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Originally published as JCO Early Release 10.1200/JCO.2007.15.3106 on May 27 2008 © 2008 American Society of Clinical Oncology. Identical Outcome After Autologous or Allogeneic Genoidentical Hematopoietic Stem-Cell Transplantation in First Remission of Acute Myelocytic Leukemia Carrying Inversion 16 or t(8;21): A Retrospective Study From the European Cooperative Group for Blood and Marrow Transplantation
From the Department of Hematology, Hôpital Saint Antoine; Acute Leukemia Working Party Registry, European Cooperative Group for Blood and Marrow Transplantation Data and Study Office, Faculté de Médecine St-Antoine Université Pierre et Marie Curie and Institut National de la Santé et de la Recherche Médicale (INSERM) Unit U832; Department of Hematology–Bone Marrow Transplantation (BMT), Hôpital St. Louis, Paris; Centre Hospitalier Universitaire (CHU) Bordeaux Hôpital Haut-Leveque, Pessac; Department of Hematology, Hôpital Purpan CHU, Toulouse; Unité de Transplantation et de Thérapie Cellulaire, Institut Paoli Calmettes, INSERM Unité Medicale de Recherche 599, Marseille; BMT Unit, Hôpital E. Herriot, Lyon; Service d‘Hématologie, Hôpital Jean Minjoz, Besancon; Department of Hematology, Hotel Dieu, Nantes, France; Department of Hematology, Ospedale San Martino, Genova; Dip. Biotecnologie Cellulari ed Ematologia, University La Sapienza, Rome, Italy; and Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands Corresponding author: Norbert C. Gorin, MD, Hopital Saint-Antoine and Université Pierre et Marie Curie UPMC, 184 Rue du Faubourg Saint-Antoine, Cedex 12 Paris, France 75571; e-mail: norbert-claude.gorin{at}sat.aphp.fr
Purpose Patients with acute myelocytic leukemia carrying inversion 16 (inv16) or t(8;21) have a better initial response to high-dose cytarabine than patients without these chromosomal abnormalities. They presently do not undergo transplantation in first remission (CR1), but there is concern about late relapses. Patients and Methods From 1990 to 2004, 325 adult patients received transplantations in CR1 (159 patients with inv16 and 166 patients with t(8;21), including 35 and 60 patients, respectively, with additional chromosomal abnormalities). Genoidentical allografts were performed in 64 patients with inv16 and 81 patients with t(8;21), and autografts were performed in 95 patients with inv16 and 85 patients with t(8;21). Results In patients with inv16, after allogeneic and autologous transplantation, the 5-year leukemia-free survival (LFS) rates were 59% and 66% (P = .5), the relapse incidence (RI) rates were 27% and 32% (P = .45), and the transplantation-related mortality (TRM) rates were 14% and 2% (P = .003), respectively. Female patients had a lower RI and a higher LFS. Additional chromosomal abnormalities, compared with no additional abnormalities, were associated with lower RI rate (12% v 34%, respectively; P = .01) and higher 5-year LFS rate (78% v 59%, respectively; P = .04). In patients with t(8;21), after allogeneic and autologous transplantation, the 5-year LFS rates were 60% and 66% (P = .69), the RI rates were 15% and 28% (P = .03), and the TRM rates were 24% and 6% (P = .003), respectively. Younger age and a lower WBC count at diagnosis were associated with a lower TRM and a better LFS. The TRM was lower and the RI was higher in patients with autologous transplantations versus allogeneic transplantations. Conclusion Both autologous and allogeneic transplantation resulted in similar outcomes.
In the last 20 years, a considerable number of studies have shown the importance of cytogenetics in classifying acute myelocytic leukemia (AML). Three risk categories have been defined, with the most favorable category consisting of leukemias with mutations in the core binding factor (CBF) such as inversion 16 (inv16) and translocation t(8;21). Compared with patients with other AMLs, patients with these chromosomal abnormalities have a higher rate of first complete remission (CR1) and a higher rate of cure with high-dose cytarabine (HDARA-C).1-4 In recently devised treatment protocols used throughout the world, these patients are excluded from hematopoietic stem-cell transplantation (HSCT), as are patients with acute promyelocytic leukemias (M3) inCR1. However, some randomized studies comparing allogeneic or autologous stem-cell transplantation and conventional consolidation chemotherapy have shown better results with autologous stem-cell transplantation in these patients with favorable cytogenetics.5-8 There has recently been some concern that the rate of relapse after HDARA-C is higher than previously reported.9,10 Moreover, some recent reports identify subgroups of patients with inv16 or t(8;21) with poor prognostic factors who might benefit from more intensive treatment.11,12 With the objective of studying risk factors for outcomes after HSCT in patients with AML with mutations in the CBF, we studied patients reported to the European Cooperative Group for Blood and Marrow Transplantation (EBMT) who received an autograft or a genoidentical allogeneic transplantation as consolidation in CR1. We studied separately HSCT recipients with inv16 and t(8;21) chromosomal abnormalities.
Patients From January 1990 to December 2004, a total of 325 adult patients with inv16 or t(8;21) received a transplantation in CR1. Inv16 was present in 159 patients, 35 of whom had other abnormalities. t(8;21) was present in 166 patients, including 60 with other abnormalities. A genoidentical allograft was performed in 64 patients with inv16 and 81 patients with t(8;21). An autograft was performed in 95 patients with inv16 and 85 patients with t(8;21). Appendix Table A1 (online only) lists the characteristics of patients with inv(16). As expected, 75% of the allografted and 80% of the autografted patients had M4 disease by the French-American-British (FAB) classification. Of note, the median WBC counts were high in the allogeneic group and the autograft group (67,000/µL v 35,000/µL, respectively; P = .06). As usual, allograft recipients were younger, were transplanted earlier after diagnosis, and were more likely to have received total-body irradiation than autograft recipients. Whether or not the patients received HDARA-C (defined as a total dose per course > 3 g/m2)1 before the transplantation period was recorded in only 91 patients (57% of the population); within this population, 19% of the allograft recipients and 46% of the autograft patients received HDARA-C (P = .001). The median follow-up time was 44 months (range, 2 to 164 months). Appendix Table A2 (online only) lists the characteristics of the patients with t(8;21) translocation; as expected, 84% of the allografted patients and 79% of the autografted patients had M2 disease by FAB classification. As for patients with inv16, allograft recipients were younger, were transplanted earlier after diagnosis, and were more likely to have received total-body irradiation than the autograft recipients. In contrast to patients with inv16, those with t(8;21) did not have elevated WBC counts at diagnosis (7,700 and 8,600/µL for allograft and autograft patients, respectively). Information on whether the patients received HDARA-C before transplantation was available in only 103 patients (62%) with t(8;21) mutations; within this population, 28% of the allograft recipients and 45% of the autograft recipients received HDARA-C (P = .09). The median follow-up time was 63 months (range, 2 to 172 months).
End Points
Statistics Factors differing in distribution between autografts and allografts and factors associated with outcome, with a P < .20 in univariate analyses, were included in multivariate analyses. A stepwise backward procedure was then used to construct a set of independent predictors of each end point. All predictors were removed if the P value in the multiple model was > .05. The type of transplantation was forced into the final model. All tests were two-sided. Cumulative incidence curves were used in a competing risks setting,13 with death being treated as a competing event to calculate probabilities of TRM and relapse. Probabilities of survival and LFS were calculated using the Kaplan-Meier estimate; the log-rank test was used for univariate comparisons. Associations of graft characteristics with outcomes were evaluated in multivariate analyses using Cox proportional hazards for LFS and survival; the Fine and Gray model for proportional subdistribution hazard regression was applied to other outcomes.14 Statistical analyses were performed with SPSS (SPSS Inc, Chicago, IL) and S-Plus (MathSoft Inc, Seattle, WA) software packages.
Reasons for Transplantation
Patients With inv16 Overall outcome. Among all the patients with inv16, the 5-year LFS rate was 63% ± 4%. The relapse incidence (RI) rate was 30% ± 4%, and the TRM rate was 7% ± 2%. For recipients of allogeneic and autologous transplantations, the 5-year LFS rates were 59% ± 7% and 66% ± 5% (P = .5; Fig 1), the RI rates were 27% ± 6% and 32% ± 4% (P = .45; Fig 2), and the TRM rates were 14% ± 4% and 2% ± 2% (Fig 3), respectively (P = .003).
Univariate analyses. The results of the univariate analyses are listed in Appendix Table A3 (online only). Patient with more recent transplantations (after January 2001) were compared with those with earlier transplantations and found to have a lower RI rate (21% ± 5% v 38% ± 5%, respectively; P = .03) and a better 5-year LFS rate (71% ± 6% v 55% ± 6%, respectively; P = .04). Female patients, compared with male patients, had a lower RI rate (20% ± 4% v 37% ± 5%, respectively; P = .05) and a better LFS rate (74% ± 6% v 54% ± 6%, respectively; P = .03). Autologous transplantations were associated with a lower TRM rate (2% ± 2%) than allogeneic transplantations (14% ± 4%; P = .003). The presence, versus the absence, of additional chromosome abnormalities was associated with a lower RI rate (12% ± 5% v 34% ± 4%, respectively; P = .01) and a better 5-year LFS rate (78% ± 7% v 59% ± 5%, respectively; P = .04). The WBC count and use of HDARA-C before transplantation had no correlation with outcome. Multivariate analysis. The results of the multivariate analysis are listed in Table 1. The TRM was significantly lower for patients who had transplantations after January 2001. Female patients had a significantly lower RI and a higher LFS than male patients. The existence of additional chromosome abnormalities was associated with a lower RI (relative risk [RR] = 0.55; 95% CI, 0.32 to 0.93; P = .03) and a better LFS (RR = 2.38; 95% CI, 1.08 to 5.3; P = .03).
Autologous transplantations were associated with a lower TRM than allogeneic transplantations (RR = 0.15; 95% CI, 0.03 to 0.74; P = .02). The LFS did not differ between patients with autologous and allogeneic transplantations.
Patients With t(8;21) Univariate analyses. Appendix Table A4 (online only) lists the results of the univariate analyses. Patients younger than 39.6 years, compared with older patients, had a lower TRM rate (6% ± 2% v 25% ± 4%, respectively; P = .002) with a trend for a better 5-year LFS rate (P = .09).There was no difference in the outcome according to sex.
Lower WBC counts at diagnosis were associated with a better 5-year LFS rate than higher WBC counts (68% ± 9% for WBC Multivariate analysis. Table 2 lists the results of the multivariate analysis. Younger age and a lower WBC count at diagnosis were associated with a lower TRM and a better LFS. Sex was not an independent predictor of outcome. The TRM was significantly lower and the RI significantly higher after autologous transplantation compared with allogeneic transplantation. The LFS did not differ between autologous and allogeneic transplantation.
Reasons for Transplantation The following data are based on the analysis of the questionnaire completed by each transplantation center. For 59% of the allogeneic transplantations and 87% of the autologous transplantations, the reason indicated for transplantation was the general policy of the institution at the time of treatment. In 34% of the allograft and 9% of the autograft recipients, the reason given was the existence of poor risk prognostic factors.
The CBF complex consists of a heterodimer of two proteins, CBF-  (or AML1) and CBF-β. The CBF normally activates genes critical for normal myeloid development. In AML, this factor is disrupted by one of at least three known translocations, which include inversion of chromosome 16 and translocation t(8;21).15-17 Both fusion transcripts can be evidenced and quantified by specific reverse transcriptase polymerase chain reaction assays. These assays may also be used to monitor minimal residual disease.18,19 AML with inv16 is frequently associated with the FAB M4 cytologic subtype with an abnormal eosinophil component (M4eo). AML with t(8;21) is morphologically associated with the FAB M2 subtype, the presence of Auer rods, sometimes eosinophilia or mastocytosis, and the development of extramedullary localizations. CBF AML, which accounts for less than 20% of all AML, has been generally classified as good risk in terms of clinical response to chemotherapy and repeated courses of HDARA-C more than 3 g/m2.1-3,6,8,20 This has recently resulted in the exclusion of patients with CBF AML from receiving HSCT in CR1. However, there are few reports focusing only on patients with CBF AML. The French AML intergroup recently presented two surveys compiling patients entered onto six multicenter trials since 1987. The first trial included 110 patients with AML with inv16/t(16;16).11 The overall 3-year LFS rate was 48%; this rate was 67% for patients younger than 35 years of age and only 30% for patients older than 35 years of age. The RI was 29% in the younger group and 55% in the older group. There was no significant difference between patients treated with chemotherapy and those treated with allogeneic stem-cell transplantation, but only 14 patients actually received transplantations. None received an autologous stem-cell transplantation. The second survey involved 161 patients with t(8;21).12 The overall 5-year LFS rate was 52%. The WBC count was the only prognostic factor significantly correlated with outcome. In the analysis, patients were divided into groups based on a WBC index, which was calculated as the product of WBC and the ratio of marrow blasts. On the basis of this index, patients were divided into three groups with 3-year LFS rates of 74%, 57%, and 33% corresponding to low, intermediate, or high marrow blast infiltration, respectively, at diagnosis. There was no significant difference between the 127 patients treated with chemotherapy and the 34 patients treated with allogeneic stem-cell transplantation. From these two studies, one would conclude that patients with inv16 and age greater than 35 years and patients with t(8;21) and a high WBC count at presentation represent a fraction of patients with a worse prognosis who may benefit from more aggressive therapy. A recent report has drawn attention to poorer results in patients with t(8;21) AML with CD56 positivity after either HDARA-C or allogeneic stem-cell transplantation.10 There have been several cooperative group trials in the past decade comparing the respective values of conventional chemotherapy, autologous stem-cell transplantation, and allogeneic stem-cell transplantation in AML. In the British Medical Research Council (MRC) study,6 which included 1,365 patients with AML, virtually all patients (98%) with t(8;21) achieved CR, but the CR rate for inv16 did not differ from that of patients with normal karyotypes. Using the conventional definition for risk groups by cytogenetics,1,6 the overall survival rate at 5 years was 65% in the favorable group [which includes inv16 + t(8;21)], 41% in the intermediate group, and 14% in the adverse group. Regarding postremission random assignment in the favorable category [inv16 + t(8;21)], 242 patients were in the no transplantation arm, 50 patients received a genoidentical allogeneic transplantation, and 50 patients received an autologous stem-cell transplantation. The RI rates at 3 years were significantly lower after allogeneic (8%) and autologous (20%) transplantations compared with chemotherapy alone (38%). The overall survival rates were 62% for allogeneic transplantations, 78% for autologous transplantations, and 76% for chemotherapy. The US intergroup study5 has been of particular interest because the conventional chemotherapy arm included HDARA-C (36g/m2), which is known to be highly effective in CBF AML.7 A total of 609 patients with previously untreated AML were included in this trial; 263 of the patients were registered for postremission therapy. The probability of surviving 5 years after achieving CR when evaluated by cytogenetics risk groups was 57% in good-risk patients with CBF AML and t(15;17), 48% in the intermediate-risk group, and 23% in the unfavorable group. Among patients with favorable karyotypes, those who received autografts had the best survival after transplantation (71% at 5 years) compared with those who received allografts (63%) or chemotherapy (35%). Finally, in the European Organisation for Research and Treatment of Cancer/Gruppo Italiano Malattie Ematologiche dell'Adulto AML 10 trial, all adult patients with AML younger than 46 years old were assigned to receive high-dose intensification followed either by an allogeneic genoidentical transplantation (donor group) or an autologous stem-cell transplantation (no donor group). The results were analyzed based on intent-to-treat and cytogenetics. In the good-risk group, which consisted of 123 patients with inv16 or t(8;21), the 5-year LFS rate was 65.7% in the autograft arm and 62.1% in the allograft arm; the overall survival rates were 68.1% and 73.9%, respectively (not significantly different).21 The present EBMT retrospective study demonstrates several results. On the basis of a relatively large series of CBF leukemias treated in CR1 with allogeneic or autologous stem-cell transplantations, 5-year LFS rate was approximately 60% for patients with either inv16 or t(8;21). The WBC count at diagnosis had no impact on LFS in patients with inv16 but strongly influenced outcome in those with t(8;21). This finding is similar to that of the previous French study dealing mostly with conventional chemotherapy.12 Of further interest was the absence of impact of the use of HDARA-C in the pretransplantation period. This finding was already observed in a previous EBMT study that included all adult patients with AML who received transplantation in CR1 before the year 2000.22 An additional finding of potential importance in patients with inv16 was that female patients had a significantly lower incidence of relapse and a higher LFS. This finding is not surprising because other studies by the EBMT and in patients with other diseases, such as lymphoma, have reported similar observations. When we designed the study, it was unclear whether we should separate or group together patients with inv16 and t(8;21). Because the prognostic factors in the two populations, such as WBC count, were different, we decided to analyze the populations separately. It was also unclear whether we should separate pure chromosomal abnormalities and those associated with additional abnormalities. Indeed, there are mainly two classifications of AML by cytogenetics, the MRC and the Southwest Oncology Group classifications. In the MRC classification, all patients with t(8;21) are considered favorable, despite the addition of del(9q) or complex karyotypes. In contrast, in the Southwest Oncology Group classification, only patients with t(8;21) lacking these additional abnormalities belong to the favorable group.1,6 For t(8;21), we found that the addition of other abnormalities did not change the prognosis. For inv16, the finding was unexpected in that additional chromosome abnormalities significantly improved prognosis, leading to a 5-year LFS rate of 78% ± 7% with additional chromosomal abnormalities as opposed to 59% ± 5% without additional chromosomal abnormalities (P = .03). We analyzed these additional abnormalities in an effort to find a distinctive pattern; 19 of 35 patients had hyperdiploid clones (4 trisomy 8), nine patients had a trisomy 22, and three patients had combined inv(16) and t(9;22), the Philadelphia chromosome. The remaining instances of additional abnormalities were one of a kind. Regarding the association of a trisomy 22, our findings do not support the results from the French study in which trisomy 22 was found to be a poor prognosis factor.11 This series bears the numerous limitations typical of retrospective registry studies. However, information is currently limited on the outcome of CBF leukemias treated with HSCT, with a noticeable absence of any prospective trials in the so-called good-risk categories. The reasons why our patients received transplantations are unknown. The high WBC count in the inv16 population may suggest that these patients were thought to have a high risk, unlike those with t(8;21). A similar series of 274 patients with CBF AML with the t(8;21) translocation, from a Japanese registry, has recently been presented; however, in this study, patients who received transplantations in CR1 and in second CR were mixed in an unknown ratio. The overall survival rate at 5 years was 59.2% after allogeneic stem-cell transplantation and 65.9% after autologous stem-cell transplantation.23 It is not surprising that autologous stem-cell transplantation in our particular set of patients has resulted in outcomes identical to allogeneic transplantation because the value of autologous stem-cell transplantation has always been maximal in chemotherapy-sensitive patients. In view of its low TRM and the fact that optimal in vivo purging can be achieved and monitored with molecular biology24,25 and that the entire treatment can be completed within 6 months, autologous stem-cell transplantation remains, for the time being, an acceptable treatment option for patients with CBF AML. We believe that it would be of interest to compare autologous stem-cell transplantation with HDARA-C in new randomized prospective trials strictly focused on CBF leukemias.
The author(s) indicated no potential conflicts of interest.
Conception and design: Norbert-Claude Gorin, Myriam Labopin, Francesco Frassoni, Emmanuelle Polge, Vanderson Rocha Financial support: Vanderson Rocha Administrative support: Norbert-Claude Gorin, Vanderson Rocha Provision of study materials or patients: Myriam Labopin, Noel Milpied, Michel Attal, Didier Blaise, Giovanna Meloni, Anna P. Iori, Mauricette Michallet, Roel Willemze, Eric Deconninck, Jean-Luc Harousseau Collection and assembly of data: Norbert-Claude Gorin, Myriam Labopin, Emmanuelle Polge, Vanderson Rocha Data analysis and interpretation: Norbert-Claude Gorin, Myriam Labopin, Vanderson Rocha Manuscript writing: Norbert-Claude Gorin, Myriam Labopin, Roel Willemze, Vanderson Rocha Final approval of manuscript: Norbert-Claude Gorin, Myriam Labopin, Francesco Frassoni, Noel Milpied, Michel Attal, Didier Blaise, Giovanna Meloni, Anna P. Iori, Mauricette Michallet, Roel Willemze, Eric Deconninck, Jean-Luc Harousseau, Emmanuelle Polge, Vanderson Rocha
The following institutions reported data for this study: CIC 267, Noel Milpied, H Haut-Leveque, Pessac, France; CIC 624, Michel Attal, H Purpan, Toulouse, France; CIC 230, Didier Blaise, Paoli Calmettes, Marseille, France; CIC 232, Roberto Foa, Emat, ‘La Sapienza‘, Rome, Italy; CIC 213, Norbert C. Gorin, St Antoine, Paris, France; CIC 671, Mauricette Michallet, H E Herriot, Lyon, France; CIC 203, Roelof Willemze, Univ H, Leiden, Netherlands, The; CIC 233, Eric Deconinck, H Jean Minjoz, Besancon, France; CIC 253, J.L. Harousseau, Hotel Dieu, Nantes, France; CIC 222, Bernard Rio, Hotel Dieu, Paris, France; CIC 242, Arturo Iriondo Atienza, Valdecilla, Santander, Spain; CIC 249, Dr. Witz, Hôpital Méd et Hémat, NANCY, France; CIC 515, Tapani Ruutu, Univ Central H, Helsinki, Finland; CIC 237, A. Schattenberg, St Radboud, Nijmegen, Netherlands, The; CIC 523, Nicole Gratecos, H de l‘ARCHET I, Nice, France; CIC 207, Gérard Socié, St Louis, Paris, France; CIC 672, Oberling, F./Lioure, B., H Hautepierre, STRASBOURG, France; CIC 239, Leo F. Verdonck, University, Utrecht, Netherlands, The; CIC 667, Caillot, D., H d‘Enfants, Dijon, France; CIC 250, Guyotat, D./Oriol, P., St Etienne, Saint Etienne, France; CIC 270, Jean Yves Cahn, H A Michallon, Grenoble, France; CIC 286, E. Paolo Alessandrino, S Matteo, Pavia, Italy; CIC 650, Prof N Ifrah, CHRU, Angers, France; CIC 661, Dr. Bergeron/Le Gall/(Leprise), H Sud/Pontchaillou, Rennes, France; CIC 959, Alain Delmer, Robert Debre, Reims, France; CIC 209, Dr. Johan Maertens, Univ H, Leuven, Belgium; CIC 215, Dominique Bron, Jules Bordet, Brussels, Belgium; CIC 944, P. Henon, Emile Mulller, Mulhouse, France; CIC 132, Mario Petrini, Oncologia e trapianti, Pisa, Italy; CIC 160, Agnes Buzyn, H Necker, Paris, France; CIC 217, Andrea Bacigalupo, S Martino, Genova, Italy; CIC 234, Augustin Ferrant, St. Luc, Brussels, Belgium; CIC 246, J.J. Cornelissen, Erasmus den Hoed, Rotterdam, Netherlands, The; CIC 264, F. Guilhot, H La Miletrie, Poitiers, France; CIC 277, J.P. Jouet, H Claude Huriez, Lille, France; CIC 614, Axel R. Zander, Univ H, Hamburg, Germany; CIC 622, Nicholas Harhalakis, Evangelismos H, Athens, Greece; CIC 642, Dolores Carrera Fernández, H Covadonga, Oviedo, Spain; CIC 727, Dolores Caballero, H Clinico, Salamanca, Spain; CIC 214, Emili Montserrat, H Clinic, Barcelona, Spain; CIC 231, Michele Falda, S. Giovanni (CTO), Torino, Italy; CIC 272, P. Colombat, H Bretonneau, Tours, France; CIC 389, Dietger Niederwieser, Univ, Hemat/Oncol, Leipzig, Germany; CIC 574, Karel Indrák, Univ H, Olomouc, Czech Republic; CIC 660, Luigi Gugliotta, S Maria Nuova, Reggio Emilia, Italy; CIC 676, Bordigoni, P. M.D., H d‘Enfants, Vandoeuvre Les Nancy, France; CIC 713, A.E. Hunter, FRCP, Royal Infirmary, Leicester, United Kingdom; CIC 772, Peter Jacobs, Constantiaberg, Cape Town, South Africa; CIC 792, Giuseppe Milone, Osp Ferrarotto, Catania, Italy; CIC 977, Dominique Bordessoule, CHRU, Limoges, France; CIC 202, Alois Gratwohl, 202, Basel, Switzerland; CIC 204, Donald Bunjes, Priv.Doz., Medizin Kl/Polikl, Ulm, Germany; CIC 225, Kari Remes, University, Turku, Finland; CIC 227, Hildegard T. Greinix, Medizinische Univ, Vienna, Austria; CIC 245, Vittorio Rizzoli, Centro Trapianti, Parma, Italy; CIC 247, H. Van den Berg, Acad Ziekenhuis, Amsterdam, Netherlands, The; CIC 248, Paolo Di Bartolomeo, Osp Civile, Pescara, Italy; CIC 255, Tim Littlewood, Radcliffe H, Oxford, United Kingdom; CIC 260, Jorge Sierra, SCreu i S Pau, Barcelona, Spain; CIC 261, Jakob Passweg, 261, Geneva, Switzerland; CIC 262, Jean-Paul Vernant, Pitie-Salpetrriere, Paris, France; CIC 273, Jacques-Olivier Bay, Jean Perrin, Clermont-Ferrand, France; CIC 281, Nicholas C. Zoumbos, Univ H, Patras, Greece; CIC 287, Ignazio Majolino, S Camillo - Forlanini, Rome, Italy; CIC 295, Rainer Blasczyk, Medical Univ, Hannover, Germany; CIC 307, Giuseppe Leone, Univ S Cuore, Rome, Italy; CIC 321, Francesco Lauria, Le Scotte, Siena, Italy; CIC 335, Jose David González San Miguel, H Insular, Las Palmas De Gran Canaria, Spain; CIC 339, Pierre Zachée, AZ Stuivenberg, Antwerp, Belgium; CIC 360, M.R. Schaafsma, MedSpTwente, Enschede, Netherlands, The; CIC 387, C. Craddock, Queen Elizabeth, Birmingham, United Kingdom; CIC 397, Mahmoud Aljurf, King Faisal, Riyadh, Saudi Arabia; CIC 566, Charles Crawley, Addenbrookes H, Cambridge, United Kingdom; CIC 577, Encarnacion Pérez Equiza, H de Navarra, Pamplona, Spain; CIC 606, Andrea Gallamini, S Croce e Carle, Cuneo, Italy; CIC 640, Joze Pretnar, Univ Med Ctr, Ljubljana, Slovenia; CIC 677, J. Holowiecki, Silesian Med Acad, Katowice, Poland; CIC 692, Maurizio Musso, La Maddalena, Palermo, Italy; CIC 718, Vladimir Koza, Charles Univ H, Pilsen, Czech Republic; CIC 722, J. Besalduch, Son Dureta, Palma De Mallorca, Spain; CIC 725, B.V. Afanassiev, Pavlov Med Univ, St. Petersburg, Russia; CIC 754, Arnon Nagler, Chaim Sheba M.C., Tel-Hashomer, Israel; CIC 756, Prof. William Arcese, Univ Tor Vergata, Rome, Italy; CIC 766, Bruno Rotoli, Federico II, Napoli, Italy; CIC 810, Jürgen Finke, University, Freiburg, Germany.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article. published online ahead of print at www.jco.org on May 27, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test for categoric variables and the Mann-Whitney U test for continuous variables. For prognostic analyses, continuous variables were categorized; each variable was first divided into five categories according to the percentiles. If the relative event rates in two or more adjacent categories were not substantially different, then these categories were grouped. If a linear trend was observed in the relative event rates, then the variable was used as a continuous factor. Otherwise, the median was used as a cutoff point. 
21 x 109/L v 53% ± 9% for WBC > 21 x 109/L; P = .05). Autologous transplantations, compared with allogeneic transplantations, were associated with a lower TRM rate (6% ± 1% v 24% ± 3%, respectively; P = .003) but a higher RI rate (28% ± 3% v 15% ± 2%, respectively; P = .03). The presence of additional chromosomal abnormalities and the use of HDARA-C before transplantation had no apparent impact on outcome. 
