This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Eapen, M. Articles by Wagner, J. E. Search for Related Content PubMed PubMed Citation Articles by Eapen, M. Articles by Wagner, J. E.

Comparable Long-Term Survival After Unrelated and HLA-Matched Sibling Donor Hematopoietic Stem Cell Transplantations for Acute Leukemia in Children Younger Than 18 Months

From the Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin; Medical College of Wisconsin, Milwaukee, WI; New York Blood Center; Columbia University, New York, NY; Cincinnati Children's Hospital and Medical Center, Cincinnati, OH; Duke University Medical Center, Durham, NC; Utah Blood and Marrow Transplant Program, Salt Lake City, UT; University of Minnesota, Minneapolis, MN; Hospital Materno-Infantil, Barcelona, Spain; Hospital for Sick Children, Toronto, Ontario, Canada

Address reprint requests to Mary Eapen, MD, Statistical Center, Center for Blood and Marrow Transplant Research, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226; e-mail: meapen{at}mail.mcw.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: To describe outcomes after unrelated donor stem cell transplantation (HCT) in children (< 18 months at diagnosis) with acute leukemia and compare these with outcomes after human leukocyte antigen (HLA)-matched sibling donor HCT.

PATIENTS AND METHODS: We compared the results of unrelated donor HCT with bone marrow (n = 85) or cord blood grafts (n = 81) and HLA-matched sibling donor HCT with bone marrow grafts (n = 101) for acute myeloid or acute lymphoblastic leukemia using Cox proportional hazards models. Unrelated donor HCT recipients were younger, more likely to have MLL gene rearrangement, to have advanced leukemia, and to receive irradiation before HCT.

RESULTS: Treatment-related mortality rates were 6%, 15%, and 31% after matched sibling, unrelated donor bone marrow, and cord blood HCT, respectively. Risks of relapse, overall and leukemia-free survival were significantly associated with disease status at transplantation. Though leukemia recurrence was lowest after unrelated donor HCT in first clinical remission (CR), overall survival, and leukemia-free survival rates were similar after matched sibling and unrelated donor HCT, after adjustment for disease status. Relapse, overall and leukemia-free survival did not differ by graft type (bone marrow v cord blood) or type of leukemia. Three-year probabilities of leukemia-free survival were 49% and 54% after HLA-matched sibling and unrelated donor transplantation in first CR, respectively. Corresponding rates for those with advanced leukemia were 20% and 30%.

CONCLUSION: Unrelated donor HCT should be considered for infants with acute leukemia in first CR using the same eligibility criteria as are currently used for those with HLA matched sibling donors.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Acute leukemia in infancy accounts for only 2.5% to 5% of acute lymphoblastic leukemia (ALL) and 6% to 14% of acute myeloid leukemia (AML) in children.¹ Though infant ALL and AML share some biologic and clinical characteristics, laboratory findings and treatment strategies differ.^1,2 While infants with ALL receive intensified treatment regimens compared to older children with ALL, infants with AML receive the same therapy as older children.^1-9 In North America, children with AML who have a human leukocyte antigen (HLA)-matched sibling donor routinely undergo hematopoietic stem-cell transplantation (HCT) in first complete remission (CR) as transplantation is associated with improved overall and leukemia-free survival.⁹ In contrast, results for ALL in younger children do not show a survival advantage with allogeneic transplantation in first CR.^2,10,11 Yet, when an HLA-matched sibling donor is available, transplantation is often considered for infants with ALL who achieve a first CR; for those without an HLA-matched sibling with a suitably matched unrelated donor, transplantation is delayed until after relapse. As numbers are limited, and results in younger children are not always reported separately from overall study results, it is difficult to determine whether allogeneic transplantation as first-line therapy improves overall and leukemia-free survival in very young children.^1-3,9,12-18 The optimal study design requires randomization to intensive chemotherapy versus transplantation. However, for multiple reasons, this has proved difficult especially in the absence of a matched-sibling donor. Therefore, we utilized transplant/outcome data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and the New York Cord Blood Placental Program (NCBP) to evaluate the role of unrelated donor transplantation in infants with leukemia by comparing outcomes after unrelated donor and HLA-matched sibling donor transplants.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Data Collection
Data on patients undergoing transplantation were obtained from the CIBMTR and the NCBP. The CIBMTR is a working group of more than 450 transplant teams worldwide. Participating centers register basic information on consecutive transplantations to a statistical center located at the Medical College of Wisconsin. Detailed demographic and clinical data are collected on a representative sample of registered transplantations using a weighted randomization scheme. Computerized error checks, physician review of submitted data, and onsite audits of participating centers ensure data quality. Centers obtaining cord blood grafts from the NCBP are required to report transplant outcome data under United States Food and Drug Administration investigational new drug rules. CIBMTR observational studies are conducted with a waiver of informed consent and are in compliance with HIPPA regulations as determined by the institutional review board and the privacy officer of the medical college of Wisconsin.

Inclusion Criteria
Patients with ALL or AML diagnosed before 18 months of age and receiving an HLA-matched sibling donor transplant or an HLA-matched or 1 antigen-mismatched unrelated donor transplant (HLA A, B defined using serologic techniques and DRB1 using high resolution molecular typing identifying all WHO-recognized specificities current at time of transplantation) between January 1, 1990 and December 31st, 2001, and reported to the CIBMTR and NCBP were included in this analysis. One hundred one recipients of HLA-matched sibling donor, 85 unrelated donor bone marrow, and 81 cord blood transplants were eligible. Patients who failed a prior transplant, who received peripheral blood grafts, or who received more than 1 antigen-mismatched unrelated donor bone marrow or cord blood transplant were excluded.

End Points
Transplant outcomes examined included hematopoietic recovery, acute and chronic graft-versus-host disease (GVHD), treatment-related mortality, relapse, leukemia-free survival, treatment failure (relapse or death, inverse of leukemia-free survival), and overall survival. Neutrophil recovery was defined as achieving an absolute neutrophil count 500/µL for three consecutive measurements; platelet recovery was defined as achieving platelets 20,000/µL for 7 days without transfusion support. The incidence of grades 2 to 4 acute GVHD was evaluated in all patients¹⁹; chronic GVHD was evaluated in patients surviving 90 days or longer.²⁰ Treatment-related mortality was defined as death in continuous complete remission. Relapse was defined as hematologic recurrence; patients who failed to achieve remission after transplantation were considered to have had a recurrence at day 1. Leukemia-free survival was defined as survival in continuous complete remission.

Statistical Analysis
Patient-, disease-, and transplant-related variables were compared between the groups using the ² statistic for categoric variables and the Kruskal-Wallis test for continuous variables. Probabilities of overall and leukemia-free survival were calculated using the Kaplan-Meier estimator.²¹ For analyses of survival, death from any cause was considered an event and patients surviving at last follow-up were censored. For leukemia-free survival, relapse or death (treatment failure) were considered events, and patients surviving in continuous CR were censored at last follow-up. Probabilities of neutrophil and platelet recovery, acute and chronic GVHD, treatment-related mortality, and relapse were calculated using the cumulative incidence function estimator.²¹ For neutrophil and platelet recovery and acute and chronic GVHD, death without an event was the competing risk; patients alive without the event were censored at last follow-up. For treatment-related mortality, relapse was the competing event and for relapse, treatment-related mortality was the competing event. For both treatment-related mortality and relapse, patients alive in continuous complete remission were censored at last follow-up. 95% CIs were calculated with the use of a log transformation.²¹ Adjusted probabilities of overall and leukemia-free survival were estimated with the use of the Cox proportional hazards regression model with consideration of the variables in the final multivariate models.²²

Multivariate models were built with the use of forward stepwise selection with a P value of .05 or less considered to indicate statistical significance; all variables met the proportional hazards assumption. The primary objective of this study was to compare outcomes after HLA-matched sibling donor transplantation versus matched or 1-antigen mismatched unrelated donor transplantation. Therefore, the variable for donor type was held in all steps of the model. Other variables considered were sex, type of leukemia (AML v ALL), age at diagnosis (< 6 months v 6 to12 months v >12 months), age at transplantation (12 v > 12 months), cytogenetics (normal v MLL rearrangement versus other abnormalities), disease status at transplantation (first CR v second CR v relapse), presence or absence of extra-medullary disease, graft type (bone marrow v cord blood), HLA disparity (matched v 1-antigen mismatched), conditioning regimen (irradiation v nonirradiation), GVHD prophylaxis (T-depletion v no T-depletion), and year of transplantation (1990 to1995 v 1996 to 2001). Whenever variables initially classified into more than two categories showed no statistically significant differences between categories, categories were collapsed to create the fewest possible groups (such as, disease status at transplantation: CR1 v CR2/relapse). Before comparing HLA-identical sibling and unrelated donor transplants, we analyzed the effect of graft type in recipients of unrelated donor transplants (bone marrow v cord blood). There were no statistically significant differences in relapse, treatment failure, and overall mortality between patients who received unrelated donor bone marrow and cord blood grafts. When significant differences were observed, outcomes by donor/graft type are shown separately (hematopoietic recovery, GVHD, and treatment-related mortality). All multivariate models were examined for center effects by using a random effects or frailty model and there were none.²³ Completeness of follow-up (the ratio of the sum of the observed follow-up time to the sum of the potential follow-up time for all patients in the study) was assessed using the C statistic.²⁴ All P values are two sided. All analyses were done using PROC PHREG in SAS version 8.2 (SAS Institute, Cary, NC).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Patient and Transplant Characteristics
Patient-, disease-, and transplant-related characteristics are shown in Table 1. The decision to proceed to transplantation and all aspects of the transplant regimen including choice of donor and graft type were determined by transplant centers. All recipients of HLA-matched sibling transplants received bone marrow grafts. Fifty-one percent of unrelated donor transplant recipients received bone marrow grafts and 49% received cord blood. Twenty-four of 85 (28%) unrelated donor bone marrow transplants and 69 of 82 (85%) unrelated donor cord blood transplants were mismatched at a single antigen. Recipients of HLA-matched sibling and unrelated donor transplants were similar in sex, type of leukemia, age at transplantation, and donor-recipient sex match, but differed in that recipients of unrelated donor transplants tended to be younger at diagnosis and were more likely to have advanced disease (CR2/relapse at transplantation) and/or MLL gene abnormalities, to receive irradiation and to be transplanted more recently. Bone marrow grafts from HLA-matched sibling donors were not T-cell depleted; 32 of 85 (38%) unrelated donor bone marrow grafts were T-cell depleted. Patient- and disease- characteristics of recipients of unrelated donor bone marrow and unrelated donor cord blood grafts were similar (recipients of unrelated donor bone marrow or cord blood grafts were similar in sex [male, 52% v 44%, P = .35], type of leukemia [ALL: 62% v 54%; AML: 38% v 46%; P = .29], age at diagnosis [< 6 months: 44% v 37%; 6-12 months: 40% v 43%; >12 to 18 months: 16% v 20%; P = .68], age at transplant [ 12 months: 33% v 31%; >12 months: 67% v 69%; P = .77], cytogenetic abnormality [normal: 5% v 11%; MLL rearrangement: 55% v 44%; other: 22% v 27%; unknown: 18% v 17%; P = .32], disease status at transplant [CR1: 54% v 43%; CR2 26% v 38%; relapse 20% v 18%; P = .22]); their transplant characteristics differed in that bone marrow recipients were more likely to receive irradiation (71% v 46% of cord blood graft recipients; P = .001) and 86% of cord blood transplants occurred after 1996. Sixty-one of 85 (72%) bone marrow grafts were matched at HLA A, B and DRB1 and 24 of 85 (28%) were mismatched at a single antigen locus. Twelve of 81 (15%) cord blood grafts were matched at HLA A, B and DRB1 and 69 of 81 (85%) were mismatched at a single antigen locus. Total nucleated cell doses were available for 86 of 101 (85%), 65 of 85 (76%), and 76 of 81 (94%) recipients of HLA-matched sibling, unrelated donor bone marrow, and unrelated donor cord blood transplants, respectively; corresponding median doses infused were 4.9 (range, 0.2 to 13) x 10⁸/kg, 3.8 (range, 0.2 to 20) x 10⁸/kg and 1.1 (range, 0.2 to 13) x 10⁸/kg. Though the total nucleated cell doses of cord blood grafts were significantly lower than that of bone marrow grafts (P < .0001), only three of 76 assessable cord blood recipients received fewer than 0.25 x 10⁸/kg cells. As unrelated donor transplantations were performed more frequently after 1996, the median follow-up of survivors of these procedures was shorter than the follow-up of survivors after HLA-matched sibling transplantation (59 v 91 months, P = .0004). The completeness of follow-up, for both the related and unrelated donor groups, was 90%.²⁴

Platelet recovery times were significantly longer after unrelated donor bone marrow or unrelated donor cord blood transplantation than after HLA-matched sibling transplantation and among unrelated donor transplant recipients, recovery times were significantly longer after cord blood transplantation. Median times to platelet recovery were 26 (range, 14 to 101), 31 (range, 14 to 271), and 61 (range, 16 to 272) days after HLA-matched sibling, unrelated donor bone marrow and unrelated donor cord blood transplantation, respectively (P < .0001). The cumulative incidence of platelet recovery at any time after transplantation was highest after HLA-matched sibling donor transplantation. The cumulative incidence of platelet recovery was significantly higher after unrelated donor bone marrow than after unrelated donor cord blood transplantation at all times examined (66% v 59% at day 60, P < .0001).

Acute and Chronic Graft Versus Host Disease
Grades 2 to 4 acute GVHD were significantly more frequent after transplantation of non–T-cell depleted unrelated donor bone marrow and unrelated donor cord blood than after HLA-matched sibling transplantation (RR 3.03, 95% CI, 1.80 to 5.36, P < .0001 and RR 2.37, 95% CI, 1.39 to 4.04, P = .002, respectively). Grades 2 to 4 acute GVHD were also more frequent after transplantation of non–T-cell depleted unrelated donor bone marrow and unrelated donor cord blood compared to T-cell depleted unrelated donor bone marrow transplantation (RR 3.14; 95% CI, 1.37 to 7.17; P = .01 and RR 2.45; 95% CI, 1.08 to 5.54; P = .03, respectively). Risks of grade 2 to 4 acute GVHD were similar after unrelated donor T-cell depleted bone marrow and HLA-matched sibling transplants (RR 0.97; 95% CI, 0.42 to 2.25; P = .9). Corresponding risks were similar after transplantation of unrelated donor cord blood and unrelated donor non T-cell depleted bone marrow transplants (RR 0.78; 95% CI, 0.47 to 1.29; P = .3). Grades 3 to 4 acute GVHD were also more frequent after unrelated donor non–T-cell depleted bone marrow transplantation than after HLA-matched sibling transplantation (RR 3.44; 95% CI, 1.47 to 8.06; P = .005). We did not observe significant differences in risks of grades 3 to 4 acute GVHD after HLA-matched sibling donor, T-cell depleted unrelated donor bone marrow, and unrelated donor cord blood transplantation.

Ninety-one recipients of HLA-matched sibling transplants and 112 recipients of unrelated donor transplants were assessable for chronic GVHD. Chronic GVHD was higher after unrelated donor transplants than after HLA-matched sibling transplants (RR 3.50; 95% CI, 1.31 to 9.33; P = .01). There were no significant differences in risks of chronic GVHD after unrelated donor bone marrow (T-cell depleted and non–T-cell depleted) and cord blood transplants (RR 1.10; 95% CI, 0.48 to 2.55; P = .8). Severity of chronic GVHD did not differ by graft type after unrelated donor transplants though small numbers of patients may have prevented us from detecting a difference.

Treatment-Related Mortality
Treatment-related mortality was significantly higher after unrelated donor transplants than after HLA-matched sibling transplants (RR 3.10; 95% CI, 1.18 to 8.02; P = .02; and RR 6.01; 95% CI, 2.47 to 14.66; P < .0001, after unrelated donor bone marrow and cord blood transplants respectively, compared to HLA-matched sibling transplants). Among recipients of unrelated donor transplants, treatment-related mortality was significantly higher after cord blood than after bone marrow transplantation (RR 1.95; 95% CI, 1.02 to 3.76; P = .05). We did not observe a significant association between treatment-related mortality and infusion of T-cell depleted bone marrow grafts. One-and 3-year treatment-related mortality rates were 6% (95% CI, 2% to 11%), 15% (8% to 23%) and 31% (21% to 41%) after HLA-matched sibling, unrelated donor bone marrow and unrelated donor cord blood transplantation, respectively.

Relapse
Leukemia recurrence after transplantation was lowest after unrelated donor transplantation in first CR (Table 2). For children in first CR, 3-year relapse rates were 47% (36% to 58%) and 24% (15% to 33%) after HLA-matched sibling and unrelated donor transplantation, respectively (P = .002, Fig 1). There were no significant differences in leukemia recurrence after HLA-matched sibling and unrelated donor transplantation in children with advanced disease. Corresponding relapse rates were 65% (43% to 84%) and 45% (35% to 56%) (P = .10). Risks of relapse were similar after unrelated donor bone marrow and unrelated donor cord blood transplantation, (RR 0.85; 95% CI, 0.34 to 2.16; P = .7) and (RR 0.64; 95% CI, 0.34 to 1.22; P = .2) for those transplanted in first CR and advanced disease, respectively. We did not observe an association between leukemia recurrence and infusion of T-cell depleted grafts.

View larger version (13K): [in this window] [in a new window]   Fig 1. Adjusted cumulative incidence of relapse. CR, complete remission; HLA, human leukocyte antigen.

View larger version (13K): [in this window] [in a new window]   Fig 2. Adjusted probabilities of leukemia-free survival. CR, complete remission; HLA, human leukocyte antigen.

View larger version (13K): [in this window] [in a new window]   Fig 3. Adjusted probabilities of overall survival. CR, complete remission; HLA, human leukocyte antigen.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The objective of this study was to determine outcomes after unrelated donor transplantation for very young children with acute leukemia and to compare these with outcomes after HLA-matched sibling donor transplantation. There were no differences in long-term rates of overall and leukemia-free survival following unrelated donor transplantation as compared to HLA-matched sibling transplantation following adjustment for disease status, the only significant prognostic variable. Overall and leukemia-free survival rates were significantly higher for children transplanted in first remission compared with those transplanted in second remission or relapse. This confirms that reported by others that disease status at transplantation rather than donor type is the most important determinant of outcome after transplantation.^25-27 Notably, there were no differences in relapse, overall and leukemia-free survival between recipients of unrelated donor bone marrow and unrelated donor cord blood transplantation despite the fact that 85% of cord blood grafts were mismatched compared to 28% of bone marrow grafts. HLA-disparity limited to a single antigen and selection of cord blood grafts with adequate total nucleated cell doses may explain why we did not observe significant differences by type of donor or graft infused.

The pattern of treatment failure differed after HLA-matched sibling donor and unrelated donor transplantation. While relapse was the most frequent cause of treatment failure after HLA-matched sibling donor transplantation, treatment-related mortality was the most frequent cause of failure after unrelated donor bone marrow or unrelated donor cord blood transplantation. The higher proportion of patients with advanced leukemia at transplantation, slower myeloid recovery, higher rates of GVHD and infections may have contributed to higher treatment-related mortality after unrelated donor transplantation. Higher rates of early treatment-related mortality after cord blood transplantation is reported by others and is presumed secondary to slower myeloid recovery and higher rates of infection-related deaths.^28-30 Strategies to improve hematopoietic recovery such as ex vivo expansion of cord blood cells, infusion of HLA-haploidentical CD34+ cells, transplantation of double cord blood grafts, and use of fludarabine may decrease early mortality after cord blood transplantation.^31-33 The higher proportion of patients with advanced leukemia among unrelated donor bone marrow or cord blood recipients is reflective of the practice of transplantation as a treatment option after initial relapse in patients without a HLA-matched sibling donor.

We did not observe differences in transplant-outcome by type of leukemia. To further examine the effect of type of leukemia and outcomes after transplantation, we examined recurrence, overall and leukemia-free survival for each type of leukemia separately. After adjustment for disease status at transplantation, risks of recurrence, treatment failure, and overall mortality were similar after HLA-identical sibling and unrelated donor transplantation (data not shown). Higher dose-intensities associated with allogeneic transplantation as well as graft versus leukemia effects may have resulted in fewer relapses for both types of leukemia and may explain the equivalent outcomes observed in the current study. The relative efficacy of HLA-matched sibling bone marrow and unrelated donor bone marrow or unrelated donor cord blood grafts did not differ by age at diagnosis or other known prognostic factors such as age (< 6 months), white cell count, extra-medullary disease, 11q23 abnormalities, or other cytogenetic abnormalities.^{1,4,6,10,11,34-37} Nevertheless, these factors and chemotherapy received before transplantation may have influenced the likelihood of achieving and sustaining CR, the only significant prognostic factor in our cohort.

Our study is limited by lack of information on neurocognitive development and other late medical complications either as a result of intensified therapy or radiation associated with transplantation. These complications are important considerations in balancing the risk and benefits of transplantation versus intensive chemotherapy^27,38 and future studies should address the long-term consequences of aggressive treatment in larger cohorts of very young children and especially the use of irradiation-containing regimens for transplantation.

Any observational study that compares different interventions is subject to bias from complex selection criteria that underlie the choice of intervention and our study is no exception. But our ability to adjust for key known risk factors made a controlled though not randomized comparison possible. Further, this study cannot address the relative merits and demerits of intensive chemotherapy versus transplantation. Our data suggest that the same criteria currently used for advocating transplantation for those with an HLA-matched sibling donor should be extended to those with a HLA-matched or 1-antigen mismatched unrelated adult or cord blood.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Mary Eapen, Mary M. Horowitz, John E. Wagner Provision of study materials or patients: Mary Eapen, John J. Doyle, Joanne Kurtzberg, Juan J. Ortega, John E. Wagner, Pablo Rubinstein, Cladd Stevens, Andromachi Scaradavou, Stella M. Davies Collection and assembly of data: Mary Eapen, Pablo Rubinstein, Cladd Stevens Data analysis and interpretation: Mary Eapen, Mei-Jie Zhang, John J. Doyle Manuscript writing: Mary Eapen, Pablo Rubinstein, Bruce M. Camitta, Cladd Stevens, Stella M. Davies, John J. Doyle, Joanne Kurtzberg, Michael A. Pulsipher, Mary M. Horowitz, John E. Wagner Final approval of manuscript: Mary Eapen, Pablo Rubinstein, Mei-Jie Zhang, Bruce M. Camitta, Cladd Stevens, Mitchell S. Cairo, Stella M. Davies, John J. Doyle, Joanne Kurtzberg, Michael A. Pulsipher, Juan J. Ortega, Andromachi Scaradavou, Mary M. Horowitz, John E. Wagner

 

	NOTES

 
Supported by Public Health Service Grant U24-CA76518 from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute, and a Clinical Research Career Development Award from the American Society of Clinical Oncology (ME).

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 Authors' Disclosures of... Author Contributions REFERENCES

 
1. Biondi A, Cimino G, Pieters R, et al: Biological and therapeutic aspects of infant leukemia. Blood 96:24-33, 2000[Free Full Text]

2. Chessells JM, Harrison CJ, Kempski H, et al: Clinical features, cytogenetics and outcome in acute lymphoblastic and myeloid leukaemia of infancy: Report from the MRC Childhood Leukaemia working party. Leukemia 16:776-784, 2002[CrossRef][Medline]

3. Chessells JM, Harrison CJ, Watson SL, et al: Treatment of infants with lymphoblastic leukaemia: Results of the UK Infant Protocols 1987-1999. Br J Haematol 117:306-314, 2002[CrossRef][Medline]

4. Reaman GH, Sposto R, Sensel MG, et al: Treatment outcome and prognostic factors for infants with acute lymphoblastic leukemia treated on two consecutive trials of the Children's Cancer Group. J Clin Oncol 17:445-455, 1999[Abstract/Free Full Text]

5. Frankel LS, Ochs J, Shuster JJ, et al: Therapeutic trial for infant acute lymphoblastic leukemia: The Pediatric Oncology Group experience (POG 8493). J Pediatr Hematol Oncol 19:35-42, 1997[CrossRef][Medline]

6. Silverman LB, McLean TW, Gelber RD, et al: Intensified therapy for infants with acute lymphoblastic leukemia: Results from the Dana-Farber Cancer Institute Consortium. Cancer 80:2285-2295, 1997[CrossRef][Medline]

7. Dordelmann M, Reiter A, Borkhardt A, et al: Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia. Blood 94:1209-1217, 1999[Abstract/Free Full Text]

8. Ferster A, Benoit Y, Francotte N, et al: Treatment outcome in infant acute lymphoblastic leukemia. Blood 95:2729-2730, 2000[Free Full Text]

9. Woods WG, Neudorf S, Gold S, et al: A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukaemia in remission: A report from the Children's Cancer Group. Blood 97:56-62, 2001[Abstract/Free Full Text]

10. Pui CH, Gaynon PS, Boyett JM, et al: Outcome of treatment in childhood acute lymphoblastic leukemia with rearrangements of the 11q23 chromosomal region. Lancet 359:1909-1915, 2002[CrossRef][Medline]

11. Pui CH, Chessells JM, Camitta B, et al: Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements. Leukemia 17:700-706, 2003[CrossRef][Medline]

12. Webb DK, Harrison G, Stevens RF, et al: Relationships between age at diagnosis, clinical features, and outcome of therapy in children treated in the Medical Research Council AML 10 and 12 trials for acute myeloid leukemia. Blood 98:1714-1720, 2001[Abstract/Free Full Text]

13. Emminger W, Emminger-Schmidmeier W, Haas OA, et al: Treatment of infant leukemia with busulfan, cyclophosphamide ± etoposide and bone marrow transplantation. Bone Marrow Transplant 9:313-318, 1992[Medline]

14. von Bueltzingsloewen A, Esperou-Bourdeau H, Souillet G, et al: Allogeneic bone marrow transplantation following a busulfan-based conditioning regimen in young children with acute lymphoblastic leukemia: A cooperative study of the Societe Francaise de Greffe de Molle. Bone Marrow Transplant 16:521-527, 1995[Medline]

15. Saarinen UM, Mellander L, Nysom K, et al: Allogeneic bone marrow transplantation in first remission for children with very high-risk acute lymphoblastic leukemia: A retrospective case-control study in the Nordic countries. Bone Marrow Transplant 17:357-363, 1996[Medline]

16. Woolfrey AE, Gooley TA, Sievers EL, et al: Bone marrow transplantation for children less than 2 years of age with acute myelogenous leukemia or myelodysplastic syndrome. Blood 92:3546-3556, 1998[Abstract/Free Full Text]

17. Pirich L, Haut P, Morgan E, et al: Total body irradiation, cyclophosphamide, and etoposide with stem cell transplant as treatment for infants with acute lymphocytic leukemia. Med Pediatr Oncol 32:1-6, 1999[CrossRef][Medline]

18. Marco F, Bureo E, Ortega JJ, et al: High survival rate in infant acute leukemia treated with early high-dose chemotherapy and stem-cell support. J Clin Oncol 18:3256-3261, 2000[Abstract/Free Full Text]

19. Przepiorka D, Weisdorf D, Martin P, et al: 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant 15:825-828, 1995[Medline]

20. Flowers ME, Kansu E, Sullivan KM: Pathophysiology and treatment of graft-versus-host disease. Hematol Oncol Clin North Am 13:1091-1112, 1999[CrossRef][Medline]

21. Klein JP, Moeschberger ML: Survival Analysis: Techniques of censored and truncated data (2 ed.), New York, NY, Springer-Verlag, 2003

22. Cox DR: Regression models and life tables. J R Stat Soc B 34:187-200, 1972

23. Andersen PK, Klein JP, Zhang MJ: Testing for center effects in multi-center survival studies: A Monte Carlo comparison of fixed and random effects tests. Stat Med 18:1489-1500, 1999[CrossRef][Medline]

24. Clark TG, Altman DG, De Stavola BL: Quantification of the completeness of follow up. Lancet 359:1309-1310, 2002[CrossRef][Medline]

25. Leung W, Pitts N, Bumette K, et al: Allogeneic bone marrow transplantation for infants with acute leukemia or myelodysplastic syndrome. Bone Marrow Transplant 27:717-722, 2001[CrossRef][Medline]

26. Kosaka Y, Koh K, Kinukawa N, et al: Infant acute leukemia with MLL gene rearrangements: Outcome following intensive chemotherapy and hematopoietic stem cell transplantation. Blood 104:3527-3534, 2004[Abstract/Free Full Text]

27. Sanders JE, Im HJ, Hoffmeister PA, et al: Allogeneic hematopoietic stem cell transplantation for infants with acute lymphoblastic leukemia. Blood 105:3749-3756, 2005[Abstract/Free Full Text]

28. Rocha V, Cornish J, Sievers EL, et al: Comparison of outcomes of unrelated bone marrow and umbilical cord blood transplants in children with acute leukemia. Blood 97:2962-2971, 2001[Abstract/Free Full Text]

29. Michel G, Rocha V, Chevret S, et al: Unrelated cord blood transplantation for childhood acute myeloid leukemia: A Eurocord Group analysis. Blood 102:4290-4297, 2003[Abstract/Free Full Text]

30. Hamza NS, Lisgaris MV, Yadavalli GK, et al: Kinetics of myeloid and lymphocyte recovery and infectious complications after unrelated umbilical cord blood versus HLA-matched unrelated donor allogeneic transplantation in adults. Br J Haematol 124:488-498, 2004[CrossRef][Medline]

31. Jaroscak J, Goltry K, Smith A, et al: Augmentation of umbilical cord blood (UCB) transplantation with ex vivo-expanded UCB cells: Results of a phase I trial using Aastrom Replicell System. Blood 101:5061-5067, 2003[Abstract/Free Full Text]

32. Fernandez MN, Regidor C, Cabrera R, et al: Unrelated umbilical cord blood transplants n adults: Early recovery of neutrophils by supportive co-transplantation of a low number of highly purified peripheral blood CD34+ cells from an HLA-haploidentical donor. Exp Hematol 31:535-544, 2003[CrossRef][Medline]

33. Barker JN, Weisdorf DJ, DeFor TE, et al: Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood 105:1343-1347, 2005[Abstract/Free Full Text]

34. Pui CH, Ribeiro RC, Campana D, et al: Prognostic factors in the acute lymphoid and myeloid leukemias of infants. Leukemia 10:952-956, 1996[Medline]

35. Heerema NA, Sather HN, Ge J, et al: Cytogenetic studies of infant acute lymphoblastic leukemia: Poor prognosis of infants with t(4;11) –a report from the Children's Cancer Group. Leukemia 13:679-686, 1999[CrossRef][Medline]

36. Kersey JH, Wang D, Oberto M: Resistance of t(4;11) (MLL-AF4 fusion gene) leukemias to stress-induced cell death: Possible mechanism for extensive extramedullary accumulation of cells and poor prognosis. Leukemia 12:1561-1564, 1998[CrossRef][Medline]

37. Pui-CH, Raimondi SC, Srivastava DK, et al: Prognostic factors in infants with acute myeloid leukemia. Leukemia 14:684-687, 2000[CrossRef][Medline]

38. Leung W, Hudson M, Zhu Y, et al: Late effects in survivors of infant leukemia. Leukemia 14:1185-1190, 2000[CrossRef][Medline]

Submitted April 20, 2005; accepted October 5, 2005.

This article has been cited by other articles:

				N. S. Fox, F. A. Chervenak, and L. B. McCullough Ethical Considerations in Umbilical Cord Blood Banking Obstet. Gynecol., January 1, 2008; 111(1): 178 - 182. [Abstract] [Full Text] [PDF]

				S. Malempati, P. S. Gaynon, H. Sather, M. K. La, and L. C. Stork Outcome After Relapse Among Children With Standard-Risk Acute Lymphoblastic Leukemia: Children's Oncology Group Study CCG-1952 J. Clin. Oncol., December 20, 2007; 25(36): 5800 - 5807. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Eapen, M. Articles by Wagner, J. E. Search for Related Content PubMed PubMed Citation Articles by Eapen, M. Articles by Wagner, J. E.