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217 North American Leukemia‚ Intergroup Phase III Randomized Trial of Single Agent Clofarabine As Induction and Post-Remission Therapy‚ and Decitabine As Maintenance Therapy in Newly-Diagnosed Acute Myeloid Leukemia in Older Adults (Age ≥60 Years): A Trial of the ECOG-ACRIN Cancer Research Group (E2906)Clinically Relevant Abstract

Acute Myeloid Leukemia: Commercially available Therapy, excluding Transplantation
Program: Oral and Poster Abstracts
Type: Oral
Session: 615. Acute Myeloid Leukemia: Commercially available Therapy, excluding Transplantation: New Approaches Using Older Drugs
Sunday, December 6, 2015: 9:30 AM
W109, Level 1 (Orange County Convention Center)

James M. Foran, MD1, Zhuoxin Sun, PhD2*, David F. Claxton, MD3, Hillard M. Lazarus, MD4, Mary L. Thomas, RN, MS5*, Ari Melnick, MD6, Ross L. Levine, MD7, Elisabeth Paietta, PhD8, Daniel Arber9, Yangming Zhang, MD10*, Jacob M. Rowe, MD11, John E. Godwin, MD, MS12, Jessica K. Altman, MD13, Selina Luger, MD14, Aref Al-Kali, MD15, Hong Zheng, MD, PhD16, Keith Pratz, MD17, E. Randolph Broun, MD18, Bayard L. Powell, MD19, Kristen O'Dwyer, MD20*, Mark R Litzow, MD21 and Martin S Tallman, MD7

1Mayo Clinic Cancer Center, Jacksonville, FL
2Dana-Farber Cancer Institute, Boston, MA
3Penn State Hershey Cancer Institute, Hershey, PA
4Ireland Cancer Center, University Hospitals of Cleveland Case Medical Center, Cleveland, OH
5VA Palo Alto Health Care System, Palo Alto, CA
6Department of Medicine, Weill Cornell Medical College, New York, NY
7Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
8Cancer Center, The North Division of Montefiore Medical Center, Bronx, NY
9Department of Pathology, Stanford University School of Medicine, Palo Alto, CA
10Cytogenetics, Northwestern University, Chicago, IL
11Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel
12Providence Onc/Hem Care Clinic, Portland, OR
13Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL
14Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
15Mayo Clinic, Rochester, MN
16Department of Medicine, Penn State Hershey Medical Center, Hershey, PA
17Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
18The Jewish Hospital, Cincinnati, OH
19Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC
20James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY
21Division of Hematology, Mayo Clinic, Rochester, MN

Background: Induction therapy with daunorubicin (Dauno) & cytarabine (Ara-C) [DA] has been the standard of care for eligible older adults (age ≥ 60 years) with newly diagnosed acute myeloid leukemia (AML) for over 2 decades. Single agent Clofarabine (CLO) induction & consolidation (Consol.) therapy has demonstrated important clinical activity in this age group in large phase II studies. Lower induction mortality (IM) & similar reported complete remission rate (CR) & overall survival (OS), as well as notable activity in those with higher risk disease features [including unfavorable cytogenetics, therapy-related AML (t-AML) & prior antecedent hematologic disorder (AHD)] raises the possibility that a non-Ara-C-based regimen could achieve similar or superior OS with lower toxicity.

Methods: We performed a randomized United States Intergroup Phase III trial of single agent CLO [30mg/m2 x 5 days induction; 20 mg/m2 re-induction (if indicated) & 2 cycles Consol.] vs. standard DA therapy [Dauno 60mg/m2 D1-3 & Ara-C 100mg/m2 D1-7 induction x 1-2 cycles; 2 cycles Consol. with Ara-C (1.5g/m2 Q12hrs D1-6 age 60-69; once daily if age 70+)] in patients (pts) age ≥ 60 yrs with newly diagnosed AML. Patients with serum creatinine >1.0 (or GFR <60 mL/min) and those with AML-M3 and ECOG performance status >3 (PS>2 if age 70+ yrs) were excluded. Randomization was stratified by age (60-69 vs. 70+), t-AML, & AHD. Pts with HLA-matched donor were eligible for allogeneic transplantation (AlloHCT) after induction, and those completing Consol. were eligible for randomization #2 (R#2) to maintenance decitabine [20mg/m2 x 3D, monthly x 1 year] versus observation. With a target accrual of 747, E2906 was powered to determine non-inferiority [and possible superiority] of CLO vs. standard DA, and primary endpoint was OS. A weighted statistical analysis was performed to account for confounding impact of R#2. AlloHCT patients were censored at transplant in this analysis. Responses & cytogenetics were confirmed centrally and OS & CR rates were monitored by an independent Data Safety Monitoring Committee (DSMC) at pre-specified time points.

Results: As of Feb 23, 2015, 727 pts were randomized. Median age was 68 years (range 60-86); 57% were male, and 38% were age ≥70 yrs. Treatment arms are well balanced for all baselineclinical & AML characteristics, & 30% had unfavorable cytogenetics. Of 659 with complete treatment information reported, 30.4% on DA vs. 40.1% on CLO received 2 cycles of induction (p=0.006). 

Median follow-up of surviving patients is 7.6 months.

Table 1 shows early treatment results (CR, toxicity) for the 686 pts randomized as of Dec 23, 2014 (2 months prior to study end, & excluding 90 with ongoing response evaluation).

Table 1








30-day mortality




60-day mortality




Gr 4-5 Non-Heme Tox.





Gr 4-5 Non-Heme Tox.





374 pts have died (174, DA; 200, CLO) & significantly inferior OS was observed for CLO vs. DA [Hazard Ratio (HR) 1.41 (95% CI 1.12-1.78)] (Fig. 1). Planned subgroup analyses were performed (Table 2) demonstrating significant differences in OS after CLO for patients age 60-69 yrs, without AHD, & with intermediate risk cytogenetics; but not for those with Unfav. Cytogen. (Fig. 2) or t-AML.Based on the primary weighted analysis, DSMC recommended suspension of new accrual to E2906 on Feb 23, 2015 & all active patients on CLO were transitioned to DA Arm.

Table 2


HR CLO/Standard (95% CI)

*Weighted OS


1.41 (1.12-1.78)

Unweighted OS


1.23 (1.00-1.50)

Age 60-69


1.48 (1.10-1.99)

Age 70+


1.34 (0.93-1.93)

Intermed. Risk Cytogen.


1.77 (1.27-2.47)

Unfav. Risk Cytogen.


0.96 (0.65-1.43)



1.46 (1.13-1.89)



1.22 (0.74-2.00)

De novo AML


1.52 (1.18-1.96)

Therapy-related AML


0.94 (0.54-1.61)

Conclusions: Despite similar CR & IM, OS after single agent CLO is inferior to standard DA therapy for pts age ≥60 years with newly diagnosed AML who are fit for intensive therapy, and DA remains the standard of care.  However no difference in OS was observed after CLO in some pre-specified high risk AML subgroups. R#2 & AlloHCT arms continue in E2906 for pts already enrolled. Embedded prospective minimal residual disease study at CR is being performed to identify pts at higher risk after CLO & DA.

Fig. 1. Weighted Kaplan-Meier Curves for OS

Text Box: Fig. 1. Weighted Kaplan-Meier Curves for OS

Fig. 2. Unfavorable Cytogenetics OS by Therapy

Text Box: Fig. 2. Unfavorable Cytogenetics OS by Therapy

Disclosures: Foran: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding . Off Label Use: Use of clofarabine in AML, and maintenance therapy with decitabine in AML. Claxton: Medimmune: Research Funding ; BMS: Consultancy ; Astellas: Research Funding ; Cyclacel: Research Funding ; Merck: Research Funding ; Ambit: Research Funding . Levine: Loxo Oncology: Membership on an entity’s Board of Directors or advisory committees ; CTI BioPharma: Membership on an entity’s Board of Directors or advisory committees ; Foundation Medicine: Consultancy . Altman: Seattle Genetics: Consultancy ; BMS: Consultancy ; Spectrum: Consultancy ; Astellas: Consultancy ; Ariad: Consultancy ; Novartis: Consultancy . Al-Kali: Novartis: Research Funding .

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