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Journal of Clinical Oncology, Vol 25, No 1 (January 1), 2007: pp. 16-24
© 2007 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2006.06.8312
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Comparison of Intensive Chemotherapy, Allogeneic, or Autologous Stem-Cell Transplantation As Postremission Treatment for Children With Very High Risk Acute Lymphoblastic Leukemia: PETHEMA ALL-93 Trial

Jose-Maria Ribera, Juan-José Ortega, Albert Oriol, Pilar Bastida, Carlota Calvo, José-María Pérez-Hurtado, María-Elvira González-Valentín, Victoria Martín-Reina, Antonio Molinés, Fernando Ortega-Rivas, Maria-José Moreno, Concepción Rivas, Izaskun Egurbide, Inmaculada Heras, Concepción Poderós, Eva Martínez-Revuelta, José-Maria Guinea, Eloy del Potro, Guillermo Deben

From the Institut Català d'Oncologia-Hospital Universitari Germans Trias i Pujol; Hospital Universitari Vall d'Hebron, Barcelona; Hospital Infantil Miguel Servet, Zaragoza; Hospital Universitario Virgen del Rocío, Sevilla; Hospital Materno-Infantil Carlos Haya, Málaga; Hospital Universitario Virgen de la Victoria, Málaga; Hospital Puerta del Mar, Cadiz; Hospital Materno Infantil, Las Palmas; Hospital Río Carrión, Palencia; Hospital General, Alicante; Hospital de Aranzazu, San Sebastián; Hospital Morales Meseguer, Murcia; Hospital Xeral, Vigo; Hospital Central de Asturias; Hospital Txagorritxu, Vitoria; Hospital Clínico San Carlos, Madrid; and Hospital Juan Canalejo, La Coruña, Spain

Address reprint requests to Jose-María Ribera, Servicio de Hematología Clínica, Institut Català d'Oncologia-Hospital Universitari Germans Trias i Pujol, C/ Canyet S/N, 08916 Badalona, Spain; e-mail: jribera{at}iconcologia.net


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Purpose The optimal postremission therapy for children with very high-risk (VHR) acute lymphoblastic leukemia (ALL) is not well established. This randomized trial compared three options of postremission therapy: chemotherapy and allogeneic or autologous stem-cell transplantation (SCT).

Patients and Methods All 106 VHR-ALL patients received induction with five drugs followed by intensification with three cycles of chemotherapy. Patients in complete remission (CR) with an HLA-identical family donor were assigned to allogeneic SCT (n = 24) and the remaining were randomly assigned to autologous SCT (n = 38) or to delayed intensification followed by maintenance chemotherapy up to 2 years in CR (n = 38).

Results Overall, 100 patients achieved CR (94%). With a median follow-up of 6.5 years, 5-year disease-free survival (DFS) and overall survival (OS) probabilities were 45% (95% CI, 37% to 54%) and 48% (95% CI, 40% to 57%), respectively. The three groups were comparable in the main pretreatment ALL characteristics. Intention-to-treat analysis showed no differences for donor versus no donor in DFS (45%; 95% CI, 27% to 65% v 45%; 95% CI, 37% to 55%) and OS (48%; 95% CI, 30% to 67% v 51%; 95% CI, 43% to 61%), as well as for autologous SCT versus chemotherapy comparisons (DFS: 44%; 95% CI, 29% to 60% v 46%; 95% CI, 32% to 62%; OS: 45%; 95% CI, 31% to 62% v 57%; 95% CI, 43% to 73%). No differences were found within the different subgroups of ALL and neither were differences observed when the analysis was made by treatment actually performed.

Conclusion This study failed to prove that, when a family donor is available, allogeneic SCT produces a better outcome than autologous SCT or chemotherapy in children with VHR-ALL.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
With the chemotherapy trials designed between 1985 and 1995, 10-year disease-free survival (DFS) was attained by 70% to 80% of children with acute lymphoblastic leukemia (ALL).1-9 However, for patients with very high-risk (VHR) ALL, the DFS has been less than 45% in most multicenter studies.10-20

The intensification of consolidation has not improved the outcome of children with VHR-ALL.1,2,21 In these patients the role of allogeneic stem-cell transplantation (SCT) in first remission has not been well defined,22-29 although advantages of allogeneic SCT over chemotherapy have been specially significant in patients with the t(9;22).14-16 Only one study has prospectively compared the outcomes of VHR patients receiving allogeneic SCT or chemotherapy by genetic randomization and intention-to-treat analysis.26 A significantly better DFS was found for patients with a donor (56.7% v 40.6%), but this advantage did not translate into a better overall survival (OS). In addition there are no comparative studies published evaluating the efficacy of autologous SCT as postconsolidation treatment in children with VHR-ALL.

The main objective of the present trial was to compare three options of postconsolidation therapy: chemotherapy and allogeneic and autologous SCT, in 106 children with VHR-ALL.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Appendix
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Eligibility
Patients were eligible if they fulfilled at least one of the following criteria: age younger than 1 year; WBC count ≥ 300 x 109/L in B-lineage ALL; ≥ 100 x 109/L in T-lineage ALL; or t(9;22), t(4;11), or other 11q23 rearrangements. Patients without these criteria but slow (> 25% blasts in bone marrow at day 14 of therapy) or partial (persistence of 5% to 25% blasts in bone marrow at day 35) response to induction therapy (common to all PETHEMA [Programa de Estudio y Tratamiento de las Hemopatías Malignas] protocols for ALL) were also eligible for this study.

Patients were centrally registered before treatment on receipt of consent from parents or guardians, and random assignment was performed when family donor availability was obtained. The study was approved by the investigational review boards at the participating institutions and was initiated in January 1993 and was closed for patient inclusion in October 2002. ALL diagnosis was made by morphological30 and flow cytometry analyses. Chromosomal analyses were performed at diagnosis in institutional laboratories and the results were centrally reviewed.31

Treatment
The therapeutic schedule is presented in Table 1. Patients not achieving complete remission (CR) received the first cycle of early intensification and if CR was not achieved were excluded from the protocol. Patients in CR with a HLA-identical sibling were genetically randomly assigned to allogeneic SCT whereas the remaining patients were randomly assigned to autologous SCT or delayed intensification chemotherapy followed by maintenance treatment.


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  		Table 1. PETHEMA ALL-93 Chemotherapy Schedule

 
Criteria for Response, Relapse, and Follow-Up
Hematologic CR was defined as normal marrow cytology (< 5% blasts and > 25% cellularity), neutrophil counts more than 1.5 x 109/L, platelet counts more than 100 x 109/L, and no extramedullary disease. Early death was considered as death occurring during induction (without fulfilling the definition of CR or resistant disease [RD]). Partial response (PR) was defined as the persistence of 5% to 25% blasts at the end of the induction therapy. RD was considered if the patient survived the induction but the leukemia persisted. Relapse was defined as disease recurrence at any site after achieving CR. The DFS was calculated from the date of CR until the date of first relapse, death by any cause, or the last follow-up for patients alive in first CR. OS was measured from the time of entry in the protocol to the time of death or last follow-up.

Statistical Analysis
The primary study objective was DFS in the different postremission therapeutic options by intention-to-treat analysis. Secondary objectives were OS according to the different strategies and DFS and OS according to the treatment actually received by the patients. The null hypothesis was that there were no differences between patients with or without a donor on an intention-to-treat basis. With predefined errors {alpha} = .05 and ß = .2, it was calculated that 108 events had to be observed. Thus, assuming a CR rate of 90% and a ratio 1:2 of patients with and without a donor, 198 patients had to be recruited. Given the scarcity of children with VHR-ALL an intermediate analysis was planned after the inclusion of 100 patients to prematurely close the study if statistical differences among groups were already found or if differences were very unlikely to emerge with a larger sample (< 10% probability). DFS and OS curves were plotted by the Kaplan-Meier method32 and were compared by the log-rank test.33,34 All relapse and survival data were updated on July 15, 2005. A logistic regression model was used to identify predictive factors for CR attainment, whereas multivariate analyses for DFS and OS were performed using the Cox proportional hazards regression model.35,36 The significance level was fixed at P = .05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Appendix
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Patient Entry
A total of 119 children with VHR-ALL had been registered of whom 106 were eligible. Causes of noneligibility were: absence of criteria of VHR-ALL (six patients), lymphoblastic lymphoma,4 and Burkitt's leukemia.3 The median follow-up was 6.5 years (range, 1.3 to 12.4 years).

Pretreatment Characteristics
The main characteristics of the patients are presented in Table 2. Seventy patients had VHR-ALL at diagnosis. Among them, 12 were infants, seven had t(9;22), 13 carried t(4;11) (n = 11) or other 11q23 rearrangements (n = 2), 35 (67%) had WBC count ≥ 100 x 109/L and T-cell ALL (T-ALL), and 17 (33%) had WBC count ≥ 300 x 109/L and B-lineage ALL.


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  		Table 2. Patient Characteristics for All Eligible Patients and for Patients Assigned to Allogeneic SCT, or Randomly Assigned to Autologous SCT or to Chemotherapy

 
Thirty-six patients (34%) without VHR features presented slow response (n = 26) or PR (n = 10) to induction therapy and were incorporated for postremission therapy.

Results of Induction Therapy
Overall, 100 patients attained CR. CR was attained in 64 of 70 patients (91%) with baseline VHR features, the reasons for failure were early death in two patients (3%) and RD in four patients (6%). Slow response was observed in 29 assessable patients with baseline VHR-ALL (Table 2), with five patients failing to attain CR and 24 attaining CR. Of 26 patients without baseline VHR-ALL, but with slow response to therapy, 26 achieved CR at the end of the induction. Ten patients with PR achieved CR after the cycle 1 of early intensification.

Assignment of the Patients
Twenty four of the 100 eligible patients had an HLA-matched sibling and were genetically randomly assigned to allogeneic SCT, 38 patients were randomly assigned to autologous SCT, and 38 were randomly assigned to chemotherapy (Fig 1). The three groups were comparable for pretreatment ALL characteristics (Table 2). The proportion of infants, T-ALL, t(9;22), or t(4;11) patients was not significantly different among groups on a donor versus no donor basis and on the basis of treatment actually received. Although the patients with a donor appeared to present a slower clearance of blasts of peripheral blood on day 8 with a borderline significance (P = .1), this was not confirmed in the bone marrow evaluation on day 14. Twenty three (96%) of the 24 patients with donors completed the intensification therapy and 17 patients (74%) received an allogeneic SCT. The median time from CR documentation to allogeneic SCT was 22 weeks (range, 12 to 67). Of the 38 patients randomly assigned to autologous SCT, 37 patients (97%) completed the three cycles and 25 patients (68%) were autografted. The median time from CR to autologous SCT was 20 weeks (range, 9 to 75 weeks). All patients randomly assigned to chemotherapy (n = 38) completed the early intensification. Delayed intensification was started in 30 patients (79%) at a median of 14 weeks (range, 9 to 20) after CR. Time from CR to the delayed intensification was significantly shorter than time to allogeneic or autologous SCT (P = .001).


Figure 1
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  		Fig 1. Schema of the PETHEMA acute lymphoblastic leukemia (ALL) 3-93 trial. VHR, very high risk; Dx, diagnosis; SCT, stem-cell transplantation; CHT, chemotherapy; MUD, matched unrelated donor; TRM, transplantation-related mortality; CR, complete remission.

 
DFS and OS of the Whole Series
Seventeen patients relapsed before SCT or delayed intensification, 11 during delayed intensification or maintenance and 17 after completion of therapy. Eleven patients refused to continue their assigned treatment plan (Fig 1). Median DFS was 2.4 years and 5-year DFS probability was 45% ± 8%. DFS of patients with T-ALL was significantly shorter than in the remaining patients (median, 0.9 years; 5-year DFS, 34%; Appendix Fig A1, online only). Median OS was of 3.6 years, with OS probability at 5 years of 48% ± 7%. Median OS for T-ALL patients was 2.1 years with a 5-year probability for OS of 33% ± 13%, significantly shorter than the OS of the remaining patients (P = .007). T-cell phenotype was the only variable associated with adverse prognosis in univariate and multivariate analyses for DFS and OS (odds ratio [OR], 2.0; 95% CI, 1.1 to 3.8; P = .02; and OR, 2.1; 95% CI, 1.2 to 3.6; P = .008, respectively). The same results were obtained when treatment was considered as a covariate. A trend for significance of t(9;22) (OR 2.32; 95% CI, 0.84 to 6.44; P = .1) was observed but did not change after adjustment for treatment.

Analysis by Intention-To-Treat
At the moment of interim analysis (106 eligible patients included), the probability of one group having a 10% superior outcome over the other was 4%. Further recruitment was considered unjustified and patients already recruited were observed. At the point of final analysis, the statistical power of a log-rank test was calculated to be 90% for a DFS difference of 10%. The 24 patients who achieved CR and had an available matched relative presented a median survival of 3 years and 5-year OS probability of 48% (95% CI, 30 to 67). Their median DFS was 1.4 years with 5-year DFS probability of 45% (95% CI, 27 to 65). Their OS and DFS (Fig 2) did not significantly differ from those of patients without a donor (Table 3).


Figure 2
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  		Fig 2. Comparison of disease-free survival curves on a donor versus no donor basis. CR1, first complete remission.

 

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  		Table 3. Comparison of DFS, OS, and Relapse Probability for the Subgroups of Patients According to Donor Versus No Donor and, in the Latter Group, According to Arm of Random Assignment on an Intention-to-Treat Basis

 
In autologous SCT arm, 10 patients relapsed before autologous SCT and nine patients relapsed after the procedure. There were two transplantation-related deaths. In the chemotherapy arm, three patients relapsed after early intensification, two during delayed intensification cycles, nine during maintenance, and four after completion of therapy. There were no chemotherapy-related deaths. After a median follow-up of 6.4 years, no statistically significant differences in DFS (Appendix Fig A2, online only) or OS between the two groups were detected (Table 3).

Time to Relapse According to Actual Postremission Treatment Received
Twenty-two patients actually received an allogeneic SCT, 25 patients received an autologous SCT, and 36 patients received late intensification plus maintenance. The 5-year cumulative relapse probability from SCT or from first late intensification cycle ranged from 33% (allogeneic SCT) to 47% (chemotherapy). Differences in relapse probabilities among the three groups were not statistically significant (Table 3). The conditioning regimen was total-body irradiation (TBI) based in 31 patients and busulfan based in the remaining 16 patients. In patients submitted to either allogeneic or autologous SCT the 5-year relapse probabilities were 55% ± 27% for busulfan-based schedules and 25% ± 15% for TBI-based regimens, although this difference was not statistically significant (P = .22). On exclusion of the 16 patients treated with busulfan-based regimens the results did not change (5-year DFS, 45% for donor v 47% for no-donor patients; P = .94).

Analysis of Subgroups
Infant ALL. None of the 12 infants had a matched sibling donor. Of the five patients randomly assigned to autologous SCT, two relapsed before and two refused SCT and continued with late intensification chemotherapy. Of the five patients randomly assigned to chemotherapy, one relapsed before late intensification, one relapsed during maintenance, and two underwent a matched unrelated donor (MUD) SCT. Six patients remained in first CR. OS and DFS were identical for patients assigned to autologous SCT or late intensification therapy on an intention-to-treat basis (Table 4).


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  		Table 4. DFS of Patients According to Intention-to-Treat Assignment and Probability of Relapse From SCT or the Beginning of Late Intensification According to Treatment Actually Performed for Specific ALL Subgroups

 
ALL with specific cytogenetic translocations. A matched sibling donor was available in three of 17 CR patients (allogeneic SCT was performed in two). Autologous SCT was performed to six of seven randomly assigned patients and maintenance was completed in three of seven patients randomly assigned to chemotherapy. Six patients remained in CR (two after allogeneic SCT, two after autologous SCT, and two after maintenance therapy). No significant differences between autologous SCT and chemotherapy were detected (Table 4).

B-lineage ALL without specific rearrangements. Allogeneic SCT was performed in six of seven patients (five remained in CR). Autologous SCT was performed in seven of nine patients (five remained in CR). Six patients assigned to chemotherapy relapsed and seven maintained CR. No differences in DFS for any subgroup were observed (Table 4).

T-cell ALL. Fourteen of 44 CR patients had a matched sibling donor, nine received an allogeneic SCT, and four remained in CR. Autologous SCT was performed in 11 of 17 randomly assigned patients, and six remained in first CR. Of 13 patients randomly assigned to chemotherapy five patients remained in first CR. No treatment option emerged as significantly superior (Table 4).

Slow and partial responders to induction therapy. In all, 60 slow responders achieving CR were evaluated for postremission therapy (24 with baseline VHR features and 36 without initial VHR features but with slow response or PR to induction). No variables associated to slow response and no statistically significant differences in the initial characteristics of slow responders among the treatment groups were found.

Of 17 with a donor, 12 were allotransplanted and seven remained in CR. Autologous SCT was performed in 16 of 22 randomly assigned patients, of whom eight remained in first CR. Finally, of 21 patients randomly assigned to chemotherapy 10 remained in CR. Five-year DFS probability for slow responders was 42% (95% CI, 31 to 53) and no treatment option appeared to provide any advantage over the others (DFS probabilities of 40%, 40%, and 47%, respectively, for allogeneic SCT, autologous SCT, and chemotherapy).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Appendix
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
This clinical trial failed to prove that, when a family donor is available, allogeneic SCT produces a better outcome than autologous SCT or chemotherapy in children with VHR-ALL in first CR. VHR patients comprised 13% of the total ALL patients included in the different PETHEMA protocols, a proportion similar to that observed in Medical Research Council (MRC) studies25 and Italian studies13 and slightly higher than 9% to 11% of others.26

The value of allogeneic SCT in VHR patients compared with intensive consolidation therapies has been the object of a few studies.23-27 In the Nordic retrospective case-control study,23 hematopoietic SCT showed a significant advantage in DFS (73% v 50%). No differences were observed in an Italian study24 (58.5 v 47.7%). The MRC study25 compared bone marrow transplantation and chemotherapy based on availability of a matched histocompatible donor. The decision to proceed to HLA typing and SCT was taken by the individual clinicians. No significant differences were observed in 10-year EFS probability (50.4% for no donor v 39.7% for donor). Patients actually undergoing transplantation showed fewer relapses (31%) compared with the chemotherapy group (55%), a feature which was counterbalanced by more deaths in the allogeneic SCT (18%) than in the chemotherapy group (3%). According to therapy actually given, event-free survival of patients receiving a SCT was 47% versus 38% of patients who received chemotherapy.25

An international prospective study was addressed to compare additional intensified chemotherapy with a compatible related-donor SCT by genetic random assignment.26 Definition of VHR-ALL and adherence to treatment allocation were similar to those of this study. The intention-to-treat analysis showed a significantly better DFS for patients with a donor (56.7% v 40.6%; P = .02). However, this advantage in DFS did not translate into a superior OS (50.1% v 56.4% in the chemotherapy and SCT arms, respectively) indicating that some patients with relapse after chemotherapy could be rescued in second CR with matched unrelated donor SCT. When analysis was performed by treatment actually received, the advantage of allogeneic SCT over chemotherapy in DFS did not attain a statistical significance (45% v 62.7%; P = .08).26

Contrarily to the previous study26 our trial failed to show an advantage in DFS of allogeneic SCT over autologous SCT or chemotherapy in VHR-ALL in first CR. However, some limitations could be pointed out. The first is the small number of patients, consistent with the low frequency of VHR patients according to the present criteria. The small number in significant subsets of patients such as those with t(9;22) and t(4;11) did not allow us to obtain any conclusion on the possible benefit of SCT in those cases as has been shown in several studies, especially in the t(9;22) subset.14-16,27 Another limitation refers to the time frame between CR and the undertaking of the assigned therapy. This time frame was longer for the patients allocated to SCT than for patients who received chemotherapy, reflecting a delay for some patients having to be referred to centers with SCT units. Another limitation was the lack of strict rules for the preparative regimen before SCT. Although cyclophosphamide and TBI was the recommended regimen, 33% of patients received busulfan instead of TBI due to age (< 3 years) or to logistic reasons. There is evidence for a better DFS in TBI-based regimens than in busulfan-based regimens in children with ALL.37,38 In our small series, we observed a similar trend in survival or in relapse probability, although without statistical significance. Finally, a genetic instead of a true randomization was used for allocation of patients in the allogeneic SCT arm, as occurs in all the comparative studies evaluating the role of allogeneic SCT in ALL either in children or in adults.26,39,40

In this study the DFS probability for the whole series was similar to most studies10-20,25,29 and only inferior to a few recent trials.10,13,26 When the analysis was made according to the therapy actually received, no differences were observed in favor of any arm but the relapse rate was lower in patients receiving allogeneic SCT. Analysis of results in different subgroups did not show an advantage of SCT over chemotherapy for any subgroup although the low number of patients with specific genetic translocations receiving transplants does not allow any conclusion to be derived.

In this trial a randomized comparative study between late intensified chemotherapy and autologous SCT was performed in patients without a family donor. To our knowledge, this is the first study addressing this issue. No differences were found between these two postremission strategies, either by intention to treat or by actual therapy received, suggesting that autologous SCT, particularly if performed with TBI, does not appear to be inferior to other postremission modalities.

The overall results attained in this trial confirm that the prognosis in the subset of VHR-ALL children remains poor even with SCT. It is probable that the routine use of minimal residual disease for therapeutic decisions,19,20 the progressive lower mortality rate attained in allogeneic SCT and the optimization of the use of the chemotherapy contribute to a further improvement in results.13 In addition, the development of specific therapeutic regimens for certain subtypes of VHR-ALL (ie, t(4;11)17,18,28,29 and the use of targeted therapies for BCR-ABL ALL41-43) will modify the prognosis of these patients. Consequently, the indications of SCT in children with VHR-ALL should be continuously evaluated. The low frequency of VHR-ALL in childhood makes international collaboration necessary.44,45


   Appendix
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Go


Figure 3
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  		Fig A1. Disease-free survival curves of actually treated patients according to the phenotype of acute lymphoblastic leukemia (ALL). CR1, first complete remission; T-ALL, T-cell ALL.

 
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Figure 4
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  		Fig A2. Comparison of disease-free survival curves by the arm of randomization (autologous stem-cell transplantation v chemotherapy). CR1, first complete remission.

 

   AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 AUTHORS' DISCLOSURES OF...
AUTHOR CONTRIBUTIONS
 REFERENCES
 
The authors indicated no potential conflicts of interest.


   AUTHOR CONTRIBUTIONS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
REFERENCES
 
Conception and design: Jose-Maria Ribera, Juan-José Ortega

Administrative support: Albert Oriol

Provision of study materials or patients: Jose-Maria Ribera, Juan-José Ortega, Albert Oriol, Pilar Bastida, Carlota Calvo, José-María Pérez-Hurtado, María-Elvira González-Valentín, Victoria Martín-Reina, Antonio Molinés, Fernando Ortega-Rivas, Maria-José Moreno, Concepción Rivas, Izaskun Egurbide, Inmaculada Heras, Concepción Poderós, Eva Martínez-Revuelta, José-Maria Guinea, Eloy del Potro, Guillermo Deben

Collection and assembly of data: Jose-Maria Ribera, Juan-José Ortega, Albert Oriol, Pilar Bastida, Carlota Calvo, José-María Pérez-Hurtado, María-Elvira González-Valentín, Victoria Martín-Reina, Antonio Molinés, Fernando Ortega-Rivas, Maria-José Moreno, Concepción Rivas, Izaskun Egurbide, Inmaculada Heras, Concepción Poderós, Eva Martínez-Revuelta, José-Maria Guinea, Eloy del Potro, Guillermo Deben

Data analysis and interpretation: Jose-Maria Ribera, Juan-José Ortega, Albert Oriol, Pilar Bastida, Carlota Calvo, José-María Pérez-Hurtado, María-Elvira González-Valentín, Victoria Martín-Reina, Antonio Molinés, Fernando Ortega-Rivas, Maria-José Moreno, Concepción Rivas, Izaskun Egurbide, Inmaculada Heras, Concepción Poderós, Eva Martínez-Revuelta, José-Maria Guinea, Eloy del Potro, Guillermo Deben

Manuscript writing: Jose-Maria Ribera, Juan-Jose Ortega, Albert Oriol

Final approval of manuscript: Jose-Maria Ribera, Juan-José Ortega, Albert Oriol, Pilar Bastida, Carlota Calvo, José-María Pérez-Hurtado, María-Elvira González-Valentín, Victoria Martín-Reina, Antonio Molinés, Fernando Ortega-Rivas, Maria-José Moreno, Concepción Rivas, Izaskun Egurbide, Inmaculada Heras, Concepción Poderós, Eva Martínez-Revuelta, José-Maria Guinea, Eloy del Potro, Guillermo Deben


   ACKNOWLEDGMENTS
 
The following institutions and clinicians participated in the study: Institut Català d'Oncologia-Hospital Universitari Germans Trias i Pujol, Badalona: J.M. Ribera, A. Oriol, E. Feliu; Hospital Vall d'Hebron, Barcelona: J.J. Ortega, M.P. Bastida, T. Olivé; Hospital Infantil Miguel Servet, Zaragoza: C. Calvo, A. Carboné; Hospital Universitario Virgen del Rocío, Sevilla: J.M. Perez Hurtado, R. Parody; Hospital Materno-Infantil Carlos Haya, Málaga: M.E. González-Valentín; Hospital Puerta del Mar, Cadiz: V. Martín-Reina, J.L. Gil; Hospital Materno Infantil, Las Palmas: A. Molinés, V. Lodos; Hospital Río Carrión, Palencia: F. Ortega-Rivas; Hospital Universitario Virgen de la Victoria, Málaga: M.P. Queipo de Llano, M.J. Moreno; Hospital General, Alicante: C. Rivas, P. Fernández-Abellán; Hospital de Aranzazu, San Sebastián: I. Egurbide; Hospital Morales Meseguer, Murcia: M. Heras, J.M. Moraleda; Hospital Xeral, Vigo: C. Poderós; Hospital Central de Asturias: E. Martínez-Revuelta; Hospital Txagorritxu, Vitoria: J.M. Guinea; Hospital Clínico San Carlos, Madrid: E. del Potro, J. Díaz-Mediavilla; Hospital Juan Canalejo, La Coruña: G. Deben.


   NOTES
 
Supported by Grant No. 97/1049 from Fondo de Investigaciones Sanitarias and Grant No. FIJC P-EF/04 from José Carreras International Leukemia Foundation.

Presented in part at the 47th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 10-13, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
1. Pui CH, Evans WE: Treatment of acute lymphoblastic leukemia. N Engl J Med 354:166-178, 2006[Free Full Text]

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