RETROSPECTIVE INDEPENDENT REVIEW OF ARTERIAL OCCLUSIVE EVENTS (AOES) IN THE PHASE 2 PACE TRIAL OF PONATINIB IN PHILADELPHIA CHROMOSOME POSITIVE (PH+) LEUKEMIA
Author(s): ,
James Januzzi
Affiliations:
Massachusetts General Hospital,Boston,United States
,
Joseph Garasic
Affiliations:
Massachusetts General Hospital,Boston,United States
,
Scott Kasner
Affiliations:
University of Pennsylvania,Philadelphia,United States
,
Vickie McDonald
Affiliations:
Barts Health NHS Trust,London,United Kingdom
,
Mark Petrie
Affiliations:
University of Glasgow,Glasgow,United Kingdom
,
Jonathan Seltzer
Affiliations:
ACI Clinical,Bala Cynwyd,United States
,
Michael Mauro
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Kevin Croce
Affiliations:
Brigham and Women's Hospital, Harvard Medical School,Boston,United States
,
Ellin Berman
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Michael Deininger
Affiliations:
Huntsman Cancer Institute, The University of Utah,Salt Lake City,United States
,
Andreas Hochhaus
Affiliations:
Jena University Hospital,Jena,Germany
,
Javier Pinilla-Ibarz
Affiliations:
H. Lee Moffitt Cancer Center & Research Institute,Tampa,United States
,
Franck Nicolini
Affiliations:
Centre Hospitalier Lyon-Sud, Pierre-Bénite,Lyon,France
,
Dong-Wook Kim
Affiliations:
Catholic Hematology Hospital, Seoul St. Mary's Hospital, Leukemia Research Institute, The Catholic University of Korea,Seoul,Korea, Republic Of
,
Daniel DeAngelo
Affiliations:
Dana-Farber Cancer Institute,Boston,United States
,
Hagop Kantarjian
Affiliations:
The University of Texas MD Anderson Cancer Center,Houston,United States
,
Jing Xu
Affiliations:
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited,Cambridge,United States
,
Tracey Hall
Affiliations:
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited,Cambridge,United States
,
Shouryadeep Srivastava
Affiliations:
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited,Cambridge,United States
,
Daniel Naranjo
Affiliations:
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited,Cambridge,United States
Jorge Cortes
Affiliations:
Georgia Cancer Center,Augusta,United States
EHA Library. Januzzi J. 06/12/20; 294677; EP759
James Januzzi
James Januzzi
Contributions
Abstract

Abstract: EP759

Type: e-Poster

Background
The final 5-year analysis of the phase 2 Ponatinib Ph+ ALL and CML Evaluation (PACE) trial (NCT01207440), which evaluated use of ponatinib in patients with refractory chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL), identified a 25% incidence of AOEs (Cortes, Blood 2018) from a search utilizing >400 preferred terms (PTs) defined by Medical Dictionary for Regulatory Activities (MedDRA) and related to vascular ischemia or thrombosis.

Aims
To perform a retrospective review using an independent Endpoint Adjudication Committee (EAC) to better understand clinically relevant AOE rates in PACE.

Methods
The EAC consisted of 3 cardiologists, 1 hematologist (not a PACE investigator), and 1 neurologist to review AOEs (identified using >500 terms) in PACE using American College of Cardiology/American Heart Association (ACC/AHA) definitions for major adverse cardiovascular events (MACE), and to review patient profiles including event, severity, concomitant medication, and hospitalization data. These results were compared with MedDRA PT search results. The EAC was blind to dose, dose modification, and investigator causality opinion.

Results
This retrospective review of PACE included 449 heavily pretreated patients with Ph+ leukemia (median age, 59 y; 47% female; 93% ≥2 tyrosine kinase inhibitors). With median follow-up 37.3 mo in all patients, AOEs were identified by MedDRA PT search in 25% of patients and EAC-verified in 17% (Table). In each category listed in the table, the EAC verification identified fewer AOEs and serious AOEs. Serious AOEs were identified by MedDRA PT search in 20% of patients and EAC-verified in 16%. Events that were not associated with a cardiovascular etiology or failed to meet the ACC/AHA MACE definition were determined by the EAC as not to be an AOE.

Conclusion
The independent EAC review showed a lower rate of clinically relevant AOEs than was reported in PACE (25% vs 17%), suggesting an earlier possible overestimation that may not accurately reflect the risk of AOEs with ponatinib. The ongoing ponatinib dose-ranging OPTIC study will further evaluate the incidence of AOEs in a dose-dependent manner.

Session topic: 08. Chronic myeloid leukemia - Clinical

Keyword(s): Chronic myeloid leukemia, Thromboembolic events, Tyrosine kinase inhibitor

Abstract: EP759

Type: e-Poster

Background
The final 5-year analysis of the phase 2 Ponatinib Ph+ ALL and CML Evaluation (PACE) trial (NCT01207440), which evaluated use of ponatinib in patients with refractory chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL), identified a 25% incidence of AOEs (Cortes, Blood 2018) from a search utilizing >400 preferred terms (PTs) defined by Medical Dictionary for Regulatory Activities (MedDRA) and related to vascular ischemia or thrombosis.

Aims
To perform a retrospective review using an independent Endpoint Adjudication Committee (EAC) to better understand clinically relevant AOE rates in PACE.

Methods
The EAC consisted of 3 cardiologists, 1 hematologist (not a PACE investigator), and 1 neurologist to review AOEs (identified using >500 terms) in PACE using American College of Cardiology/American Heart Association (ACC/AHA) definitions for major adverse cardiovascular events (MACE), and to review patient profiles including event, severity, concomitant medication, and hospitalization data. These results were compared with MedDRA PT search results. The EAC was blind to dose, dose modification, and investigator causality opinion.

Results
This retrospective review of PACE included 449 heavily pretreated patients with Ph+ leukemia (median age, 59 y; 47% female; 93% ≥2 tyrosine kinase inhibitors). With median follow-up 37.3 mo in all patients, AOEs were identified by MedDRA PT search in 25% of patients and EAC-verified in 17% (Table). In each category listed in the table, the EAC verification identified fewer AOEs and serious AOEs. Serious AOEs were identified by MedDRA PT search in 20% of patients and EAC-verified in 16%. Events that were not associated with a cardiovascular etiology or failed to meet the ACC/AHA MACE definition were determined by the EAC as not to be an AOE.

Conclusion
The independent EAC review showed a lower rate of clinically relevant AOEs than was reported in PACE (25% vs 17%), suggesting an earlier possible overestimation that may not accurately reflect the risk of AOEs with ponatinib. The ongoing ponatinib dose-ranging OPTIC study will further evaluate the incidence of AOEs in a dose-dependent manner.

Session topic: 08. Chronic myeloid leukemia - Clinical

Keyword(s): Chronic myeloid leukemia, Thromboembolic events, Tyrosine kinase inhibitor

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