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163 A Pivotal Phase 2 Trial of Ponatinib in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Resistant or Intolerant to Dasatinib or Nilotinib, or with the T315I BCR-ABL Mutation: 12-Month Follow-up of the PACE Trial

Program: Oral and Poster Abstracts
Type: Oral
Session: 632. Chronic Myeloid Leukemia - Therapy I
Sunday, December 9, 2012: 4:30 PM
A411-A412, Level 4, Building A (Georgia World Congress Center)

Jorge E. Cortes, MD1, Dong-Wook Kim, MD2, Javier Pinilla-Ibarz, MD, PhD3*, Philipp le Coutre, MD4, Ron Paquette, MD, PhD5*, Charles Chuah, MD6*, Franck E Nicolini, MD, PhD7, Jane Apperley8, H. Jean Khoury9, Moshe Talpaz, MD10, John F. DiPersio, MD, PhD11, Daniel J. DeAngelo, MD, PhD12, Elisabetta Abruzzese13, Delphine Rea, MD, PhD14*, Michele Baccarani, MD15, Martin C Muller16*, Carlo Gambacorti-Passerini, MD17, Stephane Wong, PhD18, Stephanie Lustgarten19*, Victor M. Rivera, PhD19, Tim Clackson, PhD19, Christopher D. Turner, MD, FAAP19, Frank G Haluska, MD, PhD19, Francois Guilhot, MD20, Michael W. Deininger, MD, PhD21, Andreas Hochhaus, MD22*, Timothy Hughes23, John M Goldman, MD24, Neil Shah, MD, PhD25, Hagop M Kantarjian, M.D.26 and The PACE Study Group19*

1Department of Leukemia, University of Texas, MD Anderson cancer center, Houston, TX
2Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
3H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
4Hematology/Oncology, Charité Universitätsmedizin Berlin, Berlin, Germany
5Ronald Reagan UCLA Medical Center, University of California, Los Angeles, CA
6Hematology, Singapore General Hospital/Duke-NUS Graduate Medical School, Singapore, Singapore
7Pierre Benite, Centre Hospitalier Lyon Sud, Pierre Benite, France
8Imperial College, Department of Haematology, Hammersmith Hospital, London, United Kingdom
9Emory Winship Cancer Institute, Atlanta, GA
10Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI
11Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO
12Dana-Farber Cancer Institute, Boston, MA
13Ospedale S. Eugenio, Rome, Italy
14Hematology department, Hôpital Saint Louis, Paris, France
15Dept. Hematology and Medical Oncology, University of Bologna, Bologna, Italy
16Universitätsmedizin Mannheim, III. Med. Klinik, Mannheim, Germany
17Dept. of Hematology, Università  Milano Bicocca and S. Gerardo Hospital, Monza, Italy
18MolecularMD Corp, Portland, OR
19ARIAD Pharmaceuticals, Inc., Cambridge, MA
20CIC Inserm 0802, CHU de Poitiers, Poitiers, France
21Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT
22Universitätsklinikum Jena, Jena, Germany
23Institute of Medical and Veterinary Science, Adelaide, Australia
24Department of Hematology, Imperial College, London, United Kingdom
25Department of Medicine, University of California San Francisco, San Francisco, CA
26Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, Houston, TX

Background: Despite progress in Ph+ leukemia therapy, patients who experience failure of tyrosine kinase inhibitors (TKIs) and those with the T315I BCR-ABL mutation have limited treatment options. Ponatinib is an oral TKI developed using computational and structure‑based design with optimal binding to the BCR‑ABL active site. At clinically achievable concentrations, ponatinib demonstrated potent in vitro activity against native BCR‑ABL and all BCR-ABL mutants tested, including T315I. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with Ph+ leukemia were evaluated in a phase 2, international, open-label clinical trial.

Methods: 449 patients resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I mutation confirmed at entry were enrolled and assigned to 1 of 6 cohorts: chronic phase (CP)-CML R/I (N=203), CP‑CML T315I (N=64), accelerated phase (AP)-CML R/I (N=65), AP-CML T315I (N=18), blast phase (BP)‑CML/Ph+ALL R/I (N=48), BP‑CML/Ph+ALL T315I (N=46). Five patients (3 CP‑CML, 2 AP-CML) without confirmed T315I and not R/I to dasatinib or nilotinib were treated, but not assigned to a cohort; they were included in safety analyses. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 months for CP-CML and major hematologic response (MaHR) at any time within 6 months for advanced Ph+ leukemia. The trial is ongoing. Data as of 23 July 2012 are reported: median follow-up 11 (0.1 to 21) months; minimum follow-up 9 months.

Results: Median age was 59 (18-94) yrs; 53% were male. Median time from diagnosis to ponatinib was 6 (0.3‑28) yrs. Patients were heavily pretreated: 96% received prior imatinib, 84% dasatinib, 65% nilotinib; median number of prior TKIs was 3, with 53% exposed to all 3 approved TKIs. In patients previously treated with dasatinib or nilotinib (N=427), 88% had a history of resistance and 12% were purely intolerant to dasatinib or nilotinib. Best prior response to most recent dasatinib or nilotinib was 26% MCyR or better in CP-CML, and 23% MaHR or better in advanced Ph+ leukemia. Frequent BCR-ABL mutations confirmed at entry were: 29% T315I, 8% F317L, 4% E255K, 4% F359V, 3% G250E. No mutations were detected in 44%. The primary endpoint response rates (see Table) in each cohort exceeded the prespecified statistical criteria for success. In CP‑CML and AP‑CML R/I (the 3 largest cohorts), 95% CIs exceeded the prespecified response rate. Median time to response (for responders) was 84 days in CP‑CML, 112 days in AP-CML, 55 days in BP-CML/Ph+ALL. Responses were durable; the estimated (Kaplan‑Meier) probability of responders maintaining the primary endpoint at 1 yr was 91% in CP‑CML, 42% in AP‑CML, 35% in BP‑CML/Ph+ALL. In CP-CML, 46% had complete cytogenetic response and molecular response rates were 32% MMR, 20% MR4, and 12% MR4.5. Response rates were higher in patients exposed to fewer prior TKIs and those with shorter disease duration. Similar response rates were observed in patients with and without BCR‑ABL mutations. In CP-CML, response rates were higher in those with T315I; however, a post hoc analysis found that presence of T315I was not a predictor of response. Instead, the difference in response rate was explained by T315I patients’ younger age, shorter duration of leukemia, and exposure to less prior therapy. At the time of analysis, 52% of patients remained on therapy (66% CP-CML). The most frequent reasons for discontinuation were progression (18%) and AEs (12%). The most common drug‑related AEs were thrombocytopenia (36%), rash (33%), and dry skin (31%). Pancreatitis was the most common drug‑related SAE (5%); however, it occurred early and was managed with dose modification (1 patient discontinued due to pancreatitis).

Conclusions:Ponatinib has substantial activity and is generally well tolerated in these heavily pretreated Ph+ leukemia patients who have limited available treatment options. Data with a minimum follow-up of 12 months will be presented.





Primary Endpoint





n/N (%)

95% CI


n/N (%)

95% CI


n/N (%)

95% CI


101/203 (50)


38/65 (58)


17/48 (35)



45/64 (70)


9/18 (50)


15/46 (33)



146/267 (55)


47/83 (57)


32/94 (34)


Baseline MaHR counted as non-responder. Prespecified null and interesting rates: CP-CML R/I, MCyR 20% and 35%; CP-CML T315I, MCyR 10% and 35%; advanced cohorts, MaHR 10% and 30%.

Disclosures: Cortes: Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Research Funding; Ariad, Pfizer, Teva: Consultancy. Kim: Novartis, BMS, Pfizer, ARIAD, Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pinilla-Ibarz: Novartis, BMS: Research Funding, Speakers Bureau. le Coutre: Novartis and BMS: Honoraria. Paquette: ARIAD: Consultancy. Chuah: Novartis, Bristol-Myers Squibb: Honoraria. Nicolini: Novartis, Bristol Myers Squibb, Pfizer, ARIAD: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Apperley: Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz: Deciphera: Research Funding; ARIAD: Research Funding; Celgene: Research Funding; Millenium: Research Funding; Sanofi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; BMS: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity’s Board of Directors or advisory committees. Abruzzese: BMS, Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Rea: Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani: ARIAD, Novartis, Bristol Myers Squibb, Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller: ARIAD: Consultancy. Wong: MolecularMD Corp: Employment, Equity Ownership. Lustgarten: ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera: ARIAD: Employment, Equity Ownership. Clackson: ARIAD: Employment, Equity Ownership. Turner: ARIAD: Employment, Equity Ownership. Haluska: ARIAD: Employment, Equity Ownership. Guilhot: ARIAD: Honoraria. Hochhaus: ARIAD, Novartis, BMS, Pfizer, MSD: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Hughes: Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman: Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah: ARIAD: Consultancy, Research Funding; Briston-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Kantarjian: Novartis: Consultancy, Research Funding; BMS: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding.

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