Abstract
Despite the success of contemporary treatment protocols in childhood acute lymphoblastic leukaemia (ALL), relapse within the central nervous system (CNS) remains a challenge. To better understand this phenomenon, we have analysed the changes in incidence and pattern of CNS relapses in 5564 children enrolled in four successive Medical Research Council-ALL trials between 1985 and 2001. Changes in the incidence and pattern of CNS relapses were examined and the relationship with patient characteristics was assessed. The factors affecting outcome after relapse were determined. Overall, relapses declined by 49%. Decreases occurred primarily in non-CNS and combined relapses with a progressive shift towards later (⩾30 months from diagnosis) relapses (P<0.0001). Although isolated CNS relapses declined, the proportional incidence and timing of relapse remained unchanged. Age and presenting white blood cell (WBC) count were risk factors for CNS relapse. On multivariate analysis, the time to relapse and the trial period influenced outcomes after relapse. Relapse trends differed within biological subtypes. In ETV6-RUNX1 ALL, relapse patterns mirrored overall trends whereas in high hyperdiploidy (HH) ALL, these seem to have plateaued over the latter two trial periods. Intensive systemic and intrathecal chemotherapy have decreased the overall CNS relapse rates and changed the patterns of recurrence. The heterogeneity of therapeutic response in the biological subtypes suggests room for further optimization using currently available chemotherapy.
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References
Schrappe M, Camitta B, Pui CH, Eden T, Gaynon P, Gustafsson G et al. Long-term results of large prospective trials in childhood acute lymphoblastic leukemia. Leukemia 2000; 14: 2193–2194.
Pui CH, Howard SC . Current management and challenges of malignant disease in the CNS in paediatric leukaemia. Lancet Oncol 2008; 9: 257–268.
Henze G, Fengler R, Hartmann R, Kornhuber B, Janka-Schaub G, Niethammer D et al. Six-year experience with a comprehensive approach to the treatment of recurrent childhood acute lymphoblastic leukemia (ALL-REZ BFM 85). A relapse study of the BFM group. Blood 1991; 78: 1166–1172.
Wheeler K, Richards S, Bailey C, Chessells J . Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukaemia: the MRC UKALLX experience. Medical Research Council Working Party on Childhood Leukaemia. Br J Haematol 1998; 101: 94–103.
Lawson SE, Harrison G, Richards S, Oakhill A, Stevens R, Eden OB et al. The UK experience in treating relapsed childhood acute lymphoblastic leukaemia: a report on the medical research council UKALLR1 study. Br J Haematol 2000; 108: 531–543.
Einsiedel HG, von Stackelberg A, Hartmann R, Fengler R, Schrappe M, Janka-Schaub G et al. Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: results of trial acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Munster Group 87. J Clin Oncol 2005; 23: 7942–7950.
Roy A, Cargill A, Love S, Moorman A, Stoneham S, Lim A et al. Outcome after first relapse in childhood acute lymphoblastic leukaemia—lessons from the United Kingdom R2 trial. Br J Haematol 2005; 130: 67–75.
Malempati S, Gaynon PS, Sather H, La MK, Stork LC . Outcome after relapse among children with standard-risk acute lymphoblastic leukemia: Children's Oncology Group study CCG-1952. J Clin Oncol 2007; 25: 5800–5807.
Gaynon PS, Qu RP, Chappell RJ, Willoughby ML, Tubergen DG, Steinherz PG et al. Survival after relapse in childhood acute lymphoblastic leukemia: impact of site and time to first relapse—the Children's Cancer Group experience. Cancer 1998; 82: 1387–1395.
Mullighan CG, Phillips LA, Su X, Ma J, Miller CB, Shurtleff SA et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 2008; 322: 1377–1380.
Nguyen K, Devidas M, Cheng SC, La M, Raetz EA, Carroll WL et al. Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children's Oncology Group study. Leukemia 2008; 22: 2142–2150.
Hagedorn N, Acquaviva C, Fronkova E, von Stackelberg A, Barth A, zur Stadt U et al. Submicroscopic bone marrow involvement in isolated extramedullary relapses in childhood acute lymphoblastic leukemia: a more precise definition of “isolated” and its possible clinical implications, a collaborative study of the Resistant Disease Committee of the International BFM study group. Blood 2007; 110: 4022–4029.
Hill FG, Richards S, Gibson B, Hann I, Lilleyman J, Kinsey S et al. Successful treatment without cranial radiotherapy of children receiving intensified chemotherapy for acute lymphoblastic leukaemia: results of the risk-stratified randomized central nervous system treatment trial MRC UKALLXI (ISRC TN 16757172). Br J Haematol 2004; 124: 33–46.
Chessells JM, Bailey C, Richards SM . Intensification of treatment and survival in all children with lymphoblastic leukaemia: results of UK Medical Research Council trial UKALLX Medical Research Council Working Party on Childhood Leukaemia. Lancet 1995; 345: 143–148.
Mitchell CD, Richards SM, Kinsey SE, Lilleyman J, Vora A, Eden TO . Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Br J Haematol 2005; 129: 734–745.
Chessells JM, Bailey CC, Richards S . MRC UKALLX. The UK protocol for childhood ALL: 1985–1990. The Medical Research Council Working Party on Childhood Leukaemia. Leukemia 1992; 6 (Suppl 2): 157–161.
Hann I, Vora A, Richards S, Hill F, Gibson B, Lilleyman J et al. Benefit of intensified treatment for all children with acute lymphoblastic leukaemia: results from MRC UKALLXI and MRC ALL97 randomised trials. UK Medical Research Council's Working Party on Childhood Leukaemia. Leukemia 2000; 14: 356–363.
Hann I, Vora A, Harrison G, Harrison C, Eden O, Hill F et al. Determinants of outcome after intensified therapy of childhood lymphoblastic leukaemia: results from Medical Research Council United Kingdom acute lymphoblastic leukaemia XI protocol. Br J Haematol 2001; 113: 103–114.
Vora A, Mitchell CD, Lennard L, Eden TO, Kinsey SE, Lilleyman J et al. Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial. Lancet 2006; 368: 1339–1348.
Mitchell C, Payne J, Wade R, Vora A, Kinsey S, Richards S et al. The impact of risk-stratification by early bone marrow response in childhood acute lymphoblastic leukaemia: results from the United Kingdom Medical Research Council trial ALL97 and ALL97/99. Br J Haematol 2009; 146: 424–436.
Harrison CJ, Martineau M, Secker-Walker LM . The Leukaemia Research Fund/United Kingdom Cancer Cytogenetics Group Karyotype Database in acute lymphoblastic leukaemia: a valuable resource for patient management. Br J Haematol 2001; 113: 3–10.
Harrison CJ, Moorman AV, Barber KE, Broadfield ZJ, Cheung KL, Harris RL et al. Interphase molecular cytogenetic screening for chromosomal abnormalities of prognostic significance in childhood acute lymphoblastic leukaemia: a UK Cancer Cytogenetics Group Study. Br J Haematol 2005; 129: 520–530.
Pintilie M . Competing Risks: A Practical Perspective. John Wiley & Sons Ltd: West Sussex, England, 2006.
Roy A, Bradburn M, Moorman AV, Burrett J, Love S, Kinsey SE et al. Early response to induction is predictive of survival in childhood Philadelphia chromosome positive acute lymphoblastic leukaemia: results of the Medical Research Council ALL97 trial. Br J Haematol 2005; 129: 35–44.
Seibel NL, Steinherz PG, Sather HN, Nachman JB, Delaat C, Ettinger LJ et al. Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood 2008; 111: 2548–2555.
Stams WAG, den Boer ML, Holleman A, Appel IM, Beverloo HB, van Wering ER et al. Asparagine synthetase expression is linked with L-asparaginase resistance in TEL-AML1-negative but not TEL-AML1-positive pediatric acute lymphoblastic leukemia. Blood 2005; 105: 4223–4225.
Loh ML, Goldwasser MA, Silverman LB, Poon WM, Vattikutti S, Cardoso A et al. Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer Institute Consortium Protocol 95-01. Blood 2006; 107: 4508–4513.
Sharathkumar A, DeCamillo D, Bhambhani K, Cushing B, Thomas R, Mohamed AN et al. Children with hyperdiploid but not triple trisomy (+4,+10,+17) acute lymphoblastic leukemia have an increased incidence of extramedullary relapse on current therapies: a single institution experience. Am J Hematol 2008; 83: 34–40.
Whitehead VM, Vuchich MJ, Lauer SJ, Mahoney D, Carroll AJ, Shuster JJ et al. Accumulation of high levels of methotrexate polyglutamates in lymphoblasts from children with hyperdiploid (greater than 50 chromosomes) B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood 1992; 80: 1316–1323.
Harker-Murray PD, Thomas AJ, Wagner JE, Weisdorf D, Luo X, DeFor TE et al. Allogeneic hematopoietic cell transplantation in children with relapsed acute lymphoblastic leukemia isolated to the central nervous system. Biol Blood Marrow Transplant 2008; 14: 685–692.
Eapen M, Zhang MJ, Devidas M, Raetz E, Barredo JC, Ritchey AK et al. Outcomes after HLA-matched sibling transplantation or chemotherapy in children with acute lymphoblastic leukemia in a second remission after an isolated central nervous system relapse: a collaborative study of the Children's Oncology Group and the Center for International Blood and Marrow Transplant Research. Leukemia 2008; 22: 281–286.
Yoshihara T, Morimoto A, Kuroda H, Imamura T, Ishida H, Tsunamoto K et al. Allogeneic stem cell transplantation in children with acute lymphoblastic leukemia after isolated central nervous system relapse: our experiences and review of the literature. Bone Marrow Transplant 2006; 37: 25–31.
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.
Acknowledgements
We acknowledge the enormous contributions of Professors Judith Chessells, John Lilleyman, Frank Hill and Ian Hann as well as of members of the Leukaemia Lymphoma Division, Children's Cancer and Leukaemia Group during this period. An immense debt of gratitude is owed to all patients and parents who participated in these trials. This work is supported by grants from Cancer Research UK (to VS), Leukaemia Research Fund (to AM), the Medical Research Council (to CM, SR and AV) and the Teenage Cancer Trust (to TOBE).
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The Medical Research Council, which funded these studies, had no role in the study design or in the collection, analysis or interpretation of data. All authors had full access to study data and all shared in the decision to submit for publication.
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VS conceived and designed the study. SK, RW, CP, VS and SR analysed data. AM provided cytogenetic data. CM, SEK, TOBE and AV were trial coordinators and reviewed the final draft. VS and SR interpreted the analysed data. SK, RW, SR, AV, AM, TOBE and VS wrote the paper.
Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)
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Krishnan, S., Wade, R., Moorman, A. et al. Temporal changes in the incidence and pattern of central nervous system relapses in children with acute lymphoblastic leukaemia treated on four consecutive Medical Research Council trials, 1985–2001. Leukemia 24, 450–459 (2010). https://doi.org/10.1038/leu.2009.264
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DOI: https://doi.org/10.1038/leu.2009.264
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