Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial

Abstract

Background: Although survival of children with acute lymphoblastic leukaemia has improved greatly in the past two decades, the outcome of those who relapse has remained static. We investigated the outcome of children with acute lymphoblastic leukaemia who relapsed on present therapeutic regimens.

Methods: This open-label randomised trial was undertaken in 22 centres in the UK and Ireland and nine in Australia and New Zealand. Patients aged 1-18 years with first relapse of acute lymphoblastic leukaemia were stratified into high-risk, intermediate-risk, and standard-risk groups on the basis of duration of first complete remission, site of relapse, and immunophenotype. All patients were allocated to receive either idarubicin or mitoxantrone in induction by stratified concealed randomisation. Neither patients nor those giving interventions were masked. After three blocks of therapy, all high-risk group patients and those from the intermediate group with postinduction high minimal residual disease (≥10(-4) cells) received an allogenic stem-cell transplant. Standard-risk and intermediate-risk patients with postinduction low minimal residual disease (<10(-4) cells) continued chemotherapy. The primary outcome was progression-free survival and the method of analysis was intention-to-treat. Randomisation was stopped in December, 2007 because of differences in progression-free and overall survival between the two groups. This trial is registered, reference number ISCRTN45724312.

Findings: Of 239 registered patients, 216 were randomly assigned to either idarubicin (109 analysed) or mitoxantrone (103 analysed). Estimated 3-year progression-free survival was 35·9% (95% CI 25·9-45·9) in the idarubicin group versus 64·6% (54·2-73·2) in the mitoxantrone group (p=0·0004), and 3-year overall survival was 45·2% (34·5-55·3) versus 69·0% (58·5-77·3; p=0·004). Differences in progression-free survival between groups were mainly related to a decrease in disease events (progression, second relapse, disease-related deaths; HR 0·56, 0·34-0·92, p=0·007) rather than an increase in adverse treatment effects (treatment death, second malignancy; HR 0·52, 0·24-1·11, p=0·11).

Interpretation: As compared with idarubicin, mitoxantrone conferred a significant benefit in progression-free and overall survival in children with relapsed acute lymphobastic leukaemia, a potentially useful clinical finding that warrants further investigation.

Funding: Cancer Research UK, Leukaemia and Lymphoma Research, Cancer Council NSW, and Sporting Chance Cancer Foundation.

Figure 1

Risk stratification (A) and trial design (B) (A) Stratification according to immunophenotype, site of relapse, and time to relapse. Risk groups: very early refers to less than 18 months from first diagnosis; early refers to 18 months or more after first diagnosis and less than 6 months from stopping therapy; and late refers to 6 months or more after stopping therapy. (B) MRD sampling TPs are marked. At TP1, standard-risk and intermediate-risk patients with MRD lower than 10⁻⁴ cells were ineligible, and high-risk and intermediate-risk patients with MRD of 10⁻⁴ cells or more were eligible for allo-SCT. Localised radiotherapy was given to those with extramedullary disease and not proceeding to allo-SCT. When MRD assessment was not possible in intermediate-risk patients, allo-SCT was allowed provided relapse occurred within 24 months of stopping therapy. Details of the phases are provided in table 1. MRD=minimal residual disease. TP=timepoint. Allo-SCT=allogenic stem-cell transplant.

Figure 2

Trial profile All patients were scheduled to receive two doses of anthracycline. Data for having received the drug were not available for 12 patients, six in each group.

Figure 3

Kaplan Meier estimates of progression-free (A) and overall (B) survival by randomised treatment 3-year estimated survival percentages (95% CI) are presented.

Figure 4

Randomised drug effect on progression-free survival by patient characteristics, from Cox models with interactions p values for interaction test the hypothesis that the randomised treatment effect varies between the different subgroups. Hazard ratios indicate that all subgroups show a treatment effect favouring mitoxantrone. HR=hazard ratio. MRD=minimal residual disease. Cyto=cytogenetic subgroups. *Poor refers to poor outcome after relapse (webappendix p 2).