Outcomes of patients with childhood B-cell precursor acute lymphoblastic leukaemia with late bone marrow relapses: long-term follow-up of the ALLR3 open-label randomised trial.

backgroundThe ALLR3 trial investigated outcomes of children with B-cell precursor acute lymphoblastic leukaemia who had late bone marrow relapses. We analysed long-term follow-up outcomes of these patients.

methodsALLR3 was an open-label randomised clinical trial that recruited children aged 1-18 years with B-cell precursor acute lymphoblastic leukaemia who had late bone marrow relapses. Eligible patients were recruited from centres in Australia, Ireland, the Netherlands, New Zealand, and the UK. Patients were randomly assigned from Jan 31, 2003, to Dec 31, 2007, and the trial closed to recruitment on Oct 31, 2013. Randomly assigned patients were allocated to receive either idarubicin or mitoxantrone in induction by stratified concealed randomisation; after randomisation stopped in Dec 31, 2007, all patients were allocated to receive mitoxantrone. After three blocks of therapy, patients with high minimal residual disease (≥10

findingsBetween Feb 2, 2003, and Oct 28, 2013, 228 patients with B-cell precursor acute lymphoblastic leukaemia and late bone marrow relapses were treated. After a median follow-up of 84 months (IQR 48-109), progression-free survival of all randomly assigned patients was 60% (95% CI 54-70). 220 patients achieved second complete remission, and minimal residual disease was evaluable in 192 (87%). 110 patients with late bone marrow relapses and high minimal residual disease at the end of induction were allocated to undergo stem-cell transplantation, and 82 patients with low minimal residual disease at the end of induction were allocated to receive chemotherapy. In the patients allocated to undergo stem-cell transplantation, four relapses and three deaths were reported before the procedure, and 11 patients were not transplanted. Of the 92 patients transplanted, 58 (63%) remained in second complete remission, 13 (14%) died of complications, and 21 (23%) relapsed after stem-cell transplantation. In patients allocated to receive chemotherapy, one early treatment-related death was reported and 11 patients were transplanted. Of the 70 patients who continued on chemotherapy, 49 (70%) remained in second complete remission, two (3%) died of complications, and 19 (27%) relapsed. Progression-free survival at 5 years was 56% (95% CI 46-65) in those with high minimal residual disease and 72% (60-81) in patients with low minimal residual disease (p=0·0078). Treatment-related serious adverse events were not analysed in the long-term follow-up.

interpretationPatients with B-cell precursor acute lymphoblastic leukaemia with late bone marrow relapses and low minimal residual disease at end of induction had favourable outcomes with chemotherapy without undergoing stem-cell transplantation. Patients with high minimal residual disease benefited from stem-cell transplantation, and targeted therapies might offer further improvements in outcomes for these patients.

fundingBloodwise (Formerly Leukaemia and Lymphoma Research) UK, Cancer Research UK, Sporting Chance Cancer Foundation, National Health and Medical Research Council Australia, KindreneKankervrij Netherlands, European Union Seventh Framework Programme, India Alliance Wellcome DBT Margdarshi Fellowship.