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Journal of Clinical Oncology, Vol 24, No 36 (December 20), 2006: pp. 5750-5762 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.1225 Pathways Through Relapses and Deaths of Children With Acute Lymphoblastic Leukemia: Role of Allogeneic Stem-Cell Transplantation in Nordic Data
From the Hospital for Children and Adolescents, University of Helsinki, Finland; Department of Pediatrics, Juliane Marie Center, Rigshospitalet, Copenhagen; Aarhus University Hospital, Skejby, Aarhus, Denmark; Karolinska University Hospital, Huddinge; University Children's Hospital, Uppsala; Queen Silvia Children's Hospital, University of Göteborg, Göteborg; University Children's Hospital, Lund; Childrens Hospital, University of Umeå, Umeå; Childhood Cancer Research Unit, Karolinska Institute, Stockholm, Sweden; Rikshospitalet, Oslo, Norway; and Landspitalinn, Reykjavik, Iceland Address reprint requests to Ulla M. Saarinen-Pihkala, Hospital for Children and Adolescents, University of Helsinki, PO Box 281, 00029 HUS, Helsinki, Finland; e-mail: ulla.pihkala{at}hus.fi
PURPOSE: Our focus was on patients with pediatric acute lymphoblastic leukemia (ALL) who experienced relapse or died without becoming transplantation candidates. The purpose was to outline measures needed to improve the outcome. PATIENTS AND METHODS: We analyzed our population-based 20-year data on 3,385 Nordic children with ALL treated on Nordic Society for Pediatric Hematology and Oncology ALL protocols, and described the flow of these patients through relapses, remissions, and deaths as a result of toxicity, demonstrating where major patient losses occurred.
RESULTS: In total, 854 patients (25%) had a first and 274 patients (8%) had a second ALL relapse. P for survival after the first relapse was .35 ± .02. The induction mortality (2.2%, primary; 10.3%, first relapse; 26.3%, second relapse) and remission mortality (1%, first complete remission [1CR]; 19%, second CR [2CR]) were significant; transplantation-related mortality (TRM) only represented 15% (69 of 459) of the deaths as a result of toxicity. Of the 766 patients entering 2CR, 29% underwent transplantation (P for survival, .46 ± .04), whereas 71% continued receiving chemotherapy (P for survival, .39 ± .02). Children with stem-cell transplantation indications in 2CR, if they did not undergo transplantation, generally died or had a second relapse. The patient groups that underwent transplantation in 1CR (n = 84), 2CR (n = 220), and
CONCLUSION: Major patient losses occurred through mortality as a result of toxicity and resistant disease during the pathways before allo-SCT. After relapse, more patients were lost to mortality as a result of toxicity during conventional chemotherapy compared with TRM. After second relapse, the chance for rescue by allo-SCT in
Currently, approximately 80% of pediatric acute lymphoblastic leukemia (ALL) can be cured.1-5 However, emphasis needs to be put on the 20% who still have a poor outcome. The therapy of choice for many patients with recurrent ALL is allogeneic stem-cell transplantation (allo-SCT), in which major developments have been made. In pediatric ALL, allo-SCT has been investigated extensively.6 However, rarely, if ever, have patients undergoing transplantation been analyzed against the background of the whole population of pediatric ALL to describe the pathways of the patients selected or not selected for allo-SCT. Randomized studies have been difficult to conduct in evaluating the risks of allo-SCT versus those of conventional chemotherapy.7 In the Nordic pediatric ALL material, we have achieved survival results that compare favorably in the European context.3,8 With our 100% population-based data, the extended follow-up allowed us to describe the flow of ALL patients through repeat and late relapses, remissions, and deaths as a result of toxicity to illustrate the role of allo-SCT as a whole. Our aim was to focus on patients who died during the process before allo-SCT, to determine where major patient losses occurred and where the improvements in therapy need to be made.
Patients This population-based Nordic data from Denmark, Finland, Iceland, Norway, and Sweden includes 100% of children diagnosed with ALL during 1981 through December 31, 2001 (Table 1). For this analysis we excluded those younger than 1 year (n = 106) and  15 years of age at diagnosis (n = 86), and B-cell ALL (n = 49).
Bone marrow (BM) relapse was defined morphologically with 5% blasts in the BM. CNS relapse was diagnosed as 5 WBC/µL in the CSF with blasts, or with defined neurologic symptoms. Testicular relapse was defined as a painless enlargement verified by biopsy. Two relapse categories, group 1 and group 2, were defined. At the first relapse, group 1 included BM relapses within 36 months of diagnosis. Group 2 included all other relapses (ie, isolated extramedullary relapses and all relapses beyond 36 months after diagnosis). At the second relapse, group 1 included BM relapses, and group 2 included the other relapse types.
Therapy for ALL For ALL relapse, both Nordic HR ALL protocols10 and BFM ALL relapse protocols11 were used. Patients with CNS relapses received craniospinal irradiation (24 Gy cranial, 12 Gy spinal), and patients with testicular relapses received 24 Gy to both testicles. High-dose chemotherapy with autologous stem-cell rescue was administered to 49 patients in second complete remission (2CR), who are included in the chemotherapy group in this analysis. Allo-SCT was performed in children with very HR ALL in first complete remission (1CR), earlier using HLA-identical sibling donors12 and later also with unrelated donors (URDs).10 The transplantation indications applied for ALL in 1CR and 2CR, the preparative regimens, and use of graft-versus-host disease (GVHD) prophylaxis have been described.10,12-14 The patients underwent transplantation at seven Nordic centers. We focused specifically on the 62 children who underwent transplantation in or beyond third remission (3CR; Table 2). The preparative regimens were without total body irradiation (n = 18) or with total body irradiation (n = 44). GVHD prophylaxis was mostly cyclosporine plus short-course methotrexate. HLA-identical sibling donors were used in 24 transplantations, phenotypically compatible parental donors were used in three transplantations, and URDs were used in 35 transplantations. Of the URDs, 31 were six of six and four were five of six matched. Standard nucleated cell doses and unmanipulated grafts were used.
Statistical Methods SPSS statistical software (SPSS Inc, Chicago, IL) was used.15 The events and end points after each relapse and SCT were death as a result of toxicity, next relapse, or second malignancy (SMN). The overall survival (OS) and event-free survival (EFS) for 1CR, 2CR, and 3CR were calculated by the Kaplan-Meier method.16 Differences in outcome were compared with the log-rank test.17 A stepwise multiple regression analysis according to Cox was used to identify prognostic factors. Patient accrual for the entire data set discontinued on January 1, 2002, and accrual for the first relapses discontinued on January 1, 2004. The data were frozen for follow-up at January 1, 2006, allowing a minimum follow-up of 2 years for the patients experiencing relapses. The mean follow-up time for survivors after the first relapse was 17 years for patients diagnosed during 1981 to 1991, and 9 years for those diagnosed during 1992 to 2001.
The majority (68%) of our Nordic ALL patients survive in continuous complete first remission after the original chemotherapy (Fig 1). During the latter time period, the proportion in 1CR increased, whereas the induction deaths and first relapses decreased, and those undergoing allo-SCT in 1CR more than tripled (Fig 2A and 2B).
First ALL Relapse In total, 884 children (26%) experienced a first malignant event: 854 were ALL relapses and 30 were SMNs (Fig 3A). Median time from diagnosis to first relapse was 28 months (range, 2 to 227 months). The subsequent outcomes of these patients are illustrated in Figure 3A. Of the first ALL relapses, 417 (49%) were group 1 (Fig 3B), and 437 (51%) group 2 relapses. After the first relapse, P for 10-year overall survival was .35 ± .02 years.
After the first ALL relapse, 88 patients (10%) died within 3 months. These were deaths as a result of toxicity due to severe infections, often with resistant underlying disease. These 88 patients had over-representation of HR-ALL and T-cell ALL (T-ALL; Table 3) compared with the entire Nordic Society for Pediatric Hematology and Oncology (NOPHO) data (Table 1), with 90% relapsing within 36 months of diagnosis.
ALL in Second Remission Of the 766 children who achieved 2CR, 220 (29%) underwent allo-SCT in 2CR, and 546 (71%) continued receiving chemotherapy (Fig 3A; Table 3). The relapse risk categories group 1 and group 2 were 52% and 48% in children proceeding to allo-SCT, and 44% and 56% in those continuing on chemotherapy, respectively (P < .01; Table 3). Of the low-risk cytogenetic changes, 50 hyperdiploidy occurred similarly (25%) in both groups, and t(12;21) occurred in 11% (five of 46) of the SCT and 28% (23 of 83) of the chemotherapy patients (P < .05). Of the 220 children treated with allo-SCT in 2CR, 110 have died, whereas 110 are alive (Fig 3A). Details on allo-SCT in 2CR have been published.13,14 In total, 546 children continued receiving chemotherapy (Figs 3A and 4), with a P for survival, .39 ± .02, and P for EFS in second remission at 10 years (2EFS) of .28 ± .02 at 10 years. In total, 103 patients (19%) have died in 2CR as a result of toxicity, whereas 274 patients (50%) have experienced a second relapse.
Mortality as a result of toxicity was 20% in the transplantation group, and 19% in the chemotherapy group (Fig 4), and the proportion experiencing relapse and death was 30% and 42%, respectively (Fig 4). The 10-year survival in these somewhat dissimilar cohorts was .46 ± .04 in the SCT and .39 ± .02 in the chemotherapy group (P < .01).
Figure 3A and Table 4 illustrate the children who achieved 2CR and received conventional chemotherapy. Age at diagnosis, initial risk category, immunophenotype, time in 1CR, site of first relapse, and first relapse category were all significant prognostic factors in univariate analyses (Table 4). The risk of second relapse or death in 2CR was associated with an early (< 36 months) BM relapse (P 2EFS, .11; Fig 5A), initial HR-ALL (P 2EFS, .15; Fig 5B), and T-ALL (P 2EFS, .10 v .30 in precursor B immunophenotype; P < .01; Table 4). Combined BM plus extramedullary relapses had an outcome inferior to isolated extramedullary relapses (Fig 5C). Those age
Among late BM relapses and isolated extramedullary relapses, there were subgroups that did not do well. The P for 2EFS of those with late (> 36 months) BM relapses but initial HR-ALL (.30 v non-HR ALL, .48), P for 2EFS of those with on-therapy (< 24 months) extramedullary relapses (.28 v > 24 months, .57), and P for 2EFS of those with combined BM plus extramedullary relapses (.28; Fig 5C) are suboptimal and inferior to the outcome in more favorable subgroups (Table 4; Fig 5A, 5B, 5C). Outcomes of subgroups, parallel for chemotherapy and allo-SCT, are presented in Table 5.
Of the low-risk cytogenetic changes, 50 hyperdiploidy was seen in 36% v 21% (P < .05), and t(12;21) was seen in 34% (12 of 35) versus 20% (eight of 39; not significant) of the 2CR survivors versus those with a second relapse, respectively [entire NOPHO data, > 50 hyperdiploidy, 25% to 30%; t(12;21), 22%].
Second Relapse
Allo-SCT 3CRAllo-SCT was performed in 31% of the 3CR patients (n = 62), constituting 11% of the 546 who continued receiving chemotherapy in 2CR (Fig 3A). This transplantation group (Table 2) had several favorable features, mostly (74%) with SR-ALL or IR-ALL, precursor B immunophenotype (91%), a slow disease with long duration of both 1CR and 2CR, and the first relapse mostly (79%) late or extramedullary (Table 6). Indications for allo-SCT present already in 2CR were analyzed. Clear SCT indications were recognized in 12 (19%) of 62 patients: BM relapses while receiving therapy (n = 7) or less than 6 months while not receiving therapy (n = 2), extramedullary relapse with T-ALL while receiving therapy (n = 2), and very high risk ALL with WBC more than 400 x 105/L (n = 1). The reasons patients did not receive transplantations were lack of donor (n = 2), lack of time (n = 7; only 2 to 4 months from first to second relapse, all with URDs), and unknown (n = 3). No transplant indication in 2CR was revealed in 16 (26%) of 62 patients with late relapses; nine in BM with SR-ALL, and seven isolated extramedullary. Controversial indications included the 22 patients with late BM relapses (14 IR-ALL, eight HR-ALL), and 12 patients with isolated extramedullary relapses while receiving therapy or less than 6 months while not receiving therapy (not T-ALL or very high risk ALL). The outcome of this highly selected group was encouraging (Fig 3A), with a 10-year survival P of .37 ± .07 (P < .01 compared with chemotherapy in 3CR). Twelve patients (19%) died as a result of treatment-related mortality (TRM; GVHD, n = 3; aspergillosis, n = 3; cytomegalovirus pneumonitis, n = 1; sepsis/severe infections, n = 5). Twenty-three patients died as a result of a post-transplantation relapse, and two patients died as a result SMN (brain tumor/primitive neuroectodermal tumor, and Epstein-Barr virus–lymphoma, respectively). Related versus URDs gave similar survival (P, .44 v .31; P = .2).
Summary of Survivors Among Nordic Data
Induction Mortality, Remission Mortality, and TRM Table 8 illustrates all deaths as a result of toxicity among the patients studied. We categorized all induction deaths as deaths as a result of toxicity despite of the possible role of a resistant disease. Mortality on conventional chemotherapy was reduced substantially during the latter time period. Nevertheless, the numbers remained higher (n = 109) than transplantation-related deaths (n = 45). TRM represented only 15% of the deaths as a result of toxicity in total. The TRM for allo-SCT in 1CR, 2CR, and 3CR combined was 69 (18.9%) of 366.
In the population-based Nordic ALL data from 20 years, we analyzed the flow of children through relapses and subsequent remissions before allo-SCT. This analysis illustrates the sites of major patient losses and the points where additional efforts need to be focused.
The pathways leading to allo-SCT in 2CR or
The use of caution before allogeneic transplants were performed, particularly with URDs, has been based on high TRM rates. For the entire NOPHO-ALL transplant data from 1981 to 2001, including transplants in 1CR, 2CR, and
Transplantations in ALL 3CR have had similar18 or often poorer19-21 outcome than those in 2CR. Our data showed a post-transplantation 10-year survival of 46% for 2CR and 37% for Major controversy lies in allo-SCT indications in 2CR of ALL. Time and site of the first relapse are powerful prognostic factors.22 There is broad consensus that children with early BM relapses or relapses while receiving therapy should undergo transplantation, and those with late extramedullary relapses or extramedullary relapses while not receiving therapy should not undergo transplantation. Between the two extremes, differences in views and recommendations exist. For example, recommendations applied in the United States6 are not identical to the current German protocol (BFM-Rez 2002, data not published). In the present Nordic data, we especially looked at the 546 children who continued receiving chemotherapy in 2CR (Figs 3A, 3B, 5A, 5B, 5C; Table 4). The patients who experienced relapse or died while receiving chemotherapy were characterized by early (within 36 months) BM relapses, IR or HR ALL, and over-representation of T-ALL. Age older than 10 years at diagnosis was an unfavorable factor. We found subgroups within the favorable relapse categories who did not do well on conventional chemotherapy after achieving a 2CR. These were the patients with late BM relapses but initial HR ALL, extramedullary relapses while receiving therapy, and combined BM plus extramedullary relapses. Although these groups were small with limited statistical power, we believe that allo-SCT should be considered for these patients. Patients with extramedullary relapses during therapy also had poor outcomes in a recent report from the United Kingdom.23 Our combined BM relapses did not fare significantly better than those with isolated BM relapses (Fig 5C), in contrast to other studies. Response to relapse induction therapy and minimal residual disease at follow-up are important factors in evaluating allo-SCT indications at present. The 2CR patients destined to continue receiving conventional chemotherapy require frequent minimal residual disease monitoring. Allocation of patients to SCT versus chemotherapy in second remission (Table 3) indicates that many patients with transplantation indications still continued receiving conventional chemotherapy. Our data clearly demonstrate that if patients with HR relapses did not undergo transplantation in 2CR (Fig 3B), they were likely to die in 2CR or have a subsequent relapse with induction failure. Clearly, the children with transplantation indications in 2CR were not the patients who underwent allo-SCT in 3CR; the latter were a different group of patients with favorable features and slow disease who were believed to have a good outcome with conventional chemotherapy in 2CR. The argument that by offering conventional chemotherapy in 2CR, the patient could later be rescued by allo-SCT in the event of an additional relapse18,23 has no solid background. The chances for rescue later were unexpectedly small. We emphasize that with transplantation indications present in 2CR, allo-SCT should be pursued even with alternative donors. The long-term quality of life has been good post transplantation.14 The remission induction rates decreased from the 98% at the primary induction to 90% at the first and 74% at the second ALL relapse (Fig 3). Others have achieved remission induction rates ranging from 65% to 97% at the first ALL relapse,7,11,24-33 with lower remission rates in early11,26,27,29,30,33 and higher rates in late relapses.11,24,25,28,29,33 Our relapse induction mortality represents 5% of the entire NOPHO ALL data: this result need not be inevitable. Better relapse protocols have to be launched. Within NOPHO, the first Nordic ALL relapse protocol is underway with a response-guided design. In conclusion, major patient losses occurred through mortality as a result of toxicity, and resistant disease during therapy before allo-SCT. After relapse, more patients were lost to mortality as a result of toxicity while receiving conventional chemotherapy than as a result of TRM. After second relapse, the chance for rescue by allo-SCT in 3CR was minimal. These problems need to be addressed by emphasizing and re-evaluating indications for allo-SCT in 2CR and by improving relapse induction therapy.
The authors indicated no potential conflicts of interest.
Supported by Research Funding of the Helsinki University Hospitals, Helsinki, Finland (U.S.-P.), Foundation for Pediatric Research, Helsinki, Finland (U.S.-P.), and by Swedish Child Cancer Foundation, Stockholm, Sweden (G.G.). Presented in part at the Annual Nordic Society for Pediatric Hematology and Oncology Meeting, May 7-9, 2006, Tampere, Finland. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Schrappe M, Reiter A, Ludvig WD, et al: Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: Results of trial ALL-BFM 90. Blood 95:3310-3322, 2000 2. Gaynon PS, Trigg ME, Heerema NA, et al: Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983-1995. Leukemia 14:2223-2233, 2000[CrossRef][Medline] 3. Gustafsson G, Schmiegelow K, Forestier E, et al: Improving outcome through two decades in childhood ALL in the Nordic countries: The impact of high-dose methotrexate in the reduction of CNS irradiation. Leukemia 14:2267-2275, 2000[CrossRef][Medline] 4. Silverman LB, Gelber RD, Dalton VK, et al: Improved outcome for children with acute lymphoblastic leukemia: Results of Dana Farber Consortium Protocol 91-01. Blood 97:1211-1218, 2001 5. Pui CH, Sandlund JT, Pei D, et al: Results of therapy for acute lymphoblastic leukemia in black and white children. JAMA 290:2001-2007, 2003 6. Davies SM, Ramsay NKC, Kersey JH: Allogeneic transplantation for acute lymphoblastic leukemia in children. In: Thomas ED, Blume KG, Forman SJ (eds): Hematopoietic Stem Cell Transplantation (ed 2). Malden, MA, Blackwell Science, 1999, pp 859-871 7. Gaynon PS, Harris RE, Altman AJ, et al: Bone marrow transplantation versus prolonged intensive chemotherapy for children with acute lymphoblastic leukemia and an initial bone marrow relapse within 12 months of the completion of primary therapy: Children's Oncology Group study CCG-1941. J Clin Oncol 24:3150-3156, 2006 8. Gatta G, Corazziari I, Magnani C, et al: Childhood cancer survival in Europe. Ann Oncol 14:v119-v127, 2003 (suppl 5) 9. Gustafsson G, Kreuger A, Clausen N, et al: Intensified treatment of childhood acute lymphoblastic leukemia has improved prognosis, especially in non-high-risk patients: The Nordic experience of 2648 patients diagnosed between 1981 and 1996. Acta Paediatr 87:1151-1161, 1998[CrossRef][Medline] 10. Saarinen-Pihkala UM, Gustafsson G, Carlsen N, et al: Outcome of children with high-risk acute lymphoblastic leukemia (HR-ALL): Nordic results on an intensive regimen with restricted central nervous system irradiation. Pediatr Blood Cancer 42:8-23, 2004[CrossRef][Medline] 11. Henze G, Fengler R, Hartmann R, 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 78:1166-1172, 1991 12. Saarinen UM, Mellander L, Nysom K, et al: Allogeneic bone marrow transplantation in first remission for children with very high-risk acute lymphoblastic leukemia: A retrospective case-control study in the Nordic countries. Bone Marrow Transplant 17:357-363, 1996[Medline] 13. Schroeder H, Gustafsson G, Saarinen-Pihkala UM, et al: Allogeneic bone marrow transplantation in second remission of childhood acute lymphoblastic leukemia: A population-based case-control study from the Nordic countries. Bone Marrow Transplant 23:555-560, 1999[CrossRef][Medline] 14. Saarinen-Pihkala UM, Gustafsson G, Ringden O, et al: No disadvantage in outcome of using matched unrelated donors as compared with matched sibling donors for bone marrow transplantation in children with acute lymphoblastic leukemia in second remission. J Clin Oncol 19:3406-3414, 2001 15. Norusis MJ: SPSS statistical software. SPSS: Base and Advanced Statistics 13.0. Chicago, IL, SPSS Inc, 2003 16. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 17. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II. Analysis and examples. Br J Cancer 35:1-39, 1977[Medline] 18. Borgmann A, Baumgarten E, Schmid H, et al: Allogeneic bone marrow transplantation for a subset of children with acute lymphoblastic leukemia in third remission: Conceivable alternative? Bone Marrow Transplant 20:939-944, 1997[CrossRef][Medline] 19. Balduzzi A, Gooley T, Anasetti C, et al: Unrelated donor marrow transplantation in children. Blood 86:3247-3256, 1995 20. Bordigoni P, Esperou H, Souillet G, et al: Total body irradiation, high-dose cytosine arabinoside and melphalan followed by allogeneic bone marrow transplantation from HLA-identical siblings in the treatment of children with acute lymphoblastic leukemia after relapse while receiving chemotherapy: A Societe Francaise de Greffe de Moelle study. Br J Haematol 102:656-665, 1998[CrossRef][Medline] 21. Woolfrey AE, Anasetti C, Storer B, et al: Factors associated with outcome after unrelated marrow transplantation for treatment of acute lymphoblastic leukemia in children. Blood 99:2002-2008, 2002 22. Gaynon PS, Qu RP, Chappell RJ, 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 82:1387-1395, 1998[CrossRef][Medline] 23. Roy A, Cargill A, Love S, et al: Outcome after first relapse in childhood acute lymphoblastic leukemia: Lessons from the United Kingdom R2 trial. Br J Haematol 130:67-75, 2005[CrossRef][Medline] 24. Sadowitz PD, Smith SD, Shuster J, et al: Treatment of late bone marrow relapse in children with acute lymphoblastic leukemia: A Pediatric Oncology Group Study. Blood 81:602-609, 1993 25. Rivera GK, Hudson MM, Liu Q, et al: Effectiveness of intensified rotational combination chemotherapy for late hematologic relapse of childhood acute lymphoblastic leukemia. Blood 88:831-837, 1996 26. Feig SA, Harris RE, Sather HN: Bone marrow transplantation versus chemotherapy for maintenance of second remission of childhood acute lymphoblastic leukemia: A study of the Children's Cancer Group (CCG-1884). Med Pediatr Oncol 29:534-540, 1997[CrossRef][Medline] 27. Buchanan GR, Rivera GK, Pollock BH, et al: Alternating drug pairs with or without periodic reinduction in children with acute lymphoblastic leukemia in second bone marrow remission: A Pediatric Oncology Group Study. Cancer 88:1166-1174, 2000[CrossRef][Medline] 28. Lawson SE, Harrison G, Richards S, et al: The UK experience in treating relapsed childhood acute lymphoblastic leukemia: A report on the Medical Research Council UKALLR1 study. Br J Haematol 108:531-543, 2000[CrossRef][Medline] 29. Leahey AM, Bunin NJ, Belasco JB, et al: Novel multiagent chemotherapy for bone marrow relapse of pediatric acute lymphoblastic leukemia. Med Pediatr Oncol 34:313-318, 2000[CrossRef][Medline] 30. Uderzo C, Conter V, Dini G, et al: Treatment of childhood acute lymphoblastic leukemia after the first relapse: Curative strategies. Haematologica 86:1-7, 2001 31. Hijiya N, Gajjar A, Zhang Z, et al: Low-dose oral etoposide-based induction regimen for children with acute lymphoblastic leukemia in first bone marrow relapse. Leukemia 18:1581-1586, 2004[CrossRef][Medline] 32. Thomson B, Park JR, Felgenhauer J, et al: Toxicity and efficacy of intensive chemotherapy for children with acute lymphoblastic leukemia (ALL) after first bone marrow or extramedullary relapse. Pediatr Blood Cancer 43:571-579, 2004[CrossRef][Medline] 33. Einsiedel HG, von Stackelberg A, Hartmann R, 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-Münster Group 87. J Clin Oncol 23:7942-7950, 2005 Submitted May 31, 2006; accepted October 5, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
