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Prepublished online as a Blood First Edition Paper on April 17, 2002; DOI 10.1182/blood-2001-11-0057. This Article Abstract Full Text (PDF) All Versions of this Article: 2001-11-0057v1 100/2/724    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Urbano-Ispizua, A. Articles by Montserrat, E. Search for Related Content PubMed PubMed Citation Articles by Urbano-Ispizua, A. Articles by Montserrat, E. Related Collections Transplantation Brief Reports Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 July 2002, Vol. 100, No. 2, pp. 724-727 BRIEF REPORT Risk factors for acute graft-versus-host disease in patients undergoing transplantation with CD34+ selected blood cells from HLA-identical siblings Alvaro Urbano-Ispizua, Ciril Rozman, Pedro Pimentel, Carlos Solano, Javier de la Rubia, Salut Brunet, Jaime Pérez-Oteyza, Christelle Ferrá, Javier Zuazu, Dolores Caballero, Joan Bargay, Alzira Carvalhais, Jose Luis Díez, Ildefonso Espigado, Adrián Alegre, Montserrat Rovira, Fernando Campilho, Jesús Odriozola, Miguel Angel Sanz, Jordi Sierra, Javier García-Conde, and Emili Montserrat From the Spanish Group for Allogeneic Peripheral Blood Transplantation (Grupo Español de Trasplante Hemopoyético) and Instituto Português de OncologiaPorto. Participating centers are listed in the Appendix at the end of this article.     Abstract Top Abstract Introduction Study design Results and discussion Appendix References A study on 315 patients undergoing transplantation with CD34+ selected blood cells from HLA-identical siblings was performed to determine risk factors for acute GVHD (aGVHD). Recipients of a dose of CD34+ cells (× 106/kg) of 2 or less, more than 2 to 4, and more than 4 had a cumulative incidence of aGVHD grades I-IV of 21%, 35%, and 43%, respectively (log-rank P = .01); similarly, recipients of a dose of CD3+ cells (× 106/kg) of 0.05 or less, more than 0.05 to 0.1, and more than 0.1 had a cumulative incidence of aGVHD grades I-IV of 18%, 35%, and 44%, respectively (log-rank P = .007). Using a Cox regression model, 4 independent factors for aGVHD I-IV were identified: increased CD34+ cell dose (P = .02), increased CD3+ cell dose (P = .02), female patients (P = .01), and higher patient age (> 42 years) (P = .007). This study shows, for the first time in T-cell-depleted transplantations, a positive correlation between the number of CD34+ cells and aGVHD and, also, that the number of CD3+ cells necessary to initiate aGVHD is lower than previously reported. (Blood. 2002;100:724-727) © 2002 by The American Society of Hematology.     Introduction Top Abstract Introduction Study design Results and discussion Appendix References Acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality after allogeneic stem cell transplantation.1,2 Although widely accepted risk factors for aGVHD have been identified in patients receiving unmodified grafts,3-6 these parameters may not have the same predictive value in patients receiving a graft in which donor T cells, the major determinant of GVHD, have been depleted. The isolation of risk factors for aGVHD in T-cell-depleted transplantations could be useful to identify individual patients at a high probability of developing this complication. The present study was directed at identifying factors predictive of aGVHD in 315 adult patients receiving an HLA-identical sibling transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells T-cell depleted by means of CD34+ selection (allo-PBT/CD34+). We observed a strong association between the incidence of aGVHD and 2 controllable variables: the number of CD34+ and CD3+ cells infused.     Study design Top Abstract Introduction Study design Results and discussion Appendix References This study included 315 consecutive adult patients with hematologic malignancies treated with an allo-PBT/CD34+ from an HLA-identical sibling donor between March 1995 and December 2000. Granulocyte colony-stimulating factor administration and leukapheresis procedures have been previously described.7 This study was approved by local ethic committees and by the Spanish Department of Health. Informed consent was provided according to the Declaration of Helsinki. Patient and donor characteristics are shown in Table 1. CD34+ cells and CD3+ cells were quantified as previously published.7 There was no correlation between CD34+ and CD3+ cell dose (Pearson correlation coefficient 0.04; P = .47). Phase of disease, time to engraftment, diagnosis of graft failure, and transplantation-related mortality (TRM) have been previously defined.8 The diagnosis and grading of aGVHD was established according to the Seattle criteria.9                                View this table: [in this window] [in a new window]   Table 1. Patient and donor characteristics Probabilities of aGVHD were calculated by the cumulative incidence method (marginal probability) and statistically compared by Gray method.10,11 In this study, graft failure or relapse, without aGVHD, were considered competing risks. Characteristics considered for the analysis are described in Table 2. Three groups of CD34+ and CD3+ cells were established (CD34+ cells [× 106/kg]:  2, > 2 to 4, > 4; CD3+ cells [× 106/kg]:  0.05, > 0.05 to 0.1, > 0.1) based on results showing that these cell doses influenced outcome in T-cell-depleted transplantations.12-17 All prognostic variables in the cumulative incidence study with P  .2 were included in the stepwise proportional hazard Cox regression model (SPSS 9.0.1;1999).16 The proportional hazard assumption was rejected for the covariate irradiation, which was included in the Cox model as a stratum.                                View this table: [in this window] [in a new window]   Table 2. Univariate analysis of association with acute GVHD     Results and discussion Top Abstract Introduction Study design Results and discussion Appendix References The cumulative incidence for aGVHD grades I-IV was 36% (95% confidence interval [CI], 34%-38%) and for aGVHD grades II-IV was 16% (95% CI, 12%-20%). Acute GVHD grades I and II were associated with a similar TRM at 3 years (32% vs 34%, respectively; log-rank P = .7). Therefore, characteristics of donors and patients were analyzed on the incidence of aGVHD I-IV grades. Using a Cox regression model, 4 independent factors for aGVHD grades I-IV were identified: increased CD34+ cell dose (P = .02), increased CD3+ cell dose (P = .02), female patients (P = .01), and higher patient age (> 42 years) (P = .007) (Table 3). A multivariate analysis was also performed in the group of patients with grades II-IV aGVHD. The same risk factors were found, although with an inferior statistical significance: higher patient age (> 42 years) (P = .02), female patients (P = .02), increased CD3+ cell dose (P = .04), and increased CD34+ cell dose (P = .1). Although the sex-mismatch combination most frequently associated with aGVHD in unmodified transplantations is male recipients from a female donor,6,17,18 this finding has not been identified in either this or in other T-cell-depleted series.                                View this table: [in this window] [in a new window]   Table 3. Factors associated with aGVHD in multivariate analysis The rate of aGVHD grades I-IV increased with increasing doses of CD34+ cells (× 106/kg): Recipients of 2 or fewer, more than 2 to 4, and more than 4 had a cumulative incidence of 21%, 35%, and 43%, respectively (log-rank P = .01) (Figure 1A) (Table 3). Similarly, an association of aGVHD grades I-IV with increasing numbers of CD3+ cells was observed: infusion of CD3+ cells (× 106/kg) of 0.05 or fewer, more than 0.05 to 0.1, and more than 0.1 was associated with a cumulative incidence of aGVHD grades I-IV of 18%, 35%, and 44%, respectively (log-rank P = .007) (Figure 1B) (Table 3). The aGVHD rate remained fairly stable when further analyzed in subgroups of patients receiving numbers of CD34+ and CD3+ cells above 4 × 106/kg and 0.1 × 106/kg, respectively. The cell doses required to initiate GVHD might differ depending on whether or not GVHD posttransplantation prophylaxis is administered. A comparison of graft failure, relapse, TRM, and overall survival as a function of the CD34+ and CD3+ groups is presented in Table 4. View larger version (18K): [in this window] [in a new window]   Figure 1. Cumulative incidence of acute GVHD grades I-IV depending on the quantity of infused cells. (A) CD34+ cells infused. (B) CD3+ cells infused. (C) The combination of CD34+ and CD3+ cells infused.* indicates × 106/kg.                                View this table: [in this window] [in a new window]   Table 4. Association of the numbers of CD34+ and CD3+ cells with the outcome Przepiorka et al,19 in a series of unmanipulated transplantations, have suggested an increased rate of aGVHD in patients receiving more than 8 × 106/kg CD34+ cells. This was attributed to a rapidly expanding myeloid cell population, which could have released cytokines that exacerbate GVHD. In the current study there was a correlation between the number of CD34+ cells and early engraftment, but the speed of the engraftment did not influence aGVHD rate. This would suggest that the effect of CD34+ on the incidence of aGVHD might be due to a direct participation of these cells in allogeneic reactions20,21 rather than by accelerating the engraftment. The association of high numbers of CD34+ cells with aGVHD would explain our recent data, which showed that the administration of a quantity of CD34+ cells more than 3 × 106/kg had a negative effect on clinical outcome,8 with a similar trend being observed in the present series (Table 4). The optimal quantity of CD34+ cells for recipients of an allo-PBT/CD34+ from HLA-identical siblings might therefore be in the range of 1 × 106/kg to 3 × 106/kg. In human beings, a T-cell dose more than 106/kg of recipient weight has been associated with increased GVHD rate.22-25 The data herein presented not only confirm the relationship between CD3+ cell dose and aGVHD but also show that the quantity of T cells increasing aGVHD rate is lower than previously reported (Figure 1B).22-25 Kernan et al13 estimated that a number of 0.1 × 106/kg T cells was necessary to initiate clinically detectable aGVHD in an HLA-identical host. The present study supports the importance of this threshold on the incidence of aGVHD and also shows that infusion of fewer than 0.1 × 106/kg CD3+ cells does not totally prevent severe GVHD: of 143 patients receiving this quantity of CD3+ cells, 11 developed aGVHD grades II-IV and 4 of them died due to this complication, despite the use of posttransplantation cyclosporine. In this series, the rate of aGVHD for recipients of a quantity of CD3+ cells inferior to 0.1 × 106/kg was low but was associated with a high incidence of graft failure (Table 4), confirming previous results from our group.16 This observation supports the concept that both complications behave as "mirror images" and suggests that there is no standard quantity of T cells low enough to totally prevent severe GVHD while high enough to totally avoid graft failure. A T-cell dose to attenuate both complications might be in the range of 0.1 × 106/kg to 0.3 × 106/kg, followed by posttransplantation immunosuppression. These results could be used for graft engineering in allo-PBT/CD34+. The number of CD34+ and CD3+ cells associated with aGVHD might be different for recipients of a bone marrow inoculum.     Acknowledgments The authors express their gratitude to Mrs Terry Smith of MD Anderson, Houston, TX, for supplying the software for the calculation of cumulative incidence (marginal probability) and to Drs F. Prosper and G. Socié for their critical review of the manuscript.     Footnotes Submitted November 27, 2001; accepted March 13, 2002. Prepublished online as Blood First Edition Paper, April 17, 2002; DOI 10.1182/blood-2001-11-0057. Supported in part by grants FIJC-01/P-CR and FIJC-01/P-EM from the José Carreras International Foundation. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: A. Urbano-Ispizua, Department of Hematology, Hospital Clínic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain; e-mail: aurbano{at}clinic.ub.es.     References Top Abstract Introduction Study design Results and discussion Appendix References 1. Van Bekkum D. Graft-versus-host disease. In: van Bekkum DW,Lowenberg B, eds. Bone Marrow Transplantation: Biological Mechanisms and Clinical Practice. New York, NY: Dekker; 1985:147-155. 2. Van Bekkum DW. Retrospectives and perspectives in bone marrow transplantation. Bone Marrow Transplant. 1989;4(suppl 4):47-53. 3. Storb R, Prentice RL, Buckner CD, et al. Graft-versus-host disease and survival in patients with aplastic anemia treated by marrow grafts from HLA-identical siblings. Beneficial effect of a protective environment. N Engl J Med. 1983;308:302-307[Abstract]. 4. Bortin MM, Gale RP, Rimm AA. Allogeneic bone marrow transplantation for 144 patients with severe aplastic anemia. JAMA. 1981;245:1132-1139[Abstract/Free Full Text]. 5. Gale RP, Bortin MM, Van Bekkum DW, et al. Risk factors for acute graft-versus-host disease. Br J Haematol. 1987;67:397-406[Medline] [Order article via Infotrieve]. 6. Nash RA, Pepe MS, Storb R. Acute graft-versus-host disease. Analysis of risk factors after allogeneic marrow transplantation and prohylaxis with cyclosporine and methotrexate. Blood. 1992;80:1838-1845[Abstract/Free Full Text]. 7. Urbano-Ispizua A, Solano C, Brunet S, et al. Allogeneic transplantation of selected CD34+ cells from peripheral blood: experience of 62 cases using immuno-adsorption or immunomagnetic technique. Spanish Group of Allo-PBT. Bone Marrow Transplant. 1998;22:519-525[CrossRef][Medline] [Order article via Infotrieve]. 8. Urbano-Ispizua A, Carreras E, Marín P, et al. Allogeneic transplantation of CD34+ selected cells from peripheral blood from HLA-identical siblings: detrimental effect of a high number of donor CD34+ cells? Blood. 2001;98:2352-2357[Abstract/Free Full Text]. 9. Thomas ED, Storb R, Clift RA, et al. Bone marrow transplantation. N Engl J Med. 1975;292:832-843[Medline] [Order article via Infotrieve]. 10. Pepe MS, Mori M. Kaplan-Meier. Marginal or conditional probability curves in summarizing competing risk failure time data? Stat Med. 1993;12:187-200. 11. Gray RJ. A class of K-sample test for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16:1141-1154[CrossRef]. 12. Mavroudis D, Read E, Cottler-Fox M, et al. CD34+ cell dose predicts survival, posttransplant morbidity, and rate of hematological recovery after allogeneic marrow transplants for hematological malignancies. Blood. 1996;88:3223-3229[Abstract/Free Full Text]. 13. Kernan NA, Collins NH, Juliano L, et al. T lymphocytes in T-cell depleted bone marrow transplants correlate with development of graft versus host disease. Blood. 1986;68:770-773[Abstract/Free Full Text]. 14. Nakamura R, Bahceci E, Read EJ, et al. Transplant dose of CD34+ and CD3+ cells predicts outcome in patients with haematological malignancies undergoing T cell-depleted peripheral blood stem cell transplants with delayed donor lymphocyte add-back. Br J Haematol. 2001;115:95-104[CrossRef][Medline] [Order article via Infotrieve]. 15. Bahceci E, Read EJ, Leitman S, et al. CD34+ cell dose predicts relapse and survival after T-cell-depleted HLA-identical haematopoietic stem cell transplantation (HSCT) for haematological malignancies. Br J Haematol. 2000;108:408-414[CrossRef][Medline] [Order article via Infotrieve]. 16. Urbano-Ispizua A, Rozman C, Pimentel P, et al. The number of donor CD3+ cells is the most important factor for graft failure after allogeneic transplantation of CD34+ selected cells from peripheral blood from HLA-identical siblings. Blood. 2001;97:383-387[Abstract/Free Full Text]. 17. Storb R, Prentice RL, Thomas ED, et al. Treatment of aplastic anemia by marrow transplantation from HLA identical siblings. Prognostic factors associated with graft versus host disease and survival. J Clin Invest. 1977;59:625-632[Medline] [Order article via Infotrieve]. 18. Atkinson K, Farrell C, Chapman G, et al. Female marrow donors increase the risk of acute graft-versus-host disease: effect of donor age and parity and analysis of cell subpopulations in the donor marrow inoculum. Br J Haematol. 1986;63:231-239[Medline] [Order article via Infotrieve]. 19. Przepiorka D, Smith TL, Folloder J, et al. Risk factors for acute graft-versus-host disease after allogeneic blood stem cell transplantation. Blood. 1999;94:1465-1470[Abstract/Free Full Text]. 20. Rondelli D, Anasetti C, Fortuna A, et al. T cell alloreactivity induced by normal G-CSF-mobilized CD34+ blood cells. Bone Marrow Transplant. 1998;21:1183-1191[CrossRef][Medline] [Order article via Infotrieve]. 21. Ryncarz RE, Anasetti C. Expression of CD86 on human marrow CD34(+) cells identifies immunocompetent committed precursors of macrophages and dendritic cells. Blood. 1998;91:3892-3900[Abstract/Free Full Text]. 22. Marmont A, Horowitz MM, Gale RP, et al. T-cell depletion of HLA-identical transplants in leukemia. Blood. 1991;78:2120-2130[Abstract/Free Full Text]. 23. Lowenberg B, Wagemaker G, van Bekkum DW, et al. Graft-versus-host disease following transplantation of `one log' versus `two log' T-lymphocyte-depleted bone marrow from HLA-identical donors. Bone Marrow Transplant. 1986;1:133-140[Medline] [Order article via Infotrieve]. 24. Wagner JE, Santos GW, Noga SJ, et al. Bone marrow graft engineering by counterflow centrifugal elutriation: results of a phase I-II clinical trial. Blood. 1990;75:1370-1377[Abstract/Free Full Text]. 25. Schattenberg A, De Witte T, Preijers F, et al. Allogeneic bone marrow transplantation for leukemia with marrow grafts depleted of lymphocytes by counterflow centrifugation. Blood. 1990;75:1356-1363[Abstract/Free Full Text].     Appendix Top Abstract Introduction Study design Results and discussion Appendix References Participating centers include Hospital Clinic, Barcelona, Spain (A. Urbano-Ispizua, C. Rozman, M. Rovira, E. Montserrat); Instituto Português de OncologiaCentro do Porto, Oporto, Portugal (P. Pimentel, F. Campilho, A. Carvalhais); Hospital Clínico, Valencia, Spain (C. Solano, J. García-Conde); Hospital La Fe, Valencia, Spain (J. de la Rubia, M. A. Sanz); Hospital Sant Pau, Barcelona, Spain (S. Brunet, J. Sierra); Hospital Ramón y Cajal, Madrid, Spain (J. Pérez-Oteyza, J. Odriozola); Hospital Duran i Reynals, Barcelona, Spain (C. Ferrá); Hospital Vall d'Hebron, Barcelona, Spain (J. Zuazu); Hospital Clínico, Salamanca, Spain (D. Caballero); Hospital Gregorio Marañón, Madrid, Spain (J. L. Díez); Hospital Virgen del Rocío, Sevilla, Spain (I. Espigado); Hospital La Princesa, Madrid, Spain (A. Alegre); and Hospital Son Dureta, Mallorca, Spain (J. Bargay). © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? 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[Abstract] [Full Text] [PDF] This Article Abstract Full Text (PDF) All Versions of this Article: 2001-11-0057v1 100/2/724    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Urbano-Ispizua, A. Articles by Montserrat, E. Search for Related Content PubMed PubMed Citation Articles by Urbano-Ispizua, A. Articles by Montserrat, E. Related Collections Transplantation Brief Reports Clinical Trials and Observations Social Bookmarking                   What's this?

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