Clofarabine Plus Cytarabine May Provide Less Toxic Option for Newly Diagnosed Pediatric Patients With AML

For children newly diagnosed with acute myeloid leukemia (AML), treatment with a combination of clofarabine plus cytarabine was associated with similar survival rates when compared with treatment with high-dose cytarabine, daunorubicin, and etoposide (HD-ADE). The results, which were published in the Journal of Clinical Oncology, indicate that clofarabine plus cytarabine could represent an alternative, effective, and less toxic induction therapy for these patients.

“We are excited by this result because the successful reduction of daunorubicin exposure by 150 mg/m2 is not trivial and promises to improve quality of life and perhaps long-term survival of our patients,” study author Jeffrey E. Rubnitz, MD, PhD, of St. Jude Children’s Research Hospital and the University of Tennessee Health Science Center, told ASH Clinical News. “Our results also suggest that poor response to initial treatment can be overcome by the use of a different subsequent treatment course. Thus, minimal residual disease (MRD) levels after one course of therapy are not always an accurate surrogate endpoint for long-term outcome as long as another effective treatment is available.”

This randomized phase III trial enrolled a total of 262 pediatric patients with untreated AML who were younger than 22 years of age. Participants were randomized to receive one of the following induction regimens:

  • clofarabine + cytarabine: clofarabine 52 mg/m2 on days 1-5 plus cytarabine 1 g/m2 on days 1-5 (n=129)
  • HD-ADE: high-dose cytarabine 3 g/m2 every 12 hours on days 1, 3, and 5 plus daunorubicin 50 mg/m2 on days 2, 4, and 6, and etoposide 100 mg/m2 on days 2-6 (n=133)

In the second induction phase, patients received low-dose ADE, consisting of cytarabine (100 mg/m2 every 12 hours on days 1-8) with the same daunorubicin and etoposide doses given in the first induction phase. A subset of patients with higher-risk disease (defined as high-risk cytogenetics or greater MRD burden) also received sorafenib 400 mg/m2 per day starting on day 9 for 21 doses (if they had FLT3-ITD mutation) or vorinostat 300 mg/m2 per day on days -2, -1, and zero (if they did not have FLT3-ITD mutation).

Consolidation therapy comprised two or three additional courses of chemotherapy (for patients with low-risk or standard-risk AML) or hematopoietic cell transplantation (HCT; for patients with high-risk AML).

Baseline characteristics were similar between the clofarabine and HD-ADE groups; median ages were 9.4 years (range = 0.05-20.3) and 9.9 years (range = 0.29-19.9), respectively, and similar proportions of patients had high-risk genetics.

Of the 121 patients in each treatment group who were evaluable for MRD at day 22 (the study’s primary endpoint), 57 in the clofarabine group (47%) and 42 in the HD-ADE group (35%) were MRD-positive. This translated to an 86% higher likelihood that patients treated with clofarabine would have MRD positivity, compared with the HD-ADE group (p=0.04). However, following the completion of the induction II phase, there was no significant difference in MRD positivity between the groups (20% with clofarabine vs. 14% with HD-ADE; odds ratio = 1.62; 95% CI 0.72-3.67; p=0.26).

Despite the greater prevalence of MRD-positivity on day 22 among clofarabine-treated patients, the morphologic complete remission rates after two courses of induction therapy also did not differ significantly between the two groups: 93.0% versus 92.5% (p=1.0).

Similarly, there were no significant differences between the clofarabine and HD-ADE groups in:

  • 3-year event-free survival rates: 52.9% vs. 52.4% (p=0.95)
  • 3-year cumulative incidence of relapse: 25.3% vs. 28.6% (p=0.54)
  • 3-year overall survival rate: 74.8% vs. 64.6% (p=0.1)

Also, no significant differences were found between the clofarabine and HD-ADE groups in 30-day mortality (0.8% vs. 2.2%; p=0.16) and refractory leukemia (6.0% vs. 5.3%; p=0.77).

The authors also noted that, among patients who were MRD-negative at day 22 of induction, event-free and overall survival rates were similar between treatment groups.

However, they found that regardless of achieving early MRD negativity, patients treated with clofarabine appeared to have better survival outcomes. For example, among patients who were MRD-positive at day 22, clofarabine-treated participants had a better subsequent three-year overall survival rate than those who received HD-ADE (62.2% vs. 42.7%; p=0.03), and, of those who remained MRD-positive after both induction phases, clofarabine-treated patients had “markedly better” three-year overall-survival (47.9% vs. 6.2%; p<0.01).

These results show that “one must use caution when applying MRD after one course of therapy as a surrogate endpoint for determining superiority between treatment regimens,” the investigators wrote. “The explanation for the excellent outcome among patients treated in the [clofarabine] arm despite high day-22 MRD levels is multifactorial and may include small differences in treatment-related mortality, outcome after HCT, and salvage rates after relapse.”

A major limitation of the trial was the lack of a long-term follow-up. “Thus, the impact of the reduction in anthracycline exposure on long-term cardiac health and survival has yet to be determined,” Dr. Rubnitz commented. “Toward this end, we believe that clofarabine is warranted to be studied further in childhood AML, not only to confirm our findings but to determine if it can replace additional doses of daunorubicin and etoposide.”

The authors report relationships with Genzyme, which sponsored this study.

Reference

Rubnitz JE, Lacayo NJ, Inaba H, et al. Clofarabine can replace anthracyclines and etoposide in remission induction therapy for childhood acute myeloid leukemia: the AML08 multicenter, randomized phase III trial. J Clin Oncol. 2019;37:2072-81.

SHARE