe drugs cause select side effects so as to better risk-stratify patients and mitigate risk," Dr. Mauro said.
In perspective, however, he added, "although such medicines (TKIs in CML) have risk, they continue to set a new standard for smarter, safer and more patient-friendly ways of treating dangerous conditions like leukemia, and in comparison to prior therapies have represented a major paradigm shift."
The authors reported no external funding, though two declared relationships with pharmaceutical companies.
SOURCE: http://bit.ly/1nLEuiy
JAMA Oncol 2016.

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