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High-Dose Therapy and Autologous Stem-Cell Support for Chemosensitive Transformed Low-Grade Follicular Non-Hodgkin’s Lymphoma: A Case-Matched Study From the European Bone Marrow Transplant Registry

From the Department of Hematology, University College Hospital, and Departments of Medical Oncology and Histopathology, St Bartholomew’s Hospital, London, United Kingdom; Norwegian Radium Hospital, Oslo, Norway; Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Lyon, France; and Department of Internal Medicine, University of Kiel, Germany.

Address reprint requests to Catherine Williams, MD, Department of Medical Oncology, Christie Hospital, Wilmslow Road, Manchester, United Kingdom M20 4BX; email: catherine.williams{at}christie-tr.nwest.nhs.uk

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: To assess the outcome of high-dose therapy with autologous stem-cell support in patients with histologic transformation of low-grade follicular non-Hodgkin’s lymphoma (NHL) and identify significant prognostic factors, as well as to compare survival of these patients with that of patients with matched low-grade and de novo high- or intermediate-grade NHL undergoing the same procedure.

PATIENTS AND METHODS: Fifty patients with transformed low-grade NHL have been reported to the European Bone Marrow Transplant registry. Outcome from high-dose therapy and significant prognostic factors were analyzed. Their survival was also compared with that of 200 patients with matched low-grade NHL and 200 patients with matched de novo high- or intermediate-grade NHL by a case-matched analysis.

RESULTS: The procedure-related death rate among the 50 transformed NHL patients was 18%. Overall survival (OS) and progression-free survival (PFS) rates were 51% and 30% at 5 years, respectively. Median PFS time was 13 months. Raised lactate dehydrogenase levels at transformation (P = .0031) was identified as the only adverse significant predictor of PFS on multivariate analysis. A subgroup of patients with residual chemosensitive disease who attained complete remission after high-dose therapy had the best outcome, with an OS at 5 years of 69%. A comparison with matched patients with low-grade disease and with de novo high- or intermediate-grade lymphoma showed no significant difference in OS (P = .939 and P = .438, respectively).

CONCLUSION: Patients with chemosensitive transformed lymphoma should be seriously considered for high-dose therapy and autologous stem-cell support.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
THE TRANSFORMATION OF low-grade follicular lymphoma to high- or intermediate-grade histology is well recognized, occurring in up to 70% of patients during the course of their disease.^1-5 The occurrence of histologic transformation (HT) seems to be unrelated to prior therapy, with the incidence similar in those patients who were treated immediately after diagnosis and in those for whom therapy was delayed.¹ The prognosis of these patients is poor, with a median survival after transformation of under 1 year despite further conventional therapy.⁶ However, a subgroup of patients with limited disease and no previous exposure to chemotherapy may have a relatively long-term survival.⁷

High-dose myeloablative treatment (HDT) with autologous stem-cell support is being used increasingly in patients with both relapsed high-grade and low-grade non-Hodgkin’s lymphoma (NHL).^8,9 Studies have shown that some patients with relapsed low-grade NHL may experience prolonged disease-free survival after high-dose therapy.^10-12 However, outcome in patients with transformed disease remains unclear, with only a few series reported.^13,14 Of particular interest is the controversial issue of whether these patients would benefit from HDT early in the course of their disease with low-grade lymphoma or whether their prognosis is similar by delaying high-dose therapy until transformation has occurred. Several studies show no significant difference in survival between the two groups, but others suggest a worse prognosis in the transformed NHL patients.^11,14,15 Similarly, the question as to how these patients do compared with those undergoing HDT with de novo high- or intermediate-grade disease, for whom in some the procedure may prove curative, remains unanswered.

In this article, we report the results of 50 patients with transformed low-grade follicular lymphoma from the European Bone Marrow Transplant (EBMT) Lymphoma Registry who have undergone HDT with autologous stem-cell support. We also address the question of how these patients’ outcome compares with that of those patients undergoing the same procedure who have either low-grade NHL or de novo high- or intermediate-grade lymphoma by means of case-controlled analysis, matching the groups for any statistically significant factors.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
By January 1, 1996, 3,780 patients with NHL who had undergone autologous bone marrow transplantation had been reported to the EBMT Lymphoma Registry. Of these, 68 were identified as having received HDT and autologous stem cells with HT of follicular lymphoma. The classification used was the National Cancer Institute’s Working Formulation. The criterion for transformation was a follicular small cleaved-cell lymphoma or follicular mixed small cleaved-cell and large-cell cleaved lymphoma that had subsequently transformed to a diffuse large-cell, diffuse mixed small cleaved-cell and large-cell, or any high-grade lymphoma. Exclusions were any lymphoma with follicular and mixed architecture at diagnosis, follicular large-cell lymphoma due to lack of concordance among pathologists in defining this subtype, and diffuse small cleaved-cell lymphoma at diagnosis due to its indolent course. In order to verify the information reported to the registry on these patients, a supplementary questionnaire was sent to centers asking for review and confirmation of the histology both at diagnosis and at transformation. Sixty-four questionnaires (94%) were returned, and the patients of the physicians who failed to reply were excluded from the study. Of the questionnaires returned, 14 reported that at further review, HT was not certain or did not satisfy the criteria previously defined; therefore, these patients were also excluded. Thus, a total of 50 patients were eligible for analysis. To further confirm this, central histology review was arranged of both pre- and posttransformation biopsies (either lymph node or bone marrow) on these patients. Samples for 49 patients were therefore reviewed by A.J. Norton, MD (St Bartholomew’s Hospital, London, United Kingdom), and the diagnosis was confirmed to be transformed disease. One patient, for whom samples were not available, had detailed reports of immunocytochemistry on pre- and postbiopsy lymph nodes which confirmed transformed disease. The decision was therefore made to include this patient in the study. Of these 50 patients, 18 had been included in a previous series.¹³

Significant prognostic factors for these 50 patients were determined by both univariate (log-rank) and multivariate (Cox regression) analyses. Progression-free survival (PFS) was used as the measure of prognosis. PFS was measured in months and defined as the time from day of HDT until disease progression or death from any cause. Relapse/progression was defined as disease progression.

The group of 50 HT patients were then matched for any significant prognostic factors to patients with untransformed follicular lymphoma and to those with de novo intermediate- or high-grade lymphoma who had also undergone HDT. Results of the groups were compared.

Response Criteria
Patients who achieved a greater than 50% response to therapy received after transformation and before high-dose therapy were considered to have had a partial response (PR). Patients who had achieved a greater than 75% response to therapy were considered to be very good partial responders, and patients who had achieved a less than 50% response to therapy were deemed to be primary refractory.

Several patients had relapsed disease after an initial response to therapy given after transformation. Those who showed a PR to conventional-dose salvage chemotherapy were considered to have had sensitive relapse, and those with no response to such treatment were classified as having resistant relapse. Patients who had received no conventional salvage treatment on relapse but proceeded to HDT and stem-cell support were classified as having untested relapse.

Response to HDT was reviewed at 100 days. Response was classified as complete remission (CR) if there was no residual disease, PR if there was a 50% reduction in any one site, and no response (NR) if there was relapse or progression within 3 months. Survival was calculated as of date of last contact.

Statistical Analysis
The statistical methods used to select and case match the patients have previously been described.¹⁶ Survival analysis was carried out using the method of Kaplan and Meier.¹⁷ Stratified Cox regression¹⁸ was used for comparison between matched groups and log rank¹⁹ for comparison within groups. Comparisons of incidence of patient characteristics were performed using McNemar’s test or paired t test for continuous variables.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patient Characteristics
Characteristics of the 50 patients who underwent HDT and autologous stem-cell support with transformed lymphoma at diagnosis and transformation are listed in Table 1. There was an even distribution between the various transformations with no predilection for either of the low-grade histologies to one of the transformed. The majority of patients had extensive disease (stage III or IV) at both diagnosis (84%) and transformation (80%). Twelve of the 50 patients received no chemotherapy before transformation, with five of these having radiotherapy only. Characteristics at the time of HDT and stem-cell support are listed in Table 2. Thirty-one patients (62%) received autologous bone marrow and the remaining 19 (38%) had peripheral-blood stem cells returned. Overall, 19 (38%) of 50 patients entered HDT in CR and 44 (88%) of 50 had chemosensitive disease. Only three patients had known chemoresistant disease at the time of HDT. Of the 50 patients, 22 had bone marrow involvement at some stage in their disease, with only six having it at the time of HDT.

PRDs
PRDs were described as early ( 100 days) or late (> 100 days). There were four early PRDs, all of patients who had chemosensitive disease. Cause of death was infection in two patients, interstitial pneumonitis in one patient, and failure to engraft in one patient. There were five late PRDs, one due to interstitial pneumonitis, one due to septicemia, and three due to secondary malignancies.

Survival and Relapse
Among the 50 patients who underwent HDT and autologous stem-cell support with transformed lymphoma, the median follow-up time was 4 years 11 months (range, 1 year 8 months to 7 years nine months). The overall survival (OS) rates at 2 and 5 years were 64% and 51%, respectively, and the PFS rate at 5 years was 30%. with a median PFS time of 13 months ( Fig 1). Overall, 24 of 50 patients died, nine from PRD and 15 (30%) from disease progression or relapse. Twenty-six patients (52%) are still alive; 15 of them are in CR, two are in stable PR, and nine have relapsed or progressed. Of the 31 patients whose initial response to HDT was CR, 16 have relapsed or died.

View larger version (10K): [in this window] [in a new window]   Fig 1. OS and PFS after HDT in patients with transformed low-grade follicular lymphoma.

Analysis of Prognostic Factors
To ascertain which factors may significantly effect survival, both univariate and multivariate Cox regression analyses were performed. Results are listed in Table 3. On multivariate analysis, the lactate dehydrogenase (LDH) level at transformation was found to significantly affect both OS and PFS, with those patients who had a raised level doing worse. Unfortunately, LDH was not measured in nine patients. Status at time of HDT was also found to be a significant prognostic factor for PFS, with chemosensitive patients doing better than chemoresistant patients. On univariate analysis, LDH was again significant for PFS. Histology at diagnosis and transformation, stage at diagnosis and transformation, no chemotherapy before transformation, the use of total-body irradiation in the conditioning regimen, and the time of achieving CR did not significantly affect survival.

Comparison of Outcome to Matched Group of Patients With Low-Grade Follicular Lymphoma Who Had Received HDT
To compare outcome, each of the 50 patients with transformed lymphoma was matched to four patients from the EBMT Lymphoma Registry who had undergone HDT with low-grade follicular lymphoma. The patients were matched for stage at diagnosis and status at HDT because these factors have been shown to significantly affect survival, either among the transformed group of patients or in previous analyses of patients with NHL in the EBMT registry. Unfortunately, we could not match for LDH levels because these data are not collected routinely on registry patients. Date of HDT was matched as closely as possible. Therefore, overall, 50 transformed lymphoma patients were matched to 200 patients with low-grade lymphoma who had received HDT. There was no significant difference in OS or PFS (P = .939 and P = .673, respectively) ( Figs 2 and 3).

View larger version (12K): [in this window] [in a new window]   Fig 2. OS after HDT in 50 patients with transformed low-grade follicular lymphoma compared with 200 matched patients with low-grade lymphoma (P = .939, by stratified Cox regression).

View larger version (11K): [in this window] [in a new window]   Fig 3. PFS after HDT in 50 patients with transformed low-grade follicular lymphoma compared with 200 matched patients with low-grade lymphoma (P = .673, by stratified Cox regression).

View larger version (13K): [in this window] [in a new window]   Fig 4. OS after HDT in 50 patients with transformed low-grade follicular lymphoma compared with 200 matched patients with de novo high- or intermediate-grade lymphoma (P = .438, by stratified Cox regression).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

Few studies have looked at the survival of patients after HDT for transformed lymphoma, but the OS and PFS of the transformed lymphoma patients in our study group compared favorably to these studies. At 5 years, the OS and PFS rates were 51% and 30%, respectively, in our patients. The overall PRD rate was 18%, with 8% of these within the first 100 days. This PRD rate is high compared other series of patients with nontransformed disease receiving HDT; possible causes for this high rate were examined. There was no difference in mortality for those patients who received stem cells instead of bone marrow, and the high PRD rate did not seem to relate to supportive issues. In addition, the total number of chemotherapy lines received by the nine patients who had PRD did not differ significantly from that of the other patients in this study, although these nine patients probably received more lines than patients in other series with nontransformed disease. Of note, all nine patients underwent conditioning with total-body irradiation, which, although not significant in the group as a whole in terms of OS, when combined with previous alkylating agents, may have contributed to the high incidence of secondary malignancies seen (6%).

In contrast, our PRD rate compares favorably to that reported by Schouten et al¹⁴ in 10 patients who underwent HDT for transformed lymphoma. In this study, a PRD of 70% and a median OS of 2 months were seen; however, the majority of these patients had disseminated chemoresistant disease and hence represent a very-poor-prognosis group. This compares with 88% of patients in our study who had chemosensitive disease at the time of HDT, with more than 40% of these patients being in CR possibly contributing to improved survival rates. A similar group of 18 patients was studied by Freedman et al¹¹; of these patients, 10 were in CR, with a PFS rate of 23% at 4 years. Bastion et al¹⁵ reported the outcome of peripheral-blood stem-cell transplantation in 60 patients with low-grade lymphoma, of whom 16 had transformed disease. Although the PFS of the transformed patients was significantly lower than that of the low-grade disease patients, the median time to relapse was 14 months, the same as in our study. A recent report by Foran et al¹³ of HDT in patients with transformed disease found results similar those of our own series, with 17 (63%) of 27 patients alive at a median follow-up of 2.4 years. In this series, patients were highly selected, with all having chemosensitive disease at the time of HDT.

Analysis of factors that may be prognostic for survival in our study showed that raised LDH levels at the time of transformation was the main adverse factor. Chemosensitive disease at time of HDT proved to be favorable. Yuen et al,⁷ in a recent article, examined outcome of patients with transformed low-grade lymphoma who had received conventional therapy only. Prognostic factors for survival found in this study were the stage of disease at transformation, whether chemotherapy had been given before transformation, and response to treatment (CR v PR/NR). Stage of disease at transformation will almost certainly correlate with LDH levels, as found in our study. Status at time of HDT also proved to be significant in our analysis. Those patients who were treated with HDT in CR have a survival similar to that of patients who received conventional treatment and attained CR after transformation in Yuen et al’s study. However, patients who attained PR after transformation in that study had a generally poor prognosis. This should be compared with our study, in which those patients receiving HDT who had residual chemosensitive disease achieved a PFS at 5 years of 40%, similar to the 32% seen in patients treated in CR. Of these patients with residual chemosensitive disease before HDT, a subgroup who attained CR after HDT did particularly well, with an OS and PFS at 5 years of 69% and 47%, respectively. Therefore, there does seem to be a group of patients transforming to high-grade lymphoma with residual chemosensitive disease after chemotherapy who may benefit from HDT. This may be further supported by the study by Foran et al.¹³ However, the only way to definitively compare conventional with HDT in the treatment of transformed follicular lymphoma is a matched comparison or randomized trial.

As mentioned previously, there is an increasing trend to use transplantation to treat patients with low-grade lymphoma based on evidence from several studies that freedom from disease progression may be enhanced compared with treatment with conventional chemotherapy alone.^10,21 The number of such patients reported to the EBMT Lymphoma Registry has continued to increase, with 3,069 patients reported by the end of 1999. A large percentage of these patients would have eventually transformed to high- or intermediate-grade disease. However, some patients’ disease may undergo HT before HDT can be considered, and the decision of whether to proceed to HDT becomes more difficult. Several studies have compared results of HDT in low-grade and transformed lymphoma showing no difference in OS; however, patients have not been matched for significant prognostic factors.^11,15 Our results, comparing survival in these groups of patients by matched analysis, also show no significant difference in survival between transformed and low-grade lymphoma. Unfortunately, LDH levels were not available on a sufficient number of patients for this to be included as a matching criterion. However, stage at diagnosis was matched and, as mentioned previously, may correlate with LDH levels. These results support the argument that patients with transformed lymphoma should be seriously considered for HDT. It must, however, be acknowledged that the group of patients who go on to HDT with transformed disease are almost certainly selected for good prognostic factors, such as chemosensitivity, and it cannot therefore be specifically recommended that patients with low-grade lymphoma actively wait until HT to be treated with HDT, since there can be no guarantee of fulfilling these criteria.

Similarly, we found no significant difference in either OS or PFS between patients with transformed lymphomas and those matched patients with de novo high- or intermediate-grade disease who underwent transplantation. However, median PFS time was longer in the latter group at 23 months compared with14 months in the transformed lymphoma patients, indicating that the transformed lymphoma patients may live longer after relapse or progression than those with de novo high- or intermediate-grade disease.

In conclusion, this study identified a subgroup of patients with residual chemosensitive disease after conventional therapy who may benefit from HDT by attaining CR and having a particularly good outcome. Therefore, we suggest that patients with chemosensitive transformed lymphoma should be seriously considered for HDT and autologous stem-cell support.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
We acknowledge the contributions from the following centers whose patients were included in this study:

From Italy: P. Franco, University of Genova, Genova; A. Carella, Ospedale San Martino, Genova; S. Morandi, Centro Trapianti Di Midollo Osseo, Cremona; M. Falda, Azienda Ospedaliera S. Giovanni, Torino; F. Mandelli, Univ Degli Studi La Sapienza, Rome; S. Tura, Hospital San Orsola, Bologna; V. Rizzoli, University of Parma, Parma; G. Torlontano, Ospedale Civile, Pescara; G. Lambertenghi Deliliers, Ospedale Maggiore Di Milano, IRCCS, Milan; G. Dini, Institute G. Gaslini, Genova; C. Messina, Centro Leucemie Infantili, Padova; P. Emilio, Alessandrino, IRCCS, Policlinico San Matteo, Pavia; A. De Laurenzi, S. Camillo Hospital, Rome; T. Izzi, Spedali Civili–Brescia, Brescia; R. Cairoli, Ospedale Niguarda Ca’ Granda, Milan; P. Coser, Hospital San Maurizio, Bolzano; A. Bosi, Ospedale Di Careggi, Firenze; A. Busca, University of Torin, Ospedale Regina Margherita, Torino; G. Rosti, Ospedale Civile, Ravenna; L. Giuseppe, Universita Cattolica S. Cuore, Rome; C. Battista, Ospedale Cardarelli, Napoli; F. Lauria, Ospedale Sclavo, Siena; P. Mazza, Hospedale Nord, Tarento; I. Majolino, Ospedale v Cervello, USL, Palermo; G.L. Cetto, Universita Di Verona, Ospedale Civile Maggiore, Verona; M. Mario, Greco, Hospital Casa Sollievo Della Sofferenza, San Giovanni Rotondo; F. Narni, Policlinico, Universita Di Modena, Modena; P. Pioltelli, Ospedale S. Gerardo, Universita Di Milano, Monza; F. Locatelli, IRCCS Policlinico San Matteo, University of Pavia, Pavia; P. Iacopino, Azienda Ospedaliera, Reggio Calabria; A. Gianni, Istituto Nazionale Tumori, Milan; G. Perona, University of Verona, Verona; V. Pavone, Azienda Policlinico Bari, Universita’degli Studi Di Bari, Bari; T. Barbui, Ospedale Bergamo, Bergamo; M. Baccarani, Department of Bone Marrow Transplantation, Udine; S. Amadori, Universita Tor Vergata, Rome; B. Rotoli, University of Napoli, II Faculty of Medicine and Surgery, Napoli; A. Zambelli, Fondazione S. Maugeri, Pavia; P. Leoni, Ospedale Di Torrette Di Ancona, Ancona; E. Volpe, "Giovanni Di Guglielmo," Avellino; A. Pession, University of Bologna, Bologna; G. Broccia, Ospedale Oncologico, Cagliari; R. Giustolisi, University of Catania, Catania; A. Palmas, Ospedale "San Francesco," Nuoro; M. Martelli, University of Perugia, Perugia; P. Macchia, Clinica Pediatrica, University of Pisa, Pisa; F. Rodeghiero, S Bortolo Hospital, Vicenza; G. Mariani, Univ Di Palermo/Policlinico, Palermo; and A. Rubino, Az Policlinico "Federico II," Napoli.

From France: A. Fischer, Hopital Necker, Paris; C. Gisselbrecht, Hopital St Louis, Paris; N.C. Gorin, Hopital Saint Antoine, Paris; R. Zittoun, Hotel Dieu, Paris; D. Blaise, Inst Paoli I. Calmettes, Marseille; J.-Y. Cahn, Hopital Jean Minjoz, Besançon; T. Philip, Centre Leon Berard, Lyon; Witz, Hopital De Nancy, Nancy; D. Guyotat, Hopital Nord, Saint Etienne; O. Reman, Hopital Caen, Caen; C. Cordonnier, CHU Henri Mondor, Creteil; J.L. Harousseau, Hotel Dieu, Nantes; V. Leblond, Pitie-Salpetriere, Paris; F. Guilhot, Hopital La Miletrie, Poitiers; J. Reiffers, CHR Bordeaux, Hopital Du Haut Leveque, Pessac; J.J. Sotto, Hopital A. Michallon, Grenoble; Ph. Colombat, Hopital Bretonneau, Tours; M. Legros, Centre Jean Perrin, Clermont-Ferrand; J.-P. Jouet, Hopital Claude Huriez, Lille; Belanger, Hopital Cochin, Paris; C. Coze, Hopital d’Enfants De La Timone, Marseille; O. Hartmann, Institut Gustave Roussy, Villejuif; N. Gratecos, Hopital De L’archet I, Nice; M. Janvier, Centre Rene Huguenin, St Cloud; F. Demeocq, Centre Hospitalier Universitaire, Clermont-Ferrand; M. Attal, Hopital De Purpan, Toulouse; M. Boasson, Médecine Interne-CHU, Angers; T. De Revel, Hopital Percy, Clamart; M. Michallet, Hopital E. Herriot, Lyon; J. Michon, Institut Curie, Paris; V. Izrael, Hopital Tenon, Paris; A. Baruchel, Hopital St Louis, Paris; C. Gisselbrecht, Hopital St Louis, Paris; J.F. Rossi, University Hospital, Montpellier; Tilly, Centre Rouen Becquerel, Rouen; P. Henon, Hopital Emile Muller, Mulhouse; P. Casassus, Hopital Avicienne, Bobigny; A.M. Peny, CAC Francois Baclesse, Caen; Lutz, Hopital De Hautepierre, Strasbourg; B. Desablens, Hopital Sud, Amiens; B. Pignon, CHU Robert Debre, Reims; L. Degros, Hopital St Louis, Paris; Y. Kerneis, Hopital Rene Dubos, Pontoise; M. Fabbro, CAC Val d’Aurelle, Montpellier; A. Demaille, Centre Oscar Lambret, Lille; F. Mayer, Centre GF Leclerc, Dijon; and D. Bordessoule, Centre Hospitalier Dupuytren, Limoges.

From Switzerland: A. Gratwohl, Kantonsspital, Basel; C. Stebler, SRK Basel, Basel; A. Tyndall, Felix Platter Spital, Basel; T. Kühne, Basler Kinderspital, Basel; R. Seger, University Childrens’ Hospital, Zurich; A. Tobler, University Hospital Bern, Bern; M. Starobinski, Hopital Cantonal Universitaire, Geneva; M. Wernli, Center of Oncology/Hematology and Transfusion Medicine, Aarau; and S. Leyvraz, CHUV-10, Lausanne.

From the Netherlands: J.J. Van Rood, Leiden University Medical Centre, Leiden; T. De Witte, University Hospital St Radboud, Nijmegen; L. Spronk, University Hospital, Utrecht; J.J. Cornelissen, Dr Daniel Den Hoed Cancer Center, Rotterdam; F. Loo, University Hospital, Leiden; P. Wijermans, Leyenburg Hospital, The Hague; and H. Schouten, University Hospital Maastricht, Maastricht.

From Germany: B. Kubanek, DRK-Blutspendezentrale/Universität Ulm, Ulm; L. Kanz, University Hospital, Tübingen; N. Schmitz, Christian-Albrechts-Univ, Kiel; U.W. Schaefer, University Hospital, Essen; W. Siegert, Virchow Klinikum-Humboldt Universität Berlin, Berlin; K. Welte, Medical School of Hannover, Hannover; F. Universitat Ulm, Ulm; D. Hoelzer, Zentrum Inn Medizin-Universität Frankfurt, Frankfurt; H.-J., Schmoll, Innere Medizin IV, Martin-Luther Universitat, Halle; R. Haas, Heinrich-Heine University Düsseldorf-Medizinische Einrichtungen, Düsseldorf; H.-J. Kolb, Klinikum Gro§hadern, München; G. Maschmeyer, Univ Charité Der Humboldt Universität, Berlin; J. Anhuf, St John’s Hospital, Duisburg; G. Doelken, Klinik Und Poliklinik Fur Innere Medizin C/Ernst-Moritz-Arndt Univ, Greifswald; V. Diehl, University of Köln, Köln; D. Niethammer, University Hospital, Tübingen; M. Freund, Universität Rostock, Rostock; W. Knauf, Universitätsklinikum Benjamin Franklin, Berlin; A., Zander, Universitätskrankenhaus Eppendorf, Hamburg; H. Wandt, Klinikum Nürnberg, Nürnberg; M. Wolf, Philipps-Universität Marburg, Marburg; Büchner, University of Munster, Munster; B. Metzner, Stadt Kliniken Oldenburg, Oldenburg; F. Zintl, University of Jena, Jena; L. Trümper, University of Saarland, Homburg/Saar; C. Huber, Johannes-Gutenberg-University, Mainz; R. Andreesen, Universität Regensburg, Regensburg; R. Arnold, Charite Campus Mitte, Berlin; and J. Beck, University of Erlangen, Erlangen.

From Denmark: N. Jacobsen, Rigshospitalet, Copenhagen; N. Hansen, Herlev Hospital, Herlev; and A.M. Boesen, Arhus Amtssygehus, Arhus.

From Belgium: M.A. Boogaerts, University Hospital, Leuven; D. Bron, Institut Jules Bordet, Brussels; A. Ferrant, Cliniques Universitaires St Luc, Brussels; P. Zachee, A.Z. Stuivenberg, Antwerpen; D. Selleslag, A.Z. Sint-Jan, Brugge; W. Feremans, U.L.B.-Hopital Erasme, Brussels; R. Schots, University Hospital VUB, Brussels; Y. Beguin, CHU Sart-Tilman, University of Liege, Liege; Y. Benoit, University Hospital Gent, Gent; C. Dubois, Clinique Général Saint-Jean, Brussels; and R. De Bock, AZ Middelheim, Antwerp.

From Sweden: B. Bjorkstrand, Huddinge Hospital, Huddinge; B. Simonsson, University Hospital, Uppsala; A.N. Békássy, University Hospital, Lund; M. Björkholm, Karolinska Hospital, Stockholm; M. Brune, Sahlgrenska University Hospital, Goeteborg; K. Willman, Örebro Medical Center, Örebro; and G. Juliusson, University Hospital.

From Spain: E. Carreras, Postgraduate School of Hematology, Barcelona; J. Fernndez-Ranada, Hospital De La Princesa, Madrid; A. Torres Gomez, Cordoba Hospital, Cordoba; A. Iriondo, Hospital Universitario, Santander; J. Sierra, Hospital Santa Creu I Sant Pau, Barcelona; J. Garcia-Conde, Hospital Clinico Universitario, Valencia; E. Garcia Maldonado, Hospital Regional De Malaga, Malaga; K. Perez Equiza, Hospital De Navarra, Pamplona; A. Juliá, RG Vall Hebron, Barcelona; R. Lasa Isasti, Hospital Nuestra Senora Arnzazu, San Sebastian; M. Sanz, Hospital Universitario La Fe, Valencia; J. Besalduch, Hospital Son Dureta, Palma de Mallorca; D. Caballero, Hospital Clinico, Salamanca; M. Fernndez, Clinica Puerta De Hierro, Madrid; J.M. Moraleda, Hospital General Universitario, Murcia; A. Grañena, Clinica Corachan, Barcelona; A. Grañena, Institut Catala d’Oncologia, Barcelona; and J.M. Rodriguez Fernandez, Hospital Universitario "Virgen Del Rocio," Sevilla.

From the United Kingdom: H.G. Prentice, Royal Free Hospital, London; A.C. Parker, Western General Hospital, Edinburgh; I. Franklin, Glasgow Royal Infirmary, Glasgow; D.L. Barnard, St James’s University Hospital, Leeds; T. Littlewood, The Oxford Radcliffe Hospital, Oxford; S. Mccann, St James Hospital Trinity College, Dublin, Ireland (Rep); P.J. Gravett, The London Clinic, London; S.J. Proctor, Royal Victoria Infirmary, Newcastle on Tyne; D.W. Milligan, Birmingham Heartlands Hospital, Birmingham; A.K. Burnett, College of Medicine, University of Wales, Cardiff; T. Fitzsimons, The Western Infirmary, Glasgow; P. Mahendra, University Hospital Birmingham National Health Service Trust, Birmingham; R.E. Clark, Royal Liverpool University Hospital, Liverpool; D. Samson, Hammersmith Hospital, London; R. Marcus, Addenbrookes Hospital, Cambridge; C.R.J. Singer, Royal United Hospital, Bath; J.W. Sweetenham, Southampton General Hospital, University of Southampton, Southampton; N.H. Russell, Nottingham City Hospital, Nottingham; D.T. Bowen, Ninewells Hospital, Dundee, Scotland; S.A. Schey, Guy’s Hospital, London; H. Parry, North West Wales National Health Service Trust, Bangor Gwynedd; T.C.M. Morris, Belfast City Hospital, Belfast; G.J. Mufti, King’s Healthcare National Health Service Trust, London; D. Wright, Pontefract General Hospital, Pontefract, West Yorks; H. Myint, Royal Bournemouth Hospital, Bournemouth; A.Rohatiner, St Bartholomew’s and The Royal London Hospital, London; E. Vandenberghe, The Royal Hallamshire Hospital, Sheffield; L. Anderson, The Children’s Hospital, Sheffield; G. Morgenstern, Christie National Health Service Trust Hospital, Manchester; and P. Lorigan, Weston Park Hospital, Sheffield.

From Finland: U. Pihkala, University of Helsinki, Helsinki; K. Remes, Central Hospital/Turku University, Turku; L. Volin, Helsinki University Central Hospital, Helsinki; and P. Kellokumpu-Lehtinen, Tampere University Hospital, Tampere.

From Austria: H. Greinix, University of Vienna, Vienna; D. Nachbaur, University Hospital, Innsbruck; W. Linkesch, University of Graz, Graz; Fridrik, Linz; Baumgartner, Vienna; H. Gadner, St Anna Kinderspital, Vienna; D. Lutz, Elisabethinen-Hospital, Linz; R. Reisner, Hanuschkrankenhaus, Vienna; and H. Ludwig, Wilhelminenspital, Vienna.

From Israel: S. Slavin, Hadassah University Hospital, Jerusalem; I. Ben-Bassat, Tel-Aviv University, Tel-Hashomer; and I. Yaniv, Rabin Medical Center, Schneider Children’s Medical Center of Israel, Petach-tikva.

From Greece: A. Fassas, The George Papanicolaou General Hospital, Exokhi; N. Harhalakis, Evangelismos Hospital, Athens; and G. Karianakis, Diagnostic & Therapeutic Center of Athens, Athens.

From Australia: R.M. Green, The Queen Elizabeth Hospital, Woodville; V. Smith, Royal Perth Hospital, Perth; and P. Shaw, The New Children’s Hospital, Sydney.

From Portugal: P. Pimentel, Inst Portugues Oncologia, Centro Porto, Porto; and M. Abecasis, Inst Portugues Oncologia, Lisboa.

From Turkey: E. Kansu, University Hospital Hacettepe, Ankara; M. Bayik, Marmara Universitesi Hastanesi, Istanbul; Y. Tangün, Istanbul Medical School, Istanbul; and B. Ferhanoglu, Cerrahpasa Medical School, Istanbul.

From Croatia: B. Labar, University Hospital Centre-Rebro, Zagreb.

From the Czech Republic: T. Kozak, University Hospital of the 3rd Medical School, Prague; J. Vorlìcek, Masaryk University Hospital, Brno; J. Stary, University Hospital Motol, Praha; V. Koza, Charles University Hospital, Pilsen; S. Filip, Charles University; and M. Apltauerova, Charles University Hospital, Praha.

From Slovakia: H. Mocikova, Roosevelt Hospital, Banska Bystrica.

From Hungary: K. Paloczi, National Institute of Hematology and Immunology, Budapest; and S. Fekete, St Laszlo Hospital Budapest, Budapest.

From South Africa: N. Novitzky, UCT Medical School, Capetown; and P. Jacobs, Constantiaberg Medi-Clinic, Cape Town Plumstead.

From Poland: A. Lange, K. Dluski Hospital and Institute of Immunology and Experimental Therapy, Wroclaw; J. Hansz, K. Marcinkowski University of Medical Science, Poznan; and J. Walewski, Centre of Oncology/Maria Sklodowska-Curie-Mem Institute, Warszawa.

From Iran: A. Ghavamzadeh, Shariati Hospital, Tehran.

From Russia: B.V. Afanasiev, I Pavlov State Medical Universite, St Petersburg.

From Argentina: L. Feldman, Antarartida Hospital Privado, Buenos Aires.

From Norway: S. Kvaloy, The Norwegian Radium Hospital, Oslo.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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Submitted April 24, 2000; accepted September 26, 2000.

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