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Originally published as JCO Early Release 10.1200/JCO.2004.09.958 on November 1 2004 © 2004 American Society of Clinical Oncology.
Allogeneic Peripheral Blood Versus Bone Marrow Transplantation: Children Are Small Adults and MoreTexas Transplant Institute, San Antonio, TX This issue of the Journal of Clinical Oncology reports the controversial findings of the International Bone Marrow Transplant Registry retrospective review comparing allogeneic stem-cell sources—bone marrow (BM) versus granulocyte colony-stimulating factor (G-CSF) –mobilized peripheral-blood stem cells (PBSC)—in children and adolescents.1 In their review of 143 PBSC and 630 BM human leukocyte antigen–identical sibling donor transplants in children with leukemia aged 8 to 20 years, Eapen et al found a higher rate of chronic graft-versus-host disease (GVHD) and treatment-related mortality (with similar relapse risk) in children receiving PBSC compared with BM. Overall, there was poorer survival when PBSC were used as the donor source, even after adjusting for relative risks. This is an unsettling finding, given that in 2003, close to 30% of pediatric matched sibling transplants reported to the International Bone Marrow Transplant Registry used PBSC as the donor source. The shift in clinical practice from using BM to G-CSF–mobilized PBSC as the hematopoietic progenitor cell source has arguably been among the most rapid and sweeping changes in clinical hematopoietic allogeneic transplantation this decade, second only to changes in the management of chronic myelogenous leukemia after the introduction of imatinib. Since it is common practice in pediatrics to extrapolate from adult therapy, the transition has occurred in both pediatrics and adult transplantation. In general, this is a reasonable approach, especially if there are no clear developmental or physiologic reasons to expect differences in efficacy or toxicity between children and adults. The biologic differences between the two stem-cell products include differences in both intermediate hematopoietic progenitors and T cells.2 In multiple animal and human trials, there has consistently been a strong correlation between the number of T cells in the transplanted graft and development of GVHD. The 10-fold increase in T cells in a PBSC graft initially made allogeneic transplant physicians hesitant to use PBSC as a stem-cell product, but experience has shown that PBSC can be safely used as an allogeneic stem-cell source. In the process of mobilization, the T cells have been exposed to G-CSF, which is known to modify T-cell responses in the direction of the T-helper-2 response, potentially explaining the tolerable GVHD observed. Early, predominately adult, experience with PBSC, frequently in patients with advanced malignancies, demonstrated more rapid count recovery and less early transplant-related mortality (TRM), which translated into improved survival. As reviewed in the article by Eapen et al, subsequent results of randomized trials have been mixed. The overall conclusion is that PBSC transplantation outcomes are at least equivalent to, if not better than, BM as an allogeneic stem-cell source.3,4 Hence, there has been a rapid transition in clinical practice to the use of G-CSF–mobilized PBSC as the allogeneic donor source, with the rationale that more rapid postcollection recovery of the donor and more rapid post-transplantation recovery of hematopoiesis (with resultant shortening of hospital stay and decreased early transplant-related mortality in patients, especially those with advanced disease or poor performance status at the time of transplantation) were all important outcome goals, even if survivals was equivalent. The transition of clinical practice to use of G-CSF–mobilized PBSC has been slower in pediatrics, partially due to concerns of donor safety since donors are often minors. With increased experience in young child apheresis, there has been a growing acceptance that even young children can safely receive G-CSF and undergo apheresis, as recently reviewed by the Pediatric Blood and Marrow Transplant Consortium.5 It is important to appreciate that this report captures the early experience in pediatrics with the use of PBSC in the allogeneic setting. This series has a high representation of patients for whom physicians performing transplantation felt that the benefits of more rapid engraftment would outweigh the possible risk of GVHD. Some of these factors, such as disease state at time of transplantation, are captured and controlled for in this analysis. However, other risk features are more difficult to define in retrospective surveys, such as prior serious infections, donor recipient size discrepancy, or more aggressive leukemia (all second remission patients with acute lymphocytic leukemia are not alike). The concept that infusing a greater number of T cells would enhance the graft-versus-leukemia effect of the graft is frequently the verbalized reason for using PBSC in children. That such factors are influencing the data set in this retrospective study is supported by the fact that a higher percentage (22%) of the PBSC cohort were in relapse or primary induction failure at the time of transplantation. It will be important to repeat this analysis in the current practice setting, where many centers have transitioned to exclusive use of PBSC for all their allogeneic transplants, which will remove that selection bias. This question is currently being prospectively addressed in the Blood and Marrow Transplant Clinical Trials Network trial comparing PBSC with BM as the source of stem cells in the unrelated-donor setting. It is critical that a similar trial comparing these procedures in children with human leukocyte antigen–matched sibling donors (controlling for disease [leukemia, nonmalignant disorders] and disease state at time of transplant) also be performed before PBSC is considered the standard of care in pediatric matched sibling donor allogeneic transplantation. To date, there is only a limited set of pediatric data; based on the retrospective review by Eapen et al, the benefit of PBSC is in question. Assuming that the unbalanced assignment of stem-cell source had a relatively minor impact in this study, why was there inferior survival in children with PBSC as the donor source? The answer is likely two-fold, and attributable in large part to children being smaller and younger. When BM is used as the donor source, the donor, who is likely close in age, will also be young and tend to have a rich harvest. This translates into children routinely receive 3 x 107 to 5 x 107 cells/kg in the marrow inoculum, which is the equivalent of "rich bone marrow" reported as being the ideal stem-cell source by Gorin et al.6 Thus, a better BM product is being used compared with those used in adult transplant series. Secondly, the T-cell number infused in the PBSC has not been carefully followed and can be much higher in pediatric apheresis products; this may be a setting where more T cells are not better. More research is needed into the optimal T cell dose for PBSC transplants. Additionally, children are better able to tolerate the organ toxicity of myeloablative regimens and prolonged periods of neutropenia. Thus, a maneuver that reduces the period of neutropenia by a few days is likely to have a lesser impact on survival than in adults. With early time points being less influential on outcome, the impact of chronic GVHD becomes more important. Since PBSC transplants are associated with higher rates of chronic GVHD, it likely that GVHD is a major contributor to the inferior survival in this review. Thus, it very well may be that PBSC do not offer a benefit over BM in pediatrics. It is critical that this question be carefully studied by prospectively identifying the patients, diseases, and clinical settings in which clinical benefit is likely to be observed. Currently, patients and families need to be informed about the risks of increased transplant-related morbidity, including chronic GVHD and the equivalent risk of relapse when PBSC are used as the donor source. A secondary observation in the article is that the negative impact of early post-transplantation G-CSF administration on transplant outcome and has recently been reported in this journal.7 Patients who received G-CSF during the first 2 weeks post-transplantation to stimulate early neutrophil recovery had inferior outcome, regardless of stem-cell source. Again, this is another clinical practice that became established with limited prospective comparison trials and needs to be explored further. We are brought back to the importance of the T cell in the allogeneic graft—too many, too few, too skewed, too tolerant... Author’s Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES
1. Eapen M, Horowitz MM, Klein JP, et al: 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 Registry. J Clin Oncol 22:4872-4880, 2004 2. Favre G, Beksac M, Bacigalupo A, et al: Differences between graft product and donor side effects following bone marrow or stem cell donation. Bone Marrow Transplant 32:873-880, 2003[CrossRef][Medline]
3. Schmitz N, Beksac M, Hasenclever D, et al: Transplantation of mobilized peripheral blood cells to HLA-identical siblings with standard-risk leukemia. Blood 100:761-767, 2002
4. Couban S, Simpson DR, Barnett MJ, et al: A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies. Blood 100:1525-1531, 2002 5. Pulsipher M, Levine JE, Hayashi R, et al: Safety and efficacy of allogeneic PBSC collection in normal pediatric donors: The Pediatric Blood and Marrow Transplant Consortium Experience (PBMTC) 1996-2003. Bone Marrow Transplant (in press)
6. Gorin NC, Labopin M, Rocha V, et al: Marrow versus peripheral blood for geno-identical allogeneic stem cell transplantation in acute myelocytic leukemia: Influence of dose and stem cell source shows better outcome with rich marrow. Blood 102:3043-3051, 2003
7. Ringden O, Labopin M, Gorin NC, et al: Treatment with granulocyte colony-stimulating factor after allogeneic bone marrow transplantation for acute leukemia increases the risk 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 Related Article
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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