The New England Journal of Medicine Outcomes after Induction Failure in Childhood Acute Lymphoblastic Leukemia Martin Schrappe, M.D., Stephen P. Hunger, M.D., Ching-Hon Pui, M.D., Vaskar Saha, F.R.C.P.C.H., Paul S. Gaynon, M.D., André Baruchel, M.D., Valentino Conter, M.D., Jacques Otten, M.D., Akira Ohara, M.D., Ph.D., Anne Birgitta Versluys, M.D., Gabriele Escherich, M.D., Mats Heyman, M.D., Ph.D., Lewis B. Silverman, M.D., Keizo Horibe, M.D., Ph.D., Georg Mann, M.D., Bruce M. Camitta, M.D., Jochen Harbott, Ph.D., Hansjörg Riehm, M.D., Sue Richards, D.Phil., Meenakshi Devidas, Ph.D., and Martin Zimmermann, Ph.D. N Engl J Med 2012; 366:1371-1381April 12, 2012DOI: 10.1056/NEJMoa1110169 Comments open through April 18, 2012 Share: AbstractArticleReferencesCiting Articles (40) Comments (1) Current treatment for acute lymphoblastic leukemia (ALL) can effect a cure in approximately 80% of children with the disease.1-9 The leading cause of treatment failure is relapse, for which a number of risk factors have been identified, with inadequate therapy being one of the most important.10-19 A small but significant percentage of patients do not have a complete remission after 4 to 6 weeks of induction chemotherapy.20-23 Among patients with initial induction failure, some never have a complete remission and most others have early relapse. Because of the rarity of induction failure, affected patients have been collectively considered to be a very-high-risk patient subgroup and are offered allogeneic hematopoietic stem-cell transplantation as the treatment of choice.24 Our intergroup collaboration has identified marked clinical heterogeneity in a number of high-risk pediatric ALL subtypes, including those characterized by the Philadelphia chromosome,25 an 11q23 chromosomal rearrangement,26 and hypodiploidy.27 We examined the outcomes in patients 0 to 18 years of age with ALL who had induction failure to identify distinct patient subgroups with different outcomes, related to disease characteristics and treatments administered. METHODS Study Conduct and Study Patients We performed a retrospective analysis of data from 14 cooperative study groups (Table 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org) in Europe, North America, and Asia. From January 1985 through December 2000, the study groups had enrolled in clinical trials a total of 44,017 children and adolescents with newly diagnosed ALL. The enrollment period was chosen to allow for sufficient follow-up. Each study group was asked to identify all patients who fulfilled the individual study groups definition of induction failure during that period. Individual patient data were then collected to form a common database that included information on predefined clinical, biologic, and genetic characteristics, as well as data on treatments, early treatment responses, and survival outcomes. All data were reviewed for completeness and consistency. The median follow-up time for surviving patients was 8.3 years (range, 1.5 to 22.1); 80% of the patients without an event were followed for more than 5 years, and only 3% of the deaths occurred beyond 5 years. By general agreement, none of the participating groups are identified with their data sets in this report. All the clinical trials from which data were used in this analysis had previously received approval from the relevant institutional review boards or ethics committees, and written informed consent had been obtained from patients who were 18 years of age or from parents or guardians of patients who were younger than 18 years of age. Study Group Definitions of Induction Failure The response to induction therapy was evaluated between 28 and 43 days after treatment initiation. Induction failure occurred in 1041 patients (2.4%). The rate varied slightly among the study groups, ranging from 1.4% to 4.9%, since the duration and the intensity of induction therapy, as well as the definition of induction failure, differed among the study groups (Table 1 in the Supplementary Appendix). The most commonly used definition of induction failure was the persistence of leukemic blasts in the bone marrow (M2 marrow, defined as marrow with 5 to 24% blasts, or M3 marrow, defined as marrow with ≥25% blasts, as compared with M1 marrow, defined as marrow with
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