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Clinical Trial
. 2014 Oct 3;9(10):e108107.
doi: 10.1371/journal.pone.0108107. eCollection 2014.

Outcome of central nervous system relapses in childhood acute lymphoblastic leukaemia--prospective open cohort analyses of the ALLR3 trial

Ashish Narayan Masurekar  1 , Catriona A Parker  1 , Milensu Shanyinde  2 , Anthony V Moorman  3 , Jeremy P Hancock  4 , Rosemary Sutton  5 , Philip J Ancliff  6 , Mary Morgan  7 , Nicholas J Goulden  6 , Chris Fraser  8 , Peter M Hoogerbrugge  9 , Tamas Revesz  10 , Philip J Darbyshire  11 , Shekhar Krishnan  12 , Sharon B Love  2 , Vaskar Saha  12
Affiliations
Clinical Trial

Outcome of central nervous system relapses in childhood acute lymphoblastic leukaemia--prospective open cohort analyses of the ALLR3 trial

Ashish Narayan Masurekar et al. PLoS One. .

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: Controlled-Trials.com ISRCTN45724312.

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Conflict of interest statement

Competing Interests: Hospira provided help for the data entry for the Australian and New Zealand patients by providing a non-conditional educational grant for ANZCHOG. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Consort diagram.
Showing the details of patients with central nervous system (CNS) relapse. c-CNS = combined bone marrow and CNS relapse; i-CNS = isolated CNS relapse; TRM = treatment related mortality; SCT = allogenic bone marrow transplant; CRT = chemo-radiotherapy. *1 patient planned for SCT received CRT and vice-versa; #9 patients planned for SCT received CRT; +9 patients planned for SCT received CRT and 2 patients planned for CRT got SCT. No patients with i-CNS had detectable MRD in the marrow at the end of induction. Twenty four patients with c-CNS has detectable marrow disease at week 5; 13 MRD positive and 9 MRD negative.
Figure 2
Figure 2. Temporal pattern of relapses.
Isolated (iCNS) and combined (c-CNS) relapses occur significantly earlier than those with isolated bone marrow (iBM) relapses (Log rank p = <0.001). Figures in parenthesis show mean duration of remission in months for each group with ± standard deviation.
Figure 3
Figure 3. Age at relapse (<10 or ≥10 years) effect on progression-free survival by patient characteristics, from Cox models with interactions.
White cell count is the presenting count (×109/L) at first diagnosis. Relative risk ratios indicate that all subgroups show a poorer outcome in those ≥10 years, except good risk cytogenetics.
Figure 4
Figure 4. Cumulative percentage of events, in those aged <10 and ≥10 years at first relapse.
(A) Therapeutic failure, which includes both induction failures and second relapses. (B) Treatment related deaths.
See this image and copyright information in PMC

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