Abstract
Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1T315I. The pivotal phase 2 Ponatinib Ph1 ALL and CML Evaluation (PACE) trial evaluated efficacy and safety of ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) resistant/intolerant to dasatinib or nilotinib, or with BCR-ABL1T315I. This analysis focuses on chronic-phase CML (CP-CML) patients (n 5 270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and 4.5-log molecular response, respectively. The probability of maintaining MCyR for 5 years was 82% among responders. Dose reductions were implemented in October 2013 to decrease the risk of arterial occlusive events (AOEs); ‡90% of CP-CML patients who had achieved MCyR or MMR maintained response 40 months after elective dose reductions. Estimated 5-year overall survival was 73%. In CP-CML patients, the most common treatment-emergent adverse events were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). The cumulative incidence of AOEs in CP-CML patients increased over time to 31%, while the exposure-adjusted incidence of new AOEs (15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively) did not increase over time. These final PACE results demonstrate ponatinib provides durable and clinically meaningful responses, irrespective of dose reductions, in this population of heavily pretreated CP-CML patients. This trial was registered at www.clinicaltrials.gov as #NCT01207440.
| Original language | English |
|---|---|
| Pages (from-to) | 393-404 |
| Number of pages | 12 |
| Journal | Blood |
| Volume | 132 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published or Issued - 26 Jul 2018 |
ASJC Scopus subject areas
- Biochemistry
- Immunology
- Hematology
- Cell Biology
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Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia : final 5-year results of the phase 2 PACE trial. / Cortes, Jorge E.; Kim, Dong Wook; Pinilla-Ibarz, Javier; le Coutre, Philipp D.; Paquette, Ronald; Chuah, Charles; Nicolini, Franck E.; Apperley, Jane F.; Khoury, H. Jean; Talpaz, Moshe; DeAngelo, Daniel J.; Abruzzese, Elisabetta; Rea, Delphine; Baccarani, Michele; Müller, Martin C.; Gambacorti-Passerini, Carlo; Lustgarten, Stephanie; Rivera, Victor M.; Haluska, Frank G.; Guilhot, François; Deininger, Michael W.; Hochhaus, Andreas; Hughes, Timothy; Shah, Neil P.; Kantarjian, Hagop M.
In: Blood, Vol. 132, No. 4, 26.07.2018, p. 393-404.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia
T2 - final 5-year results of the phase 2 PACE trial
AU - Cortes, Jorge E.
AU - Kim, Dong Wook
AU - Pinilla-Ibarz, Javier
AU - le Coutre, Philipp D.
AU - Paquette, Ronald
AU - Chuah, Charles
AU - Nicolini, Franck E.
AU - Apperley, Jane F.
AU - Khoury, H. Jean
AU - Talpaz, Moshe
AU - DeAngelo, Daniel J.
AU - Abruzzese, Elisabetta
AU - Rea, Delphine
AU - Baccarani, Michele
AU - Müller, Martin C.
AU - Gambacorti-Passerini, Carlo
AU - Lustgarten, Stephanie
AU - Rivera, Victor M.
AU - Haluska, Frank G.
AU - Guilhot, François
AU - Deininger, Michael W.
AU - Hochhaus, Andreas
AU - Hughes, Timothy
AU - Shah, Neil P.
AU - Kantarjian, Hagop M.
N1 - Funding Information: Conflict-of-interest disclosure: J.E.C. has received research funding from ARIAD, Bristol-Myers Squibb, Novartis, Pfizer, and Teva, and has served as a consultant for ARIAD, Bristol-Myers Squibb, Novartis, and Pfizer. D.-W.K. has received research funding from ARIAD. J.P.-I. has received honoraria from Bristol-Myers Squibb; has received research funding from ARIAD and Novartis; and has served as a consultant or speaker for ARIAD, Bristol-Myers Squibb, Novartis, Pfizer, and Teva. P.D.l.C. has received honoraria from ARIAD, Bristol-Myers Squibb, Novartis, and Pfizer, and research funding from ARIAD. R.P. has received honoraria from, and has served as a speaker for, ARIAD, Bristol-Myers Squibb, Incyte, and Novartis; has served in a consulting or advisory role for AstraZeneca; and has received research funding from ARIAD. C.C. has received research funding from ARIAD. F.E.N. has received honoraria from ARIAD, Bristol-Myers Squibb, and Novartis; has served in a consulting or advisory role for Bristol-Myers Squibb and Novartis; has served on speakers’ bureaus for ARIAD, Bristol-Myers Squibb, and Novartis; has received research funding from ARIAD and Novartis; and has received travel, accommodations, or other expense reimbursements from Bristol-Myers Squibb and Novartis. J.F.A. has received honoraria from ARIAD, Bristol-Myers Squibb, MSD, Novartis, and Pfizer, and has received research funding from ARIAD and Novartis. H.J.K. received honoraria and research funding from ARIAD. M.T. has served in a consulting or advisory role for ARIAD, Novartis, and Pfizer; has received research funding from ARIAD, Incyte, Novartis, Pfizer, and Sanofi; and has received travel, accommodations, or other expense reimbursements from ARIAD, Incyte, Novartis, and Pfizer. D.J.D. has served in a consulting or advisory role for Amgen, ARIAD, Bristol-Myers Squibb, Incyte, Novartis, and Pfizer, and has received research funding from ARIAD. E.A. has served in a consulting or advisory role for ARIAD, Bristol-Myers Squibb, Novartis, and Pfizer, and has received research funding from ARIAD. D.R. has received honoraria for nonpromotional oral presentations from, and has served on advisory boards for, ARIAD, Bristol-Myers Squibb, Novartis, and Pfizer, and has received research funding from ARIAD. M.B. has served as a consultant and speaker for, and received honoraria from, ARIAD, Bristol-Myers Squibb, Novartis, and Pfizer, and has received research funding from ARIAD. M.C.M. has received honoraria for consulting or advisory roles and research funding from ARIAD, Bristol-Myers Squibb, and Novartis. C.G.-P. has served in an advisory role to Bristol-Myers Squibb and Pfizer and has received research funding from ARIAD. S.L. is an employee of, and may own stock/stock options in, ARIAD. V.M.R. is an employee of, and may own stock/stock options in, ARIAD. F.G.H. was an employee of, and may have owned stock/stock options in, ARIAD at the time the work was conducted. F.G. has received honoraria from Novartis and Pfizer; has served in a consulting or advisory role for Celgene; has received travel, accommodations, or other expense reimbursements from Novartis; and has received research funding from ARIAD. M.W.D. has served in a consulting or advisory role for ARIAD, Bristol-Myers Squibb, Incyte, Novartis, and Pfizer; has received travel, accommodations, or other expense reimbursements from ARIAD, Bristol-Myers Squibb, CTI BioPharma, Novartis, and Pfizer; has provided expert testimony for Bristol-Myers Squibb; has received honoraria from ARIAD, Bristol-Myers Squibb, CTI BioPharma, Incyte, Novartis, and Pfizer; and has received research funding from ARIAD, Bristol-Myers Squibb, Celgene, Incyte, and Novartis. A.H. has received research funding from ARIAD, Bristol-Myers Squibb, Novartis, and Pfizer. T.P.H. has received honoraria from, has served in a consulting or advisory role for, and has received research funding from ARIAD, Bristol-Myers Squibb, and Novartis, and has received travel, accommodations, or other expense reimbursements from Bristol-Myers Squibb and Novartis. N.P.S. has received research funding from ARIAD, Bristol-Myers Squibb, Daiichi-Sankyo, Pfizer, and Plexxikon. H.M.K. has received Bristol-Myers Squibb, Novartis, and Pfizer. Funding Information: The authors thank the patients, their families, and their caregivers; the PACE investigators and their team members at each study site; and colleagues from ARIAD Pharmaceuticals, Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited [ARIAD]), MolecularMD, and the CML community. M.B. acknowledges his colleague, Fausto Cas-tagnetti, for overseeing the treatment of PACE patients in Bologna, Italy. Professional medical writing assistance was provided by Lela Creutz of Peloton Advantage, LLC (Parsippany, NJ), and editorial assistance was provided by Jessica Tyler (ARIAD) and Blythe Thomson (formerly of ARIAD). J.F.A. acknowledges the support of the Imperial College National Institute for Health Research Biomedical Research Centre. This work was supported by research funding from ARIAD to the institutions of J.E.C., D.-W.K., J.P.-I., P.D.l.C., R.P., C.C., F.E.N., J.F.A., H.J.K., M.T., D.J.D., E.A., D.R., M.B., M.C.M., C.G.-P., F.G., M.W.D., A.H., and T.P.H. Professional medical writing assistance was funded by ARIAD. Conflict-of-interest disclosure: J.E.C. has received research funding from ARIAD, Bristol-Myers Squibb, Novartis, Pfizer, and Teva, and has served as a consultant for ARIAD, Bristol-Myers Squibb, Novartis, and Pfizer. D.-W.K. has received research funding from ARIAD. J.P.-I. has received honoraria from Bristol-Myers Squibb; has received research funding from ARIAD and Novartis; and has served as a consultant or speaker for ARIAD, Bristol- Myers Squibb, Novartis, Pfizer, and Teva. P.D.l.C. has received honoraria from ARIAD, Bristol-Myers Squibb, Novartis, and Pfizer, and research funding from ARIAD. R.P. has received honoraria from, and has served as a speaker for, ARIAD, Bristol-Myers Squibb, Incyte, and Novartis; has served in a consulting or advisory role for AstraZeneca; and has received research funding from ARIAD. C.C. has received research funding from ARIAD. F.E.N. has received honoraria from ARIAD, Bristol-Myers Squibb, and Novartis; has served in a consulting or advisory role for Bristol-Myers Squibb and Novartis; has served on speakers’ bureaus for ARIAD, Bristol-Myers Squibb, and Novartis; has received research funding from ARIAD and Novartis; and has received travel, accommodations, or other expense reimbursements from Bristol-Myers Squibb and Novartis. J.F.A. has received honoraria from ARIAD, Bristol-Myers Squibb, MSD, Novartis, and Pfizer, and has received research funding from ARIAD and Novartis. H.J.K. received honoraria and research funding from ARIAD. M.T. has served in a consulting or advisory role for ARIAD, Novartis, and Pfizer; has received research funding fromARIAD, Incyte, Novartis, Pfizer, and Sanofi; and has received travel, accommodations, or other expense reimbursements from ARIAD, Incyte, Novartis, and Pfizer. D.J.D. has served in a consulting or advisory role for Amgen,ARIAD, Bristol-Myers Squibb, Incyte, Novartis, and Pfizer, and has received research funding from ARIAD. E.A. has served in a consulting or advisory role for ARIAD, Bristol-Myers Squibb, Novartis, and Pfizer, and has received research funding from ARIAD. D.R. has received honoraria for nonpromotional oral presentations from, and has served on advisory boards for, ARIAD, Bristol-Myers Squibb, Novartis, and Pfizer, and has received research funding fromARIAD.M.B. has served as a consultant and speaker for, and received honoraria from, ARIAD, Bristol-Myers Squibb, Novartis, and Pfizer, and has received research funding from ARIAD. M.C.M. has received honoraria for consulting or advisory roles and research funding from ARIAD, Bristol-Myers Squibb, and Novartis. C.G.-P. has served in an advisory role to Bristol-Myers Squibb and Pfizer and has received research funding from ARIAD. S.L. is an employee of, and may own stock/stock options in, ARIAD. V.M.R. is an employee of, andmay own stock/stock options in, ARIAD. F.G.H. was an employee of, and may have owned stock/stock options in, ARIAD at the time the work was conducted. F.G. has received honoraria from Novartis and Pfizer; has served in a consulting or advisory role for Celgene; has received travel, accommodations, or other expense reimbursements from Novartis; and has received research funding from ARIAD. M.W.D. has served in a consulting or advisory role for ARIAD, Bristol-Myers Squibb, Incyte, Novartis, and Pfizer; has received travel, accommodations, or other expense reimbursements from ARIAD, Bristol-Myers Squibb, CTI BioPharma, Novartis, and Pfizer; has provided expert testimony for Bristol-Myers Squibb; has received honoraria from ARIAD, Bristol-Myers Squibb, CTI BioPharma, Incyte, Novartis, and Pfizer; and has received research funding from ARIAD, Bristol-Myers Squibb, Celgene, Incyte, and Novartis. A.H. has received research funding from ARIAD, Bristol-Myers Squibb, Novartis, and Pfizer. T.P.H. has received honoraria from, has served in a consulting or advisory role for, and has received research funding from ARIAD, Bristol-Myers Squibb, and Novartis, and has received travel, accommodations, or other expense reimbursements from Bristol-Myers Squibb and Novartis. N.P.S. has received research funding fromARIAD, Bristol-Myers Squibb, Daiichi-Sankyo, Pfizer, and Plexxikon. H.M.K. has received research funding from Amgen, Bristol-Myers Squibb, Novartis, and Pfizer. Funding Information: J.F.A. acknowledges the support of the Imperial College National Institute for Health Research Biomedical Research Centre. This work was supported by research funding from ARIAD to the institutions of J.E.C., D.-W.K., J.P.-I., P.D.l.C., R.P., C.C., F.E.N., J.F.A., H.J.K., M.T., D.J.D., E.A., D.R., M.B., M.C.M., C.G.-P., F.G., M.W.D., A.H., and T.P.H. Professional medical writing assistance was funded by ARIAD.
PY - 2018/7/26
Y1 - 2018/7/26
N2 - Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1T315I. The pivotal phase 2 Ponatinib Ph1 ALL and CML Evaluation (PACE) trial evaluated efficacy and safety of ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) resistant/intolerant to dasatinib or nilotinib, or with BCR-ABL1T315I. This analysis focuses on chronic-phase CML (CP-CML) patients (n 5 270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and 4.5-log molecular response, respectively. The probability of maintaining MCyR for 5 years was 82% among responders. Dose reductions were implemented in October 2013 to decrease the risk of arterial occlusive events (AOEs); ‡90% of CP-CML patients who had achieved MCyR or MMR maintained response 40 months after elective dose reductions. Estimated 5-year overall survival was 73%. In CP-CML patients, the most common treatment-emergent adverse events were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). The cumulative incidence of AOEs in CP-CML patients increased over time to 31%, while the exposure-adjusted incidence of new AOEs (15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively) did not increase over time. These final PACE results demonstrate ponatinib provides durable and clinically meaningful responses, irrespective of dose reductions, in this population of heavily pretreated CP-CML patients. This trial was registered at www.clinicaltrials.gov as #NCT01207440.
AB - Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1T315I. The pivotal phase 2 Ponatinib Ph1 ALL and CML Evaluation (PACE) trial evaluated efficacy and safety of ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) resistant/intolerant to dasatinib or nilotinib, or with BCR-ABL1T315I. This analysis focuses on chronic-phase CML (CP-CML) patients (n 5 270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and 4.5-log molecular response, respectively. The probability of maintaining MCyR for 5 years was 82% among responders. Dose reductions were implemented in October 2013 to decrease the risk of arterial occlusive events (AOEs); ‡90% of CP-CML patients who had achieved MCyR or MMR maintained response 40 months after elective dose reductions. Estimated 5-year overall survival was 73%. In CP-CML patients, the most common treatment-emergent adverse events were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). The cumulative incidence of AOEs in CP-CML patients increased over time to 31%, while the exposure-adjusted incidence of new AOEs (15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively) did not increase over time. These final PACE results demonstrate ponatinib provides durable and clinically meaningful responses, irrespective of dose reductions, in this population of heavily pretreated CP-CML patients. This trial was registered at www.clinicaltrials.gov as #NCT01207440.
UR - http://www.scopus.com/inward/record.url?scp=85048250671&partnerID=8YFLogxK
U2 - 10.1182/blood-2016-09-739086
DO - 10.1182/blood-2016-09-739086
M3 - Article
C2 - 29567798
AN - SCOPUS:85048250671
VL - 132
SP - 393
EP - 404
JO - Blood
JF - Blood
SN - 0006-4971
IS - 4
ER -