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© 2002 American Society for Clinical Oncology Transplantation of Peripheral Blood Stem Cells as Compared With Bone Marrow From HLA-Identical Siblings in Adult Patients With Acute Myeloid Leukemia and Acute Lymphoblastic LeukemiaByFrom the Centre for Allogeneic Stem Cell Transplantation, Huddinge, Sweden; Centre International Greffes de Moelle, Hôpital Saint-Antoine, European Group for Blood and Marrow Transplantation Data Centre, Institut des Cordeliers, and Department of Hematology, Hôpital Saint-Louis, Paris, France; Bone Marrow Transplant Unit, Ospedale San Martino, Genova, and Institute of Hematology, University La Sapienza, Rome, Italy; Department of Bone Marrow Transplantation, University Hospital, Essen, and Department of Transfusion, University Ulm, Ulm, Germany; Bone Marrow Transplantation Center, Leiden, and Bone Marrow Transplantation Unit, Department of Hematology, Nijmegen, the Netherlands; and Department of Hematology, Ankara University, Ankara, Turkey. Address reprint requests to Olle Ringdén, MD, PhD, Centre for Allogeneic Stem Cell Transplantation, Huddinge University Hospital, F79, SE-141 86 Stockholm, Sweden; email: Olle.Ringden{at}impi.ki.se
PURPOSE: Several studies show that allogeneic peripheral blood stem cells (PBSCs) engraft more rapidly than bone marrow (BM). However, the data are inconsistent with regard to acute and chronic graft-versus-host disease (GVHD), relapse, transplant-related mortality (TRM), and leukemia-free survival (LFS). PATIENTS AND METHODS: Between January 1994 and December 2000, 3,465 adult patients (older than 15 years of age) were reported to the European Group for Blood and Marrow Transplantation Registry from 224 centers. Among acute myeloid leukemia (AML) patients, 1,537 patients received BM and 757 patients received PBSC. In acute lymphoblastic leukemia (ALL) patients, the corresponding figures were 826 versus 345 patients who were analyzed for engraftment, GVHD, TRM, relapse, LFS, and survival. RESULTS: In multivariate analysis, the recovery of neutrophils and platelets was faster with PBSC than with BM (P < .0001). Chronic GVHD was associated with PBSC in patients with AML (relative risk [RR], 2.11; 95% confidence interval, 1.66 to 2.7; P < .0001) and ALL (RR, 1.56; 95% confidence interval, 1.09 to 2.27; P = .02). PBSC versus BM in patients with AML or ALL was not significantly associated with acute GVHD, TRM, relapse, survival, or LFS. In multivariate analysis of patients with AML, factors significantly associated with improved LFS included first remission at transplant (P < .0001), promyelocytic leukemia (M3) versus other French-American-British types (P < .0001), and donor age below median 37 years (P = .02). In patients with ALL, first remission (P < .0001) and methotrexate included in the immunosuppressive regimen (P = .001) were associated with improved LFS. CONCLUSION: Allogeneic PBSC results in faster neutrophil and platelet engraftment and a higher incidence of chronic GVHD than BM. However, acute GVHD, TRM, relapse, survival, and LFS were similar in patients receiving PBSCs versus BM.
MOST STUDIES THAT compare allogeneic peripheral blood stem cells (PBSC) with bone marrow (BM) as the source of stem cells for allogeneic stem cell transplantation (HSCT) have shown that PBSC results in faster engraftment of the absolute neutrophil count (ANC) and platelets.1-10 The reason for this may be the several-fold higher content of nucleated cells and CD34 cells in PBSC than in BM. Only one randomized study failed to show faster neutrophil and platelet engraftment.11 This may have been a result of the small number of patients because, with a longer follow-up, engraftment was faster with PBSC.12 However, in acute and chronic graft-versus-host disease (GVHD), relapse incidence, and leukemia-free survival (LFS), the role of PBSC versus BM remains debatable. One randomized study and a meta-analysis showed that PBSC was associated with an increased risk of acute GVHD,12,13 and other studies have found that PBSC was associated with an increased risk of chronic GVHD.5,7,8,14,15 Three studies showed that relapse incidence was reduced in patients receiving PBSC, compared with BM.5,9,16 A recent randomized study reported that disease-free survival was significantly better in patients with advanced disease who received PBSC than in patients who received BM.10 To shed some light on these inconsistent findings in patients with acute leukemia, we undertook this retrospective comparison of PBSC and BM as a source of stem cells in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) who were reported to the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT).
Patient Population All patients with AML and ALL undergoing HSCT from HLA-identical siblings between January 1, 1994, and January 31, 2001, were included in the study. Patient characteristics are given in Table 1. Patients receiving PBSC had a shorter follow-up and higher patient and donor age than those receiving BM. In addition, many patients receiving PBSC also had more advanced disease, had been given T-cell depleted grafts more often, and had received methotrexate and total-body irradiation (TBI) less frequently than patients receiving BM (Table 1). Nucleated cell dose and number of CD34 cells were significantly higher in the PBSC grafts than with BM (P < .0001). Sex, sex match, cytomegalovirus (CMV) status in recipients and donors, and French-American-British (FAB) classification in AML patients showed a similar distribution in patients receiving PBSC or BM. The reporting of data to EBMT from the various centers for retrospective studies was approved by the respective local ethics committees.
Statistical Analysis All analyses were done with the SPSS computer program (SPSS, Inc, Chicago, IL). Values reported for quantitative variables were median and range. The following patient or graft characteristics were analyzed for their prognostic value on each of the outcomes: patient and donor characteristics (age, sex and sex matching, and CMV serology), FAB classification for AML and transplant-related factors (status at transplant and complete remission [CR] 1 v CR2 v more advanced disease), conditioning regimen, GVHD prevention, year of transplant, and center used. For these prognostic analyses, continuous variables were categorized according to the median. To compare the two subgroups of patients receiving PBSC or BM, we used the  2 test for categorical variables and the nonparametric Mann-Whitney U test for continuous variables. To analyze the center effect, we used a variable with 33 classes (one class for each transplant center that reported at least 30 patients [n = 32] and one class for the other centers). Patients surviving without relapse for more than 100 days after transplant, with sustained donor engraftment, were considered assessable for chronic GVHD.17 Patients were censored at the time of relapse or at last follow-up.18 Probability of acute and chronic GVHD, hematopoietic recovery, transplant-related mortality (TRM), relapse, LFS, and overall survival were estimated by the product-limit method.18 The significance of differences between curves was estimated by the log-rank test (Mantel-Cox).19 All variables with different distributions in PBSC and BM, and all variables associated with outcome having a P value less than 0.2 in univariate analyses, were included in a multivariate analysis. In patients with AML and ALL, factors that differed in distribution were patient and donor age, status at transplant, use of T-cell depletion, use of methotrexate, conditioning regimen, and year of transplantation. The following variables were also entered in the multivariate analysis: in the case of hematopoietic recovery, patient and donor sex, female donor to male recipient (both for AML and ALL), plus patient CMV serology and M3 classification for AML; for acute GVHD in AML, patient and donor sex and female donor to male recipient; for chronic GVHD in AML, patient and donor sex and female donor to male recipient; in ALL, the same variables plus patient CMV serology; for relapse, LFS, TRM, and survival; in AML, patient and donor sex, female donor to male recipient, and M3 classification; and in ALL, patient sex, female donor to male recipient, and patient CMV serology. A backward stepwise procedure was then used to select covariates (P to enter < .10 and P to remove < .15) included in the final Cox proportional hazard model.20 All final multivariate analyses included the source of stem cells and the center used. Patient weight, CMV status of donor, and the use of cytokines after transplant could not be evaluated because more than 40% of the values were missing.
Use of PBSC According to Center Size The percentage of PBSC, according to the total number of patients, increased from less than 10% in 1994 to 40% in 1998, with a similar trend in small, intermediate, and large centers. In 2000, 40% of the patients in large centers were given PBSC, compared with 70% of patients in small and intermediate centers (Fig 1).
Hematopoietic Engraftment Engraftment occurred in 710 (95%) of the PBSC patients and in 1,432 (96%) of the BM patients with AML. In patients with ALL, engraftment occurred in 320 (95%) of the PBSC recipients and in 767 (95%) of the BM recipients. In patients with AML and ALL, time to reach an ANC > 0.5 x 109/L and platelets > 50 x 109/L was significantly faster in PBSC patients than in BM patients (P < .0001) (Table 2). In the multivariate analysis, PBSC was significantly associated with a faster engraftment for ANC and platelets in patients with AML or ALL than was BM (Table 3). Other significant factors that affected ANC were remission status at transplant, year of transplant, center used, and female donor to male recipient for AML; and center used, remission status at transplant, and methotrexate for ALL. For platelet engraftment, CR versus advanced disease, T-cell depletion, year of transplant, and center used were significant in AML, and center used was significant in ALL.
GVHD In AML patients, we found a higher incidence of acute GVHD (grade 1 to grade 4) in the univariate analysis (59% ± 1% of those receiving BM versus 49% ± 2% of those receiving PBSC [P = .0001]) and grade 2 to grade 4 acute GVHD (41% ± 2% with BM v 32% ± 2% using PBSC, P = .002; Table 2). In the multivariate analysis, we found no significant difference between PBSC versus BM in the AML and ALL patients (Table 4). Factors significantly associated with acute GVHD in AML patients included female donor, transplantation before 1997, T-cell replete graft, conditioning without TBI, and center used.
In the ALL patients, advanced disease versus CR and center used were significantly associated with acute GVHD in the multivariate analysis. Chronic GVHD was significantly more common in AML and ALL patients receiving PBSC versus BM (P < .0001 and P = .008, respectively; Table 2; Fig 2A and 2B). In the multivariate analysis, in patients with AML, chronic GVHD was associated with PBSC, non-T-cell depletion, female donor, and center used (Table 4). In patients with ALL, PBSC, non-T-cell depletion, use of methotrexate, female donor, and center used were risk factors significantly associated with chronic GVHD (Table 4).
TRM, Relapse, LFS, and Survival Rate When the source of stem cells was compared in AML and ALL patients in different stages of the disease at transplantation, we found no major differences in the various outcome parameters (Table 5) . In patients with AML in CR2, the risk of relapse was lower in those receiving PBSC than in those receiving BM (P = .05). In patients with ALL in CR1, PBSC patients had a higher risk of relapse (P = .02). When the whole population was analyzed together, the PBSC patients had a higher risk of relapse and a lower LFS.
In the multivariate analysis, PBSC, compared with BM, did not have a significant effect on TRM, relapse, LFS, or survival in patients with AML or ALL (Table 6). LFS of patients in CR1, or in patients with more advanced stages who were treated with PBSC or BM, is shown in AML patients in Fig 3 and in ALL patients in Fig 4. The most important factor for TRM, relapse, LFS, and survival in the multivariate analysis was remission status at transplant (Table 6). Other significant factors in AML patients included FAB M3 for relapse; LFS and survival; and donor age for TRM, LFS, and survival. Use of methotrexate was also associated with an increase in TRM, and female donor to male recipient and center used were associated with a reduced risk of relapse in the AML patients. In ALL patients, high recipient age was associated with an increase in TRM, and females had an increase in relapse. The use of methotrexate for immunosuppression was associated with lowered relapse, improved LFS, and survival.
This retrospective study, which included more than 3,000 patients with acute leukemia, confirms previous studies that PBSC results in a faster engraftment of neutrophils and platelets than does BM. This is most probably because PBSC contains more CD34+ cells than does BM (Table 1). Most studies using HLA-identical sibling donors, or even unrelated donors, showed no difference in acute GVHD with PBSC, compared with BM.1-11,15 The present analysis confirms this. Contrary to this finding, a randomized EBMT study, which included 350 patients, showed an increased risk of acute GVHD using PBSC.12 This EBMT study differs from the other studies because only three doses of methotrexate (rather than four doses) were given after the transplant. Three doses of methotrexate increased the risk of acute GVHD.21 Furthermore, granulocyte colony-stimulating factor (G-CSF) was given after transplant. However, a meta-analysis also found an increased risk of acute GVHD using PBSC, compared to BM,13 but T-cell depletion was not evaluated. In the present study, patients who received PBSC were given T-cell depleted grafts more often than those who received BM (Table 1). However, a prospective randomized trial in adult leukemic patients showed that the occurrence of grade 2 to grade 4 acute GVHD was similar in patients who were given T-cell-depleted grafts and in those patients who received methotrexate combined with cyclosporine.22 Therefore, there is little, if any, risk of increasing acute GVHD by PBSC or BM. Some studies found that transplantation of PBSC was associated with an increase in the risk of chronic GVHD.5,7,8,13,15 However, other studies were unable to confirm this correlation.9-12,23 This study shows that PBSC plays a major role in chronic GVHD (Tables 2 and 4; Fig 2). This may be a result of the high cell dose. The addition of donor buffy-coat, for instance, increased the risk of chronic GVHD.24 Other factors associated with chronic GVHD included T-cell replete grafts, patient age, and female donor to male recipient, in accordance with previous studies.25,26 Chronic GVHD was also highly associated with a center effect. The combination of methotrexate and cyclosporine is an effective prophylaxis for acute and chronic GVHD.27,28 However, the duration of cyclosporine treatment used in different centers may affect the risk of developing chronic GVHD.29 A study in mice showed a lower relapse rate with PBSC than with BM.30 A few clinical reports have noted reduced relapse in patients given PBSC, compared to patients given BM.9,10,16,31 Two of these clinical reports were prospective and randomized,9,10 but one report included only 39 patients, and the other report had 172 patients. These studies included patients with various diagnoses (ie, not only leukemia, but also lymphomas, myelomas, and myelodysplastic syndromes). A study of chronic myeloid leukemia by Elmaagacli et al16 also found a reduced rate of relapse in patients treated with PBSC, compared with patients treated with BM. However, this study, of more than 3,000 patients, did not show that PBSC had a better antileukemic effect than BM in patients with AML and ALL. This may seem surprising because PBSC was associated with an increase in the risk of chronic GVHD, which has a profound antileukemic effect32–34 G-CSFs mainly induce type 2 helper T-cells to produce interleukin-4 and interleukin-10.35 One may speculate that these T-cells do not have a sufficient antileukemic effect, or that a longer time is needed before the higher risk of chronic GVHD, using PBSC, reduces the relapse incidence. Another reason for the difference in relapse incidence in the various studies may be the result of a difference in CD34 cell dose. On the basis of data from the International Bone Marrow Transplant Registry, a recent study showed that a PBSC dose > 6 x 106/kg was associated with a reduced incidence of relapse and improved LFS (Ringdén et al, manuscript submitted for publication). In a randomized study by Bensinger et al,10 a G-CSF dose of 16 µg/kg/d was used to mobilize PBSC in the donors. This is higher than the dose of 10 µg/kg/d that is used in most other studies. The median CD34 cell dose per kilogram in the PBSC group in the study by Bensinger et al was 7 x 106/kg, which is slightly higher than the doses in the AML and ALL patients (5.7 x 106/kg and 6 x 106/kg, respectively) in our study. A high cell dose could also explain the low relapse rate in the study by Elmaagacli et al.16 Elmaagacli et al used a G-CSF dose, which ranged from 10 to 16 µg/kg, to mobilize PBSC from their donors, and they achieved a median CD34 cell dose of 9.5 x 106/kg. The results of improved outcome for high-risk patients using PBSC versus BM in the randomized study by Bensinger et al10 differs from this study. As discussed above, reasons for this may be that different diagnoses were included and that a higher median CD34 cell dose was used. Chance is another possibility, because the study by Bensinger et al included 80 patients with advanced disease, whereas 1,231 patients were used in our retrospective study. Analysis of the CD34 cell dose was not performed in this study because the CD34 cell dose is completely dependent on the source of stem cells. Furthermore, there were many missing values, which may bias such an analysis. A high CD34 cell dose was independently associated with a faster engraftment of ANC and platelets. However, this variable did not change the general message (ie, comparison of PBSC v BM). Furthermore, the sources of stem cells not only differ with regard to CD34 cell dose, but the PBSC graft contains 10 times more T cells, NK cells, and overall nucleated cells. BM may also contain mesenchymal stem cells, whereas PBSC does not. Among other things, mesenchymal stem cells may enhance engraftment and modulate alloreactivity (eg, GVHD). Because of the differences in composition, it is relevant to compare PBSC with BM. With regard to TRM, LFS, and survival, PBSC, compared with BM, had no effect in patients with AML or ALL (Table 6). This is consistent with what has been found in most other studies, with a few exceptions.4-16 Other factors, such as remission status at transplant, AML FAB M3, and recipient and donor age, were of importance for several of the outcome parameters, in accordance with previous experience.36-38 Because of the faster engraftment and the anticancer effect of chronic GVHD, PBSC is recommended in patients with acute leukemia and other malignancies. However, for nonmalignant disorders, BM should probably be used because these patients do not benefit from chronic GVHD.
Supported by European Group for Blood and Marrow Transplantation funds, convention 6113 from the Association pour la Recherche contre le Cancer, Villejuif, France, and grant BMH1-CT-94–0300 from the European Community. O. Ringdén was supported by grants from the Swedish Cancer Society (0070-B99-13XAC), the Children’s Cancer Foundation (1997/073), the Swedish Medical Research Council (K2000-06X-05971-20A), the Cancer Society in Stockholm, the Tobias Foundation, the Fonden för Rehabilitering och Medicinsk Forskning, and Karolinska Institutet. We are indebted to the following European Group for Blood and Marrow Transplantation physicians and teams for submitting patient data: Bacigalupo, Genova; Mandelli, Rome; Schaefer, Essen; Willemze, Leiden; Koc, Ankara; Kubanek, Ulm; Gluckman, Paris; Schattenberg, Nijmegen; Cordonnier, Creteil; Jouet, Lille; Ruutu, Helsinki; Reiffers, Pessac; Alessandrino, Pavia; Fischer, Paris; Tura, Bologna; Holowiecki, Katowice; Attal, Toulouse; Blaise, Marseille; Bartolomeo, Pescara; Harousseau, Nantes; Ljungman, Stockholm; Michallet, Lyon; Falda, Torino; Cahn, Besancon; Finke, Freiburg; Gratwohl, Basel; Rio, Paris; Bosi, Firenze; Scimé, Palermo; McCann, Dublin; Iriondo, Santander; De Souza, Campinas; Cornelissen, Rotterdam; Chapius, Geneva; Harhalakis, Athens; Koza, Pilsen; Goldstone, London; Zander, Hamburg; Leblond, Paris; Lambertenghi, Milano; Marcus, Cambridge; Boogaerts, Leuven; Fassas, Exokhi; Fauser, Idar-Oberstein; Schwarer, Melbourne; Hansz, Poznan; Kalayoglu-Besi, Istanbul; Ferrant, Brussels; Sanz, Valencia; Bourhis, Villejuif; Franklin, Glasgow; Sierra, Barcelona; Rodeghiero, Vicenza, and Brinch, Oslo; Iacopino, Reggio; Schots, Brussels; Sotto, Grenoble; Ehninger, Dresden; Leone, Rome; Boasson, Angers; Arnold, Berlin; Schouten, Maastricht; Craddock, Birmingham; Montserrat, Barcelona; Barbui, Bergamo; Hellmann, Gdansk; Littlewood, Oxford; Abecasis, Lisboa; Rodriguez Fern, Sevilla; Jacobs, Cape Town; Beelen, Homburg; Torrez Gomez, Córdoba; Simonsson, Uppsala; Gratecos, Nice; Juliá, Barcelona; Benedetti, Verona; Rotoli, Naples; Kanz, Tübingen; de Revel, Clamart; Fanin, Udine; Russell, Nottingham; Mufti, London; Remes, Turku; Rowe, Haifa; Wandt, Nürnberg; Noens, Gent; Prentice, London; Guilhot, Poitiers; Garcia-Conde, Valencia; Schwerdtfeger, Wiesbaden; Yalçin, Ankara; Caballero, Salamanca; Grañena, Barcelona; Gorin, Paris; Mistrik, Bratislava; Schey, London; Ferhanoglu, Istanbul; Alabdulaaly, Riyadh; Davies, Edinburgh; Pretnar, Ljubljana; Bayik, Istanbul; Rossi, Montpellier; Schanz, Zurich; Newland, London; Macchia, Pisa; Majolino, Rome; Lange, Wroclaw; Posliani, Monza; Ghavamzadeh, Teheran; Hamladi, Alger; Kolbe, Mainz; Slavin, Jerusalem; Bay, Clermont; Morra, Milan; Brune, Gothenburg; Wahlin, Umeå; Amadori, Rome; Jacobsen, Copenhagen; Bron, Brussels; Verdonck, Utrecht; Clark, Liverpool; Paloczi, Budapest; Ossenkoppele, Amsterdam; Zinti, Jena; Martelli, Perugia; Greinix, Vienna; Hertenstein, Hanover; Niederwieser, Leipzig; Maldonado Eloy, Málaga; Freund, Rostock; Carrera Fernán, Oviedo; Duncombe, Southampton; Hunter, Leicester; Fernández, Madrid; Morandi, Cremona; Locatelli, Pavia; Lutz, Linz; Vitek, Prague; Jebavy, Hradec Krá; Vandenberghe, Sheffield; Milligan, Birmingham; Pimentel, Porto; Mazza, Taranto; Kolb, Munich; Marsh, London; Indrák, Olomouc; Cagirgan, Bornova; Kienast, Münster; Martinez-Rubio, Madrid; Moraleda, Murcia; Patton, Christchurch; Mariani, Palermo; Goldman, London; Schmitz, Kiel; Gastl, Innsbruck; Uderzo, Monza; Haas, Düsseldorf; Selleslag, Brugge; Lucarelli, Pesaro; Skotnicki, Krakow; Schroyens, Antwerp; Beguin, Liège; Rifón, Pamplona; Juliusson, Linköping; Grafakos, Athens; Myint, Bournemouth; de Bock, Antwerp; Milone, Catania; Gramatzki, Erlangen; Powles, Sutton; Pihkala, Helsinki; Rizzoli, Parma; Van den Berg, Amsterdam; Proctor, Newcastle; Zoumbos, Patras; Messina, Padova; Linkesch, Graz; André, Charleroi; Torres, La Coruña, and Podoltseva, St. Petersburg; Cornish, Bristol; Will, Pendlebury; Ortega, Barcelona; de Pablos, Granada; Bell, Poole; Malesevic, Belgrade; Vorlicek, Brno; Isasti, San Sebastian; Unal, Kayseri; Wachowiak, Poznan; Neubauer, Marburg; Göbel, Düsseldorf; Pejin, Novi Sad; Shaw, Sydney; Besalduch, Palma de Mallorca; Feldman, Buenos Aires; Everaus, Tartu; Gedikoglu, Istanbul; Morgenstern, Manchester; Andreesen, Regenburg; Walewski, Warsaw; Bordignon, Milano; Ludwig, Vienna. We thank the data managers from all of the centers for their help in collecting data. We also thank Virginie Chesnel and Patricia Palut from the European Group for Blood and Marrow Transplantation central data office for their assistance with data management. Inger Hammarberg is thanked for excellent typing of the manuscript.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
