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© 2003 American Society for Clinical Oncology Outcome in Children With Relapsed Acute Myeloid Leukemia After Initial Treatment With the French Leucémie Aiquë Myéloïde Enfant (LAME) 89/91 Protocol of the French Society of Pediatric Hematology and ImmunologyFrom the University Hospital Centers of Bordeaux, Paris-Trousseau, Paris-Saint Louis, Nancy, Rennes, Marseille, Lille, Limoges, and Amiens, and the Public Health Institute of Epidemiology and Development, Bordeaux, France. Address reprint requests to Nathalie Aladjidi, MD, Unité d’Onco-Hématologie, Département de Pédiatrie, Hôpital des Enfants, Groupe Hospitalier Pellegrin, Place Amélie-Raba Léon, 33076 Bordeaux, France; e-mail: n_aladjidi{at}hotmail.com.
Purpose: After present first-line therapies for childhood acute myeloid leukemia (AML), nearly 40% of patients still relapse. The goals of this retrospective study were to determine whether these children could be treated successfully with a salvage regimen and to establish the optimal therapeutic strategy. Patients and Methods: In the multicentric, prospective, Leucémie Aiquë Myéloïde Enfant 89/91 protocol, 106 of the 308 children enrolled between 1988 and 1998 relapsed. Initial treatment after the first complete remission (CR1) had been allogenic HLA-identical bone marrow transplantation (BMT; n = 21) or chemotherapy (n = 85). Treatment procedures were scheduled according to the choice of each participating institution. Results: When reinduction therapy was attempted, second complete remission (CR2) was obtained in 71% of patients (68 of 96 patients). BMT was performed in 53 (78%) of these 68 patients (autograft, mainly harvested in CR1, n = 25; matched sibling-donor BMT, n = 12; or alternative-donor BMT, n = 16). The 5-year overall survival (OS) rate for all 106 patients was 33%, and the disease-free survival (DFS) rate for children in CR2 was 45%. Multivariate analysis of re-treated children showed that the 5-year OS was higher if the CR1 had been longer than 12 months compared with less than 12 months (54% v 24%, respectively; P = .001) and lower if maintenance therapy had been given after CR1 compared with chemotherapy without maintenance therapy or HLA-identical BMT (12% v 40% v 52%, respectively; P = .002). For patients attaining CR2, the 5-year DFS rate was not significantly different for matched sibling-donor BMT (60%), autograft (47%), or alternative-donor BMT (44%). Conclusion: After aggressive first-line therapy, one third of unselected, relapsing AML children could be cured. Further prospective trials are warranted to define the optimal reinduction regimen and megadose chemotherapy and to evaluate the late effects of these therapies.
IN THE main collaborative groups for treatment of acute myeloid leukemia (AML) in children, with the use of intensive induction and consolidation therapy, results have steadily improved over the last decade. Complete remission (CR) and long-term event-free survival rates have reached 75% to 90% and 40% to 51%, respectively.1–8 In the French multicentric prospective Leucémie Aiquë Myéloïde Enfant (LAME) 89/91 protocol, the first CR (CR1) rate was 90%, and the 5-year overall survival (OS), event-free survival, and disease-free survival (DFS) rates were 61%, 48%, and 55%, respectively.8 Children with a matched sibling donor were given allogenic bone marrow transplantation (BMT) in CR1 and had a better outcome compared with children treated with chemotherapy alone, including high-dose cytarabine (DFS, 72% v 48%, respectively, P = .02; relapse rate, 26% v 47%, respectively, P = .04).3 Relapse remains the main cause of treatment failure and occurs in approximately 40% of patients who had attained a CR. Intensive reinduction therapy and BMT for second CR (CR2) are still associated with undoubted treatment-related mortality and morbidity despite improved modern supportive-care procedures. The 2-year OS rate rarely exceeds 20%.9 Important questions for the management of relapsing AML in children are still unanswered. Is CR2 attainment possible for most of them? Which postremission consolidation therapy should be proposed? To help answer these questions, a retrospective study has been conducted that has recorded the treatment and outcome of all unselected children who experienced a relapse after initial treatment in LAME 89/91.
Patients Between December 1988 and December 1998, 308 children were enrolled onto the French multicentric prospective LAME 89/91 protocol, the preliminary results of which have been previously reported.3 Inclusion criteria were as follows: age under 20 years, de novo and previously untreated AML, and French-American-British (FAB) subtype ranging from M1 to M6. Briefly, children who had attained CR after induction chemotherapy were treated either with allogeneic BMT, if they had an HLA-identical sibling donor, or with chemotherapy including high-dose cytarabine (Fig 1  ). Between 1991 and 1996, in those who had been treated with chemotherapy, children were randomly assigned to either receive further maintenance chemotherapy or not to receive maintenance therapy. CNS prophylaxis was administered to patients with an initial white blood cell count higher than 50 x 109/L or with an M4 or M5 FAB subtype and consisted of five courses of intrathecal (IT) chemotherapy (cytarabine, methotrexate, and corticosteroids). Patients with CNS disease on diagnosis were given three additional IT doses and 24 Gy of cranial irradiation. An autologous marrow was harvested during CR1 for almost all children after completion of treatment. Children under 1 year old were given two thirds of the induction doses, consolidation with high-dose cytarabine without amsacrine, and, from 1993 on, an autologous BMT if they had no HLA-matched donor.
The analysis of relapsed children was completed by June 1, 2001. The clinical and biologic data were retrospectively collated from medical charts. There was no single recommended reinduction chemotherapy schedule for the management of relapsed disease, and procedures varied slightly according to the different institutions. Briefly, the main groups of treatments were standard-dose cytarabine plus other agents (group 1), high-dose cytarabine plus other agents (group 2), fludarabine plus other agents (group 3), etoposide plus carboplatin plus other agents (group 4), and miscellaneous treatments (group 5). However, all the children in CR2 were scheduled to receive high-dose chemotherapy followed by BMT, either matched sibling-donor BMT, if available, or alternative-donor BMT, or autograft.
Methods
The potential prognostic factors for CR2 attainment and OS in the patients treated with a curative prospect were sex, age at initial diagnosis, leukocyte counts (threshold, 50 x 109/L), FAB subtypes (M1 to M6) and chromosome analysis at initial diagnosis (favorable, t[8;21], t[15;17], inv[16], v others), postremission treatment in CR1 (HLA-identical allograft or conventional chemotherapy with or without maintenance), CR1 duration (threshold, 12 months), medullary or extramedullary sites of relapse, blast count at relapse (threshold, 1.8 x 109/L), and reinduction therapy. Reinduction therapy was analyzed in the following three main groups because of the high number of children who were given several lines of treatments: group A, patients given only cytarabine+fludarabine-based courses (groups 1 to 3 in Table 1
Statistical Analysis Time to an event was calculated in months. Patients who remained event-free until June 1, 2001, were right censored at that date. Univariate analysis of the association between potential prognostic factors and outcomes (CR2 attainment, OS, and DFS) was performed using the Kaplan-Meier method and log-rank test. All variables associated with a P value less than .25 were included in multivariate analyses. These analyses were performed using a Cox proportional hazards model. The proportionality of hazard was graphically checked by examining log(-log[S(t)]) versus t. Analyses were performed using SAS software, version 8.2 (SAS Institute, Inc, Cary, NC).
Patient Characteristics at Relapse By June 1, 2001, 106 children from 19 institutions had relapsed (Table 2 ). The median duration of CR1 was 10 months (range, 1 to 57 months). Over two thirds of all relapses (n = 66) occurred within 1 year from CR1, whereas relapse rates in the second, third, and fourth years from CR1 were 27%, 7%, and 4%, respectively. To date, the latest relapse was recorded 57 months after CR1. Relapses occurred off-therapy in 67% of patients and on-therapy in 33% of patients.
The main circumstances of diagnosis of relapse were routine hemograms (n = 59), poor tolerance of maintenance therapy (n = 27), and medullary failure and cutaneous or neurologic symptoms (n = 30). Bone marrow was the only site of relapse in 84 children. Extramedullary relapses occurred in 22 children, seven after allogenic BMT (10%) and 15 after chemotherapy in CR1 (7%, P = not significant). Five of the extramedullary relapses were isolated (CNS, n = 1; eye, n = 1; skin, n = 2; and testis, n = 1), and 17 were combined with bone marrow involvement, mainly simultaneously (CNS, n = 10; skin, n = 4; testis, n = 1; CNS and eye, n = 1; and CNS, eye, and skin, n = 1). The median leukocyte count at relapse was 4.1 x 109/L (range, 0.5 to 350 x 109/L), 68% of children had circulating blasts, and 80% had associated cytopenia. FAB subtypes differed from initial diagnosis in the following 12 patients: seven had different FAB subtypes, one had biphenotypic leukemia, two had pre-B acute lymphoblastic leukemia (ALL), and two had secondary therapy–related AML with 11q23-specific breakpoint that we chose to analyze with relapses. Cytogenetic analyses were available in 75% of patients at relapse, and clonal evolution was evident in most of them.
Reinduction Outcome
Reinduction therapy was attempted in 96 children (91%) with the aim of attaining a CR2 (Table 1 Fourteen toxic deaths were observed before CR2 attainment. They occurred after a mean period of 75 days (range, 9 to 163 days) from the beginning of the first course and mainly in patients exposed to secondary intense therapy. Long-lasting marrow aplasia (median, 42 days; range, 10 to 187 days) was the major cause of morbidity, resulting in severe infection (WHO grade 3 and 4) in 40 children, with 15 cases of septicemia, 10 cases of disseminated fungal infections, and 10 cases of pneumonia. CR2 was attained in 68 patients, resulting in a CR2 rate of 71%. Fifty-one percent of children were in CR2 after a single course of therapy, 67% were in CR2 after two courses of therapy, and 71% were in CR2 after three or more courses of therapy. Higher CR2 rates were obtained with standard-dose cytarabine plus other agents (group 1), high-dose cytarabine plus other agents (group 2), and fludarabine plus other agents (group 3). No patient who received a transplantation or DLI in relapse attained CR2. Three children with AML M3 entered CR2 after ATRA. Only one child given single-agent therapy attained CR2; he was treated with low-dose cytarabine for an isolated cutaneous relapse.
Treatment Allocation in CR2
After matched sibling-donor BMT, eight patients developed acute GVHD, two patients developed moderate nonextensive chronic GVHD, and two patients developed veno-occlusive disease. After alternative-donor BMT, nine patients developed acute GVHD, seven patients developed chronic GVHD, including four severe and extensive cases, and two patients developed Epstein-Barr virus–induced lymphoproliferative syndrome. Marrow failed to engraft in two children who required a second BMT. Toxic morbidity after autograft consisted mainly of grade 3 to 4 infections in half of the children, as well as prolonged marrow aplasia lasting 18 and 24 months in two patients. For the entire cohort of grafted children, these procedures resulted in eight toxic deaths (15%). After CR2 attainment, seven patients were not grafted; four previously allografted patients were given DLI, two patients with ALL followed the high-risk ALL protocol, and one patient was given high-dose cytarabine chemotherapy and interleukin-2. Thirty-three children experienced a second relapse after CR2 (11 patients before BMT and 22 after BMT) after a median period of 172 days (range, 61 to 477 days). Palliative treatment was initiated in 24 children, with a median survival of 4 months (range, 1 to 21 months). A third-line treatment was attempted with nine children. Three of these patients had relapsed before the programmed HLA-identical BMT; one patient entered third CR (CR3), was grafted, and is alive and well at 36 months after relapse; and two patients were grafted in relapse and died of AML. Six patients relapsed after BMT in CR2; two are alive and well in CR3 36 and 95 months after CR3. One of these patients was a 2.6-year-old girl who relapsed from AML M2 12 months after unrelated-donor BMT in CR2; she was treated successfully with salvage high-dose cytarabine reinduction and continuous maintenance therapy with low-dose and high-dose cytarabine for 2 years. The other patient was a 3-year-old boy who experienced a CNS relapse of AML M5 with t(9,11) after autograft in CR2; he was re-treated with salvage IT chemotherapy, three high-dose cytarabine courses, and cerebral radiotherapy.
Global Results
After BMT, 29 patients were long-term survivors, with a median follow-up of 65 months (range, 12 to 115 months). Eight children were alive after two BMTs. Of the 53 patients who underwent BMT of some form in CR2, 16 of 32 patients are alive after a TBI-containing regimen (48%), and 11 of 19 patients are alive after a non–TBI-containing regimen (57%; missing data, n = 2). At the time of evaluation, long-term sequelae according to the type of BMT are listed in Table 5 . Three cured children have presented with major consequences of their treatment; a 12-year-old boy has severe neurologic impairment of multifactorial origin, a 12.6-year-old boy has persistent aplastic anemia 6 years after autograft harvested in CR2, and a 9.7-year-old girl has chronic hemolytic autoimmune anemia and panhypopituitarism 7 years after marrow unrelated-donor BMT.
Prognostic Factors Analysis Multivariate analysis of 96 re-treated children showed that a CR1 duration of more than 12 months had a significant impact on CR2 attainment (hazard ratio [HR] = 2, P = .008), as did the type of reinduction therapy (HR for groups A, B, and C = 1, 0.6, and 0.4, respectively; P = .05; Table 6 ). The 2-year OS rate was significantly lower in patients with a CR1 duration of less than 12 months (HR = 2.5, P = .002) and in patients who received maintenance therapy after CR1 compared with chemotherapy without maintenance therapy and allograft BMT (HR = 3 v 1.5 v 1, respectively; P = .0004; Fig 3). Three of the four re-treated children with isolated extramedullary relapses were alive in CR, but the extramedullary site of relapse had no significant influence on the outcome. Sex, age at initial diagnosis, leukocytosis, FAB subtype, and medullary karyotype had no significant impact on CR2 attainment and survival. When the peripheral-blood blasts count at relapse was included in the multivariate analysis, a high count of over 1.8 x 109/L had a slight impact on survival (HR = 2.1, P = .03).
To avoid bias caused by the particular subgroups of 106 relapsing patients, the same analysis was conducted excluding nine of the patients (five patients with APL who had not been given first-line ATRA, two with 11q23 secondary AML, and two with ALL). For all 97 AML patients who relapsed, the CR2 rate, when remission was attempted, was 68%, the 5-year OS rate was 29%, and the 5-year DFS rate for children in CR2 was 39%; CR1 duration and postremission treatment in CR1 influenced the outcome significantly.
In the LAME 89/91 protocol, the 5-year OS rate in relapsing children was 33%, and the DFS rate was 45%, indicating that recovery from relapsed AML is not an unrealistic goal. There are few reports describing outcome in unselected relapsed AML in children after similar intensive and effective front-line therapy. Our policy was to offer a curative strategy to most patients. Our results are to be compared with those recently reported by the German and British groups,10,11 which have provided similar CR2 rates in re-treated patients (71% v 51% and 69%, respectively) and percentages of grafts in CR2 (79% v 83% and 72%, respectively). We speculate that the low rate of purely palliative treatments in our experience (9% v 20% and 27%, respectively) may have contributed to a better OS rate (33% at 5 years v 21% and 24% at 2 years, respectively).10,11 Lethal toxicity was high in these intensively treated children, reaching 9% after the first reinduction course and 15% after BMT. The toxic mortality rate for re-treatment of relapsing AML patients with intensive therapies is between 7% and 50%, with the highest figures in transplantation patients.9 Long-lasting marrow aplasia and the high percentage of fungal infections in our study led us to recommend laminar flow-air isolation for most reinduction courses and strong preventive measures against Candida infection. Potentially serious pneumonia was observed in 10% to 30% of children with relapsed AML, which may be precipitated by high doses of cytarabine and dysregulation of fluid balance.12 There are no data in the medical literature describing the long-term sequelae of AML in CR2. Marrow transplantation was widely performed in patients who attained CR2 in our study (78%), even after previous allograft in CR1. Moderate to severe long-term toxicity was observed in half of the patients alive after BMT. Among these patients highly treated with either a second BMT or alternative-donor BMT or a TBI-containing regimen, numerous aggressive procedures were implicated. Long-term consequences of treatment on the heart, eyes, and endocrine or pulmonary systems, mainly in cases of TBI use, require attentive monitoring.13,14 In accordance with previously published data, the duration of CR1 was the main independent prognostic factor in relapsed AML. Previous Berlin-Frankfurt-Munster studies found that the 2-year survival rate was 10% for early relapses before 18 months and 40% for relapses 18 months after CR1.11 Age less than 1 year at initial diagnosis was a strong predictor of poor outcome after relapse because of multifactorial etiologies, including treatment with palliative therapy only. The outcome of extramedullary and medullary relapses did not differ significantly. It seems that the same intensive strategy of CR2 reinduction and marrow transplantation should be recommended.15 There is widespread agreement that a better prognosis is associated with t(8,21), t(15,17), and inv(16) at initial diagnosis. These karyotypes form the basis of front-line risk-directed therapy in most multicentric trials.6,16,17 These differences in outcome persist in case of relapse. The reasons explaining why our patients who relapsed after HLA-identical allograft in CR1 had a slightly better 5-year OS rate remain unclear but may include heterogeneity in primary risk factors and statistical biases. Maintenance therapy after CR1 had a strongly unfavorable impact on survival. In a study of the first 268 enrolled children previously reported by Perel et al,8 survival and DFS were shown to be worse in children who had been randomly assigned to maintenance therapy. This unfavorable outcome, without increasing mortality or relapse rates, was related to the increased rate of failure to attain a CR2. The Children’s Cancer Group had previously reported the inferiority of maintenance therapy in AML.18 The mechanisms of the deleterious effects of maintenance therapy are unclear, but prolonged exposure to low-dose cytarabine may increase mdr gene product expression and the incidence of refractory diseases.19 CR2 was obtained in 71% of patients when it was attempted, and this should be compared with the results of other European groups.10,11 The best results in our experience were obtained with the use of high or intermediate doses of cytarabine plus anthracycline or the fludarabine, cytarabine, and granulocyte colony-stimulating factor regimen, but the diversity of regimens administered and the retrospective nonrandomized nature of our study did not enable us to evidence the superiority of any one regimen in particular or to assess differences in toxicities. Prospective studies of reinduction therapy for relapsed childhood AML are rare. Such children are often assimilated with refractory children in small retrospective series. Clearly effective reinduction regimens most commonly combine cytarabine with anthracycline or fludarabine. CR2 rates of 40% to 75% are usually attained.9 The synergic efficacy of the cytarabine, fludarabine, idarubicin, and granulocyte colony-stimulating factor regimen was recently reported by several centers.20–23 High-dose liposomal daunorubicin has given promising preliminary results; in a recent phase I to II study of adult relapsing AML, it produced a 29% CR2 rate when used alone.24 Because of the extremely small number of AML relapsing children (30 to 50 children a year in main European countries), there is clearly a need for large, multicentric, pediatric trials to address these important issues of activity and toxicity. Seventy-eight percent of CR2 children received transplantation. On the whole, an allograft from a matched sibling donor remains the best treatment after CR2 attainment, providing a 5-year DFS of 60%. It is worth noting that this includes a high proportion of patients previously treated with HLA-identical BMT in CR1. In a large series of second allografts for leukemia including both adults and children, the risks of relapse and transplantation-related mortality were as high as 44% ± 12% and 45% ± 9%, respectively.25 In accordance with our study, much lower rates were reported in children and may be considered acceptable for these high-risk patients. However, it should be noted that more than half of the patients will experience some late sequelae. When a matched sibling donor was not available, autograft or alternative-donor BMT resulted in similar DFS rates. The high rate of transplantation-related mortality in alternative-donor BMT (31%) was counterbalanced by a low relapse rate (31%). Thus, the DFS rate was still at 44%, possibly because of an enhanced antileukemic effect. Significant improvements are to be expected with strict selection of alternative sources of stem cells and optimal control of GVHD. Furthermore, recent studies conducted on AML cells suggest that blocking the Fas/Fas ligand pathway could be used to prevent GVHD without impairing the graft-versus-leukemia effect.26 On the other hand, autologous BMT seems to be a reasonable choice in AML, providing the lowest rate of transplantation-related mortality (4%) and a 5-year DFS rate of 47%. Other series of selected children reported a DFS rate of approximately 40% after autograft in CR2 for childhood AML.27 These findings further argue for a role of dose-intensity in AML relapse. However, residual leukemia cells in the graft contribute to posttransplantation relapse. Treatment of the graft to decrease the number of infused leukemia cells is controversial but was reported in AML to improve survival, with similar transplantation-related mortality and lower risks of treatment failure.28 An alternative procedure, as reported in our study, is to perform the marrow harvest after CR1 (in vivo purging). The monitoring of residual disease after CR1 may contribute to the evaluation of this approach. Cure of relapsed AML of children is a realistic goal even after aggressive first-line therapy. When CR2 is attained after initial intensive reinduction chemotherapy, prompt intensification with allograft or autograft provides similar DFS. Thus, for most patients, we recommend a therapeutic strategy including intensive reinduction and megadose intensification. In unfavorable cases, the CR2 rate remains low with the use of conventional intensive chemotherapy. At the present time, therapeutic options may include further intensified schedules but also modulation of multidrug resistance mechanisms,29 immunomodulatory approaches,30 or anti-CD33 monoclonal antibodies.31 For survivors, the increased intensity and duration of treatment certainly result in long-term morbid consequences. The risk of impaired quality of life may have an impact on medical decisions and warrants further studies.
The following institutions and investigators participated in the LAME protocols: Centre Hospitalo-Universitaire, Bordeaux, Nathalie Aladjidi, Yves Perel, MD, and Antoine Bénard, PhD; Centre Hospitalo-Universitaire, Paris-St Louis, Thierry Leblanc, MD, Andre Baruchel, MD, and Gerard Schaison, MD; Centre Hospitalo-Universitaire, Paris-Trousseau, Anne Auvrignon, MD, Judith Landman-Parker, MD, and Guy Leverger, MD; Centre Hospitalo-Universitaire, Marseille, Gerard Michel, MD, and Isabelle Thuret, MD; Centre Hospitalo-Universitaire, Lille, Brigitte Nelken, MD, and Jean-Hugues Dalle, MD; Centre Hospitalo-Universitaire, Nancy, Claudine Schmitt, MD; Centre Hospitalo-Universitaire, Rennes, Virginie Gandemer, MD; Centre Hospitalo-Universitaire, Rouen, Jean-Pierre Vannier, MD; Centre Hospitalo-Universitaire, Tours, Jean-Pierre Lamagnere, MD; Centre Hospitalo-Universitaire, Limoges, Lionel De Lumley, MD; Centre Hospitalo-Universitaire, Paris-Bicetre, Brigitte Bader-Meunier, MD; Institut Gustave Roussy, Jose Pico, MD; Centre Hospitalo-Universitaire, Dijon, Gerard Couillaud, MD; Centre Hospitalo-Universitaire, Nantes, Françoise Mechinaud, MD; Centre Hospitalo-Universitaire, Paris-Necker, Alain Fischer, MD; Centre Hospitalier Intercommunal Creteil, Sophie Lemerle, MD; Centre Hospitalo-Universitaire, Brest, Christian Berthou; and Centre Hospitalo-Universitaire, Clermont-Ferrand, François Demeocq.
The authors indicated no potential conflicts of interest.
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19. Hu XF, Slater A, Kantharidis P, et al: Altered multidrug resistance phenotype caused by anthracycline analogues and cytosine arabinoside in myeloid leukemia. Blood 93:4086–4095, 1999 20. Fleischhack G, Hasan C, Graf N, et al: IDA-FLAG (idarubicin, fludarabine, cytarabine, G-CSF), an effective remission-induction therapy for poor-prognosis AML of childhood prior to allogeneic or autologous bone marrow transplantation: Experience of a phase II trial. Br J Haematol 102:647–655, 1998[CrossRef][Medline] 21. McCarthy AJ, Pitcher LA, Hann IM, et al: FLAG (fludarabine, high-dose cytarabine and G-CSF) for refractory and high-risk relapsed acute leukemia in children. Med Pediatr Oncol 32:411–415, 1999[CrossRef][Medline] 22. Yalman N, Sarper N, Devecioglu O, et al: Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of relapsed or poor risk childhood acute leukemia. Turk J Pediatr 42:198–204, 2000[Medline] 23. Luczynski W, Muszynska-Roslan K, Kravczuk-Rybak M, et al: Results of IDA-FLAG program in the treatment of recurrent acute myeloblastic leukemia: Preliminary report. Med Sci Monit 7:125–129, 2001[Medline] 24. Cortes J, Estey E, O’Brien S, et al: High-dose liposomal daunorubicin and high-dose cytarabine combination in patients with refractory or relapsed acute myelogenous leukemia. Cancer 92:7–14, 2001[CrossRef][Medline] 25. Michallet M, Tanguy ML, Socié G, et al: Second allogeneic hematopoietic stem cell transplantation in relapsed acute and chronic leukemias for patients who underwent a first allogeneic bone marrow transplantation: A survey of the Société Française de Greffe de Moelle. Br J Haematol 108:400–407, 2000[CrossRef][Medline]
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
