Unrelated Donor Bone Marrow Transplantation for Myelodysplastic Syndrome in Children

Article Outline

• Abstract
• Introduction
• Patients and Methods
  • Patients
  • Endpoints
  • Statistical Analysis
• Results
  • Neutrophil and Platelet Recovery
  • GVHD
  • TRM
  • Recurrent Disease
  • DFS
• Discussion
• Acknowledgments
• References
• Copyright

We describe long-term disease-free survival (DFS) after unrelated donor bone marrow transplantation (BMT) for myelodysplastic syndrome (MDS) in 118 patients aged ≤18 years. Forty-six patients had refractory cytopenia (RC), 55 refractory anemia with excess blasts (RAEB), and 17 refractory anemia with excess blasts in transformation (RAEB-t). Transplant-related mortality was higher after mismatched BMT (relative risk [RR] 3.29, P = .002). Disease recurrence was more likely with advanced stages of MDS at the time of BMT: RAEB (RR 6.50, P = .01) or RAEB-t (RR 11.00, P = .004). Treatment failure (recurrent disease or death from any cause; inverse of DFS) occurred in 68 patients. Treatment failure was higher after mismatched BMT (RR 2.79, P = .001) and in those with RAEB-t (RR 2.38, P = .02). Secondary MDS or chemotherapy prior to BMT was not associated with recurrence or treatment failure. Similarly, cytogenetic abnormalities were not associated with transplant outcomes. Eight-year DFS for patients with RC after matched and mismatched unrelated donor BMT was 65% and 40%, respectively. Corresponding DFS for patients with RAEB and RAEB-t was 48% and 28%, respectively. When a matched adult unrelated donor is available, BMT should be offered as first-line therapy, and children with RC can be expected to have the best outcome.

Key Words: Pediatric myelodysplastic syndrome, Unrelated donor, Bone marrow transplantation

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Introduction 

Myelodysplastic syndrome (MDS) in childhood is a rare disorder, with an estimated incidence of 3.2 per million [1]. Childhood MDS responds poorly to acute myeloid leukemia (AML)-type chemotherapy, and hematopoietic cell transplantation (HCT) is the only known curative treatment option. However, apart from juvenile myelomonocytic syndrome (JMML) or MDS transformed to AML, there exists few reports for children with MDS after allogeneic HCT. Disease-free survival (DFS) rates support HCT when an HLA-matched sibling donor is available 2, 3. Given that only a third of patients have an HLA-matched sibling, it is clinically relevant to understand the outcomes and risk factors associated with DFS after unrelated donor HCT. Thus far, reports of unrelated donor HCT for children with MDS have been limited by sample size, heterogeneity of donor type, and the inclusion of adults with MDS 4, 5, 6. Furthermore, the standard International Prognostic Scoring System (IPSS) for adults with MDS is of little prognostic value in children [7]. Therefore, we examined outcomes after unrelated donor HCT for MDS in patients aged ≤18 years after applying a standard scoring system appropriate for childhood MDS based on morphology as recommended by the European Working Group for Myelodysplasia (EWOG-MDS) [7].

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Patients and Methods 

Patients 

Patients with MDS aged <18 years at transplantation who received a bone marrow (BM) graft from an unrelated adult donor in the United States were identified from the Center for International Blood and Marrow Transplant Research (CIBMTR). The CIBMTR collects patient, disease, and transplant characteristics on all unrelated donor transplantations in the United States. All patients are followed longitudinally annually. MDS subtypes included refractory cytopenia (RC), refractory anemia with excess blasts (RAEB), or refractory anemia with excess blasts in transformation (RAEB-t), and were assigned retrospectively by the CIBMTR according to the European Group for Childhood MDS (EWOG-MDS) criteria [7]. Donor-recipient HLA-match was considered at the allele level for HLA-A, -B, -C, -DRB1. Donor and recipients were considered to be matched when matched at HLA-A, -B, -C, -DRB1 and mismatched when a mismatch existed at 1 or 2 loci. Excluded were patients who had received prior autologous or allogeneic BMT, peripheral blood progenitor cell (PBPCs), or cord blood (CB) transplant, those with Down syndrome, Fanconi anemia, JMML, or MDS with progression to AML. This study was approved by the institutional review board of the Medical College of Wisconsin.

Endpoints 

Neutrophil recovery was defined as the first of 3 consecutive days with an absolute neutrophil count (ANC) ≥0.5 × 10⁹/L. Patients who failed to achieve ANC ≥0.5 × 10⁹/L within 28 days after HCT or experienced a sustained decline in ANC (<0.5 × 10⁹/L) after initial recovery were considered to have graft failure. Platelet recovery was defined as the first of 7 consecutive days with an unsupported platelet count ≥20 × 10⁹/L. Acute and chronic graft-versus-host disease (aGVHD, cGVHD) were diagnosed and classified by the transplant center according to published criteria 8, 9. Recurrent disease after BMT was defined by the evolution of RC to RAEB or for RAEB/RAEB-t by the recurrence of blasts or progression to AML. Death from any cause in the absence of recurrent disease was defined as transplant-related mortality (TRM). All surviving patients were censored at last follow-up.

Statistical Analysis 

The probabilities of neutrophil and platelet recovery, aGVHD and cGVHD, TRM, and disease recurrence were calculated using the cumulative incidence function estimator [10]. For neutrophil and platelet recovery and GVHD, death was the competing event. For TRM, recurrence was the competing event, and for recurrence, TRM the competing event. The probability of DFS was calculated using the Kaplan-Meier estimator [11]. The 95% confidence intervals (CI) were calculated using log transformation. The following variables were considered in multivariate analysis: gender, age at transplantation (≤10 versus >10 years), disease status (RC versus RAEB versus RAEB-t), cytogenetics (monosomy 7 versus other abnormalities versus normal cytogenetics), de novo versus secondary MDS, donor-recipient HLA match (matched versus mismatched), year of transplantation (≤1994 versus >1994), and conditioning regimen (total body irradiation [TBI]-containing versus chemotherapy-only regimens). Multivariate models for aGVHD and cGVHD, TRM, disease recurrence, and treatment failure (inverse of DFS; recurrent disease or death from any cause) were built using Cox regression and a forward selection procedure [12]. Only variables that attained a P value ≤.05 were retained in the final multivariate model. All variables tested met the proportionality assumption. All tests are 2-sided. Analyses were performed with SAS version 9.1 (Cary, NC).

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Results 

There were 118 unrelated donor bone marrow transplantations (BMT) for pediatric patients with MDS in the United States between 1990 and 2005. Patient, disease, and transplant characteristics are shown in Table 1. The median age at BMT was 8 years. Approximately 40% of patients had RC and 60%, RAEB or RAEB-t at the time of BMT. For each patient, the most advanced disease stage at anytime prior to BMT was considered. Six patients with RC at diagnosis progressed to RAEB, and 7 patients with RAEB, at diagnosis progressed to RAEB-t before BMT. Thirty-six patients (31%, n = 9 RC, n = 19 RAEB, and n = 8 RAEB-t) received chemotherapy before BMT. The median time from diagnosis to BMT was 7 months for RC and 6 months for RAEB/RAEB-t. Thirty patients (25%; 12 with RC, 15 with RAEB, and 3 with RAEB-t) had secondary MDS that resulted from chemotherapy and/or radiotherapy for a prior malignancy (n = 18), or evolved from acquired or congenital bone marrow failure (n = 11) or systemic lupus erythematosus (n = 1). Cytogenetic abnormalities were identified in 64% of cases, and the most common abnormality was monosomy 7 (33%). A third of BM grafts were T cell depleted. Transplant conditioning regimens were exclusively myeloablative, and approximately 70% of regimens contained TBI. The median follow-up of surviving patients is 8 years.

Table 1. Patient, Disease, and Transplant Characteristics

Variable	Number (%)
Patients	118
Age at transplant, years
≤5	30 (25)
6-10	38 (32)
11-18	50 (43)
Male	70 (59)
Performance score prior to transplantation
<90%	20 (17)
90%-100%	91 (77)
Not reported	7 ( 6)
MDS classification (EWOG-MDS)
Refractory cytopenia	46 (39)
Refractory anemia with excess blasts∗	55 (47)
Refractory anemia with excess blasts in transformation∗	17 (14)
Interval from diagnosis to transplant, months
≤6	57 (48)
7-12	31 (26)
>12	30 (26)
Cytogenetics
Normal karyotype	27 (23)
Monosomy 7 ± other abnormalities	39 (33)
Complex karyotype (≥3 abnormalities)	18 (15)
Other karyotypes	19 (16)
Not reported	15 (13)
Conditioning regimen
Total body irradiation + cyclophosphamide	80 (68)
Total body irradiation + other	3 (3)
Busulfan + cyclophosphamide	30 (25)
Busulfan + other	4 (3)
Melphalan + other	1 (1)

Characteristics of patients	N (%)
Graft-versus-host disease prophylaxis
T cell depletion	39 (33)
Cyclosporine alone	7 (6)
Cyclosporine + methotrexate	62 (52)
Tacrolimus + alone	1 (1)
Tacrolimus + methotrexate	9 (8)
Donor-recipient sex match
Male donor–male recipient	44 (37)
Male donor–female recipient	17 (14)
Female donor–male recipient	26 (22)
Female donor–female recipient	31 (26)
Donor-recipient HLA match
Matched at HLA-A, -B, -C, -DRB1	36 (31)
Mismatched at 1 or 2-loci	82 (69)
Donor-recipient cytomegalovirus serostatus
Donor (−)–recipient (−)	43 (36)
Donor (−)–recipient (+)	19 (16)
Donor (+)–recipient (−)	30 (26)
Donor (+)–recipient (+)	23 (19)
Unknown	3 (3)
Year of transplant
1990-1994	22 (19)
1995-1999	63 (53)
2000-2005	33 (28)
Median (range) follow-up of survivors, months	92 (3-195)

EWOG-MDS indicates European Working Group for Myelodysplasia.

Neutrophil and Platelet Recovery 

Most patients achieved hematopoietic recovery. The day 28 cumulative incidence of neutrophil recovery was 89% (95% CI 82-94), and the 6-month cumulative incidence of platelet recovery was 74% (95% CI 65-81).

GVHD 

Fifty-five patients developed grade 2-4 aGVHD (n = 20 grade 2, n = 24 grade 3, and n = 11 grade 4). Grade 2-4 aGVHD occurred more frequently after non–T cell–depleted BMT (relative risk [RR] 2.33, 95% CI, 1.20-4.52, P = .01). The day-100 probabilities of grade 2-4 aGVHD were 55% (95% CI 44-66) and 26% (95% CI 14-41) after non–T cell–depleted BMT and T cell–depleted BMT, respectively. Forty-five children developed either limited (n = 13) or extensive (n = 32) cGVHD. The 8-year cumulative incidence of cGVHD was 40% (95% CI 31-50). Chronic GVHD rates were higher after conditioning that included TBI (RR 2.97, 95% CI 1.58-5.58, P < .001), in patients aged >10 years (RR 3.01, 95% CI 1.49-6.04, P = .002), and transplantation period 1990-1994 (RR 3.14, 95% CI 1.44-6.89, P = .004).

TRM 

Forty-eight deaths occurred from transplant-related complications that occurred mostly within the first year after transplantation. In multivariate analysis, the only factor associated with TRM was donor-recipient HLA mismatch. Mismatched transplant recipients were more likely to experience TRM (RR 3.29, 95% CI 1.54-7.03, P = .002). TBI-containing conditioning regimens were not associated with excess TRM (RR 0.68, 95% CI 0.34-1.39, P = .29). Secondary MDS was also not associated with excess TRM (RR 0.63, 95% CI 0.31-1.30, P = .21). The relatively small numbers of patients in the current analysis with secondary MDS prevented us from examining for an effect by etiology of secondary MDS. It is likely that in a larger cohort, TRM rates may differ in patients with MDS secondary to a malignant disease and those who develop MDS secondary to aplastic anemia. The 1- and 8-year probabilities of TRM after HLA-matched transplants were 13% and 26%, respectively. Corresponding probabilities after HLA-mismatched transplants were 42% and 52%, respectively.

Recurrent Disease 

Recurrence was defined as morphologic evidence of RAEB, RAEB-t, or AML after BMT. Twenty patients had recurrent disease. Recurrent disease was more likely when patients were in RAEB (RR 6.50, 95% CI 1.45-29.03, P = .01) or RAEB-t (RR 11.00, 95% CI 2.13-56.78, P = .004). The 8-year probability of recurrent disease was 4% when BMT occurred for RC compared to 23% and 29% when BMT occurred for RAEB and RAEB-t, respectively (Figure 1). Risk of disease recurrence was similar in patients with primary and secondary MDS (RR 1.14, 95% CI 0.34-3.80, P = .84). Treatment prior to BMT for patients with RAEB/RAEB-t was not associated with higher relapse (RR 1.85, 95% CI 0.70-4.88, P = .21). However, there were only 27 patients who received prior treatment and most received low-dose chemotherapy. The development of acute (RR 0.42, 95% CI 0.14-1.30, P = .13) and cGVHD (RR 0.71, 95% CI 0.24-2.08, P = .53) was not associated with disease recurrence posttransplant. Although the risk of relapse with TBI-containing conditioning regimen appears to be lower, this did not reach statistical significance in this analysis (RR 0.53, 95% CI 0.18-1.62, P = .27).

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• Figure 1 

  The 8-year probabilities of recurrent disease after BMT: 4% when transplantation was performed for RC, 23% when transplantation was performed for RAEB, and 29% for when transplantation was performed for RAEB-T.

DFS 

The probability of DFS is shown in Figures 2A and B. Treatment failure (recurrent disease or death from any cause; inverse of DFS) occurred in 68 patients. Recipients of mismatched transplants (RR 2.79, 95% CI 1.51-5.14, P = .001) and those with RAEB-t at transplantation (RR 2.38, 95% CI 1.17-4.84, P = .02) were more likely to experience treatment failure. Secondary MDS was not associated with higher treatment failure (RR 0.67, 95% CI 0.36-1.26, P = .22). Chemotherapy prior to transplantation was also not associated with treatment failure (RR 0.87, 95% CI 0.49-1.53, P = .63). The causes of death are shown in Table 2. Early death (within 100 days after BMT) occurred in 25 patients, and death beyond this period occurred in 41 patients. GVHD and veno-occlusive disease accounted for most early deaths. Beyond the early period, recurrent disease and GVHD were the most common causes. Most GVHD-related deaths occurred after mismatched BMT.

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• Figure 2 

  (A) The 8-year probabilities of disease-free survival after BMT: 57% for patients received matched BMT (matched at HLA A, B, C, DRB1), 33% for patients received mismatched BMT. (B) The 8-year probabilities of disease-free survival after BMT: 51% when transplantation was performed for RC, 35% when transplantation was performed for RAEB, and 29% for when transplantation was performed for RAEB-T.

Table 2. Causes of Death

EBV-PTLD indicates Epstein-Barr virus-posttransplant lymphoproliferative disease.

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Discussion 

Sibling donor BMT has been used for many years as a primary approach to treatment of MDS, with survival rates of approximately 70%. As most children with MDS will not have a matched family donor, there is increased interest in investigating whether unrelated donor transplantation is a suitable alternative, especially for children with RC. In this report, we analyzed a large pediatric cohort with a median follow-up of 8 years after transplantation to determine outcomes of unrelated donor BMT facilitated by the National Marrow Donor Program in the United States, and to identify risk factors that predict for a successful outcome.

Disease status at transplantation and donor-recipient matching are important predictors for a successful outcome. Recurrent disease was more likely when disease status had advanced beyond RC. Other factors such as pretransplant chemotherapy, secondary MDS, and cytogenetic abnormality were not associated with disease recurrence TRM or DFS. The relatively few patients (n = 18) with complex cytogenetic abnormalities in the current analysis may have prevented us from detecting an effect of this generally considered high-risk feature on disease recurrence and DFS. Similarly, the relatively small number of patients in the current analysis may have prevented us from detecting an effect of pretransplant chemotherapy or secondary MDS on TRM and DFS.

TRM was higher after mismatched BMT, and the effect was independent of transplantation period. The transplants reported herein span over a decade, and donor selection practices have evolved, the most important being the definition of an appropriately matched donor as one who is matched at HLA-A, -B, -C, -DRB1 with allele-level HLA typing [13]. Most donor-recipient pairs in this analysis were mismatched, with only about a third of recipients who received BM grafts from donors matched at HLA-A, -B, -C, -DRB1. Consequently, rates of aGVHD and cGVHD were high and likely contributed to morbidity and subsequent mortality. Although donor-recipient HLA disparity was not associated with higher risks of aGVHD in this analysis, larger series have shown this to be true [13]. Year of transplantation, a surrogate for donor-selection practices, was associated with higher cGVHD. We observed an effect of transplant-conditioning regimen on risks of cGVHD. In the current analysis, TBI-containing regimens increased the risk of cGVHD, whereas reports in adults with MDS suggest GVHD rates were comparable after TBI-and non–TBI-containing conditioning regimens 14, 15. Although we do not have a satisfactory explanation for this observation, TBI-containing regimens were not associated with higher risks of TRM and was suggestive for lower relapse risks, although this did not reach statistical significance. Although aGVHD was lower in recipients of T cell–depleted transplants, TRM and DFS rates were not different in recipients of T cell–depleted and non–T cell–depleted transplants.

Recent advances in transplantation strategies such as use of reduced intensity conditioning (RIC) regimens and CB grafts have been employed for children with MDS, and it remains to be seen whether the observed success after myeloablative regimens and unrelated donor BMT are comparable to that after RIC or CB transplantation. Strahm and colleagues [16] from the EWOG-MDS recently reported 3-year event-free survival (EFS) of 74% among 19 children with RC who received a uniform RIC regimen and unrelated donor HCT. Although 3 of 19 patients experienced graft failure, 2 were rescued with CD34⁺ cell boosts. These results are encouraging, but longer follow-up of surviving patients are needed as well as validation in a larger cohort prior to widespread adoption of RIC regimens for MDS in children. Umbilical CB grafts has also been used for MDS in children 17, 18. In the largest series, describing 42 children with MDS (n = 21 RC and n = 21 RAEB/RAEB-t), the 2-year probabilities of TRM and DFS were 56% and 32%, respectively, after umbilical CB transplantation [18]. The current analysis suggests TRM is lower and DFS higher after matched BMT, although only a direct comparison of outcomes after transplantation of unrelated BM and umbilical CB will aid clinicians to select the optimal graft type in the absence of a HLA-matched sibling. Similarly, only a direct comparison of the intensity of conditioning regimens used can satisfactorily address the question of the optimal conditioning regimen. Given the rarity of this disease in children, it may take several more years before sufficient numbers of patients are available for comparison of transplant conditioning regimens and/or unrelated donor graft sources.

Our data support best results after unrelated donor BMT when patients are transplanted in RC and when the donor and recipient are matched at HLA-A, -B, -C, and DRB1. If a matched unrelated donor is available, waiting for disease progression before proceeding to transplantation will only increase the risk of recurrent disease. Therefore, unrelated donor BMT when a matched donor is available should be offered to children with MDS using the criteria currently used for advocating transplantation for children with a matched sibling donor. In the absence of a matched unrelated donor, transplantation of unrelated umbilical CB transplantation is a reasonable alternative if offered at centers experienced in unrelated CB transplantation.

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Acknowledgments 

Financial disclosure: The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); 2 grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from AABB; Aetna; American Society for Blood and Marrow Transplantation; Amgen, Inc.; anonymous donation to the Medical College of Wisconsin; Astellas Pharma US, Inc.; Baxter International, Inc.; Bayer HealthCare Pharmaceuticals; Be the Match Foundation; Biogen IDEC; BioMarin Pharmaceutical, Inc.; Biovitrum AB; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Buchanan Family Foundation; Canadian Blood and Marrow Transplant Group; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Centers for Disease Control and Prevention; Children’s Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Cubist Pharmaceuticals; Cylex Inc.; CytoTherm; DOR BioPharma, Inc.; Dynal Biotech, an Invitrogen Company; Eisai, Inc.; Enzon Pharmaceuticals, Inc.; European Group for Blood and Marrow Transplantation; Gamida Cell, Ltd.; GE Healthcare; Genentech, Inc.; Genzyme Corporation; Histogenetics, Inc.; HKS Medical Information Systems; Hospira, Inc.; Infectious Diseases Society of America; Kiadis Pharma; Kirin Brewery Co., Ltd.; The Leukemia & Lymphoma Society; Merck & Company; The Medical College of Wisconsin; MGI Pharma, Inc.; Michigan Community Blood Centers; Millennium Pharmaceuticals, Inc.; Miller Pharmacal Group; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Nature Publishing Group; New York Blood Center; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Pall Life Sciences; Pfizer Inc; Saladax Biomedical, Inc.; Schering Corporation; Society for Healthcare Epidemiology of America; Soligenix, Inc.; StemCyte, Inc.; StemSoft Software, Inc.; Sysmex America, Inc.; THERAKOS, Inc.; Thermogenesis Corporation; Vidacare Corporation; Vion Pharmaceuticals, Inc.; ViraCor Laboratories; ViroPharma, Inc.; and Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, or any other agency of the U.S. Government.

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