Defining the Optimal Total Number of Chemotherapy Courses in Younger Patients With Acute Myeloid Leukemia: A Comparison of Three Versus Four Courses

Abstract

Purpose: The optimum number of treatment courses for younger patients with acute myeloid leukemia (AML) is uncertain. The United Kingdom National Cancer Research Institute AML17 trial randomly assigned patients who were not high risk to a total of three versus four courses.

Patients and methods: Patients received two induction courses based on daunorubicin and cytarabine (Ara-C), usually with gemtuzumab ozogamicin. Following remission, 1,017 patients were randomly assigned to a third course, MACE (amsacrine, Ara-C, and etoposide), plus a fourth course of MidAc (mitoxantrone and Ara-C) and following an amendment to one or two courses of high-dose Ara-C. Primary end points were cumulative incidence of relapse (CIR), relapse-free survival (RFS), and overall survival (OS). Outcomes were correlated with patient characteristics, mutations, cytogenetics, induction treatments, and measurable residual disease (MRD) postinduction.

Results: In logrank analyses, CIR and RFS at 5 years were improved in recipients of four courses (50% v 58%: hazard ratio [HR] 0.81 [0.69-0.97], P = .02 and 43% v 36%: HR 0.83 [0.71-0.98], P = .03, respectively). While OS was not significantly better (63% v 57%: HR 0.84 [0.69-1.03], P = .09), the noninferiority of three courses to four courses was not established. The impact on relapse was only significant when the fourth course was Ara-C. In exploratory analyses, although MRD impacted survival, a fourth course had no effect in either MRD-positive or MRD-negative patients. A fourth course was beneficial in patients who lacked a mutation of FLT3 or NPM1, had < 3 mutations in other genes, or had a presenting WBC of < 10 × 10⁹ L^-1.

Conclusion: Although a fourth course of high-dose Ara-C reduced CIR and improved RFS, it did not result in a significant OS benefit. Subsets including those with favorable cytogenetics, those lacking a mutation of FLT3 or NPM1, or those with < 3 other mutations may derive survival benefit.

FIG 1.

Protocol flow diagram. *Following closure of the CEP-701 randomly assigned, patients were guided by risk score to either poor risk or nonpoor risk options. **Following closure of the mTOR inhibition random assignment, patients in this group received DA 50mg alone. ***Following closure of the D Clofarabine arm, patients were recommended to receive FLAG-Ida (which was also the case if renal criteria were not met). †Following closure of the high-dose daunorubicin arm, patients were allocated DA60. ADE, Ara-C, daunorubicin, and etoposide; APL, acute promyelocytic leukemia; CBF, core binding factor; DA, daunorubicin and Ara-C; FLAG-Ida, fludarabine, Ara-C, granulocyte colony-stimulating factor, and idarubicin; GO, gemtuzumab ozogamicin; MACE, amsacrine, Ara-C, and etoposide; MidAc, mitoxantrone and Ara-C; mTor, mammalian target of Rapamicin.

FIG 2.

CONSORT diagram. AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; CR, complete remission; mTor, mammalian target of Rapamicin.

FIG 3.

Cumulative incidence of relapse. AML, acute myeloid leukemia; CIR, cumulative incidence of relapse; HR, hazard ratio; MACE, amsacrine, Ara-C, and etoposide; MidAc, mitoxantrone and Ara-C.

FIG 4.

Overall survival. AML, acute myeloid leukemia; HR, hazard ratio; MACE, amsacrine, Ara-C, and etoposide; MidAc, mitoxantrone and Ara-C.

FIG 5.

Effect of measurable residual disease (MRD). AML, acute myeloid leukemia; HR, hazard ratio.

FIG 6.

Analysis stratified by mutation status. AML, acute myeloid leukemia; ITD, internal tandem duplication; OR, odds ratio; TKD, tyrosine kinase domain; WT, wild type.

FIG A1.

Patients' score derived from multiplying each relevant characteristic by the value derived from the Cox model: 0.01325*age (in years) + 0.16994*sex (1 = male, 0 = female) + 0.22131*diagnosis (1 = de novo, 2 secondary) + 0.65082*cytogenetics (1 = favorable, 2 = intermediate, 3 adverse) + 0.19529*status post C1 (1 = complete remission, 2 = partial remission, 3 = no response) + 0.00169* WBC (x109/l). Distribution of patients in MRC AML10,12 trials by index: Taking into account the apparent bimodality of the curve, patients with an index of 2 or below were deemed good risk, and the data were arbitrarily divided at the 75th centile between standard and poor risk. Survival index from complete remission in AML10,12 according to the risk groups was validated on data from MRC AML15 Trial.⁵

FIG A2.

Relapse-free survival (RFS). AML, acute myeloid leukemia; CR, complete remission; MACE, amsacrine, Ara-C, and etoposide; MidAc, mitoxantrone and Ara-C.

FIG A3.

Stratified analysis of relapse-free survival. AML, acute myeloid leukemia; CR, complete remission; MACE, amsacrine, Ara-C, and etoposide; MidAc, mitoxantrone and Ara-C; MRD, measurable residual disease; OR, odds ratio.

FIG A4.

Stratified analysis of overall survival. AML, acute myeloid leukemia; CR, complete remission; MACE, amsacrine, Ara-C, and etoposide; MidAC, mitoxantrone and Ara-C; OR, odds ratio.

FIG A5.

Analysis stratified by prior treatment and MRD status. ADE, Ara-C, daunorubicin, and etoposide; AML, acute myeloid leukemia; CR, complete remission; DA, daunorubicin and Ara-C; GO, gemtuzumab ozogamicin; MACE, amsacrine, Ara-C, and etoposide; MidAC, mitoxantrone and Ara-C; MRD, measurable residual disease; OR, odds ratio.

FIG A6.

Sanger sequencing.

FIG A7.

Analysis stratified by Sanger sequencing. AML, acute myeloid leukemia; OR, odds ratio.