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

Cancer Research UK Children's Cancer Group, School of Cancer and Enabling Sciences, University of Manchester, Manchester Academic Health Science Centre, Central Manchester University Hospitals Foundation Trust, Manchester, UK.
The Lancet (Impact Factor: 45.22). 12/2010; 376(9757):2009-17. DOI: 10.1016/S0140-6736(10)62002-8
Source: PubMed


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

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    • "MRD was measured from marrow samples obtained at relapse for those with c-CNS at the end of induction using clonotypic markers for Ig/TCR rearrangements, by quantitative PCR as previously described [22]. MRDlo was defined as fewer than 10−4 cells with two sensitive markers (quantitative range 10−4) and MRDhi as at least one marker of 10−4 cells or more at the end of induction. "
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    ABSTRACT: The outcomes of Central Nervous System (CNS) relapses in children with acute lymphoblastic leukaemia (ALL) treated in the ALL R3 trial, between January 2003 and March 2011 were analysed. Patients were risk stratified, to receive a matched donor allogeneic transplant or fractionated cranial irradiation with continued treatment for two years. A randomisation of Idarubicin with Mitoxantrone closed in December 2007 in favour of Mitoxantrone. The estimated 3-year progression free survival for combined and isolated CNS disease were 40.6% (25·1, 55·6) and 38.0% (26.2, 49.7) respectively. Univariate analysis showed a significantly better survival for age <10 years, progenitor-B cell disease, good-risk cytogenetics and those receiving Mitoxantrone. Adjusting for these variables (age, time to relapse, cytogenetics, treatment drug and gender) a multivariate analysis, showed a poorer outcome for those with combined CNS relapse (HR 2·64, 95% CI 1·32, 5·31, p = 0·006 for OS). ALL R3 showed an improvement in outcome for CNS relapses treated with Mitoxantrone compared to Idarubicin; a potential benefit for matched donor transplant for those with very early and early isolated-CNS relapses. Trial Registration ISRCTN45724312
    Full-text · Article · Oct 2014 · PLoS ONE
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    • "Overall, the 5-year survival rates for patients with acute lymphoblastic leukaemia (ALL) and patients with acute myelogenous leukaemia (AML) are nearly 85% and 50–60%, respectively (Jemal et al., 2008). Among children with relapsed acute leukaemia, 30–50% can be treated successfully with a combination of chemotherapy and allogeneic stem cell transplantation (SCT) (Hijiya et al., 2004; Raetz et al., 2008; Parker et al., 2010; Tallen et al., 2010). Despite these successes, children who fail to attain complete remission after relapse, relapse after an SCT, experience a primary induction failure, or relapse with a very unfavourable cytogenetic risk profile have very poor prognoses (Gaynon, 2005). "
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    • "A multi-institutional Children’s Oncology Group (COG) Phase 1 trial combined 3-weekly IV temsirolimus (10 mg/m2, de-escalated to 7.5 mg/m2) with an intensive four drug re-induction backbone per the UKALL R3 relapse protocol (NCT01403415) (39, 61). Due to significant infectious toxicity, the trial was suspended and recently reopened with two doses of temsirolimus at 7.5 mg/m2. "
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