title: Impact of dose intensity of ponatinib on selected adverse events: Multivariate analyses from a pooled population of clinical trial patients.
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.
authors: ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA, 02139-4234, USA. Electronic address: david.dorer@ariad.com.
authors: David J
authors: DJ
authors: Dorer
authors: ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA, 02139-4234, USA. Electronic address: ronald.knickerbocker@ariad.com.
authors: Ronald K
authors: RK
authors: Knickerbocker
authors: Department of Hematology and Oncology, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy. Electronic address: michele.baccarani@unibo.it.
authors: Michele
authors: M
authors: Baccarani
authors: Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 428, 77030, Houston, TX, USA. Electronic address: jcortes@mdanderson.org.
authors: Jorge E
authors: JE
authors: Cortes
authors: Department of Hematology and Medical Oncology, Jena University Hospital, Erlanger Allee 101, 07747, Jena, Germany. Electronic address: andreas.hochhaus@med.uni-jena.de.
authors: Andreas
authors: A
authors: Hochhaus
authors: Division of Hematology/Oncology, Comprehensive Cancer Center, University of Michigan, 1500 East Medical Center Drive, Room 4302, Ann Arbor, MI, 48109-5936, USA. Electronic address: mtalpaz@med.umich.edu.
authors: Moshe
authors: M
authors: Talpaz
authors: ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA, 02139-4234, USA. Electronic address: frank.haluska@ariad.com.
authors: Frank G
authors: FG
authors: Haluska
mesh_terms: D002986:Clinical Trials as Topic; D005076:Exanthema / Q000139:chemically induced; D006333:Heart Failure / Q000139:chemically induced; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000150:complications / Q000188:drug therapy*; D008875:Middle Aged; D015999:Multivariate Analysis; D010195:Pancreatitis / Q000139:chemically induced; D011724:Pyridazines / Q000008:administration & dosage / Q000009:adverse effects*; D013997:Time Factors
chemical_list: D007093:Imidazoles; D011724:Pyridazines; C545373:ponatinib
keywords: BCR-ABL1; Chronic myeloid leukemia; Dose intensity; Philadelphia chromosome; Ponatinib; Tyrosine kinase inhibitor