General AML

Clofarabine-based consolidation in young adults with AML in first remission: results from the ALFA 0702 trial, CLARA

The standard option for post-remission chemotherapy in Acute Myeloid Leukemia (AML) patients is not very clear. To date, the use of High Dose cytarabine (HDAC) as consolidation therapy has been regarded as the standard option in AML patients. However, the optimum use of HDAC is unclear and outcomes from HDAC-based consolidation is far from satisfactory.1 In patients who have not received a transplant, new consolidation options are required to improve their outcomes. One of these agents is clofarabine, a deoxyadenosine nucleoside analog, which has been shown to be effective as a single agent or in combination with cytarabine in AML patients.2,3

In order to investigate whether Intermediate Dose cytarabine (IDAC) in combination with clofarabine (CLARA) may provide any benefit for younger AML patients (18–59 years) during post-remission, the Acute Leukemia French Association (ALFA) carried out a phase II randomized study where they compared the efficacy and safety of CLARA versus HDAC as post-remission chemotherapy in young patients with intermediate or unfavorable risk AML in CR1 and no identified donor for allogenic Stem Cell Transplantation (SCT). The primary endpoint of the study was Relapse Free Survival (RFS).1 The results of the study were published ahead of print on 21st February 2017 in the Journal of Clinical Oncology, by Xavier Thomas et al. from the Lyon-Sud University Hospital.

In this study, 221 AML patients (median age = 48 years) in CR1 were randomly assigned to receive either 3 consolidation cycles of HDAC (n = 114) or CLARA (n = 107). Among the randomly assigned patients, 110 patients (HDAC, n = 55; CLARA, n =55) found a donor and received SCT in CR1.

The key results of the study were:
  • 2-year RFS in patients that received CLARA and HDAC; 58.5% vs 46.5%, Hazard Ratio (HR) = 0.76, P = 0.13
  • For CLARA vs HDAC, the HR for RFS before or in the absence of SCT; 0.65, P = 0.041
  • 2-year RFS in patients that received SCT in CR1 in the CLARA arm and HDAC arm; 53.3% vs 31.0%, HR = 0.63, P = 0.043
  • 2-year Cumulative Incidence of Relapse (CIR) in patients that received CLARA and HDAC; 33.9% vs 46.4%, HR = 0.61, P = 0.025
  • There were more hematologic toxicities, infections, and non-hematologic grade 3–4 toxicity in the CLARA arm compared to the HDAC arm

In summation, consolidation with CLARA can prolong RFS in younger adult patients with AML in CR1. The effect of CLARA on RFS was mostly due to the reduced relapse incidence observed in this group of patients. Additionally, the authors noted that the toxicities associated with the CLARA combination “seemed acceptable” and these toxicities “did not translate into higher incidence of death in remission”.

Thomas et al. concluded by stating that “Although HDAC represented an advance in the early 1990s, it is certainly time for another move forward in AML chemotherapy. We have shown here that clofarabine-based consolidation may improve RFS in younger patients with intermediate- and unfavorable-risk AML as compared with HDAC”. The authors further suggested that CLARA combination may be considered as a good post-remission therapy for AML patients with intermediate- and unfavorable-risk AML, especially when a donor is unavailable at the time they achieved first remission. 

Abstract
Purpose

To evaluate the efficacy and safety of a clofarabine-based combination (CLARA) versus conventional high-dose cytarabine (HDAC) as postremission chemotherapy in younger patients with acute myeloid leukemia (AML).

Patients and Methods

Patients age 18 to 59 years old with intermediate- or unfavorable-risk AML in first remission and no identified donor for allogeneic stem-cell transplantation (SCT) were eligible. Two hundred twenty-one patients were randomly assigned to receive three CLARA or three HDAC consolidation cycles. The primary end point was relapse-free survival (RFS). To handle the confounding effect of SCT that could occur in patients with late donor identification, hazard ratios (HRs) of events were adjusted on the time-dependent treatment × SCT interaction term.

Results

At 2 years, RFS was 58.5% (95% CI, 49% to 67%) in the CLARA arm and 46.5% (95% CI, 37% to 55%) in the HDAC arm. Overall, 110 patients (55 in each arm) received SCT in first remission. On the basis of a multivariable Cox-adjusted treatment × SCT interaction, the HR of CLARA over HDAC before or in absence of SCT was 0.65 (95% CI, 0.43 to 0.98; P = .041). In a sensitivity analysis, when patients who received SCT in first remission were censored at SCT time, 2-year RFS was 53.3% (95% CI, 39% to 66%) in the CLARA arm and 31.0% (95% CI, 19% to 43%) in the HDAC arm (HR, 0.63; 95% CI, 0.41 to 0.98; P = .043). Gain in RFS could be related to the lower cumulative incidence of relapse observed in the CLARA arm versus the HDAC arm (33.9% v 46.4% at 2 years, respectively; cause-specific HR, 0.61; 95% CI, 0.40 to 0.94; P = .025). CLARA cycles were associated with higher hematologic and nonhematologic toxicity than HDAC cycles.

Conclusion

These results suggest that CLARA might be considered as a new chemotherapy option in younger patients with AML in first remission.

References
  1. Thomas X. et al. Randomized Phase II Study of Clofarabine-Based Consolidation for Younger Adults With Acute Myeloid Leukemia in First Remission. J Clin Oncol. 2017 Feb 21. DOI: 1200/JCO.2016.70.4551. [Epub ahead of print].
  2. Tiley S. & Claxton D. Clofarabine in the treatment of acute myeloid leukemia in older adults.Ther Adv Hematol. 2013 Feb; 4(1): 5–13. DOI: 1177/2040620712461666.
  3. Fozza C. The role of clofarabine in the treatment of adults with acute myeloid leukemia. Crit Rev Oncol Hematol. 2015 Mar; 93(3): 237–245. DOI: 1016/j.critrevonc.2014.10.009. Epub 2014 Oct 22.