Efficacy and Safety of Ponatinib in Patients with Accelerated Phase or Blast Phase Chronic Myeloid Leukemia (AP-CML or BP-CML) or Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL): 12-Month Follow-up of the PACE Trial
Authors: Kantarjian Hagop M. , Kim Dong-Wook , Pinilla-Ibarz Javier , le Coutre Philipp , Paquette Ronald , Chuah Charles , Nicolini Franck E. , Apperley Jane , Khoury H. Jean , Talpaz Moshe , DiPersio John F. , DeAngelo Daniel , Abruzzese Elisabetta , Rea Delphine , Baccarani Michele , Muller Martin C , Gambacorti-Passerini Carlo , Wong Stephane , Lustgarten Stephanie , Rivera Victor M. , Clackson Tim , Turner Christopher D. , Haluska Frank G , Guilhot Francois , Deininger Michael W. , Hochhaus Andreas , Hughes Timothy P. , Goldman John , Shah Neil , Cortes Jorge E. , Group The PACE Study 
Published: October 2019

Abstract
Abstract 915

Background:
Many patients (pts) with advanced Ph+ leukemias experience failure of all currently available tyrosine kinase inhibitors (TKIs) targeting BCR-ABL and have limited treatment options. Ponatinib is a potent pan-BCR-ABL inhibitor that is active against native and mutated forms of BCR-ABL, including the TKI resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally once daily) in pts with AP-CML, BP-CML, or Ph+ ALL were evaluated in a phase 2, international, open-label clinical trial.

Methods:
The PACE trial enrolled 449 pts, including 85 AP-CML, 62 BP-CML, and 32 Ph+ ALL. Pts were resistant or intolerant (R/I) to dasatinib or nilotinib, or had the T315I mutation at baseline. AP-CML, BP-CML, and Ph+ ALL pts were assigned to 1 of 4 cohorts: AP-CML R/I, AP-CML T315I, BP-CML/Ph+ ALL R/I, BP-CML/Ph+ ALL T315I. Two AP-CML pts were not assigned to a cohort (post-imatinib, did not have T315I at baseline) and were excluded from efficacy analyses and included in safety analyses. The primary endpoint was major hematologic response (MaHR) at any time within 6 mos after treatment initiation. Data as of 23 July 2012 are reported, with a minimum follow-up of 9 mos (median 13 [4 to 21], 6 [0.1 to 18], and 6 [0.1 to 16] mos for AP-CML, BP-CML, and Ph+ ALL, respectively).

Results:
The median age for AP-CML, BP-CML, and Ph+ ALL pts was 60, 53, and 62 yrs, respectively. Median time from initial disease diagnosis to start of ponatinib was 7, 4, and 1.5 yrs, respectively. Pts were heavily pretreated: 94% received prior imatinib, 88% dasatinib, 61% nilotinib; 8% received 1 prior approved TKI, 39% received 2, and 53% received 3. Sixteen percent had undergone prior stem cell transplant. In pts previously treated with dasatinib or nilotinib (N=171), 94% had a history of resistance to dasatinib or nilotinib, 6% were purely intolerant. Reported MaHR rates with the most recent dasatinib or nilotinib therapy were 35% AP-CML, 16% BP-CML, 43% Ph+ ALL.
At the time of analysis, 59% of AP-CML, 8% of BP-CML, and 9% of Ph+ ALL pts remained on study. Overall, the most common reasons for discontinuation were progressive disease (19%, 50%, and 53%, respectively) and adverse events (AEs; 11%, 16%, and 6%, respectively). Hematologic and cytogenetic response rates are shown in the table; MaHR and MCyR were observed across cohorts. MMR was achieved by 14% of AP-CML pts (14% R/I, 17% T315I). There was a trend for higher response rates among pts who received fewer prior approved TKIs. In AP-CML pts, the differences in MaHR rates by number of prior approved TKIs (1: 3/4 [75%]; 2: 20/33 [61%]; 3: 24/46 [52%]) were not significant (Fisher's Exact); differences in MCyR rates (1: 4/4 [100%]); 2: 13/33 [39%]; 3: 15/46 [33%]) were significant for pts treated with 1 vs 2 (p=0.0360) and 1 vs 3 prior approved TKIs (p=0.0168).
Of pts achieving MaHR, 42% of AP-CML and 35% of BP-CML/Ph+ ALL pts were projected (Kaplan-Meier) to remain in MaHR at 1 yr. In AP-CML, the median progression-free survival (PFS) was estimated (Kaplan-Meier) as 80 (range 6 to 88) wks; the probability of maintaining PFS at 6 mos and 1 yr was estimated as 80% and 57%, respectively. Median overall survival (OS) had not yet been reached; the probability of OS at 6 mos and 1 yr was estimated (Kaplan-Meier) as 96% and 85%, respectively. In BP-CML/Ph+ ALL, median PFS was estimated as 18 (range 0.1 to 74) wks; the probability of maintaining PFS at 6 mos and 1 yr was estimated as 34% and 20%, respectively. Median OS was estimated as 30 (range 0.4 to 77) wks; the probability of OS at 6 mos and 1 yr was estimated as 54% and 34%, respectively. Ponatinib was generally well-tolerated; the most common treatment-related AEs were thrombocytopenia (29%), rash (25%), and neutropenia (22%). The most common serious treatment-related AEs were thrombocytopenia (3%) and pancreatitis (3%). Rash was generally grade 1 or 2 in severity. Thrombocytopenia, neutropenia, and pancreatitis were typically reported early in treatment and were manageable with dose modification.

Conclusions:
Ponatinib was generally well-tolerated and had substantial activity in pts with AP-CML, BP-CML, or Ph+ ALL, regardless of mutation status or prior therapy. Data with a minimum follow-up of 12 mos will be presented

Disclosures:
Kantarjian: Novartis: Consultancy; Pfizer: Research Funding; BMS: Research Funding; Novartis: Research Funding; ARIAD: Research Funding. Off Label Use: ponatinib. Kim:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and 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 and 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:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Celgene: Research Funding; ARIAD: Research Funding; Deciphera: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: 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, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hochhaus:ARIAD, Novartis, Bristol Myers-Squibb, Pfizer, and 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, Amgen: Honoraria. Shah:ARIAD Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Cortes:Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding.