CPX-351 TREATMENT OF PREVIOUSLY UNTREATED OLDER AML PATIENTS WITH HIGH RISK AML MARKEDLY INCREASES THE RESPONSE RATE OVER 7+3 IN PATIENTS WITH FLT3 MUTATIONS.
Author(s): ,
Jeffery Lancet
Affiliations:
H. Lee Moffitt Cancer Center and Research Institute,Tampa,United States
,
Geoffrey Uy
Affiliations:
Washington University School of Medicine,St. Louis,United States
,
Jorge Cortes
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Laura Newell
Affiliations:
Oregon Health and Science University,Portland,United States
,
Tara Lin
Affiliations:
University of Kansas Cancer Center,Westwood,United States
,
Ellen Ritchie
Affiliations:
Weill Cornell Medical College/New York Presbyterian Hospital,New York,United States
,
Stephen Strickland
Affiliations:
Vanderbilt-Ingram Cancer Center,Nashville,United States
,
Robert Stuart
Affiliations:
Medical University of South Carolina,Charleston,United States
,
Donna Hogge
Affiliations:
BC Cancer Research Center,Vancouver,Canada
,
Scott Solomon
Affiliations:
The Blood and Marrow Transplant Group - Northside Hospital,Atlanta,United States
,
Richard Stone
Affiliations:
Dana Farber Cancer Institute,Boston,United States
,
Dale Bixby
Affiliations:
University of Michigan Comprehensive Cancer Center,Ann Arbor,United States
,
Jonathan Kolitz
Affiliations:
North Shore University Hospital - LIJ Health System,Lake Success,United States
,
Gary Schiller
Affiliations:
UCLA Medical Center,Los Angeles,United States
,
Matthew Wieduwilt
Affiliations:
Moores UC San Diego Cancer Center,La Jolla,United States
,
Arati Rao
Affiliations:
Duke University Medical Center,Durham,United States
,
Stephen Rubenstein
Affiliations:
Franciscan St. Francis Health,Indianapolis,United States
,
Wendy Stock
Affiliations:
University of Chicago,Chicago,United States
,
Matthew Foster
Affiliations:
University of North Carolina at Chapel Hill,Chapel Hill,United States
,
Harry Erba
Affiliations:
University of Alabama at Birmingham Comprehensive Cancer Center,Birmingham,United States
,
Stuart Goldberg
Affiliations:
The John Theuer Cancer Center at Hackensack University Medical Center,Hackensack,United States
,
Bayard Powell
Affiliations:
Wake Forest Baptist Health,Winston-Salem,United States
,
Nikolai Podoltsev
Affiliations:
Yale University School of Medicine,New Haven,United States
,
Ehab Atallah
Affiliations:
Froedtert and the Medical College of Wisconsin,Milwaukee,United States
,
Erica Warlick
Affiliations:
University of Minnesota,Minneapolis,United States
,
Karen Yee
Affiliations:
Princess Margaret Hospital,Toronto,Canada
,
John Pagel
Affiliations:
Fred Hutchinson Cancer Research Center,Seattle,United States
,
Maxim Norkin
Affiliations:
University of Florida College of Medicine,Gainesville,United States
,
Stephan Barta
Affiliations:
Montefiore Medical Center,Bronx,United States
,
Irwindeep Sandhu
Affiliations:
University of Alberta Hospital,Edmonton,Canada
,
Olga Frankfurt
Affiliations:
Northwestern University,Chicago,United States
,
Marc Gautier
Affiliations:
Dartmouth-Hitchcock Medical Center,Lebanon,United States
,
Melissa Larson
Affiliations:
Rush University Medical Center,Chicago,United States
,
Karen Seiter
Affiliations:
New York Medical College,Hawthorne,United States
,
Moshe Levy
Affiliations:
Baylor Charles A. Sammons Cancer Center,Dallas,United States
,
Julie Bergeron
Affiliations:
University of Montreal, Hopital Maisonneuve-Rosemont,Montreal,Canada
,
Jesus Berdeja
Affiliations:
Sarah Cannon Research Institute,Nashville,United States
,
Patricia Kropf
Affiliations:
Temple BMT Program, Jeanes Hospital,Philadelphia,United States
,
Lynn Shemanski
Affiliations:
Cancer Research And Biostatistics,Seattle,United States
,
Daniel Ryan
Affiliations:
University of Rochester,Rochester,United States
,
Michael Chiarella
Affiliations:
Celator Pharmaceuticals,Ewing,United States
,
Kimberly Paulsen
Affiliations:
Celator Pharmaceuticals,Ewing,United States
,
Arthur Louie
Affiliations:
Celator Pharmaceuticals,Ewing,United States
Bruno Medeiros
Affiliations:
Stanford University,Stanford,United States
EHA Learning Center. Lancet J. Jun 11, 2016; 135258
Jeffrey Lancet
Jeffrey Lancet
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Abstract
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Abstract: S502

Type: Oral Presentation

Presentation during EHA21: On Saturday, June 11, 2016 from 16:15 - 16:30

Location: Hall A3

Background
CPX-351 is a nano-scale liposomal formulation of 5:1 molar ratio cytarabine and daunorubicin that exhibits marked efficacy improvements among poor risk AML patients.  A phase III study of CPX-351 vs. 7+3 treatment in older high-risk (e.g. secondary) AML patients is nearing completion (NCT01696084).

Aims
This report correlates induction response (CR+CRi) with baseline FLT3 ITD/TKD+, NPM1+, and CEBPA+ mutations from the Phase III study.

Methods
Patients 60-75 years of age with t-AML, MDSAML, CMMLAML and de novo AML with MDS cytogenetic abnormalities were eligible for this open label randomized study.  153 patients were randomized to CPX-351 (100 units/m2, days 1, 3, and 5) and 156 patients to 7+3 (cytarabine 100 mg/m2/day x 7 days, daunorubicin 60 mg/m2 days 1, 2, and 3) induction.  Data for response was reviewed independently and in a blinded manner by the study’s hematopathologist.  Patients were assessed at baseline for FLT3, NPM1, and CEBPA mutations.

Results
Mutation status was determined in 278/309 (90%) patients for FLT3 ITD, 275/309 (89%) for FLT3 TKD, 282/309 (91%) for NPM1, and 270/309 (87%) for CEBPA.  FLT3 mutations (ITD+ and/or TKD+) were found in 44 (16%) patients.  Mutations occurred in 26 pt (9%) for NPM1, and 15 pt (6%) for CEBPA.  The complete remission data stratified by FLT3 ITD+, FLT3 TKD+, NPM1+, and CEBPA+ status are presented in the table below.
 CR+CRi Rate n(%) 
Group:CPX-351 Arm7+3 Armp-value
All patients73/153 (47.7)52/156 (33.3) 
FLT3 mutated (all)15/22 (68.2)6/22 (27.3)0.0148
FLT3 ITD+/TKD-10/16 (62.5)2/11 (18.2) 
FLT3 ITD+/TKD+2/3 (66.7)1/3 (33.3) 
FLT3 ITD-/TKD+3/3 (100)3/8 (37.5) 
FLT3 ITD+/NPM1-8/15 (53.3)2/11 (18.2) 
NPM-1mutated (all)12/13 (92.3)7/13 (53.9) 
NPM1+/FLT3 wt5/6 (83.3)6/7 (85.7) 
NPM1+/FLT3 mutated6/6 (100)1/5 (20.0) 
NPM1+/FLT3 unknown1/1 (100)0/1 (0.0) 
CEBPA mutated (all)3/11 (27.3)1/4 (25.0) 
Compared to control, CPX-351 treatment produced higher response rates among all patients (47.7% vs. 33.3%), all FLT3 mutated patients (68.2% vs. 27.3%, p=0.148), FLT3 ITD+ patients (12/19 (63.2%) vs. 3/14 (21.4%)), FLT3 TKD+ patients (5/6 (83.3%) vs. 4/11 (36.4%)), and NPM1+ patients (92.3% vs. 53.9%).  Most FLT3 ITD+ patients were NPM1- (26/33, 78.8%) with responses in 8/15 (53.3%) CPX-351 vs. 2/11 (18.2%) in 7+3 patients. 

Conclusion
Treatment with CPX-351 appears to be associated with improved response rates in patients with common AML mutations, including those associated with poor outcomes, such as FLT3 ITD mutations.  Preliminary findings from cytotoxicity assays using fresh AML patient blasts suggest that AML blasts exhibiting FLT3 ITD mutations were more sensitive to CPX-351 than FLT3 WT blasts.  Moreover, increased cytotoxicity was associated with increased uptake of CPX-351 liposomes by AML blasts.  While the clinical findings are based on small patient numbers, the remission data presented here, combined with the early preclinical data provide a provocative hypothesis for how CPX-351 might be advantageous for specific types of AML mutations and provide a rationale for expanded trials of CPX-351, particularly in the FLT3 ITD mutated population, which is expected to respond poorly to conventional treatment regimens.

Session topic: New Compounds in AML Treatment

Keyword(s): FLT3, Phase III, Randomized
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