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To determine the results of allogeneic hematopoietic stem cell (HSC) transplantation for chronic myelogenous leukemia (CML) at various stages of the disease ...
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Chronic Myeloid Leukaemia Allogeneic bone marrow transplantation for chronic myeloid leukemia in childhood: a report from the Socie´te´ Franc¸aise de Greffe de Moelle et de The´rapie Cellulaire (SFGM-TC) F Millot1, H Esperou2, P Bordigoni3, J-H Dalle4, M Michallet5, G Michel6, JL Bourhis7, M Kuenz8, D Blaise9, F Garban10, E Plouvier11, A Rome1, J Guilhot1 and F Guilhot1 1

Centre Hospitalier Universitaire, Poitiers, France; 2Hoˆpital Saint Louis, Paris; 3Centre Hospitalier Universitaire, Vandoeuvre, France; 4Hoˆpital Jeanne de Flandre, Lille, France; 5Hoˆpital Edouard Herriot, Lyon, France; 6Hoˆpital La Timone, Marseille, France; 7 Institut Gustave Roussy, Villejuif, France; 8Hoˆpital Henri Mondor, Cre´teil, France; 9Institut Paoli Calmette, Marseille, France; 10 Hopital La Tronche, Grenoble, France; and 11Centre Hospitalier Universitaire Besanc¸on, France

Summary: To determine the results of allogeneic hematopoietic stem cell (HSC) transplantation for chronic myelogenous leukemia (CML) at various stages of the disease in children, a retrospective analysis was carried out on the outcome of transplants performed on 76 children and teenagers with CML between 1982 and 1998. In all, 60 patients were transplanted from a matched sibling donor (MSD) and 16 from a matched unrelated donor (MUD). There was a higher incidence of acute graft-versus-host disease after MUD transplantation (Po103). The main cause of death was transplant-related toxicity in both groups. In MSD recipients, the probability of relapse at 5 years for patients transplanted in the first chronic phase was lower than in patients transplanted in the advanced phase (relative risk (rr) ¼ 5.90; 95% confidence interval (CI), 1.85–18.82, Po0.01). The estimated 5-year eventfree survival (EFS) rate was higher after MSD vs MUD transplantation (61% (95% CI, 48–73%) vs 27% (95% CI, 4–49%), rr ¼ 0.25, Po103). In children transplanted from MSD, the 5-year EFS was higher when transplantation was performed in the first chronic phase vs the advanced phases (73% (95% CI, 59–87%) vs 32% (95% CI, 10–54%), Po103). Disease status at transplantation was the unique factor influencing survival in patients undergoing transplantation from MSD with a better outcome for those transplanted in the first chronic phase. Allogeneic HSC offers a possibility of curing childhood CML with a significant advantage for patients transplanted in chronic phase using a human leukocyte antigenidentical sibling donor. Bone Marrow Transplantation (2003) 32, 993–999. doi:10.1038/sj.bmt.1704255

Correspondence: Dr F Millot, Service d’oncologie he´matologique et de the´rapie cellulaire, Hoˆpital Jean Bernard, Poitiers 86000, France; E-mail: [email protected] Received 27 January 2003; accepted 11 June 2003

Keywords: children; chronic myelogenous leukemia; HLA-matched related donor; HLA-matched unrelated donor

Despite therapeutic advances with the use of interferon (IFN)-based regimens1,2 and the promising perspectives of targeted therapy with a specific tyrosine kinase inhibitor,3,4 allogeneic bone marrow transplantation (BMT) remains the only reported curative strategy in younger patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML).5 However, data concerning the role of allogeneic BMT in the treatment of children and teenagers with CML have been obtained on cohorts of a limited number of patients and the impact of factors affecting transplant outcome are not well defined.6–8 This report from the Socie´te´ Franc¸aise de Greffe de Moelle et de The´rapie Cellulaire (SFGM-TC) reviews 76 patients under 18 years of age suffering from CML who were given an allogeneic hematopoietic stem cell (HSC) transplant from a human leukocyte antigen (HLA)matched sibling donor (MSD) or a matched unrelated donor (MUD). We analyze the impact of patient, disease and treatment factors with transplant outcome.

Patients and methods Data collection This analysis is based on data reported to the SFGM-TC registry of bone marrow transplants performed between January 1982 and October 1998. Information concerning the donor, recipient, harvesting procedure and follow-up was collected by transplant centers using prospectively designed forms. Data included details of patient and donor age, sex, histocompatibility, dates of diagnosis and transplant, stage of disease and outcome. Stage of disease (chronic phase, accelerated phase or blastic crisis) was classified according to the criteria of the International Bone Marrow Transplant Registry (IBMTR)9 and relapse was

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defined by investigators as hematological, cytogenetic or molecular relapse.

Patients Patients under 18 years of age with CML who received allogeneic transplantation from MSD or MUD between January 1982 and October 1998 were evaluated. A total of 76 patients were registered in the SFGM-TC database. The transplants were carried out at 22 French institutions. Unrelated HSC transplants were performed after May 1989. The participating institutions and the number of patients transplanted per center are listed in Appendix 1. Patient characteristics at the time of transplantation are summarized in Table 1. Karyotyping was available for 72 (95%) patients: 71 were Philadelphia chromosome positive and BCR-ABL rearrangement was observed at the molecular level in one patient without Philadelphia positive mitosis. First-line therapy varied according to the transplant center. Different therapeutic approaches had been used before transplantation. Details regarding dose, duration and response to IFN-alpha therapy before HSC transplantation were available in only 31 patients. Before December 1991, matching criteria were based on HLA-A, Table 1

-B, DR identity using serologic testing. After January 1992, patients were DR subtyped by DNA techniques. One patient received cord blood stem cells from his HLAidentical sibling, while the remainder received bone marrow stem cells. Most patients (79%) received grafts from HLAidentical siblings. The majority of patients (62%) were in the first chronic phase when BMT was performed. In total, 38 patients (50%) underwent transplantation within 12 months of diagnosis. Recipients of grafts from MUD differed from recipient of grafts from MSD, in terms of age at transplantation (median: 12 vs 14 years, respectively, Po0.05) and stage of CML (70 vs 31% allografted in the chronic phase, respectively, Po0.01) with 26(43%) vs 12(75%) patients allografted longer than 12 months from diagnosis, respectively (Po0.05). However, the time interval from diagnosis to transplantation (median 11 vs 15 months, respectively) was not statistically different between groups. Three patients who relapsed after BMT (two patients) or developed graft failure (one patient) received a second transplant with a median interval between the first and second transplant of 9 months. The median follow-up of the 76 patients was 55 months (range, 2–217 months). It was significantly shorter in MUD recipients (Po0.001) since MUD transplants were performed after May 1989.

Patients’ characteristics HLA-identical siblings (n ¼ 60)

Unrelated donors (n ¼ 16)

Pretransplant therapy with IFN-alpha No Yes Unknown

28 17 15

0 14 2

Stage of disease at transplantation First chronic phase Othera

42 18

5 11

36/24

10/6

14 19 8 17 2

3 3 3 6 1

14.5 (4.7–17.9)

12.4 (2.9–16.3)

11 (2–117)

15 (5–41)

Conditioning regimen TBI/Cy7others TBI/Ara-C+Mel Bu/Cy7others Other chemotherapy

39 2 18 1

7 5 2 2

GVHD prophylaxis CsA7steroids MTX alone CsA+MTX CsA+MTX+others (steroids or mab or ATG) T-cell depletion

17 4 35 4 3

1 0 9 6 1

Median infused cell dose  108/kg (range) (missing)

2.78 (0.3–14)(17)

3.40 (0.3–8) (3)

Sex of recipient: ratio M/F Donor–recipient gender F–F M–M M–F F–M Missing Median age in years (range) at transplant Median time from diagnosis to transplantation in months (range)

a

Second or (higher) chronic phase, accelerated phase or blast crisis. Abbreviations: Cy, cyclophosphamide; Ara-C, cytosine arabinoside; Mel, melphalan; Bu, busulfan; CsA, cyclosporine; mab, monoclonal antibodies; ATG, antithymocyte globulin.

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The median follow-up duration for survivors after relateddonor HSC transplantation was 112 months (range, 21–217) and 40 months for unrelated-donor bone marrow recipients (range, 2–54). Two patients were lost to followup (5 and 10 years after BMT, respectively).

Preparative regimen and graft-versus-host disease (GVHD) prophylaxis Pretransplant conditioning regimens were divided into two categories according to the use of total body irradiation (TBI). In all, 53 (70%) patients were given chemotherapy and TBI, whereas 23 (30%) patients were conditioned using chemotherapy alone. Details concerning TBI were not available in five patients. In 16 patients TBI was given as a single dose, while the other 32 children received fractionated TBI. The median dose of TBI was 12 Gy (range, 9–15). Most of the patients (69%) conditioned with fractioned TBI received a total dose of 12 Gy in six fractions. GVHD prophylaxis consisted of cyclosporine (CsA) alone or in combination with steroids in 18 (24%) patients, methotrexate (MTX) alone in four (5%) patients, CsA and MTX in 54 (71%) patients (10 of whom also received steroids or monoclonal antibodies or antithymocyte globulin) and ex vivo T-cell depletion in four patients. The median number of donor-nucleated cells infused (available in 56 patients) was 2.85  108/kg recipient weight (range, 0.3–14  108/kg).

Assessment of engraftment, GVHD and relapse Engraftment was defined as recovery of granulocytes to 0.5  109/l for 3 consecutive days. Trilineage engraftment was documented by bone marrow examination in the majority of patients 3–4 weeks after transplantation. Chimerism was evaluated by karyotype analysis on bone marrow cells and blood lymphocytes, red blood cell antigen phenotyping or studying genetic polymorphism of a variable number of tandem repeated short DNA sequences. Late graft failure was defined as the occurrence of sustained neutropenia in patients who had previously engrafted. Acute and chronic GVHD were diagnosed and graded according to standard criteria.10,11 Patients who had evidence of engraftment were evaluable for acute GVHD. The probability of chronic GVHD was evaluated in patients who survived for at least 100 days with sustained engraftment. Transplant-related mortality was defined as death resulting from any causes other than relapse. Disease recurrence was defined by the detection of any type of relapse (molecular, cytogenetic or hematologic) and the need of antileukemic therapy.

Definitions of end points Survival, leukemia-free survival, transplant-related mortality, acute and chronic GVHD and relapse were calculated from BMT. As the monitoring strategy to detect disease relapse differed from one center to another, leukemia-free survival was defined as survival without hematologic, cytogenetic or molecular evidence of relapse in blood or bone marrow. Transplant-related mortality was defined as death due to causes other than disease recurrence.

Data reporting for analysis was updated as of January 1, 2001.

Statistical analysis Comparisons between groups were performed with the use of Fisher’s exact test for categorical variables and Wilcoxon’s two-sample test for continuous variables. Survival and time to events were calculated from the date of transplant. Overall survival, disease-free survival and event-free survival (EFS) distributions were estimated by the Kaplan–Meier method and compared using the logrank test. The relative risk of deaths, relapses or events was calculated using the Cox model. Survival was also estimated according to the Gratwohl risk scoring system.12 Cox’s regression and the log-rank test were used to explore the influence of prognostic factors (donor and recipient gender and cytomegalovirus serology, disease stage at transplantation, interval from diagnosis to transplantation, transplantation performed before or after 1990, TBIcontaining preparative regimen, occurrence of acute or chronic GVHD) on survival or events in univariate analyses. The small size of the patient cohort did not allow multivariate analyses. All statistical tests of significance were two tailed and analyses were performed using the SAS statistical software (SAS Institute, Cary, NC, USA).

Results Engraftment Of the 76 patients, three graft failures were observed after MUD transplantation (one patient failed to engraft and an additional two had late graft failure). The median time to achieve an absolute neutrophil count greater than 0.5  109/ l was 25 days (range, 12–60) in 63 patients. In 37 patients, chimerism studies were uninformative but these patients had sustained hematopoietic recovery. Chimerism was documented in 37 patients with engraftment: full chimerism occurred in 33 patients, mixed chimerism in two patients and autologous reconstitution occurred in two patients.

Graft-versus-host-disease In total, 75 patients were evaluable for acute GVHD (Table 2). Acute GVHD was more frequent in patients transplanted from MUD (Po0.01). Grade II–IV acute GVHD occurred in 28% of patients transplanted from HLA-identical siblings and in 80% of patients given BMT from an unrelated donor (Po0.001). Severe acute GVHD, defined as grades III and IV, occurred in 40% of patients who received unrelated bone marrow and in 15% of the recipients of sibling bone marrow (Po0.05). Chronic GVHD affected 25 (38%) of 65 children who survived more than 100 days after BMT. It was limited in nine cases and extensive in 16 cases (Table 2). A significant difference was observed in the incidence of chronic GVHD between patients transplanted using MSD and MUD (33 vs 75%, respectively, P ¼ 0.05). Bone Marrow Transplantation

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Relapses

Patients’ clinical outcome

Engraftment Yes/no Acute GVHD – no. (%) Grades 0–I Grade II Grade III Grade IV Chronic GVHD – no. (%) None Limited Extensive 5-year overall survival 5-year EFS

HLA-identical siblings (n ¼ 60)

Unrelated donors (n ¼ 16)

60/0

15/1

28+15 8 8 1

1+2 6 4 2

38 8 11

2 1 5

73% (62–84%) 61% (48–73%)

27% (4–49%) 27% (4–49%)

In all, 15 patients (14 MSD recipients and one MUD recipient) experienced a relapse: hematologic, cytogenetic and molecular relapses occurred, respectively, in 11, three and one patients resulting in a probability of relapse of 23% (95% confidence interval (CI), 12–35%) at 5 years. The median time for the occurrence of relapse for the entire group was 24 months (range, 1–78 months). In children transplanted from an MSD, the probability of relapse at 5 years was lower when transplantation was performed in the first chronic phase than in the advanced phase (15% (95% CI, 3–27) vs 52% (95% CI, 24–79%), respectively, rr ¼ 5.90, Po0.01). The median time of relapse for the first chronic phase MSD recipients and advanced phases MSD recipients was 44 months (range, 24–78 months) and 7 months (range, 2–29 months), respectively.

Survival Causes of death

Causes of death Transplant-related mortality Infections Fungal Bacterial Parasitic Viral Acute GVHD Chronic GVHD Multiorgan failure Interstitial pneumonitis ARDS Hemorrhage Secondary malignancy Relapse Unknown

HLA-identical siblings (n ¼ 60)

Unrelated donors (n ¼ 16)

12

11

2 1 1 1 3 1 1 1 1 0 0

1 0 0 0 3 2 1 1 0 1 2

5 2

1 0

GVHD, graft-versus-host disease; ARDS, acute respiratory distress syndrome.

Causes of death In all, 31 MSD patients died – 19 (32%) and 12 (75%) MUD patients. Causes of death are summarized in Table 3. The main cause of death was transplant-related complications. A total of 23 patients died from transplant-related complications between 2 months and 7 years (median, 4 months) after transplantation. Among them, 10 (43%) transplant-related deaths occurred before day 100 after transplantation (three were observed in the MSD group and seven in the MUD group). Death was associated with treatment-resistant GVHD in nine patients (four patients in the MSD group and five in the MUD group). Infections contributed to six deaths. The percentage of deaths due to transplant-related causes was 92% for patients transplanted using an unrelated donor and 63% in children given BMT from a sibling donor HLA identical. Six patients died from recurrent CML between 3 months and 14 years (median, 21 months) after transplantation. Bone Marrow Transplantation

The overall survival of the 76 patients was 64% (95% CI, 53–75%) at 5 years (Figure 1). The overall survival for children transplanted from an MSD was 73% (95% CI, 62–84%), whereas the survival rate for patients given BMT from an MUD was 27% (95% CI, 4–49%) at 5 years (rr ¼ 0.19, 95% CI, 0.09–0.41, Po104). At the time of analysis, 58% of the 76 patients were alive – 67% of those transplanted from an MSD and 25% of those transplanted from an MUD. The 5-year Kaplan–Meier EFS rate of the entire group was 54% (95% CI, 42–65%). The EFS at 5 years for children transplanted from an MSD was 61% (95% CI, 48–73%), whereas the EFS for patients given BMT from an MUD was 27% (95% CI, 4–49%) (Figure 2). At 5 years, the EFS in the first chronic phase MSD recipients was 73% (95% CI, 59–87%), while the EFS in the advanced phase MSD recipients was 32% (95% CI, 10–54%) Po0.01 (rr ¼ 0.25, Po0.01) (Figure 3). Survival at 5 years was 82% (95% CI, 64–100%), 74% (95% CI, 57–91%), 67% (95% CI, 45–89%) and 50% (95% CI, 0–100%) for patients with score 0, 1, 2 and 4, respectively, according to the Gratwohl scoring system; all patients with score 3 died at 1 year and no patients belonged to score 5. Univariate analysis of factors related to patients, CML and transplant influencing survival was performed in patients transplanted from an MSD. Within 1.0 0.9

Probability of survival

Table 3

0.8 0.7 0.6 0.5 0.4 0.3 0.2

n = 76

Deaths = 31

0.1 0.0 0

12 24

36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228

Months from transplant

Figure 1 Probability of survival of the 76 patients.

Allogeneic transplantation in childhood CML F Millot et al

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1.0 0.9 0.8 0.7

MDS: n = 60 Events = 25

0.6 0.5 0.4

MUD: n = 16 Events = 12

0.3 0.2

P < 0.0001

0.1 0.0 0

12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228

Months from transplant

Figure 2 Probability of event-free survival in patients transplanted from matched sibling donor (MSD) and matched unrelated donors (MUD).

Probability of event free survival

1.0 0.9 0.8 0.7

1st CP: n = 42

Events = 13

Others: n = 18

Events = 12

0.6 0.5 0.4 0.3 0.2 0.1

P < 0.0001

0.0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228

Months from transplant

Figure 3 Probability of event-free survival in patients transplanted in first chronic phase (1st CP) or in other phase (others) of the disease from matched sibling donor.

the limitation of the small number of patients in this cohort, disease status at transplantation was the only factor affecting survival, with a better outcome for patients transplanted in the first chronic phase (Po0.02).

Discussion CML is a rare disease in children, accounting for 2–5% of childhood leukemia cases.13 Series including exclusively pediatric patients transplanted for CML are very rare and concern cohorts of a limited number of patients.6–8 The present study of a large cohort of children and teenagers with CML indicates that HSC transplantation results in long-term survival in more than half of the patients with an MSD. The median survival of our patients transplanted in the first chronic phase from a geno-identical sibling has not yet been reached more than 10 years after BMT. Mortality from causes other than CML relapse in this subset of patients is relatively high with more than half of the patients dying of nonrelapse causes. This finding could be explained, in part, by the fact that our study included patients transplanted in the 1980s. Recent studies have reported low transplant-related mortality rates among patients transplanted from a matched sibling, who receive

modern regimens for prevention of GVHD and opportunistic infections.14 In the present study, early transplantation within the first year of diagnosis was offered to most of the children with an HLA-compatible sibling donor, but this did not influence the outcome. Our patients transplanted in the first chronic phase with related marrow grafts had a significantly lower incidence of relapse and a better outcome than did patients transplanted with an advanced phase of CML, indicating that disease status at transplantation influences ultimate survival. Similar findings are reported in adults.5 The 5-year EFS rate (73%) of our patients transplanted in the first chronic phase compares favorably with results of large cohorts of young adults transplanted from matched related donors.15–17 The influence of age on outcome is reported in various studies in which younger patients (under 30 years of age) have longer disease-free survivals and lower transplant-related mortalities than do older patients.18 In the present study, univariate analysis failed to reveal any significant factors influencing survival (except disease status at transplantation) partly because of the small size of the group analyzed. The rates of relapse in our patients who underwent HSC transplantation from HLA-identical siblings are within the expected range of 15–25% reported in adults. Late relapses among related-donor recipients transplanted in an advanced phase of CML were not recorded, while relapse more than 5 years later occurred in a first chronic phase recipient. Our study emphasizes that children and adolescents continue to be at risk for relapse for many years following related-donor transplantation in the first chronic phase of CML. A similar finding was reported in a series of 373 adults who continued to relapse at a rate of 1.5% per year more than 2 years after BMT for CML in the chronic phase.19 Post transplant relapses, including late relapses, remain a problem in patients with a matched-sibling donor.20 However, uncontrolled studies reported a longterm survival advantage for HLA-identical sibling transplants over hydroxyurea or IFN-alpha in CML.5,17,21 In our study, results obtained using unrelated matched donors have been discouraging, with a high transplantrelated mortality rate due in part to severe acute GVHD and refractory chronic GVHD. Treatment-related mortality is higher after transplantation from an unrelated donor,22 but tends to be lower because preparative regimens, stem cells sources, prophylactic regimens against GVHD and methods of supportive care have changed in recent years.23 Molecular typing of DRB1 alleles allows more accurate donor/recipient matching and improves clinical outcome after unrelated marrow transplantation.24 In our study, early and late graft failures were observed in children receiving bone marrow from an unrelated donor. The incidence of graft failure is reported to be higher in patients receiving unrelated stem cell.23,25,26 A more advanced stage of the disease at transplantation has contributed unfavorably to patient outcome in our patients transplanted from an unrelated donor. Disease stage at transplantation is an important factor that affects survival after unrelated BMT.20,27 McGlave et al 28 reported a 5-year survival rate of 64% in a series of 157 unrelated-donor bone marrow transplants in patients under 35 years of age transplanted in the early chronic phase. In addition, Bone Marrow Transplantation

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a minority of our patients transplanted from an unrelated donor received transplantation within the first year of diagnosis. A prolonged interval (more than 12 months) between diagnosis and transplant has been reported to increase the transplant-related mortality rate in unrelateddonor recipients as well as in related-donor recipients.19,12,20,27 Performing the transplant procedure as soon as possible could improve results. Our retrospective analysis of data from different transplant centers has inherent limitations. The study period was long (1982–1998) and criteria for transplantation and conditioning protocols differed throughout the study and among centers. The monitoring strategy to detect relapse differed from one center to another, implying that leukemia-free survival was defined as survival without hematologic, cytogenetic or molecular evidence of relapse in the blood or bone marrow. Moreover, complete information concerning pretransplant therapy was not available, reducing the possibility of studying subsets of patients. The optimal strategy in children with CML remains difficult to define. The usefulness of the prognostic scores used for adults with CML has not been established in children. Very little data are available concerning the use of IFN alone or in combination with chemotherapy in this age group. We previously reported that the combination of IFN and cytosine arabinoside induces complete hematologic and major cytogenetic responses and is well tolerated in children without HLA-identical donors.29 However, longterm follow-up data demonstrated persistence of a complete cytogenetic response in only a minority of adults with CML receiving IFN-based therapy. Stem cell transplantation is required in children without complete hematologic remission or major cytogenetic response, 3 and 12 months, respectively, after the start of IFN-based therapy. Scant data concerning the use of imatinib mesylate are available in children and prospective trials are needed to define the efficiency and tolerance of tyrosine kinase inhibitors in this age group. Allogeneic HSC transplantation is a potentially curative therapy in children, but long-term toxicity must be considered. This work includes the largest group of children and teenagers with CML given an allogeneic BMT reported to date. Our data support the conclusion that allogeneic BMT offers the possibility of curing most patients transplanted in the chronic phase using an HLA-identical sibling donor. The role of promising agents such as imatinib mesylate needs to be evaluated in children and adolescents with CML in order to make the optimal therapeutic choice.

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3 Druker B, Talpaz M, Resta D et al. Efficacy and safety of a specific inhibitor of the bcr-abl tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1031–1037. 4 Kantarjian H, Sawyers C, Hochhaus A et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002; 346: 645–652. 5 Silver RT, Woolf SH, Hehlmann R et al. An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: developed for the American Society of Hematology. Blood 1999; 94: 1517–1536. 6 Klingebiel T, Creutzig U, Dopfer R et al. Bone marrow transplantation in comparison with conventional therapy in children with adult type chronic myelogenous leukemia. Bone Marrow Transplant 1990; 5: 317–320. 7 Gamis AS, Haake R, McGlave P, Ramsey NK. Unrelateddonor bone marrow transplantation for Philadelphia chromosome-positive chronic myelogenous leukemia in children. J Clin Oncol 1993; 11: 834–838. 8 Munoz A, Bureo E, Ortega JJ et al. Treatment of Ph1-positive chronic myelogenous leukemia in children: comparison between allogeneic bone marrow transplantation and conventional chemotherapy. Haematologica 1998; 83: 981–984. 9 Speck B, Bortin MM, Champlin R. Bone marrow transplantation for chronic myelogenous leukemia. Lancet 1984; i: 665–668. 10 Przepiorka D, Weisdorf D, Martin P et al. Consensus conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: 825–828. 11 Sullivan KM, Agura E, Anasetti C et al. Chronic graft-versushost disease and other late complications of bone marrow transplantation. Semin Hematol 1991; 28: 250–259. 12 Gratwohl A, Hermans J, Goldman JM et al. Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Lancet 1998; 1352: 1087–1092. 13 Horibe K, Tsukimoto I, Ohno R. Clinicopathologic characteristics of leukemia in Japanese children and young adults. Leukemia 2001; 15: 1256–1261. 14 Clift RA, Bukner CD, Thomas ED et al. Marrow transplantation for chronic myeloid leukemia: a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide. Blood 1994; 184: 2036–2043. 15 Kantarjian HM, Giles FJ, O’Brien S et al. Therapeutic choices in younger patients with chronic myelogenous leukemia. Cancer 2000; 89: 1647–1658. 16 Hehlmann R, Hochhaus A, Kolb HJ et al. Interferon-alpha before allogeneic bone marrow transplantation in chronic myelogenous leukemia does not affect outcome adversely, provided it is discontinued at least 90 days before the procedure. Blood 1999; 94: 3668–3677. 17 Gale RP, Hehlmann R, Zhang MJ et al. Survival with bone marrow transplantation versus hydroxyurea or interferon for chronic myeloid leukemia. Blood 1998; 91: 1810–1819. 18 Goldman J, Apperley JF, Jones L et al. Bone marrow transplantation for patients with chronic myeloid leukemia. N Engl J Med 1986; 314: 202–209. 19 Van Rhee F, Szydlo RM, Hermans J et al. Long-term results after allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic phase: a report from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 1997; 20: 553–560. 20 Enright H, Davis SM, Defor T et al. Relapse after non-T-celldepleted allogeneic bone marrow transplantation for chronic myelogenous leukemia: early transplantation, use of an

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Appendix 1 Participating centers and center directors: Hopital Saint Louis, Paris (Pr Gluckmann, Dr Esperou); Hopital Pellegrin, Pessac (Pr Reiffers); Centre Hospitalier Universitaire, Grenoble (Dr Garban); Hopital Intercommunal, Cre´teil (Dr Kuentz); Institut Paoli Calmette, Marseille (Pr Blaise); Centre Hospitalier Universitaire, Besanc¸on (Pr Cahn, Dr Plouvier); Hopital Edouard Herriot, Lyon (Pr Michallet); Hopital d’enfants, Vandoeuvre (Pr Bordigoni); Centre Hospitalier Universitaire, Nantes (Pr Milpied); Institut Gustave Roussy, Villejuif (Dr Bourhis); Hopital Necker, Paris (Pr Fisher); Hopital Robert Debre´, Paris (Pr Vilmer); Hopital La Timone, Marseille (Pr Michel); Centre Hospitalier Universitaire, Dijon (Pr Caillot); Hopital Charle Nicolle, Rouen (Pr Vannier); Hopital Jean Bernard, Poitiers (Pr Guilhot); Hopital Calmette, Lille (Pr Jouet); Centre Hospitalier Universitaire, Clermont Ferrand (Pr Demeocq); CHU Strabourg (Dr Lioure); Centre Hospitalier Universitaire, Saint-Etienne (Pr Guyotat); Centre Hospitalier Universitaire, Toulouse (Pr Attal, Dr Rubie); Hopital Pitie´ Salpe´trie`re, Paris (Pr Vernant).

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