Supplementary appendix

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1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Vora A, Goulden N, Mitchell C, et al. Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): a randomised controlled trial. Lancet Oncol 2014; published online June 10.

2 Augmented post-remission therapy for detectable minimal residual disease in children and young people with clinical standard and intermediate risk acute lymphoblastic leukaemia (UKALL 2003): a randomised controlled trial. Ajay Vora, Nick Goulden, Chris Mitchell, Jeremy Hancock, Rachael Hough, Clare Rowntree, Anthony V Moorman, and Rachel Wade. Pages 2 7: Supplementary Tables APPENDIX Contents Table 1 : Details of 3 treatment regimens in UKALL 2003 Table 2: Cumulative doses of drugs in Regimens A, B and C with 2 delayed intensification courses Table 3 : Number of patients with dose reductions below 90% of protocol doses by regimen. Table 4 : Participating centres and principal investigators Page 8 : Supplementary Figures 1a Event-free survival in the trial overall 1b Event free survival and Relapse Rate in MRD low risk randomisation arms 1

3 Supplementary table 1. Details of 3 treatment regimens in UKALL 2003 Induction Consolidation Interim maintenance 1 Delayed intensification 1 Interim maintenance 2 Delayed intensification 2 Continuing therapy Clinical Standard Risk VCR 1.5 mg/m 2 i.v. on days 2, 9, 16 and 23 Dexamethasone 6.mg/m 2 p.o. on days units/m2 days 4 and 18 IT MTX 1 on days 1 & 8. If > 25% blasts in day 15 BM: Daunorubicin 45 mg/m 2 i.v. on days 16 and 23, if switched to HR from day 15 Steroids: Taper steroids over 7 days to zero, days 2-8 VCR 1.5 mg/m 2 i.v. on day 2 (week 5) 75 mg/m 2 p.o.. daily on days 2 29 (weeks 5 8) IT MTX 1 on days 1, 8, 15 and 22 Steroid as randomized for days 1-5 and VCR 1.5 mg/m 2 i.v. on days 1 and mg/m 2 p.o.. daily Methotrexate 20 mg/m 2 p.o. weekly on days 1, 8, 15, 22, 36, 43 and 50 Dexamethasone 10mg/m 2 p.o. on days 2-8 and VCR 1.5 mg/m 2 i.v. on days 2, 9 and 16 Doxorubicin 25 mg/m 2 i.v. on days 2, 9, units/m2 on day 4 Cyclophosphamide 1 g/m 2 i.v. on day mg/m 2 p.o.. daily. on days Cytarabine 75 mg/m 2 i.v. or s.c. on days and IT MTX 1 on days 1, 29 and 36 Dexamethasone 6.mg/m 2 p.o days 1-5 and VCR 1.5 mg/m 2 on days 1 and mg/m 2 p.o.. daily Methotrexate 20 mg/m 2 p.o. weekly on days 1, 8, 15, 22, 29, 36, 43 and 50 Dexamethasone 10 mg/m 2 p.o. on days 2-8 and VCR 1.5 mg/m 2 i.v. on days 2, 9 and 16 Doxorubicin 25 mg/m 2 i.v. on days 2, 9 and units/m2 on day 4 Cyclophosphamide 1 g/m 2 i.v. on day mg/m 2 p.o.. daily. on days Cytarabine 75 mg/m 2 i.v. or s.c. on days and IT MTX 1 on days 1, 29 and week cycles consisting of: Dexamethasone 6.mg/m 2 p.o on days 1-5, and VCR 1.5 mg/m 2 i.v. on days 1, 29 and mg/m 2 p.o.. daily Methotrexate 20 mg/m 2 p.o. weekly on days 1, 8, 22, 29, 36, 43, 50, 57, 64, 71 and 78 IT MTX 1 on day 15 Weeks 1-4 Weeks 5-8 Weeks 9-16 Weeks Weeks Weeks Weeks (girls) Weeks (boys) Clinical Intermediate risk Taper steroids.over 7 days. Same as standard risk Same as standard risk Same as standard risk Same as standard risk Same as standard risk As for standard risk plus Daunorubicin 25 mg/m 2 i.v. on days 2, 9, 16, and 23. Day 8 BM > 25% blasts change to high risk protocol at week 5. Cyclophosphamide 1g/m 2 i.v. on days 1 and 15 Cytarabine 75 mg/m 2 i.v. days 2-5, 9-12, 16-19, mg/m 2 p.o. on days 1-28 IT MTX 1 on days 1, 8, 15 and 22 Weeks 1-4 Weeks 5-9 Weeks Weeks Weeks Weeks Weeks (girls) Weeks (boys) 2

4 Supplementary table 1 continued Induction Consolidation Interim maintenance 1 Delayed intensification 1 Interim maintenance 2 Delayed intensification 2 Continuing therapy Clinical High Risk and MRD High Risk by randomized allocation Induction as for intermediate risk or as described above for standard risk with > 25% blasts in day 15 BM Steroids: Taper steroids over 7 days Augmented BFM consolidation Cyclophosphamide 1 g/m 2 i.v. on days 1 and 29 Cytarabine 75 mg/m 2 i.v. on days 2 5, 9 12, and mg/m 2 p.o. on days 1 14 and VCR 1.5 mg/m 2 i.v. on days 16, 23, 44 and iu/m 2 on days 16 and 44 Intrathecal therapy IT MTX 1 on days 1, 8, 15 and 22, Capizzi I VCR 1.5 mg/m 2 i.v. on days 2, 12, 22, 32 and 42 Methotrexate starting on day 2 at 100 mg/m 2 i.v. and increasing by 50 mg/m 2 every 10 days as permitted by toxicity 1000 iu/m 2 days 3 and 23 Intrathecal therapy IT MTX 1 on days 1 and 31 As for standard risk but with additional doses of vincristine 1.5 mg/m 2 i.v. on days 43 and 50 and PEG asparaginase 1000 iu/m 2 on days 5 and 43 Capizzi II VCR 1.5 mg/m 2 i.v. on days 2, 12, 22, 32 and 42 Methotrexate starting on day 2 at a dose 50 mg/m 2 i.v. below the dose attained in Capizzi I and increasing by 50 mg/m 2 every 10 days as permitted by toxicity 1000 iu/m 2 days 3 and 23 Intrathecal therapy IT MTX 1 on days 1 and 31 As for standard risk but with additional doses of vincristine 1.5 mg/m 2 i.v. on days 43 and 50 and PEG asparaginase 1000 iu/m 2 days 5 and 43 Same as standard risk Weeks 1-4 Weeks 5-13 Weeks Weeks Weeks Weeks Weeks (girls) Weeks (boys0 1 IT MTX dose <2yrs: 8mg; 2yrs: 10mg; 3+yrs: 12mg CNS, central nervous system; CT, continuing therapy; VCR, vincristine;;, Oncospar (Medac GmBH)IT MTX; intrathecal methotrexate; HD MTX, high dose intravenous methotrexate; p.o., oral; i.v., intravenous; s.c., sub-cutaneous; i.m., intramuscular 3

5 Supplementary Table 2 Cumulative doses of drugs in Regimens A, B and C with 2 delayed intensification courses Agents (mg/m 2 ) VCR DEX PEG ASP DNR/ DOX CYCLO ARA-C IV MTX REGIMEN A GIRLS BOYS REGIMEN B GIRLS BOYS REGIMEN C GIRLS BOYS (maximum) 4

6 Supplementary Table 3 Number of patients with dose reductions below 90% of protocol doses by regimen. Treatment regimen given <90% dose postinduction? A B C Total No Yes Total Only 5 patients crossed-over from regimen C to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided). 5

7 Supplementary Table 4: UKALL Participating centres and principal investigators Site Principal Investigator Number of eligible patients recruited Great Ormond Street Hospital Dr P Ancliff 286 Birmingham Children's Hospital Dr M Velangi 273 Our Lady's Hospital for Sick Children, Ireland Prof O Smith 250 Royal Marsden Hospital Dr D Lancaster 245 Addenbrooke's NHS Trust Dr M Gattens 186 Bristol Royal Hospital for Children / Bristol Haematology and Oncology Dr M Cummins 172 Royal Manchester Children's Hospital Dr J Grainger 159 Oxford Radcliffe Hospitals Dr G Hall 155 Alder Hey Children's Hospital Dr M Caswell 139 Southampton University Hospital Trust Dr M Morgan 137 St. James's University Hospital / Leeds General Infirmary Dr S Kinsey 142 Yorkhill NHS Trust Prof B Gibson 126 Royal Victoria Infirmary Dr S Bailey 121 University Hospital of Wales / Llandough Hospital NHS Trust Dr M Jenney 109 Sheffield Children's Hospital Prof A Vora 91 Nottingham University Hospital / Nottingham City Hospital Dr S Stokley 96 University College Hospital Dr S Daw 86 Royal Hospital for Sick Children, Edinburgh Dr A Thomas 79 Royal Belfast Hospital Dr C Macartney 75 Leicester Royal Infirmary Dr M Madi 68 Royal Aberdeen Children's Hospital / Aberdeen Royal Infirmary Dr D King 25 Christie Hospitals NHS Trust Dr A Bloor 16 Northampton General Hospital Dr B Koodiyedath 14 Royal Hallamshire Hospital Dr N Morley 7 Queen Elizabeth Hospital Dr S Chaganti 7 University Hospital of North Staffs Dr D Chandra 6 Beatson West of Scotland Cancer Centre Dr M Drummond 6 6

8 Heart of England NHS Foundation Prof D Milligan 5 Victoria Hospital, Scotland Dr S Rogers 5 Taunton & Somerset NHS Trust Dr S Bolam 4 St. Bartholomew's Hospital Dr M Smith 4 Guy's Hospital Dr R Carr 4 Western General Hospital Dr P Roddie 4 Belfast City Hospital Dr R Cuthbert 4 Royal Devon and Exeter Hospital Dr M Hamilton 3 Royal Free Hospital Dr A Fielding 4 James Cook University Hospital Dr D Plews 2 Manchester Royal Infirmary Prof J Yin 2 Poole Hospital NHS Trust Dr F Jack 2 University Hospital Coventry Dr O Chapman 1 Norfolk & Norwich University Hospital Dr J Wimperis 1 Wycombe General Hospital Dr A O Hea 1 Royal Bournemouth Hospital Dr J Chacko 1 Salisbury NHS Foundation Trust Dr J Cullis 1 Monklands District General Hospital Dr J Murphy 1 Mercy University Hospital, Ireland Dr M Madden 1 7

9 Supplementary Figures 1a 1b 8