The results from this trial clearly show that, compared with idarubicin, mitoxantrone significantly improves the outcome of children with relapsed acute lymphoblastic leukaemia. The trial ran across all 22 centres in the UK and Ireland and nine of ten centres in Australia and New Zealand. Although frontline protocols for both groups differ, the result of the randomisation was similar between the two study groups. summarises the outcomes in studies in children with relapsed acute lymphoblastic leukaemia. Randomised trials in this disorder are infrequent, and this trial reports a valuable result. Unique to this study were the randomisation of anthracyclines in induction and the choice of mitoxantrone as test drug. Although mitoxantrone was less toxic than idarubicin, the effect was mainly due to better disease control. For the UK, the 3-year overall survival of 69% achieved in the mitoxantrone group is a substantial improvement compared with the overall survival of 56% achieved in the preceding ALLR2 trial.4
Reported outcomes of trials in relapsed childhood acute lymphoblastic leukaemia
The decision to stop the randomisation was based on the significant difference in deaths between the two groups. Although we are aware of at least two other trials of childhood acute lymphoblastic leukaemia27,28
that reported early, they both recruited most of their target population. To our knowledge the closure of randomisation halfway through the trial, with this magnitude of difference attributable to one drug, is unheralded in clinical trials in childhood acute lymphoblastic leukaemia. Continuation of follow-up vindicates the decision by the data-monitoring committee to close the randomisation (webappendix p 2
). Early closure resulted in lower than calculated recruitment to the two groups of the study and the resulting disproportionate numbers within the subgroups. Nevertheless, within the limitations posed by the closure, we can be certain that mitoxantrone provided a significant survival advantage in our cohort of relapsed patients.
If the difference between the two drugs was mainly that of chemosensitivity, we would have expected to detect a difference in minimal residual disease at the first timepoint, which was not the case. To enable the quick assessment of the number of new drugs now in the pipeline, study designs are incorporating the use of minimal residual disease as a surrogate marker of outcome. If we had opted to use such a study design, mitoxantrone would have been discarded. Our experience is thus a caveat for trial designs that propose to use surrogate markers of therapeutic response, such as minimal residual disease, as a primary endpoint to assess treatment response in phase 2 and 3 trials.29,30
Both idarubicin and mitoxantrone are tissue bound after infusion and can be detected months later. Thus in the context of the results of this trial, mitoxantrone seemed to have a delayed cytotoxic effect. Mitoxantrone, unlike idarubicin, is an anthracenadione. Other than the differential action on topoisomerase II isoforms and quiescent cells, it also has the ability to create DNA adducts,31
stimulate binding of nuclear factor κB,32
and potentiate immune-based cell kill by tagging leukaemic cells with calcireticulin.33
Although all these mechanisms could have contributed to the delayed cytotoxic effect, there is another intriguing possibility. First, three of five patients given mitoxantrone who had high minimal residual disease at the first timepoint and who were not transplanted for various reasons had recurrence. Thus, in the group with high minimal residual disease, sustained remission probably needs both mitoxantrone and allo-SCT. Second, although idarubicin was more toxic than mitoxantrone, this toxic effect was mainly seen during the first 8 weeks of treatment.
For the few patients who were not transplanted and continued on chemotherapy, haematological toxic effects increased during the later phases in the mitoxantrone group. Thus, mitoxantrone might in some way affect the haemopoietic stem-cell niche, making it a less favourable environment for the leukaemic cell and more conducive to the allograft. Further analyses of the effects of mitoxantrone on malignant and normal cells are needed. Such studies have the potential to identify novel mechanisms for the eradication of this disease.
A randomised trial of mitoxantrone was previously done in childhood acute myeloid leukaemia.34
Results showed an improved disease-free survival and lower relapse rates in the mitoxantrone group compared with the daunorubicin group; however, these reduced rates did not translate into overall survival.34
Mitoxantrone has only been infrequently used in therapeutic trials in childhood acute lymphoblastic leukaemia. A perception that optimisation has been reached with available drugs has shifted focus towards newer drugs and targeted therapy. These drugs will be prohibitively expensive for many patients. Mitoxantrone is a cheap and readily available drug and clearly needs further clinical assessment in childhood acute lymphoblastic leukaemia. Most frontline protocols are now moving towards risk-stratifying treatment based on minimal residual disease after induction. Patients with positive minimal residual disease usually receive anthracycline-containing delayed intensification blocks. Logically, assessment of the potential benefit of mitoxantrone in childhood acute lymphoblastic leukaemia would be in a randomised use of mitoxantrone in the delayed intensification phase of frontline treatment for high-risk patients. Our results suggest that, while we wait for targeted therapies to become a reality, conventional cytotoxics still have a role in treatment of acute lymphoblastic leukaemia.