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Originally published as JCO Early Release 10.1200/JCO.2004.02.189 on November 1 2004 © 2004 American Society of Clinical Oncology. Higher Mortality After Allogeneic Peripheral-Blood Transplantation Compared With Bone Marrow in Children and Adolescents: The Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant RegistryFrom the International Bone Marrow Transplant Registry, Health Policy Institute, Medical College of Wisconsin, Milwaukee, WI; The University of Texas M.D. Anderson Cancer Center, Houston, TX; the Karolinska Institutet, Stockholm, Sweden; and the University of Minnesota School of Medicine, Minneapolis, MN. Address reprint requests to Mary Eapen, MBBS, MS, at the IBMTR/ABMTR Statistical Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226; e-mail: meapen{at}mail.mcw.edu
PURPOSE: Peripheral-blood stem cells (PBSC) may be used as an alternative to bone marrow (BM) for allogeneic transplantation. Despite lack of data on PBSC transplantation in children, there has been a change in clinical practice, with increasing numbers of children receiving PBSC allografts. PATIENTS AND METHODS: We compared the results of 143 PBSC and 630 BM transplants from human leukocyte antigen–identical sibling donors in children aged 8 to 20 years with acute leukemia. PBSC transplant recipients were older, and were more likely to have advanced leukemia, receive growth factors post-transplantation, and have undergone transplantation more recently. Risks of acute and chronic graft-versus-host disease (GVHD), treatment-related mortality, relapse, treatment failure (relapse or death), and overall mortality were compared using Cox proportional hazards regression to adjust for potentially confounding factors. RESULTS: Hematopoietic recovery was faster after PBSC transplantation. Risks of grade 2 to 4 acute GVHD were similar, but chronic GVHD risk was higher after PBSC transplantation (relative risk [RR], 1.85; 95% CI, 1.28 to 2.66; P = .001). In contrast to reports in adults, treatment-related mortality (RR, 1.89; 95% CI, 1.28 to 2.80; P = .001), treatment failure (RR, 1.31; 95% CI, 1.03 to 1.68; P = .03), and mortality (RR, 1.38; 95% CI, 1.07 to 1.79; P = .01) were higher after PBSC transplantation. Risks of relapse were similar. CONCLUSION: These data suggest poorer outcomes after PBSC compared with BM transplantation in children after adjusting for relevant risk factors. Given the trend toward increased use of PBSC allografts in children, prospective clinical trials are required to determine their appropriate role in this group of patients.
Major changes in the source of hematopoietic stem cells used occurred over the last decade. Peripheral-blood stem cells (PBSC) are now frequently used instead of bone marrow (BM) for allogeneic transplantation. Data from the International Bone Marrow Transplant Registry (IBMTR) suggest that approximately 70% of allogeneic transplantations performed in adults worldwide use PBSC grafts, compared with 30% in the late 1990s. PBSC are collected from donors after administration of granulocyte colony-stimulating factor (G-CSF). PBSC collection may allow donors to avoid surgery, general or spinal anesthesia, hospitalization, and potential exposure to blood products. The mobilization and safety of collecting PBSC from healthy donors have been reviewed.1 In the short-term, PBSC donation seems to have a safety profile comparable with BM harvesting, at least in adults. Mobilized PBSC grafts contain approximately 1 log more lymphocytes than BM grafts.2,3 This could affect immune reconstitution, graft-versus-host disease (GVHD) and graft-versus-leukemia effects. Prior comparative studies (PBSC v BM transplantation) in adults, including randomized clinical trials, give mixed results.4-10 While all studies document more rapid hematopoietic recovery after PBSC transplantation, data on other end points such as chronic GVHD, relapse, and survival, are less consistent.4-10 Some, but not all, studies report survival advantages with PBSC compared with BM grafts, but these seem to be limited to patients with advanced leukemia.4,7,9 Thus far, none of these studies report a poorer outcome after PBSC compared with BM transplantation in adults. Some clinicians have used the results of studies in adults to recommend PBSC instead of BM transplantation in children. Yet, there are reasons that the relative benefit of PBSC compared with BM may be different in the pediatric setting. Studies showing a survival benefit for PBSC in adults indicate improvement in early treatment-related mortality. However, treatment-related mortality after BM transplantation is already substantially lower in children than in adults, leaving less room for improvement with PBSC. Reports in children confirm safety of mobilization and collection of PBSC in younger donors and more rapid hematopoietic recovery in recipients.11-14 Data on the occurrence of GVHD are less consistent, with some studies reporting a higher incidence of chronic GVHD, and others, an incidence similar to that seen after BM transplants.12,14 Data from the IBMTR suggest PBSC grafts are increasingly used as an alternative to BM grafts in children. Approximately 30% of allogeneic transplantations performed worldwide in children now use PBSC grafts, compared with fewer than 10% a few years ago. This clearly suggests a change in clinical practice in pediatric transplantation, driven by results observed in adult recipients of PBSC transplantation. Because transplantation of PBSC has not been compared with transplantation of BM in children after adjustment for other factors known to influence outcomes after transplantation, the issue is controversial. We report a comparison of 143 PBSC and 630 BM human leukocyte antigen (HLA)–identical sibling transplantations in children.
Data Collection Data on children undergoing PBSC and BM transplantation were obtained from the Statistical Center of the IBMTR. The IBMTR is a voluntary working group of more than 400 worldwide transplant teams that contribute detailed information on their allogeneic transplant recipients to the Statistical Center of the IBMTR at the Medical College of Wisconsin (Milwaukee, WI). The IBMTR database includes information on approximately 40% of all patients who have undergone allogeneic transplantation since 1970. The IBMTR collects data at two levels: registration and research. Registration data include disease type, age, sex, pretransplantation disease stage, date of diagnosis, graft and donor type, conditioning regimen, GVHD prophylaxis, disease progression after transplant and survival, development of a new malignancy, and cause of death. Requests for data on progression or death for registered patients are made at 6-month intervals. Participating centers are required to register all consecutive transplantations. Research data are collected on subsets of registered patients by a weighted randomized scheme, and include comprehensive pre- and post-transplantation clinical information. Patients are followed longitudinally. Computerized error checks, physician review of submitted data, and on-site audits of participating centers ensure data quality.
Inclusion Criteria
End Points
Statistical Methods Multivariate models were built using a stepwise forward selection with a significance level of .05. The primary objective of this study was to compare outcomes after PBSC and BM transplantation; therefore, the variable for graft type was held in the model at each step. Other variables considered were recipient age, performance score, status with respect to cytomegalovirus (determined by serologic testing), type of leukemia and disease status at transplantation, sex of the recipient and donor, year of transplantation, conditioning regimen, type of prophylaxis against GVHD, and use or nonuse of growth factor within the first 7 days of allograft infusion to hasten neutrophil recovery. Whenever categories of variables initially classified into more than two categories showed no statistically significant differences between categories, categories were collapsed to create the fewest possible number of groups (such as age: 8 to 16 years v 17 to 20 years). Variables were tested using a time-varying covariate method to determine whether the proportional hazards assumption was met. All variables met the proportional hazards assumption. First-order interactions between graft type and each variable of interest were examined by fitting a proportional hazards model, and examining the interaction between the variable of interest and graft type. All multivariate models were examined for center effects using a random effects or frailty model.20 Completeness of follow-up was assessed using the c statistic, which gives a measure of the proportion of all potential follow-up information available for this study.21 All P values are two-sided. All analyses were done using PROC PHREG in SAS version 8.0 (SAS Institute, Cary, NC).
Patient and Transplant Characteristics Patient-, disease-, and transplant characteristics are presented in Table 1. All aspects of the transplant regimen, including graft type, were at the discretion of the transplant center. Median follow-up of survivors was 57 months (range, 4 to 92 months) and 40 months (range, 6 to 82 months) after BM and PBSC transplantation, respectively. Completeness of follow-up was 91% and 94% after BM and PBSC transplantation, respectively.21 Groups were similar in terms of patient sex, performance score, disease, French-American-British subtypes in AML and immunophenotype in ALL, cytogenetics, conditioning regimen, GVHD prophylaxis, cytomegalovirus serology, and donor-recipient sex match. Groups differed in distribution of age, disease status at transplantation, use of growth factor, total nucleated cell dose, and year of transplantation (PBSC recipients were older and more likely to have advanced leukemia [be in second CR or not in CR at transplant], more likely to receive growth factors and higher cell doses, and have undergone transplantation more recently).
Donor Characteristics PBSC donors tended to be older than BM donors (Table 1). Donor age was highly correlated with recipient age in both groups (P < .0001). Data on method of PBSC collection were available for 108 donors. Of these, 19% required placement of a central venous catheter. No collection-related complications were reported in 137 assessable PBSC donors. BM grafts were collected using standard techniques. There were four reported complications among BM donors: hypotension, nausea, vomiting, allergic reaction, and pyelonephritis, as reported verbatim on IBMTR report forms.
Hematologic Recovery
Acute and Chronic GVHD Cumulative incidences of chronic GVHD at 3 years were 33% (95% CI, 24% to 42%) and 19% (95% CI, 16% to 22%) after PBSC and BM transplantation, respectively (P = .001; Fig 1). In a multivariate analysis, chronic GVHD was significantly higher after PBSC transplantation (RR, 1.84; 95% CI, 1.28 to 2.64; P = .001). Other factors significantly associated with chronic GVHD in both groups were age older than 16 years (RR, 1.66; 95% CI, 1.21 to 2.29; P = .002) and donor-recipient sex match other than female donor and male recipient (RR, 0.61; 95% CI, 0.44 to 0.84; P = .003). Among patients with chronic GVHD, grade and organ involvement were similar after PBSC and BM transplantation (Table 2).
Treatment-Related Mortality Cumulative incidences of treatment-related mortality at 3 years were 26% (95% CI, 19% to 34%) and 14% (95% CI, 11% to 17%) after PBSC and BM transplantation, respectively (P = .001; Fig 2). Treatment-related mortality was higher after PBSC transplantation (Table 3). The use of growth factor was significantly associated with higher treatment-related mortality after both PBSC and BM transplantation.
Relapse Cumulative incidences of relapse at 3 years were 38% (95% CI, 29% to 47%) and 33% (95% CI, 29% to 37%) after PBSC and BM transplantation, respectively (P = .70). Risks of relapse were similar in both groups (Table 3). Advanced disease at transplantation and use of growth factor were significantly associated with an increased risk of relapse after both PBSC and BM transplantation. We observed a trend toward a protective effect of chronic GVHD in preventing relapse after both PBSC and BM transplantation (RR, 0.69; 95% CI, 0.47 to 1.02; P = .06).
Leukemia-Free Survival
Overall Survival Mortality was higher after PBSC than BM transplantation (Table 3). Advanced disease and use of growth factor were significantly associated with higher mortality after both PBSC and BM transplantation. Three-year probabilities of overall survival, adjusted for other significant factors, were 48% (95% CI, 40% to 56%) and 58% (95% CI, 54% to 62%) after PBSC and BM transplantation, respectively (P = .01; Fig 4).
Eighty-two (57%) of 143 recipients of PBSC transplants and 277 (44%) of 630 recipients of BM transplants died (Table 4). Recurrent disease was the most frequently reported primary cause of death in both groups. The only significant difference in causes of mortality between PBSC and BM recipients was in the proportion of deaths related to GVHD occurring more than 100 days post-transplantation—20% in the PBSC group and 5% in the BM group (P = .0007,  2 test).
Several studies, including randomized clinical trials comparing PBSC versus BM transplantation in adults, report lower early mortality, higher chronic GVHD risk, and a survival benefit in some populations. Though there are no such studies reported in children, PBSC allografts are frequently used instead of BM for pediatric transplantation. The primary objective of this study was to compare outcomes after transplantation using PBSC and BM allografts in children and adolescents with acute leukemia. There were differences in PBSC and BM recipients that might be expected to confound outcomes after transplantation, such as age, type of leukemia, disease status at transplantation, and use of growth factor. We used multivariate Cox regression models to adjust for the independent effects of each potential risk factor. After this adjustment, we found higher chronic GVHD, treatment-related mortality, treatment failure, and overall mortality after PBSC transplantation. PBSC offer more rapid hematopoeitic recovery in children, similar to reports in adults.4-10 We also observed similar risks of acute GVHD after PBSC and BM transplantations, which was again, comparable to most reports in adults.4-7,9,10 As observed in some studies of adults,4,6,8,10 chronic GVHD was significantly higher after PBSC transplantation, probably due to higher numbers of T cells in mobilized peripheral blood.22,23 However, among patients who developed chronic GVHD, grade and organ involvement were comparable in the two groups, consistent with reports in adults.4,7,24 Importantly, we observed an adverse effect of PBSC grafts on treatment-related mortality, treatment failure, and overall mortality after adjusting for other significant risk factors that may influence outcome. This has not been reported previously. Published reports in adults with acute leukemia suggest equivalent survival after PBSC and BM transplants.4,8,10,25 Higher mortality in children receiving PBSC grafts is likely due to higher chronic GVHD. Chronic GVHD after BM transplantation is lower in children than in adults. Thus in younger PBSC recipients, a higher risk of mortality from chronic GVHD may offset any measurable benefits of more rapid hematopoietic recovery in the early transplantation period. Higher mortality and treatment failure after PBSC transplantations were independent of age. To address whether the higher proportion of children (aged 17 to 20 years) in the PBSC group affected outcomes, we first examined the effect of age within each graft type and observed no differences in risks of treatment-related mortality, treatment failure, and overall mortality between children aged 8 to 16 years and 17 to 20 years. In multivariate analysis, risks of each of these outcomes after PBSC and BM transplantation were similar in recipients aged 8 to 16 years and 17 to 20 years (ie, the PBSC/age 8 to 16 years v BM 8 to 16 years, and the PBSC age 17 to 20 years v BM/age 17 to 20 years. Formal tests for interaction revealed no significant interactions between graft type and age at transplantation. Risks of relapse were similar after PBSC and BM transplantation. Thus far, previous studies in adults including randomized clinical trials, also report similar risks of relapse after PBSC and BM transplantations.4-6,8,10,24 The observed trend toward a protective effect of chronic GVHD in preventing relapse did not differ by graft type. Our study is limited to patients with acute leukemia, whereas reports that have suggested a stronger graft-versus-leukemia effect after PBSC transplantations have included patients with acute and chronic leukemia.5,9 Disease status at transplantation adversely affected leukemia recurrence, treatment failure, and overall mortality, regardless of the type of graft. Though a higher proportion of patients with ALL underwent transplantation in second CR, this was independent of graft type. In contrast, most patients with AML were transplanted in first CR but were more likely to receive PBSC grafts if they were not in CR at transplantation. We did not observe an association between transplant outcomes and disease type. Use of growth factor for neutrophil recovery had an adverse effect on relapse and mortality after PBSC and BM transplantations. Studies in animals and human volunteers have shown decreased production of inflammatory cytokines,26 increased production of interleukin-10,27 increased mobilization of T-helper-2 (Th2)–inducing dendritic cells28 and Th2 immune deviation29 with G-CSF. In recipients of mismatched T-cell–depleted transplantations, the elimination of G-CSF for hematopoietic recovery has been shown to accelerate immune recovery.30 It is possible that the use of growth factor may have resulted in slower immune recovery and subsequent higher mortality. We were unable to explain the adverse effect of growth factor on leukemia recurrence. Thus far, larger studies specifically examining the effect of growth factor use in the early post-transplantation period, report mixed results, and although growth factors activate AML cells, most reports support the contention that leukemia growth is not promoted in a clinically meaningful way.31-34 A detailed analysis of the effects of growth factor on leukemia recurrence or mortality is beyond the scope of this study. We did not perform analysis of total nucleated cell dose or CD34 cell dose, as these were surrogates for graft type. PBSC recipients received higher cell doses: 65% received total nucleated cell doses greater than 5 x 108/kg compared with 10% of BM recipients. Nevertheless, most BM recipients received an adequate cell dose and achieved hematopoietic recovery, and this may have minimized any potential benefit of PBSC grafts. We could not analyze the independent effect of donor age as this was highly correlated with recipient age in both groups. We found no evidence of confounding of main effects (transplant outcome by graft type) by center effects using a random effects model, a test specially designed for situations like the current analysis in which each center contributes relatively few cases.20 To address this further, we adjusted for the number of transplantations performed per center (1 to 5 v 6 to 10 v > 10) and geographic location (United States v Europe v other regions) in final multivariate models and found no evidence of confounding of main effects. Treatment-related mortality, treatment failure, and overall mortality were higher after PBSC transplantation after adjustment for other relevant risk factors that may influence these end points. A retrospective analysis has limitations such as selection bias for graft type and inability to adjust for unknown or unmeasured factors. These data represent the early experience of PBSC transplantation; nevertheless, these data should serve a cautionary note before widespread change in the clinical practice of using BM for allogeneic transplantation in children. Alternative graft sources must be evaluated in a controlled fashion before adoption in a population that already has a relatively good outcome after BM transplantation. We think that there is an urgent need for a properly designed clinical trial to define the role of PBSC in allogeneic transplantation in children.
In addition to the authors, other members of the International Bone Marrow Transplant Registry Working Committee on Histocompatibility and Alternate Stem Cell Sources who participated in the study are as follows: M.M. Abecasis, Instituto Portugues de Oncologica, Lisbon, Portugal; B.J. Bowell, Cleveland Clinic Foundation, Cleveland, OH; K.W. Chan, M.D. Anderson Cancer Center, Houston, TX; J. Davis, British Columbia Children's Hospital, Vancouver, BC, Canada; M.A. Diaz, Hospital Nino Jesus, Madrid, Spain; J.J. Doyle, Hospital for Sick Children, Toronto, ON, Canada; M. Gorner, University of Heidelberg, Heidelberg, Germany; G.A. Hale, St Jude Children's Research Hospital, Memphis, TN; R.E. Harris, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; M. Kletzel, Children's Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL; C.F. LeMaistre, Texas Transplant Institute, San Antonio, TX; D.I. Marks, University of Bristol, Bristol, UK; J.A. Martinez, La Fe University Hospital, Valencia, Spain; R. Maziarz, Oregon Health Sciences University, Portland, OR; S.R. McCann, St James's Hospital, Dublin, Ireland; R.S. Negrin, Stanford University Medical Center, Stanford, CA; and J.J. Ortega, Hospital Infantil Vall d'Hebron, Barcelona, Spain.
The authors indicated no potential conflicts of interest.
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 (M.E.). Presented in part at the Annual Meeting of the American Society of Hematology, Philadelphia, PA, December 6-10, 2002. Permission to publish: The Human Research Review Committee (HRRC) of the Medical College of Wisconsin, Milwaukee, U.S.A, has approve these data for analysis and publication (HRRC# 056-87). Authors' disclosures of potential conflicts of interest are found at the end of this article.
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31. Przepiorka D, Smith TL, Folloder J, et al: Controlled trial of filgrastim for acceleration of neutrophil recovery after allogeneic blood stem cell transplantationfrom human leukocyte antigen-matched related donors. Blood 97:3405-3410, 2001
32. Lowenberg B, van Wim P, Theobald M, et al: Effect of priming with granulocyte colony-stimulating factor on the outcomes of chemotherapy for acute myeloid leukemia. N Engl J Med 349:743-752, 2003
33. Appelbaum FR: Use of granulocyte colony-stimulating factor following hematopoietic stem cell transplantation: Does haste make waste? J Clin Oncol 22:390-391, 2004
34. Ringden O, Labopin M, Gorin N-C, et al: Treatment with granulocyte colony-stimulating factor after allogeneic bone marrow transplantation for acute leukemia increases the risks of graft-versus-host disease and death: A study from the acute leukemia working party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 22:416-423, 2004 Submitted February 26, 2004; accepted July 23, 2004. Related Editorial
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ABSTRACT
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500/µL for 3 consecutive days, and platelet recovery 
