TY - JOUR
T1 - Ponatinib as first-line treatment for patients with chronic myeloid leukaemia in chronic phase
T2 - A phase 2 study
AU - Jain, Preetesh
AU - Kantarjian, Hagop
AU - Jabbour, Elias
AU - Gonzalez, Graciela Nogueras
AU - Borthakur, Gautam
AU - Pemmaraju, Naveen
AU - Daver, Naval
AU - Gachimova, Evguenia
AU - Ferrajoli, Alessandra
AU - Kornblau, Steven
AU - Ravandi, Farhad
AU - O'Brien, Susan
AU - Cortes, Jorge
N1 - Funding Information:
This study was supported in part by the MD Anderson Cancer Center Support Grant CA016672 and Award Number P01 CA049639 from the National Cancer Institute (National Institutes of Health) . ARIAD Pharmaceuticals provided free drug and financial support for the study from the ponatinib investigator sponsored trial programme.
Funding Information:
The study was sponsored by MD Anderson Cancer Center. ARIAD Pharmaceuticals provided drug and partial financial support for the study from the ponatinib investigator sponsored trial programme. JC and HK designed the trial. ARIAD Pharmaceuticals reviewed and provided comments on the design of the study but did not collect, analyse, or interpret data, nor did they participate in the writing of the manuscript other than acknowledgment of the final version of the manuscript. The corresponding author had full access to all of the data and the final responsibility to submit for publication. All authors had access to the raw data.
Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.
PY - 2015
Y1 - 2015
N2 - BACKGROUND: Ponatinib has shown efficacy in patients with refractory chronic myeloid leukaemia (CML) and in those with CML with a Thr315Ile mutation. We aimed to investigate the activity and safety of ponatinib as first-line treatment for patients with chronic-phase CML. METHODS: We did a single-arm, phase 2 trial at MD Anderson Cancer Center in Houston, TX, USA. Between May 3, 2012, and Sept 24, 2013, we enrolled patients with early (<6 months) chronic-phase CML and treated them with oral ponatinib once a day. Patients enrolled before July 25, 2013, were given a starting dose of 45 mg per day; we lowered this due to tolerability issues and patients enrolled after this date were given a starting dose of 30 mg per day. After a warning by the US Food and Drug Administration (FDA) in Oct 6, 2013, for vascular complications with ponatinib, we started all patients on aspirin 81 mg daily and reduced the dose of ponatinib to 30 mg or 15 mg per day for all patients. The primary endpoint was the proportion of patients who achieved complete cytogenetic response by 6 months in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01570868. FINDINGS: We enrolled 51 patients. Median follow-up was 20·9 months (IQR 14·9-25·2). 43 patients were started on 45 mg ponatinib every day; eight patients were started on 30 mg per day. 43 (94%) of 46 evaluable patients achieved complete cytogenetic response at 6 months. Most frequent toxicities included skin-related effects (n=35; 69%) and elevated lipase (n=32; 63%). Cardiovascular events (mainly hypertension) occurred in 25 (49%) patients. Grade 3-4 myelosuppression occurred in 15 (29%) patients. Five (10%) patients developed cerebrovascular or vaso-occlusive disease. 43 (85%) patients needed treatment interruptions at some time and 45 (88%) needed dose reductions. The study was terminated June 18, 2014, at the recommendation of the FDA due to concern about the increased risk of thromboembolism with ponatinib. INTERPRETATION: Patients with newly diagnosed CML in chronic phase respond well to treatment with ponatinib, with most achieving a complete cytogenetic response. Dose adjustment, extensive monitoring, and counselling of the patients for thromboembolic events is needed for patients on ponatinib therapy. However, due to the risk of vascular thrombotic events and the availability of alternative options for these patients, other drugs should be considered first in the frontline setting. FUNDING: MD Anderson Cancer Center, National Cancer Institute, ARIAD Pharmaceutical.
AB - BACKGROUND: Ponatinib has shown efficacy in patients with refractory chronic myeloid leukaemia (CML) and in those with CML with a Thr315Ile mutation. We aimed to investigate the activity and safety of ponatinib as first-line treatment for patients with chronic-phase CML. METHODS: We did a single-arm, phase 2 trial at MD Anderson Cancer Center in Houston, TX, USA. Between May 3, 2012, and Sept 24, 2013, we enrolled patients with early (<6 months) chronic-phase CML and treated them with oral ponatinib once a day. Patients enrolled before July 25, 2013, were given a starting dose of 45 mg per day; we lowered this due to tolerability issues and patients enrolled after this date were given a starting dose of 30 mg per day. After a warning by the US Food and Drug Administration (FDA) in Oct 6, 2013, for vascular complications with ponatinib, we started all patients on aspirin 81 mg daily and reduced the dose of ponatinib to 30 mg or 15 mg per day for all patients. The primary endpoint was the proportion of patients who achieved complete cytogenetic response by 6 months in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01570868. FINDINGS: We enrolled 51 patients. Median follow-up was 20·9 months (IQR 14·9-25·2). 43 patients were started on 45 mg ponatinib every day; eight patients were started on 30 mg per day. 43 (94%) of 46 evaluable patients achieved complete cytogenetic response at 6 months. Most frequent toxicities included skin-related effects (n=35; 69%) and elevated lipase (n=32; 63%). Cardiovascular events (mainly hypertension) occurred in 25 (49%) patients. Grade 3-4 myelosuppression occurred in 15 (29%) patients. Five (10%) patients developed cerebrovascular or vaso-occlusive disease. 43 (85%) patients needed treatment interruptions at some time and 45 (88%) needed dose reductions. The study was terminated June 18, 2014, at the recommendation of the FDA due to concern about the increased risk of thromboembolism with ponatinib. INTERPRETATION: Patients with newly diagnosed CML in chronic phase respond well to treatment with ponatinib, with most achieving a complete cytogenetic response. Dose adjustment, extensive monitoring, and counselling of the patients for thromboembolic events is needed for patients on ponatinib therapy. However, due to the risk of vascular thrombotic events and the availability of alternative options for these patients, other drugs should be considered first in the frontline setting. FUNDING: MD Anderson Cancer Center, National Cancer Institute, ARIAD Pharmaceutical.
UR - http://www.scopus.com/inward/record.url?scp=84954204455&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84954204455&partnerID=8YFLogxK
U2 - 10.1016/S2352-3026(15)00127-1
DO - 10.1016/S2352-3026(15)00127-1
M3 - Article
C2 - 26436130
AN - SCOPUS:84954204455
SN - 2352-3026
VL - 2
SP - e376-e383
JO - The Lancet Haematology
JF - The Lancet Haematology
IS - 9
ER -
