The efficacy of cytarabine and idarubicin in combination with clofarabine or fludarabine was similar in newly diagnosed AML patients – a phase II study

On 14^th July 2017, in an article published ahead of print in Cancer, Elias Jabbour and colleagues from The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas, reported results from their phase II randomized study (NCT01289457), which compared the safety and efficacy of idarubicin and cytarabine combined with nucleoside analogues clofarabine (CIA) or fludarabine (FIA) in newly diagnosed Acute Myeloid Leukemia (AML) patients.

In total, 182 AML patients were enrolled in this study between August 2011–June 2016. Patients were randomized to receive CIA (median age = 53 years [n = 106]) or FIA (median age = 49 years [n = 76]). The primary endpoint of the study was to compare the Event Free Survival (EFS) rates with CIA and FIA regimens. The secondary endpoints were Overall Survival (OS), Complete Remission (CR)/CR without platelet recovery (CRp) rates, and safety of the regimens.

The key results of the study were:

• CR/CRp rate in patients in the CIA and FIA arms; 80% vs 82%, P = 0.84
• Median EFS in patients in the CIA and FIA arms; 13 vs 12 months, P = 0.91
• Median OS in patients in the CIA and FIA arms; 24 months vs not reached, P = 0.23
• Adverse Events (AEs) were more associated with the CIA regimen compared to the FIA regimen including transaminase elevation (29% vs 4%), hyperbilirubinemia (26% vs 9%), and rash (29% vs 12%)
• 60-day mortality rate in patients in the CIA and FIA arm; 4% vs 1%, P = 0.32

The authors performed an exploratory analysis to compare the outcomes of patients treated in the CIA and FIA arms with a historical control. The historical cohort used included patients (n = 92) treated with idarubicin and cytarabine (IA) at the MDACC between December 2006–October 2011.

• 2-year EFS of patients aged < 50 years in the FIA (n = 36) and IA (n = 34) arms; 58% vs 30%, P = 0.05
• 2-year OS of patients aged < 50 years in the FIA and IA arms; 72% vs 36%, P = 0.009
• 2-year EFS of patients aged < 50 years in the CIA (n = 28) and IA arms (n = 34); 33% vs 30%, P = 0.79
• 2-year OS of patients aged < 50 years in the CIA and IA arms; 46% vs 36%, P = 0.23

In summation, CIA and FIA have similar efficacy in younger patients with newly diagnosed AML. Although, FIA was shown to be associated with a better toxicity profile than CIA. Additionally, compared to a historical cohort of patients treated with IA alone, “FIA resulted in improved outcomes in patients aged < 50 years”.

The authors concluded by suggesting that “the incorporation of fludarabine into AML regimens may improve outcomes in younger AML patients”. They further added that their study argues for the use of fludarabine rather than clofarabine in future nucleoside analog-containing investigational AML regimens”.

Abstract

BACKGROUD: Fludarabine and clofarabine are purine nucleoside analogues with established clinical activity in patients with acute myeloid leukemia (AML).

METHODS: Herein, the authors evaluated the efficacy and safety of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) in adults with newly diagnosed AML. Adults with newly diagnosed AML who were deemed suitable for intensive chemotherapy were randomized using a Bayesian adaptive design to receive CIA (106 patients) or FIA (76 patients). Patients received induction with idarubicin and cytarabine, plus either clofarabine or fludarabine. Responding patients could receive up to 6 cycles of consolidation therapy. Outcomes were compared with a historical cohort of patients who received idarubicin and cytarabine.

RESULTS: The complete remission/complete remission without platelet recovery rate was similar among patients in the CIA and FIA arms (80% and 82%, respectively). The median event-free survival was 13 months and 12 months, respectively (P = .91), and the median overall survival was 24 months and not reached, respectively (P = .23), in the 2 treatment arms. CIA was associated with more adverse events, particularly transaminase elevation, hyperbilirubinemia, and rash. Early mortality was similar in the 2 arms (60-day mortality rate of 4% for CIA vs 1% for FIA; P = .32). In an exploratory analysis of patients aged <50 years, FIA was found to be associated with improved survival compared with idarubicin and cytarabine (2-year event-free survival rate: 58% vs 30% [P = .05] and 2-year overall survival rate: 72% vs 36% [P = .009]).

CONCLUSIONS: CIA and FIA have similar efficacy in younger patients with newly diagnosed AML, although FIA is associated with a better toxicity profile.