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Randomized Controlled Trial
. 2025 Feb 20;43(6):694-704.
doi: 10.1200/JCO.24.00259. Epub 2024 Nov 18.

Treatment Intensification With Either Fludarabine, AraC, G-CSF and Idarubicin, or Cladribine Plus Daunorubicin and AraC on the Basis of Residual Disease Status in Older Patients With AML: Results From the NCRI AML18 Trial

Nigel H Russell  1 , Abin Thomas  2 , Robert K Hills  3 , Ian Thomas  2 , Amanda Gilkes  4 , Nuria Marquez Almuina  2 , Sarah Burns  2 , Lucy Marsh  2 , Paresh Vyas  5 , Marlen Metzner  5 , Nicholas McCarthy  6 , Georgia Andrew  7 , Jennifer Byrne  8 , Rob S Sellar  9 , Richard Kelly  10 , Paul Cahalin  11 , Ulrik Malthe Overgaard  12 , Priyanka Mehta  13 , Mike Dennis  14 , Steven Knapper  4 , Sylvie D Freeman  6
Affiliations
Randomized Controlled Trial

Treatment Intensification With Either Fludarabine, AraC, G-CSF and Idarubicin, or Cladribine Plus Daunorubicin and AraC on the Basis of Residual Disease Status in Older Patients With AML: Results From the NCRI AML18 Trial

Nigel H Russell et al. J Clin Oncol. .

Erratum in

Abstract

Purpose: To evaluate the survival benefit of chemotherapy intensification in older patients with AML who have not achieved a measurable residual disease (MRD)-negative remission.

Methods: Five hundred twenty-three patients with AML (median age, 67 years; range, 51-79) without a flow cytometric MRD-negative remission response after a first course of daunorubicin and AraC (DA; including 165 not in remission) were randomly assigned between up to two further courses of DA or intensified chemotherapy-either fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin (FLAG-Ida) or DA with cladribine (DAC).

Results: Overall survival (OS) was not improved in the intensification arms (DAC v DA: hazard ratio [HR], 0.74 [95% CI, 0.55 to 1.01]; P = .054; FLAG-Ida v DA: HR, 0.86 [95% CI, 0.66 to 1.12]; P = .270); OS at 3 years was 34%, 46%, and 42% for DA, DAC, and FLAG-Ida, respectively. Early deaths and other adverse events were more frequent with FLAG-Ida (9% day 60 deaths v 4% after DA or DAC; P = .032). Of patients entering random assignment, 131 had MRD unknown status. In this subgroup of patients lacking evidence of residual leukemia by flow cytometry, there was no detectable survival advantage from intensification. A planned sensitivity analysis excluding these patients demonstrated a survival benefit for both DAC (HR, 0.66 [95% CI, 0.46 to 0.93]; P = .018) and FLAG-Ida (HR, 0.72 [95% CI, 0.53 to 0.98]; P = .035); OS at 3 years was 30%, 46%, and 46% for DA, DAC, and FLAG-Ida, respectively. There was a concordant reduction in relapse (DAC v DA: HR, 0.66 [95% CI, 0.45 to 0.98]; P = .039; FLAG-Ida v DA: HR, 0.70 [95% CI, 0.49 to 0.99]; P = .042). DAC benefit was maintained when survival was censored for transplant (P = .042).

Conclusion: In this study of older patients with AML considered fit and with evidence of residual disease after first induction, chemotherapy intensification improved survival. DAC intensification was better tolerated than FLAG-Ida.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Figures

FIG 1.
FIG 1.
CONSORT diagram. Patients not randomly assigned had a higher frequency in >70 years age group (37% of 492 compared with 31% of 523 randomly assigned patients) and ECOG performance status (PS ≥2, 8.5% compared with 6% of randomly assigned patients, PS ≥1, 56% compared wth 49% of randomly assigned patients) at trial entry. aAlive at day 30. bBy flow cytometric MRD. CR, complete remission; CRi, CR with incomplete count recovery; DA, daunorubicin, Ara-C; ECOG, Eastern Cooperative Oncology Group; FLAG-Ida, fludarabine, AraC, G-CSF, and idarubicin; MRD, measurable residual disease; PS, performance status.
FIG 2.
FIG 2.
OS by random assignment. (A) DA versus FLAG-Ida. (B) DA versus DAC. (C) DA versus FLAG-Ida, excluding patients with unknown MRD status. (D) DA versus DAC, excluding patients with unknown MRD status. MRD unknown includes MRD unknown not in CR/CRi (Table 1; Data Supplement, Fig S2). CR, complete remission; CRi, CR with incomplete count recovery; DA, daunorubicin, Ara-C; DAC, DA with cladribine; FLAG-Ida, fludarabine/Ara-C/G-CSF/idarubicin; HR, hazard ratio; MRD, measurable residual disease; OS, overall survival.
FIG 3.
FIG 3.
CIR by random assignment excluding patients with unknown MRD status. (A) DA versus FLAG-Ida. (B) DA versus DAC. MRD unknown includes MRD unknown not in CR/CRi (Table 1; Data Supplement, Fig S2). Results from comparison of relapse by cause-specific HRs are DAC versus DA: HR, 0.62 (95% CI, 0.47 to 0.93); P = .019; FLAG-Ida versus DA: HR, 0.67 (95% CI, 0.47 to 0.95); P = .024. CIR, cumulative incidence of relapse; CR, complete remission; CRi, CR with incomplete count recovery; DA, daunorubicin/Ara-C; DAC, DA with cladribine; FLAG-Ida, fludarabine/Ara-C/G-CSF/idarubicin; HR, hazard ratio; MRD, measurable residual disease.
FIG 4.
FIG 4.
OS by random assignment censored for allogeneic transplant, all patients. (A) DA versus FLAG-Ida and (B) DA versus DAC. In transplanted patients, post-transplant NRM (with relapse considered as a competing risk) at 3 years was DA, 35%; FLAG-Ida, 26%; and DAC, 24% (OS by random assignment censored for allogeneic transplant, excluding patients with unknown MRD, is displayed in the Data Supplement, Fig S9). DA, daunorubicin/Ara-C; DAC, DA with cladribine; FLAG-Ida, fludarabine/Ara-C/G-CSF/idarubicin; HR, hazard ratio; MRD, measurable residual disease; NRM, nonrelapse mortality; OS, overall survival; ASCT, allogeneic stem-cell transplantation.
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