Multivariate Analyses of the Clinical and Molecular Parameters Associated with Efficacy and Safety in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Treated with Ponatinib in the PACE Trial
Authors: Mauro Michael J. , Cortes Jorge E. , 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 J , Abruzzese Elisabetta , Rea Delphine , Baccarani Michele , Muller Martin C , Gambacorti-Passerini Carlo , Wong Stephane , Dorer David J. , Knickerbocker Ronald Keith , Rivera Victor M. , Clackson Tim , Turner Christopher D. , Haluska Frank G , Guilhot Francois , Deininger Michael W. , Hochhaus Andreas , Hughes Timothy , Goldman John M , Shah Neil , Kantarjian Hagop M. ,   The PACE Study Group
Published: October 2019

Abstract
Abstract 3747

Introduction:
Ponatinib is a potent, oral, pan-BCR-ABL inhibitor with activity against native and mutant forms of BCR-ABL, including the tyrosine kinase inhibitor (TKI)-resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally QD) were evaluated in a phase 2, international, open-label clinical trial (PACE). These multivariate analyses explored the impact of dose intensity and several prognostic and predictive factors on clinical responses, adverse events (AEs), and laboratory changes.

Methods:
Enrolled patients were resistant or intolerant (R/I) to dasatinib or nilotinib, or had the T315I BCR-ABL mutation at baseline. A total of 267 chronic phase (CP), 83 accelerated phase (AP), and 94 blast phase (BP) CML/Ph+ ALL patients were assigned to 1 of 6 cohorts according to disease phase (CP-, AP-, or BP-CML/Ph+ ALL), R/I to dasatinib or nilotinib, and presence of T315I. Three CP-CML and 2 AP-CML patients were treated, but not assigned to a cohort (post-imatinib, did not have T315I at baseline); these patients were excluded from efficacy analyses and included in safety analyses. For the purposes of the efficacy multivariate analyses, AP-CML, BP-CML, and Ph+ ALL patients were combined. The baseline covariates analyzed were age, time since diagnosis, number of prior TKIs, presence or absence of the T315I mutation, neutrophil and platelet counts, and weight. The primary efficacy outcome analyzed was major cytogenetic response (MCyR) in CP-CML and major hematologic response (MaHR) for all other patients. The safety outcomes analyzed were the following AEs: pancreatitis, elevated lipase, alanine aminotransferase (ALT) increase, aspartate aminotransferase (AST) increase, rash, neutropenia, thrombocytopenia, arthralgia, and hypertriglyceridemia. The impact on neutrophils, platelets, bilirubin, ALT, AST, creatinine, lipase, and triglycerides was also examined. Binary event outcomes were analyzed using logistic regression models. Data values over time were analyzed using linear mixed effects models. Laboratory values were log-transformed. Data as of 27 April 2012 were used in these analyses.

Results:
Median baseline characteristics of the CP-CML R/I and T315I cohorts, respectively, were: 61 vs 51 yrs of age, 8 vs 5 yrs since initial diagnosis, 3 vs 2 prior TKIs. The median dose intensity for the CP-CML R/I and T315I cohorts was 30 and 39 mg/day, respectively. In general, other baseline characteristics were balanced between these 2 cohorts. Multivariate analysis found statistically significant associations between MCyR and increasing dose intensity (mg/day) (p<0.0001) and decreasing age (p=0.046) in CP-CML. Despite the finding that CP-CML patients with the T315I mutation had a higher response rate than those without the T315I mutation (MCyR 70% vs 49%), presence of T315I was not a significant prognostic factor for response after adjusting for other covariates (p>0.2). This was likely because patients with T315I received a greater dose intensity, were younger, and were previously treated with fewer TKIs.
The probability of achieving MaHR in patients with AP-CML, BP-CML, and Ph+ ALL increased with increasing dose intensity (p<0.001) and with higher numbers of baseline platelets (p=0.0046). As in CP-CML, similar trends in baseline characteristics were observed, and the presence of the T315I mutation was not a significant prognostic factor for MaHR.
In all patients, the probability of AEs (pancreatitis, lipase increase, ALT and AST increase, thrombocytopenia, neutropenia, arthralgia, and rash) increased with increasing dose intensity. Hypertriglyceridemia was trend level associated with dose intensity (p=0.054). Presence of T315I was associated with a lower risk of thrombocytopenia (p<0.0001) and neutropenia (p=0.005) after adjustment for dose intensity and the other factors. In general, younger age, less time since diagnosis, and fewer prior TKIs were associated with a lower probability of AEs.

Conclusion:
These findings suggest that dose intensity and factors related to extent of disease and prior treatment were most predictive of effectiveness and tolerance of ponatinib. T315I was not a significant prognostic factor for efficacy or safety after adjustment for other factors, with the exception of thrombocytopenia and neutropenia; patients with T315I had lower predicted rates of these AEs after adjustment for dose intensity and other factors in the reduced models.

Disclosures:
Off Label Use: Ponatinib - non FDA approved (experimental) compound. Cortes:Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding. 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 : Research Funding, Speakers Bureau; Bristol-Myers Squibb: 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, and Teva: 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; Bristol Myers-Squibb: 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:Bristol Myers-Squibb and 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, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Dorer:ARIAD: Employment, Equity Ownership. Knickerbocker:ARIAD: 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, Bristol Myers-Squibb, Pfizer, and MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:Novartis: Consultancy; Bristol Myers-Squibb: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding. Kantarjian:Pfizer: Research Funding; ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding.