Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

Therapy and Follow up Studies

Benefit of intensified treatment for all children with acute lymphoblastic leukaemia: results from MRC UKALL XI and MRC ALL97 randomised trials

Leukemia volume 14, pages 356–363 (2000)Cite this article

Abstract

Treatment of children with acute lymphoblastic leukaemia (ALL) aims to cure all patients with as little toxicity as possible and, if possible, to restrict further intensification of chemotherapy to patients with an increased risk of relapse. However in Medical Research Council (MRC) trial UKALL X two short myeloablative blocks of intensification therapy given at weeks 5 and 20 were of benefit to children in all risk groups. The successor trials, MRC UKALL XI and MRC ALL97, tested whether further intensification would continue to benefit all patients by randomising them to receive, or not, an extended third intensification block at week 35. After a median follow-up of 4 years (range 5 months to 8 years), 5 year projected event-free survival was superior at 68% for the 894 patients allocated a third intensification compared with 60% for the 887 patients who did not receive one (odds ratio 0.75, 95% CI 0.63–0.90, 2P = 0.002). This difference was almost entirely due to a reduced incidence of bone marrow relapses in the third intensification arm (140 of 891 in the third intensification arm vs 171 of 883 in the no third intensification, 2P = 0.02). Subgroup analysis suggests benefit of the third intensification for all risk categories. Overall survival to date is no different in the two arms, indicating that a greater proportion of those not receiving a third intensification arm and subsequently relapsing can be salvaged. These results indicate that there is benefit of additional intensification for all risk subgroups of childhood ALL.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Rubnitz JE, Look AT . Molecular genetics of childhood leukemias J Pediatr Hematol Oncol 1998 20: 1–11

    Article  CAS  Google Scholar 

  2. Chessells JM, Swansbury GJ, Reeves B, Bailey CC, Richards SM . Cytogenetics and prognosis in childhood lymphoblastic leukaemia: results of MRC UKALL X. Medical Research Council Working Party in Childhood Leukaemia Br J Haematol 1997 99: 93–100

    Article  Google Scholar 

  3. Brisco MJ, Condon J, Hughes E, Neoh SH, Sykes PJ, Seshadri R, Toogood I, Waters K, Tauro G, Ekert H . Outcome prediction in childhood acute lymphoblastic leukaemia by molecular quantification of residual disease at the end of induction Lancet 1994 343: 196–200

    Article  CAS  Google Scholar 

  4. Cave H, van der Werff ten Bosch, Suciu S, Guidal C, Waterkeyn C, Otten J, Bakkus M, Thielemans K, Grandchamp B, Vilmer E . Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer–Childhood Leukemia Cooperative Group New Engl J Med 1998 339: 591–598

    Article  CAS  Google Scholar 

  5. van Dongen JJ, Seriu T, Panzer-Grumayer ER, Biondi A, Pongers-Willemse MJ, Corral L, Stolz F, Schrappe M, Masera G, Kamps WA, Gadner H, van Wering ER, Ludwig WD, Basso G, de Bruijn MA, Cazzaniga G, Hettinger K, van der Does-van den Berg A, Hop WC, Riehm H, Bartram CR . Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood Lancet 1998 352: 1731–1738

    Article  CAS  Google Scholar 

  6. Ochs J, Mulhern R . Long-term sequelae of therapy for childhood acute lymphoblastic leukaemia Baillières Clin Haematol 1994 7: 365–376

    Article  CAS  Google Scholar 

  7. Chessells JM, Richards SM, Bailey CC, Lilleyman JS, Eden OB . Gender and treatment outcome in childhood lymphoblastic leukaemia: report from the MRC UKALL trials Br J Haematol 1995 89: 364–372

    Article  CAS  Google Scholar 

  8. Chessells JM, Hall E, Prentice HG, Durrant J, Bailey CC, Richards SM . The impact of age on outcome in lymphoblastic leukaemia; MRC UKALL X and XA compared: a report from the MRC Paediatric and Adult Working Parties Leukemia 1998 12: 463–473

    Article  CAS  Google Scholar 

  9. Pui CH . Recent advances in the biology and treatment of childhood acute lymphoblastic leukemia Curr Opin Hematol 1998 5: 292–301

    Article  CAS  Google Scholar 

  10. Hutchinson RJ, Neerhout S, Bertolone S, Cooper HA, Roskos R, Tannous R, Wells L, Heerema N, Hummell D, Sailoer S, Sather H, Trigg M and the Children's Cancer Study Group . Should therapy be intensified for patients with good risk acute lymphoblastic leukaemia Am Soc Hematol 1996 A2662

  11. Rivera GK, Pinkel D, Simone JV, Hancock ML, Crist WM . Treatment of acute lymphoblastic leukemia. 30 years’ experience at St Jude Children's Research Hospital New Engl J Med 1993 329: 1289–1295

    Article  CAS  Google Scholar 

  12. Tubergen DG, Gilchrist GS, O'Brien RT, Coccia PF, Sather HN, Waskerwitz MJ, Hammond GD . Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: a Childrens Cancer Group phase III trial J Clin Oncol 1993 11: 520–526

    Article  CAS  Google Scholar 

  13. Reiter A, Schrappe M, Ludwig WD, Hiddemann W, Sauter S, Henze G, Zimmermann M, Lampert F, Havers W, Niethammer D, Odenwald E, Ritter J, Mann G, Welte K, Gadner H, Riehm H . Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients. Results and conclusions of the multicenter trial ALL-BFM 86 Blood 1994 84: 3122–3133

    CAS  PubMed  Google Scholar 

  14. Chessells JM, Bailey C, Richards SM . Intensification of treatment and survival in all children with lymphoblastic leukaemia: results of UK Medical Research Council trial UKALL X. Medical Research Council Working Party on Childhood Leukaemia Lancet 1995 345: 143–148

    Article  CAS  Google Scholar 

  15. Hill F, Hann I, Gibson B, Eden OB, Richards S . Comparison of high dose methotrexate with continuing intrathecal methotrexate versus intrathecal methotrexate alone in low white blood count childhood acute lymphoblastic leukaemia: preliminary results from the UKALLXI randomised trial Blood 1998 92: (Suppl. 1) 398a

    Google Scholar 

  16. White SJ, Freedman LS . Allocation of patients to treatment groups in a controlled clinical study Br J Cancer 1978 37: 849–857

    Article  CAS  Google Scholar 

  17. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, Peto J, Smith PG . Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II Analysis and examples Br J Cancer 1977 35: 1–39

    Article  CAS  Google Scholar 

  18. Early Breast Cancer Trialists’ Collaborative Group . Systemic treatment of early breast cancer by hormonal cytotoxic, or immune therapy. 133 randomised trials involving 31 000 recurrences and 24000 deaths among 75000 women Lancet 1992 339: 1–15

    Google Scholar 

  19. Cox D . The contribution of statistical methods to cancer research Cancer 1991 67: 2428–2430

    Article  CAS  Google Scholar 

  20. SAS/STAT User's Guide SAS Institute Inc: Cary, NC 1989

  21. Steinherz PG, Gaynon PS, Breneman JC, Cherlow JM, Grossman NJ, Kersey JH, Johnstone HS, Sather HN Trigg ME, Uckun FM, Bleyer WA . Treatment of patients with acute lymphoblastic leukemia with bulky extra-medullary disease and T-cell phenotype or other poor prognostic features: randomized controlled trial from the Children's Cancer Group Cancer 1998 82: 600–612

    Article  CAS  Google Scholar 

  22. Nachman JB, Sather HN, Sensel MG, Trigg ME, Cherlow JM, Lukens JN, Wolff L, Uckun FM, Gaynon PS . Augmented post-induction therapy for children with high-risk acute lymphoblastic leukaemia and a slow response to initial therapy New Engl J Med 1998 338: 1663–1671

    Article  CAS  Google Scholar 

  23. Lange B, Sather H, Weetman R, Bostrom B, McGuire P, Rackoff W, Arthur D, Trigg M for the Children's Cancer Group . Double delayed intensification improves outcome in moderate risk paediatric acute lymphoblastic leukaemia – CCG 1891 study ASH 1997 90: Suppl. 1: 559a

    Google Scholar 

  24. Henze G, Fengler R, Reiter A, Ritter J, Riehm H . Impact of early intensive reinduction therapy on event-free survival in children with low-risk acute lymphoblastic leukemia Hamatol Bluttransfus 1990 33: 483–488

    CAS  Google Scholar 

  25. Morley A . Quantifying leukemia Lancet 1998 339: 627–629

    CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to all the physicians who entered patients to these studies. Members of the MRC childhood leukaemia working party during these studies were: Bailey CC, Barton C, Broadbent V, Caswell M, Chessells JM, Darbyshire PJ, Dempsey SI, Durrant J, Eden OB (Chairman), Gibson B, Goodman A, Gray R, Hann I, Haworth C, Forman K, Hill F, Jenney M, Kernahan J, King DJ, Kinsey SE, Madden M, Mann JR, Martin J, Meller ST, Mitchell C, Oakhill A, Radford M, Reid MM, Richards SM, Smyth O, Stevens RF, Thomas A, Vargha-Khadem F, Vora AJ, Walker D, Webb D, Wheatley K, Will A, Windebank K. We also thank J Burrett for data management and all those who worked in the randomisation office.

Author information

Authors and Affiliations

  1. Great Ormond Street Children's Hospital, London, UK

    I Hann

  2. Sheffield Childrens's Hospital, UK

    A Vora

  3. Clinical Trials Service Unit, Oxford, UK

    S Richards

  4. Birmingham Children's Hospital, UK

    F Hill

  5. Royal Hospital for Sick Children, Glasgow, UK

    B Gibson

  6. Royal Hospitals, London, UK

    J Lilleyman

  7. St James Hospital, Leeds, UK

    S Kinsey

  8. John Radcliffe Hospital, Oxford, UK

    C Mitchell

  9. Royal Manchester Children's Hospital, Manchester, UK

    OB Eden

Authors
  1. I Hann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Vora
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Richards
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F Hill
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B Gibson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Lilleyman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S Kinsey
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C Mitchell
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. OB Eden
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

on behalf of the UK Medical Research Council's Working Party on Childhood Leukaemia

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hann, I., Vora, A., Richards, S. et al. Benefit of intensified treatment for all children with acute lymphoblastic leukaemia: results from MRC UKALL XI and MRC ALL97 randomised trials. Leukemia 14, 356–363 (2000). https://doi.org/10.1038/sj.leu.2401704

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2401704

Keywords

This article is cited by

Search

Advanced search

Quick links