Abstract
Despite great progress in curing childhood acute lymphoblastic leukemia (ALL), survival after relapse remains poor. We analyzed survival after relapse among 9585 pediatric patients enrolled on Children's Oncology Group clinical trials between 1988 and 2002. A total of 1961 patients (20.5%) experienced relapse at any site. The primary end point was survival. Patients were subcategorized by the site of relapse and timing of relapse from initial diagnosis. Time to relapse remains the strongest predictor of survival. Patients experiencing early relapse less than 18 months from initial diagnosis had a particularly poor outcome with a 5-year survival estimate of 21.0±1.8%. Standard risk patients who relapsed had improved survival compared with their higher risk counterparts; differences in survival for the two risk groups was most pronounced for patients relapsing after 18 months. Adjusting for both time and relapse site, multivariate analysis showed that age (10+ years) and the presence of central nervous system disease at diagnosis, male gender, and T-cell disease were significant predictors of inferior post-relapse survival. It can be noted that there was no difference in survival rates for relapsed patients in earlier vs later era trials. New therapeutic strategies are urgently needed for children with relapsed ALL and efforts should focus on discovering the biological pathways that mediate drug resistance.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Pui CH, Evans WE . Treatment of acute lymphoblastic leukemia. N Engl J Med 2006; 354: 166–178.
Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C et al. Cancer statistics, 2006. CA Cancer J Clin 2006; 56: 106–130.
Gaynon PS, Trigg ME, Heerema NA, Sensel MG, Sather HN, Hammond GD et al. Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983–1995. Leukemia 2000; 14: 2223–2233.
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.
Pui CH, Pei D, Sandlund JT, Campana D, Ribeiro RC, Razzouk BI et al. Risk of adverse events after completion of therapy for childhood acute lymphoblastic leukemia. J Clin Oncol 2005; 23: 7936–7941.
Rivera GK, Zhou Y, Hancock ML, Gajjar A, Rubnitz J, Ribeiro RC et al. Bone marrow recurrence after initial intensive treatment for childhood acute lymphoblastic leukemia. Cancer 2005; 103: 368–376.
Chessells JM, Veys P, Kempski H, Henley P, Leiper A, Webb D et al. Long-term follow-up of relapsed childhood acute lymphoblastic leukaemia. Br J Haematol 2003; 123: 396–405.
Kolb EA, Steinherz PG . A new multidrug reinduction protocol with topotecan, vinorelbine, thiotepa, dexamethasone, and gemcitabine for relapsed or refractory acute leukemia. Leukemia 2003; 17: 1967–1972.
Crooks GM, Sato JK . Ifosfamide and etoposide in recurrent childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 1995; 17: 34–38.
Bernstein ML, Abshire TC, Pollock BH, Devine S, Toledano S, Steuber CP et al. Idarubicin and cytosine arabinoside reinduction therapy for children with multiple recurrent or refractory acute lymphoblastic leukemia: a Pediatric Oncology Group study. J Pediatr Hematol Oncol 1997; 19: 68–72.
Harris RE, Sather HN, Feig SA . High-dose cytosine arabinoside and L-asparaginase in refractory acute lymphoblastic leukemia: the Children's Cancer Group experience. Med Pediatr Oncol 1998; 30: 233–239.
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.
Bleyer WA, Sather H, Hammond GD . Prognosis and treatment after relapse of acute lymphoblastic leukemia and non-Hodgkin's lymphoma: 1985. A report from the Childrens Cancer Study Group. Cancer 1986; 58 (2 Suppl): 590–594.
Wheeler K, Richards S, Bailey C, Chessells J . Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukaemia: the MRC UKALL X experience. Medical Research Council Working Party on Childhood Leukaemia. Br J Haematol 1998; 101: 94–103.
Chessells JM . Relapsed lymphoblastic leukaemia in children: a continuing challenge. Br J Haematol 1998; 102: 423–438.
Barredo JC, Devidas M, Lauer SJ, Billett A, Marymont M, Pullen J et al. Isolated CNS relapse of acute lymphoblastic leukemia treated with intensive systemic chemotherapy and delayed CNS radiation: a pediatric oncology group study. J Clin Oncol 2006; 24: 3142–3149.
Grundy RG, Leiper AD, Stanhope R, Chessells JM . Survival and endocrine outcome after testicular relapse in acute lymphoblastic leukaemia. Arch Dis Child 1997; 76: 190–196.
Wofford MM, Smith SD, Shuster JJ, Johnson W, Buchanan GR, Wharam MD et al. Treatment of occult or late overt testicular relapse in children with acute lymphoblastic leukemia: a Pediatric Oncology Group study. J Clin Oncol 1992; 10: 624–630.
Borgmann A, von Stackelberg A, Hartmann R, Ebell W, Klingebiel T, Peters C et al. Unrelated donor stem cell transplantation compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission: a matched-pair analysis. Blood 2003; 101: 3835–3839.
Kersey JH . Fifty years of studies of the biology and therapy of childhood leukemia. Blood 1997; 90: 4243–4251.
Mattano Jr LA, Sather HN, Trigg ME, Nachman JB . Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children's Cancer Group. J Clin Oncol 2000; 18: 3262–3272.
Bhatia S, Yasui Y, Robison LL, Birch JM, Bogue MK, Diller L et al. High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin's disease: report from the Late Effects Study Group. J Clin Oncol 2003; 21: 4386–4394.
Hutchinson RJ, Gaynon PS, Sather H, Bertolone SJ, Cooper HA, Tannous R et al. Intensification of therapy for children with lower-risk acute lymphoblastic leukemia: long-term follow-up of patients treated on Children's Cancer Group Trial 1881. J Clin Oncol 2003; 21: 1790–1797.
Rackoff WR, Ge J, Sather HN, Cooper HA, Hutchinson RJ, Lange BJ . Central venous catheter use and the risk of infection in children with acute lymphoblastic leukemia: a report from the Children's Cancer Group. J Pediatr Hematol Oncol 1999; 21: 260–267.
Smith M, Arthur D, Camitta B, Carroll AJ, Crist W, Gaynon P et al. Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol 1996; 14: 18–24.
Kaplan EL, Meier P . Nonparametric estimation from incomplete observations. J Am Stat Association 1958; 53: 457–481.
Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br J Cancer 1977; 35: 1–39.
Grovas A, Fremgen A, Rauck A, Ruymann FB, Hutchinson CL, Winchester DP et al. The National Cancer Data Base report on patterns of childhood cancers in the United States. Cancer 1997; 80: 2321–2332.
Bhojwani D, Kang H, Moskowitz NP, Min DJ, Lee H, Potter JW et al. Biologic pathways associated with relapse in childhood acute lymphoblastic leukemia: a Children's Oncology Group study. Blood 2006; 108: 711–717.
Ford AM, Fasching K, Panzer-Grumayer ER, Koenig M, Haas OA, Greaves MF . Origins of ‘late’ relapse in childhood acute lymphoblastic leukemia with TEL-AML1 fusion genes. Blood 2001; 98: 558–564.
Zuna J, Ford AM, Peham M, Patel N, Saha V, Eckert C et al. TEL deletion analysis supports a novel view of relapse in childhood acute lymphoblastic leukemia. Clin Cancer Res 2004; 10: 5355–5360.
Kurtzberg J, Asselin B, Pollack B, Berstein M, Buchanan G . PEG-L-asparaginase (PEGasp) vs native E. coli asparaginase (asp) for reinduction of relapsed acute lymphoblastic leukemia (ALL): Pediatric Oncology Group (POG) 8866 Phase II trial. Proceedings of the American Society of Clinical Oncology 1993; 1993: 325.
Wells RJ, Feusner J, Devney R, Woods WG, Provisor AJ, Cairo MS et al. Sequential high-dose cytosine arabinoside-asparaginase treatment in advanced childhood leukemia. J Clin Oncol 1985; 3: 998–1004.
Acknowledgements
This work has been sponsored by the Doris Duke Charitable Foundation (KN), NIH K22 CA113557, The Leukemia Lymphoma Society (LLS 2157-08), and the Frank Campini Foundation (MLL), NIH U10 CA98543-01 (ML, EAR, HS, WLC, NJW, SPH, PSG, and MLL). Dr Loh is a Clinical Scholar of the Leukemia Lymphoma Society.
Author information
Authors and Affiliations
Consortia
Corresponding author
Additional information
This paper was accepted for poster presentation at the American Society of Hematology 48th annual meeting on 9–12 December 2006 as Abstract 1855.
Rights and permissions
About this article
Cite this article
Nguyen, K., Devidas, M., Cheng, SC. et al. Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children's Oncology Group study. Leukemia 22, 2142–2150 (2008). https://doi.org/10.1038/leu.2008.251
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/leu.2008.251
Keywords
This article is cited by
-
Testicular leukaemic infiltration in relapsed acute lymphoblastic leukaemia: a case report
Egyptian Journal of Radiology and Nuclear Medicine (2024)
-
Relapsed Acute Lymphoblastic Leukemia
Indian Journal of Pediatrics (2024)
-
Acute Lymphoblastic Leukemia with Central Nervous System Involvement—Challenges in Management
Indian Journal of Pediatrics (2024)
-
Blinatumomab therapy for B cell acute lymphoblastic leukemia accompanied by persistent or relapsed low-level MRD prior to hematopoietic stem cell transplantation in Chinese children: a case series
Bulletin of the National Research Centre (2023)
-
Chromatin accessibility landscape of relapsed pediatric B-lineage acute lymphoblastic leukemia
Nature Communications (2023)