Impact of dose intensity of ponatinib on selected adverse events: Multivariate analyses from a pooled population of clinical trial patients. (September 2016)

• Record Type: Journal Article
• Authors: Dorer, David J.; Knickerbocker, Ronald K.; Baccarani, Michele; Cortes, Jorge E.; Hochhaus, Andreas; Talpaz, Moshe; Haluska, Frank G.
• Is Part Of: Leukemia research. Volume 48(2016:Sep.)
• Page Start: 84
• Page End: 91
• Publication Date: 2016-09
• Subjects: BCR-ABL1 -- Chronic myeloid leukemia -- Dose intensity -- Philadelphia chromosome -- Ponatinib -- Tyrosine kinase inhibitor; Leukemia -- Periodicals; Leukemia -- Periodicals; Leucémie -- Périodiques; Leukemia; Periodicals; Electronic journals; Electronic journals; 616.9941905
• DOI: 10.1016/j.leukres.2016.07.007
• Languages: English
• ISSNs: 0145-2126

Abstract

Highlights: Ponatinib dose intensity was shown to be associated with rates of adverse events. Pancreatitis, rash, and cardiac failure were most strongly associated with dose. Time-to-event analyses suggest a lag between changes in dose and event risk. No association between dose intensity and venous thromboembolic events was evident. Results support investigating approaches to lower average ponatinib dose intensity. Abstract: Ponatinib is approved for adults with refractory chronic myeloid leukemia or Philadelphia chromosome–positive acute lymphoblastic leukemia, including those with the T315I BCR-ABL1 mutation. We pooled data from 3 clinical trials (N = 671) to determine the impact of ponatinib dose intensity on the following adverse events: arterial occlusive events (cardiovascular, cerebrovascular, and peripheral vascular events), venous thromboembolic events, cardiac failure, thrombocytopenia, neutropenia, hypertension, pancreatitis, increased lipase, increased alanine aminotransferase, increased aspartate aminotransferase, rash, arthralgia, and hypertriglyceridemia. Multivariate analyses allowed adjustment for covariates potentially related to changes in dosing or an event. Logistic regression analysis identified significant associations between dose intensity and most events after adjusting for covariates. Pancreatitis, rash, and cardiac failure had the strongest associations with dose intensity (odds ratios >2). Time-to-event analyses showed significant associations between dose intensity and risk of arterial occlusive events and each subcategory. Further, these analyses suggested that a lag exists between a change in dose and the resulting change in event risk. No significant association between dose intensity and risk of venous thromboembolic events was evident. Collectively, these findings suggest a potential causal relationship between ponatinib dose and certain adverse events and support prospective investigations of approaches to lower average ponatinib dose intensity.