Long-Term Follow-Up Confirms Benefit of High-Dose Daunorubicin Across Molecular and Cytogenetic Groups of AML Patients

In a long-term follow-up of the Eastern Cooperative Oncology Group−American College of Radiology Imaging Network Cancer Research Group (ECOG-ACRIN) E1900 study, researchers found that treatment with high-dose daunorubicin (90 mg/m2) resulted in increased overall survival (OS) and event-free survival (EFS; primary endpoints) across a variety of subgroups of patients with acute myeloid leukemia (AML).

The original results of the ECOG-ACRIN E1900 study, published in 2009, indicated that standard-dose daunorubicin (45 mg/m2) led to increased rates of complete remission (CR) and improved OS. A subgroup analyses conducted at that time identified several factors associated with achieving clinical benefit (including age <50 years, intermediate cytogenetics, FLT3-ITD-negative type AML), as well as other variables associated with poor response, including age ≥50 years, unfavorable cytogenetics, and the presence of FLT3-ITD mutations.

In the follow-up study, Marlise R. Luskin, MD, from the Division of Hematology and Oncology at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, and colleagues evaluated longer-term outcomes for the 657 patients ranging in age from 17 to 60 with de novo untreated AML who were enrolled in ECOG-ACRIN E1900 between December 2002 and November 2008. Eligible patients received either standard or high-dose daunorubicin for three days in combination with cytarabine. The researchers examined the efficacy of high-dose daunorubicin based on patient age, cytogenetic risk, and genetic mutations.

The median patient age was 48 years, and 45.2 percent of patients were 50 years or older.

Patients’ pre-treatment cytogenetic risks were classified as one of the following:

  • Favorable: 13.6%
  • Intermediate: 40.9%
  • Unfavorable: 18.6%
  • Indeterminate: 26.9%

Patients were also classified based on the presence of the following genetic mutations:

  • FLT3-ITD (previously examined in ECOG-ACRIN E1900)
  • MLL-PTD (previously examined in ECOG-ACRIN E1900)
  • NPM1
  • DNMT3A

After a median follow-up of 80.1 months (range = 0.8-120.4 months), the median OS was longer for patients in the high-dose cohort compared with the standard-dose cohort (25.4 months vs. 16.6 months; p=0.001; Table).

In the younger patient cohort (<50 years), high-dose daunorubicin was associated with better OS compared with the standard dose (44.7 vs. 20.7 months; p=0.002), though a significant benefit of high-dose daunorubicin was not confirmed in the older patient population (≥50 years).

Treatment with high-dose daunorubicin also benefited patients with favorable-risk and intermediate-risk cytogenetics, leading to a longer median OS than the standard dose in both groups (not reached vs. 39.4 months for favorable-risk [p=0.03] and 33.5 vs. 20.1 for intermediate-risk [p=0.01]). Although results from the multivariate analysis (which adjusted for sex, age, hemoglobin level, leukocyte count, platelet count, and cytogenetic profile) suggested a benefit in those with unfavorable cytogenetic risk, with the median OS increasing slightly from 10.2 months to 10.6 months (p=0.22), a larger study focused on this patient population is needed to confirm this benefit, the authors noted.

Patients with the NPM1-, DNMT3A-, and FLT3-ITD mutations had an improved CR rate with high-dose daunorubicin, though no significant CR or OS benefit could be confirmed in MLL-PTD-mutated patients (Table).

High-dose daunorubicin was particularly beneficial in patients with NPM1-mutated AML, increasing the median OS from 16.9 months to 75.9 months and increasing the four-year OS by more than 20 percent (from 29% to 52%). The favorable prognosis associated with the presence of an NPM1 mutation is uniquely associated with higher-dose therapy, the authors added.

“These updated results of the E1900 trial demonstrate the broad ability of anthracycline intensification during induction to improve OS in patients age 60 or younger with de novo AML, including those with favorable and intermediate cytogenetics and those with mutations in FLT3-ITD, NPM1, and DNMT3A,” Dr. Luskin and colleagues wrote.

In all patients, high-dose daunorubicin was not associated with additional toxicities, according to the authors.

“[Given these results] we suggest that high-dose daunorubicin be the standard for all eligible adult patients up to 60 years of age and be the standard of comparison for future clinical trials,” Dr. Luskin and colleagues concluded. “As we enter an era of targeted therapy, including for FLT3-ITD-mutant AML in the upfront setting, it is important that these agents be tested in the context of optimal chemotherapy.”

The authors cautioned that the results of the study should be interpreted carefully due to the rarity of these mutation incidences.

The study also lacks data on FLT3-ITD allelic ratio, thus the benefit of high-dose daunorubicin in this patient subgroup requires further investigation. This follow-up study was also a secondary analysis of some results that have been reported previously.


Reference

Luskin MR, Lee JW, Fernandez HF, et al. Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups. Blood. 2016;172:1551-58.

TABLE. Median Overall Survival Among Patient Subgroups (Multivariable Analysis)*
Standard-Dose Daunorubicin(45 mg/m2/day) High-Dose Daunorubicin(90 mg/m2/day) p Value Hazard Ratio (95% CI)
Subgroup CR rate Median OS in months 4-year OS CR rate Median OS in months 4-year OS    
All patients 59% 16.6(n=246/330) 31% 71% 25.4(n=207/327) 39% 0.001 0.74(0.61-0.89)
Age
<50 years 61% 20.7(n=133/188) 35% 73% 44.7(n=96/172) 48% 0.02 0.67(0.52-0.88)
≥50 years 56% 12.6(n=113/142) 25% 68% 17.6(n=111/155) 28% 0.12 0.82(0.63-1.07)
Cytogenetic Risk
Favorable 84% 39.4(n=24/38) 46% 80% NR(n=19/51) 64% 0.02 0.44(0.24-0.82)
Intermediate 56% 20.1(n=101/141) 35% 77% 33.5(n=71/127) 45% 0.01 0.75(0.55-1.03)
Indeterminate 62% 14.3(n=66/91) 29% 67% 21.3(n=62/85) 29% 0.47 0.89(0.63-1.27)
Unfavorable 44% 10.2(n=54/59) 14% 57% 10.6(n=54/63) 19% 0.22 0.66(0.44-0.98)
Gene Mutation
NPM1 60% 16.9(n=50/65) 29% 89% 75.9(n=31/65) 52% 0.002 0.51(0.32-0.81)
FLT3-ITD 48% 10.1(n=74/83) 17% 70% 15.2(n=44/64) 28% 0.009 0.50(0.32-0.77)
DNMT3A 61% 14.1(n=55/61) 13% 79% 16.5(n=40/58) 33% 0.02 0.67(0.42-1.05)
MLL-PTD 56% 16.2(n=16/16) 6% 60% 20.6(n=10/15) 33% 0.056 0.60(0.24-1.54)
*Adjusted for sex, age, hemoglobin level, leukocyte count, platelet count, and cytogeneticsCR = complete remission; OS = overall survival; HR = hazard ratio; CI = confidence interval; NR = not reached

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