To evaluate the outcome of a large series of patients who received high-dose treatment (HDT) for follicular lymphoma (FL), 693 patients undergoing HDT (total-body irradiation (TBI)-containing regimen: 58%; autologous bone marrow (BM)/peripheral blood progenitor cells (PBPCs): 378/285 patients) were included in the study. A total of 375 patients (54%) developed recurrent lymphoma, 10-year progression-free survival (PFS) being 31%. On multivariate analysis, younger age (P=0.003) and HDT in first complete remission (CR1) (P<0.001) correlated with longer PFS. With a median follow-up of 10.3 years, 330 patients died. Ten-year overall survival (OS) from HDT was 52%. Shorter OS was associated on multivariate analysis with older age (P<0.001), chemoresistant disease (P<0.001), BM+PBPC as source of stem cells (P=0.007) and TBI-containing regimens (P=0.004). Thirty-nine patients developed secondary myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), in 34 cases having received TBI as the conditioning regimen. The 5-year non-relapse mortality (NRM) was 9%. On multivariate analysis, older age (P<0.001), refractory disease (P<0.001) and TBI (P=0.04) were associated with a higher NRM. This long follow-up study shows a plateau in the PFS curve, suggesting that a selected group of patients might be cured with HDT. On the downside, TBI-containing regimens are associated with a negative impact on survival.
Follicular lymphoma (FL) is the second commonest type of non-Hodgkin's lymphoma in Western countries.1 Although the median survival for patients with FL is relatively long in comparison with other subtypes, this disease remains incurable, with a continuous relapse pattern, the rate and duration of response decreasing in subsequent recurrences.2 Numerous attempts to improve the outcome of patients with FL have been made, including consolidation of the response with high-dose treatment (HDT) and autologous stem cell (ASC) support.3, 4, 5, 6, 7, 8, 9
The use of HDT with ASC support has increased considerably over the last 25 years.10 In recent years, three randomized trials in newly diagnosed11, 12 or relapsed patients13 have shown significantly prolonged progression-free survival (PFS) in patients receiving HDT in comparison with conventional chemotherapy. A survival advantage has also been demonstrated in one of the studies.13 However, the potential long-term toxicity of the procedure, especially the development of secondary myelodysplasia,14, 15, 16 remains a matter of concern. In addition, there is the problem of recurrence. Allogeneic transplant, the only potentially curative option for patients with FL, is associated with a prohibitive high toxicity in a relatively old and heavily pretreated population. The advent of reduced-intensity conditioning regimens (RIC) has increased the number of patients eligible for this procedure, who might also be candidates for HDT with ASC rescue. As a result and despite the widespread use of HDT, the indications for this treatment in FL and its optimal timing are still highly controversial.
The aim of this retrospective study was therefore to report the data from a large series of patients with FL who received HDT with ASC rescue before 1995, to characterize the outcome of this population with long follow-up.
Patients and methods
From 1979 to 1995, 878 patients with FL who underwent HDT with ASC rescue were reported to the EBMT registry. Patients with histological transformation at the time of HDT, those undergoing a second transplant and those with a follow-up of less than 5 years were excluded. Thus, 693 patients were included in the analysis. The clinical characteristics of the patients at the time of diagnosis and HDT are summarized in Table 1. Central review of the pathology was not carried out. The median time from diagnosis to HDT was 2.2 years (range, 1 month to 22 years), with 24% of the patients receiving HDT during the first year after diagnosis. One hundred and ninety-eight patients (29%) had never achieved a complete remission (CR) before HDT. One-fifth of the patients received HDT after achievement of first CR (CR1), 38% of them having needed more than one chemotherapy line to achieve CR1. The clinical characteristics of these patients at diagnosis and at HDT are listed in Table 1. Five hundred and sixty-three of the patients (81%) were treated after 1990. The follow-up for patients reported to the EBMT registry is updated annually. The follow-up was updated in the last 3 years for 238 of 363 (66%) living patients.
The source of progenitor cells and the conditioning regimens are detailed in Table 1. Ex vivo manipulation of the bone marrow (BM) or peripheral blood progenitor cells (PBPCs) was carried out in 283 of 633 patients with known data (45%). The commonest method of purging (75%) was negative selection with a combination of monoclonal antibodies and complement. The proportion of patients who received a total-body irradiation (TBI)-containing regimen was 51% in patients treated before 1990 and 60% in patients treated thereafter. Supportive care was given according to local protocols at each centre.
According to the EBMT guidelines,17 complete response (CR) was defined as the disappearance of tumour masses and disease-related symptoms, as well as normalization of initially abnormal tests and/or biopsies. Partial response (PR) was considered when measurable lesions decreased by at least 50%. A very good partial response (VGPR) was defined as a reduction in tumour burden of at least 90%. For the purpose of this analysis, patients achieving a PR or a VGPR were grouped together, since these definitions predate the 1999 consensus statement.18 Recurrence was defined as the occurrence of new sites of disease after a CR lasting for 3 months or longer, whereas it was considered progression when the CR had lasted less than 3 months or CR had not been achieved. Recurrence or progression was considered to be ‘chemosensitive’ if at least PR was achieved after salvage treatment, otherwise ‘chemoresistant’. The recurrence/progression was deemed ‘untested’ if the patient had no further treatment after recurrence.17
Overall survival (OS) was defined as the time from HDT to death from any cause, and surviving patients were censored at last follow-up. PFS was defined as time from HDT to recurrence, progressive disease or death from any cause. Non-relapse mortality (NRM) was defined as death from any cause without progression.
The probabilities of OS and PFS were estimated from the time of HDT using Kaplan–Meier curves, and compared by the log-rank test. Estimates of NRM and recurrence or progression were calculated using cumulative incidence (CI) rates taking into account the competing risk structure, and compared by univariate Cox regression models. The risk of secondary malignancies after HDT was investigated by CI considering death from any cause as a competing event. The univariate analysis was carried out for the main characteristics at diagnosis and at the time of HDT. For the multivariate analysis, potential prognostic factors for NRM, recurrence, PFS and OS were first entered into the model; covariates found not to be significant at the 0.10 level were removed from the Cox proportional hazards model in a stepwise backward way. In each model, the assumption of proportional hazards was tested for each variable using time-dependent covariates.19, 20 As the effect of TBI on outcome changed over time (nonproportional hazard), models were constructed to break the post-HDT time course into two periods, using the most appropriate break point.
CIs were calculated using the NCSS 97 software. All other computations were carried out in the SPSS 13.0 statistical package.
Risk of recurrence and progression-free survival
The median follow-up for living patients was 10.3 years (range: 5–19.5). Three hundred and seventy-five patients (54%) developed recurrent disease at a median of 1.5 years after HDT (range: 1 month–13.5 years). On univariate analysis, patients who received a TBI-containing regimen had a lower risk of recurrence than the remainder (43% at 5 years versus 53%). The risk of recurrence also related to disease status and interval from diagnosis to HDT. On multivariate analysis (Table 2), disease status (P<0.001) and conditioning regimen (P=0.05) retained predictive value for the risk of recurrence.
PFS for the overall series at 5, 10 and 15 years was 44, 31, and 27%, respectively (Figure 1a). The variables that predicted for a shorter PFS on univariate analysis were age at HDT⩾45 years, disease status at HDT other than CR1, time from diagnosis to HDT⩾1 year and more than two lines of treatment before HDT. Age (P=0.003) and disease status (P<0.001) remained significant on multivariate analysis (Table 2). PFS at 5, 10 and 15 years for patients treated in CR1 was 59, 48 and 39%, respectively, whereas the corresponding figures for patients treated in responses other than CR1 were 41, 28 and 26%, respectively (Figure 1b). The number of previous therapy lines had no impact on PFS for patients treated in CR1.
Overall survival and causes of death
A total of 330 patients died, the median OS being 12 years. Two hundred and thirty-seven died following disease progression: 233 due to disease and 4 due to a second malignancy. The causes of death for the 93 remaining patients were as follows: treatment-related toxicity: 61 (66%), second malignancies: 25 (27%) and other causes: 7 (7%). OS at 5, 10 and 15 years was 64, 52, and 47%, respectively (Figure 2a). Older age (⩾45 years), disease status at HDT other than CR1, interval from diagnosis to HDT⩾1 year, more than two lines of treatment before HDT and a TBI-containing regimen were all associated with shorter survival on univariate analysis. The variables that retained significance on multivariate analysis (Table 2) were age (P<0.001), disease status (P<0.001), source of the stem cells (P=0.007) and conditioning regimen (P=0.004). After 5 years of follow-up, the OS was shorter for patients receiving a TBI-containing regimen, no difference being apparent during the first 5 years of follow-up (Figure 3). OS at 5, 10 and 15 years for patients treated in CR1 was 75, 72 and 60%, respectively; when those patients were excluded from the analysis, the corresponding figures were 62, 48 and 44%, respectively (Figure 2b). Amongst patients treated in CR1, the number of previous therapy lines did not influence OS.
Ninety-three patients died without evidence of disease progression, 53 (57%) less than 1 year after HDT. The causes of death for the latter were: infection: 36 (68%) (bacterial: 12, non-specified: 9, interstitial pneumonitis: 8, viral: 5, Pneumocystis carinii: 1, fungal: 1); organ failure: 4 (7%); other causes: 5 (9%) (cardiac toxicity: 2 and veno-occlusive disease, adenocarcinoma of the jejunum, and graft failure, 1 each) (9%) and non-specified treatment-related: 8 (15%). Forty patients died without disease progression more than 1 year after HDT. Their causes of death were second malignancy: 24 (60%), HDT-related causes: 9 (22%) (non-specified treatment related: 4, organ failure: 2 and cardiac toxicity, viral infection and interstitial pneumonitis, 1 each). Seven patients died from other causes (18%) (not specified: 4, myocardial infarction: 2 and bronchiolitis: 1). NRM at 1 and 5 years was 6 and 9%, respectively, for both the overall series and for patients who were not in CR1 at the time of HDT. There was no significant difference in NRM in relation to time period. The variables that influenced NRM on univariate analysis were age, disease status and conditioning regimen. With regard to TBI, the NRM at 5 and 10 years was 4 and 6% for patients not receiving TBI and 11 and 16% for the remainder (P=0.002). On multivariate analysis (Table 2), age at HDT⩾45 years (P<0.001), chemoresistant disease at HDT (P<0.001) and a TBI-containing regimen were predictive for a higher NRM. TBI-containing regimens did not have an impact on early NRM, but were associated with a higher NRM after 5 years of follow-up (P=0.04).
Sixty-four patients (9%) developed a second malignancy at a median of 7 years after HDT (range: 1–17). The CI of second malignancies at 5, 10 and 15 years was 2, 5 and 21%, respectively, for patients treated in CR1, whereas it was 4, 9 and 15% for the remainder (P=NS). The most frequent was secondary myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML). The specific diagnoses are listed in Table 3. The median time from HDT to diagnosis of a second malignancy was 5 years for MDS/AML and 9 for the remaining second neoplasms. The diagnoses of second malignancy were made before progression of lymphoma in 53% of the patients for both MDS/AML and other malignancies. Forty-six patients with a second malignancy (72%) died (29 due to the second neoplasm and 17 due to lymphoma progression). Thirty-three of 40 patients with secondary MDS/AML died (82%), 20 due to MDS/AML (17 without having developed disease progression). Second malignancies were diagnosed in 54 patients (13.5%) who had received a TBI-containing regimen, contrasting with 10 patients (3.5%) who received a chemotherapy-only regimen (P<0.001). Likewise, the proportion of patients developing secondary MDS/AML was significantly higher in those who received TBI as part of the HDT: 34 of 401 (8.5%) versus 5 of 289 (1.7%) (P<0.001). A multivariate analysis for the risk of developing a second neoplasm was carried out (Table 2), including gender, age at HDT, number of previous lines of chemotherapy, interval from diagnosis to HDT, source of stem cells, year of HDT and conditioning regimen. The variables that predicted for a higher risk of second malignancies were (1) the use of a TBI-containing regimen (P<0.001), (2) age at HDT⩾45 years (P=0.003) and (3) more than two previous therapy lines (P=0.04). When the same analysis was repeated for patients who developed MDS/AML, the use of TBI (P=0.005) and age at HDT⩾45 years (P=0.01) were associated with a higher risk. Finally, a multivariate analysis for the risk of dying of secondary MDS/AML was carried out (Table 2) including age at HDT, gender, interval from diagnosis to HDT, year of HDT, previous lines of chemotherapy, source of stem cells and conditioning regimen. The use of a TBI-containing regimen was associated with a higher risk of dying due to MDS/AML (P=0.004), as well as age at HDT⩾45 years (P=0.009) and year of HDT <1990 (P=0.04).
This analysis describes the outcome of the largest series of patients with FL treated with HDT with a very long follow-up, indispensable to draw any meaningful conclusion in a disease with a long median survival such as FL. On the downside, it has the caveats inherent to a retrospective registry study, namely lack of histological review, heterogeneous management of patients in terms of treatment and follow-up and missing data. Nonetheless, the patients included can be regarded as representative of a standard group of patients with FL as their characteristics at diagnosis do not differ substantially from the main characteristics of patients with de novo FL,1 apart from being younger, in keeping with other series of HDT in FL. Unfortunately, the retrospective nature of this registry study, precluded obtaining accurate information on risk factors at diagnosis, including cytological grade. However, the characteristics of the patients at the time of HDT may be somewhat different from other series given that 1/5 of the patients in the current study received HDT in CR1. This is predominantly a consequence of the large proportion of patients reported from French centres, where at that time there was an open study and subsequently two randomized studies analyzing the effect of HDT in patients with FL in CR1.11, 21, 22 Nonetheless, although not formally compared, there do not seem to be significant differences between the clinical characteristics of patients treated in CR1 and the remainder (Table 1).
In the current study, after a median follow-up of 10 years, the OS and PFS at 15 years were 47 and 27%, respectively. The results here reported, even after excluding patients treated in CR1 (OS and PFS at 15 years, 44 and 26%, respectively), are better than those achieved with conventional chemotherapy, as reported in other series comparing the outcome of patients treated with HDT with those of historical controls.8, 9 A randomized study confirmed these results: the ‘CUP’ trial assigned patients with recurrent FL to receive chemotherapy, HDT with a ‘purged’ stem cell collection or ‘unpurged’ HDT.13 In this study, as in the present one, ex vivo manipulation did not influence the outcome. In the current study, the OS and the PFS stabilized after 10 years of follow-up (OS at 10 and 15 years: 52 and 47%; PFS at 10 and 15 years: 31 and 27%, respectively) with a suggestion of a plateau that has also been reported in another series with a long follow-up.23 It seems, thus, that there is a subgroup of patients with FL who remain alive and free of disease after HDT. The group that apparently obtains the greatest benefit from HDT in the current series was younger patients and those treated in CR1. Unfortunately, the nature of the EBMT registry prevented us from obtaining reliable data on variables such as haemoglobin level or number of nodal areas involved at diagnosis to be able to retrospectively calculate the follicular lymphoma international prognostic index (FLIPI) score and to assess its prognostic value.
The good prognosis of patients treated in CR1 is not surprising. A reduced number of previous lines of chemotherapy4, 6 and a short interval from diagnosis5 have been associated with a better outcome in other series. Whether it follows that patients with FL should receive HDT at first response is not a question to be addressed in a retrospective analysis. However, three randomized trials have explored this possibility. The Groupe Ouest Est d’Etude des Leucemies Aigues et Maladies du Sang (GOELAMS) study and the German Low Grade Lymphoma Study Group randomized patients to receive ‘standard’ chemotherapy or HDT. In both studies, patients in the HDT arm had a significant longer event-free survival (EFS) than patients in the chemotherapy arm, although no difference in OS was detected.11, 12 In contrast, a third randomized trial led by the Groupe d’Etude des Lymphomes de l’Adulte did not show significant differences in OS or (EFS) between the two arms after a long follow-up.22 Notwithstanding the good results of HDT, the German and the ‘GOELAMS’ studies were associated with a higher risk of second malignancies in the HDT group11, 24—which might have accounted for the lack of difference in OS—unacceptable in a population with a median survival at diagnosis of 10 years. Of note, the patients included in the latter two studies had received relatively little treatment before HDT and the conditioning regimen included TBI in both.
A critical result of the current analysis is the relationship between the diagnosis of second malignancies, especially secondary MDS/AML, and the use of a TBI-containing regimen. The diagnosis of second malignancies after HDT has been a matter of concern for many years.14, 15, 16 The factors associated with this event have been related to characteristics of the patients,14, 15, 25 previous treatment25, 26, 27, 28 and characteristics of the HDT procedure.16, 28 TBI-based regimens have been associated with a higher risk of MDS/AML in some studies,14, 27 but not in others.26, 28 The higher risk of second malignancies associated with TBI in the current series cannot be attributed to a shorter follow-up of patients who received a chemotherapy-only treatment, as the proportion of patients who received TBI before 1990 was similar to that of patients treated subsequently. Moreover, in a multivariate analysis for the risk of developing MDS/AML, including the year of HDT and number of previous lines of therapy amongst other variables, treatment with a TBI-containing regimen was associated with a fourfold increased risk of developing MDS/AML. Of note, there were not significant differences in the risk of developing MDS/AML between patients treated in CR1 and the remainder. Thus, although the use of TBI was associated with a lower incidence of recurrence in this and other studies,29 its benefit might be outweighed by the higher risk of MDS/AML. The effect of TBI on survival was a consequence of late mortality, as there were no differences in OS during the first 5 years of follow-up. In this regard, TBI-containing regimens were not only associated with a higher risk of developing MDS/AML, but also with a higher risk of dying of MDS/AML resulting in the increase in late mortality.
In conclusion, HDT results in prolonged PFS in selected groups of patients. However, the good results obtained with HDT are counterbalanced by late toxicity. In this sense, TBI-containing regimens should be avoided given their strong association with the diagnosis of secondary MDS/AML. Nevertheless, these results should be viewed against the perspective of major advances in the treatment of FL since these patients were treated, namely the use of monoclonal antibodies and the advent of RIC allograft.
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We are indebted to all transplantation centres, physicians, nurses and data managers for their continued help in EBMT studies. A list of the transplant centres and investigators of the European Blood and Marrow Transplantation Group appears in the ‘Appendix’. SM was kindly supported by a grant from Olivia Walduck's family.
Dedicated to the memory of Felix Reyes.
Agnes Buzyn, Hôpital Necker, Paris, France [FR] 3; Roelof Willemze, Leiden University Hospital, Leiden, The Netherlands [NL] 7; Jane Apperley, Imperial College, Hammersmith Hospital, London, United Kingdom [GB] 5; Niels Jacobsen, Rigshospitalet, Copenhagen, Denmark [DK] 10; J Maertens, University Hospital Gasthuisberg, Leuven, Belgium [BE] 4; Norbert C Gorin, Hopital Saint Antoine, Paris, France [FR] 38; Stephen Mackinnon, Royal Free Hospital and School of Medicine, London, United Kingdom [GB] 1; Kurt Leibundgut, University Hospital Bern, Bern, Switzerland [CH] 1; Bernard Rio, Hotel Dieu, Paris, France [FR] 8; Antony H Goldstone, University College London Hospital, London, United Kingdom [GB] 5; John M Davies, Western General Hospital, Edinburgh, United Kingdom [GB] 1; Didier Blaise, Unité de transplantation et de thérapie cellulaire, Marseille, France [FR] 22; Roberto Foa, Univ. ‘La Sapienza’, Rome, Italy [IT] 6; Eric Deconinck, Hopital Jean Minjoz, Besancon, France [FR] 10; Augustin Ferrant, Cliniques Universitaires St Luc, Brussels, Belgium [BE] 13; A Schattenber, University Medical Center St Radboud, Nijmegen, The Netherlands [NL] 8; Leo F Verdonck, University Medical Centre, Utrecht, The Netherlands [NL] 3; Michele Baccarani, Bologna University, S Orsola-Malpighi, Bologna, Italy [IT] 5; Pierre Biron, Centre Leon Berard, Lyon, France [FR] 8; Arturo Iriondo, Hospital U Marqués de Valdecilla, Santander, Spain [ES] 15; H Van den Berg, Academisch Ziekenhuis bij de Universiteit, Amsterdam, The Netherlands [NL] 1; Oumedaly Reman, Centre Hospitalier Universitaire, Caen, France [FR] 1; Catherine Cordonnier, Hôpital Henri Mondor, Creteil, France [FR] 27; JL Harousseau, Hotel Dieu, Nantes, France [FR] 37; Shimon Slavin, Hadassah University Hospital, Jerusalem, Israel [IL] 19; Anna Sureda, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain [ES][ 260] 5; JP Vernant, Hopital Pitie-Salpetriere, Paris, France [FR] 12; F Guilhot, Hopital La Miletrie, Poitiers, France [FR] 2; Gunnar Oberg, University Hospital, Uppsala, Sweden [SE] 3; Noel Milpied, CHU Bordeaux, Pessac, France [FR] 37; P Colombat, Hopital Bretonneau, Tours, France [FR] 10; Jacques-Olivier Bay, Fédération de Greffe de Moelle et de Therapie Cellulaire, Clermont-Ferrand, France [FR] 3; GH Jackson, Royal Victoria Infirmary, Newcastle- upon-Tyne, United Kingdom [GB] 1; JP Jouet, Hopital Claude Huriez, Lille, France [FR] 7; Carlos Solano, Hospital Clínico Universitario, Valencia, Spain [ES] 1; DW Milligan, Birmingham Heartlands Hospital, Birmingham, United Kingdom [GB] 3; Ignazio Majolino, Ospedale S Camillo-Forlanini, Rome, Italy [IT] 1; Keith Wilson, University of Wales, Cardiff, United Kingdom [GB] 2; Alberto Bosi, Ospedale di Careggi, Firenze, Italy [IT] 9; Giuseppe Leone, Universita Cattolica S Cuore, Rome, Italy [IT] 3; Urs Hess, Kantonsspital St Gallen, St Gallen, Switzerland [CH] 1; Rainer Haas, Heinrich Heine Universität, Düsseldorf, Germany [DE] 1; Rosanna Scimè, Ospedale V Cervello, Palermo, Italy [IT] 4; Filomena Floristan, Hospital de Cruces, Barakaldo (Bilbao), Spain [ES] 1; Tapio Nousiainen, Kuopio University Hospital, Kuopio, Finland [FI] 1; Tapani Ruutu, Helsinki University Central Hospital, Helsinki, Finland [FI] 2; Martin Hildebrandt, Charité Universitätsmedizin Berlin, Berlin, Germany [DE] 1; Nicole Gratecos, Hôpital de l’ARCHET I, Nice, France [FR] 1; M Janvier, Centre Rene Huguenin, Saint Cloud, France [FR] 3; Harry Schouten, University Hospital Maastricht, Maastricht, The Netherlands [NL][ 565] 8; Bjarne Jensen, Herlev Hospital Anker, Herlev, Denmark [DK] 3; GJ Ossenkoppel, VU University Medical Centere, Amsterdam, The Netherlands [NL] 1; Axel A Fauser, Klinik für Knochenmarktransplantation, Idar -Oberstein, Germany [DE] 1; W Feremans, ULB—Hopital Erasme, Brussels, Belgium [BE] 2; Fabio Benedetti, Policlinico GB Rossi, Verona, Italy [IT] 3; R Schots, University Hospital VUB, Brussels, Belgium [BE] 1; Elli Koivunen, Tampere University Hospital, Tampere, Finland [FI] 1; Norbert Ifrah, CHRU, Angers, France [FR] 6; Tiziano Barbui, Ospedale Bergamo, Bergamo, Italy [IT] 2; Thierry de Revel, Hôpital Percy, Clamart, France [FR] 3; Jean HenriBourhis, Institut Gustave Roussy, Villejuif, France [FR] 3; Mauricette Michallet, Hopital E Herriot, Lyon, France [FR] 9; NH Russell, Nottingham City Hospital, Nottingham, United Kingdom [GB] 2; Vladimir Koza, Charles University Hospital, Pilsen, Czech Republic [CZ] 3; J Besalduch, Hospital Universitari Son Dureta, Palma de Mallorca, Spain [ES] 1; Dolores Caballero, Hospital Clínico, Salamanca, Spain [ES] 2; M Komarnicki, K Marcinkowski University of Medical Science, Poznan, Poland [PL] 1; Anders Wahlin, Umea University Hospital, Umea, Sweden [SE] 2; José M Moraleda Jimenez ,Hospital Morales Meseguer, Murcia, Spain [ES] 6; Elisabeth Koller, Hanuschkrankenhaus, Vienna, Austria [AT] 2; Marek Trneny, Charles University Hospital, Prague, Czech Republic [CZ] 3; Jean-Pierre Lotz, Hôpital Tenon, Paris, France[FR] 1; GJ Mufti, GKT School of Medicine, London, United Kingdom [GB] 1; John Gribben, St Bartholomew’s and The Royal London Hospital, London, United Kingdom [GB] 114; Joerg Schubert, University of Saarland, Homburg, Germany [DE] 1; Massimo F Martelli, University of Perugia, Perugia, Italy [IT] 21; Francesco Rodeghiero, S Bortolo Hospital, Vicenza, Italy [IT] 2; C Gisselbrecht, Hôpital St Louis, Paris, France [FR] 49; Jean Francois Rossi, CHU Lapeyronie, Montpellier, France [FR] 7; H Tilly, Centre Henri Becqueral, Rouen, France [FR] 11; Ghandi Damaj, University of Amiens: CHU Amiens, Amiens, France [FR] 1; Alain Delmer, Hôpital Robert Debre, Reims, France [FR] 6; Laurent Degos, Institut Universitaire d’Hématologie, Paris, France [FR] 2; Dominique Bordessoule, CHRU Limoges, Limoges, France [FR] 2.
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