Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial

被引:432
作者
Cortes, Jorge E. [1 ]
Kim, Dong-Wook [2 ]
Pinilla-Ibarz, Javier [3 ]
le Coutre, Philipp D. [4 ]
Paquette, Ronald [5 ]
Chuah, Charles [6 ]
Nicolini, Franck E. [7 ]
Apperley, Jane F. [8 ]
Khoury, H. Jean [9 ]
Talpaz, Moshe [10 ]
DeAngelo, Daniel J. [11 ]
Abruzzese, Elisabetta [12 ]
Rea, Delphine [13 ,14 ]
Baccarani, Michele [15 ]
Mueller, Martin C. [16 ]
Gambacorti-Passerini, Carlo [17 ]
Lustgarten, Stephanie [18 ]
Rivera, Victor M. [18 ]
Haluska, Frank G. [18 ]
Guilhot, Francois [19 ,20 ]
Deininger, Michael W. [21 ]
Hochhaus, Andreas [22 ]
Hughes, Timothy P. [23 ]
Shah, Neil P. [24 ]
Kantarjian, Hagop M. [1 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA
[2] Catholic Univ Korea, Seoul St Marys Hosp, Leukemia Res Inst, Seoul, South Korea
[3] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA
[4] Charite Univ Med Berlin, Berlin, Germany
[5] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA
[6] Duke Natl Univ Singapore NUS, Singapore Gen Hosp, Med Sch, Singapore, Singapore
[7] Ctr Hosp Lyon Sud, Lyon, France
[8] Imperial Coll, Ctr Haematol, London, England
[9] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA
[10] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA
[11] Dana Farber Canc Inst, Boston, MA 02115 USA
[12] Tor Vergata Univ, S Eugenio Hosp, Rome, Italy
[13] Hop St Louis, Serv Hematol Adulte, Paris, France
[14] Hop St Louis, Ctr Invest Clin, Paris, France
[15] Univ Bologna, Dept Expt Diagnost & Specialty Med, Bologna, Italy
[16] Univ Med Mannheim, Med Klin 3, Mannheim, Germany
[17] Univ Milano Bicocca, San Gerardo Hosp, Monza, Italy
[18] ARIAD Pharmaceut Inc, Cambridge, MA 02139 USA
[19] INSERM, Ctr Invest Clin CIC 1402, Poitiers, France
[20] CHU Poitiers, Poitiers, France
[21] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA
[22] Jena Univ Hosp, Hematol Oncol, Jena, Germany
[23] Univ Adelaide, South Australian Hlth & Med Res Inst SAHMRI, Adelaide, SA, Australia
[24] Univ Calif San Francisco, Dept Med, Div Hematol & Oncol, San Francisco, CA USA
关键词
CHRONIC MYELOID-LEUKEMIA; TYROSINE KINASE INHIBITOR; CHRONIC MYELOGENOUS LEUKEMIA; BCR-ABL INHIBITOR; IMATINIB-RESISTANT; ADVERSE EVENTS; DASATINIB; NILOTINIB; RECOMMENDATIONS; TOLERABILITY;
D O I
10.1182/blood-2016-09-739086
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1(T315I). The pivotal phase 2 Ponatinib Ph+ 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, orwith BCR-ABL1(T315I). This analysis focuses on chronic-phase CML (CP-CML) patients (n = 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.
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页码:393 / 404
页数:12
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