Long-term follow-up of a randomized trial of fludarabine–mitoxantrone, compared with cyclophosphamide, doxorubicin, vindesine, prednisone (CHVP), as first-line treatment of elderly patients with advanced, low-grade non-Hodgkin's lymphoma before the era of monoclonal antibodies

C. Foussard1, P. Colombat2, H. Maisonneuve3, C. Berthou4, R. Gressin5, M.-C. Rousselet6, P. Rachieru1, B. Pignon7, B. Mahé8, C. Ghandour9, B. Desablens10, P. Casassus11, T. Lamy12, V. Delwail13 and E. Deconinck14,* On behalf of the Groupe Ouest-Est des Leucémies et Autres Maladies du Sang (GOELAMS)

1 Hematology Department, CHU Angers; 2 Hematology Department, CHU Tours; 3 Hematology Department, CH La Roche-sur-Yon; 4 Hematology Department, CHU Brest; 5 Hematology Department, CHU Grenoble; 6 Pathological Department, CHU Angers; 7 Hematology Department, CHU Reims; 8 Hematology Department, CHU Nantes; 9 Hematological Center, Rennes; 10 Hematology Department, CHU Amiens; 11 Hematology Department, CHU Bobigny; 12 Hematology Department, CHU Rennes; 13 Hematology Department, CHU Poitiers; 14 Hematology Department, CHU Besançon, France

* Correspondence to: Dr E. Deconinck, Service d'Hématologie, CHU Besançon, 25 030 Besançon Cedex, France. Tel: +33-3-81-66-82-32; Fax: +33-3-81-66-82-15; Email: edeconinck{at}chu-besancon.fr


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: This randomized study compared the efficacy and safety of fludarabine–mitoxantrone (FM) with mini-CHVP (cyclophosphamide, doxorubicin, vindesine, prednisone) in elderly patients with advanced, low-grade non-Hodgkin's lymphoma.

Patients and methods: End points were remission rates [overall response (OR) and complete response (CR)], failure-free survival (FFS), survival and toxicity. One hundred and fifty-five patients were randomized, 144 were evaluable for safety and 142 for response. Each treatment arm was given as six monthly cycles, followed by three bimonthly cycles. FM comprised fludarabine (20 mg/m2 i.v.), days 1–5, plus mitoxantrone (10 mg/m2 i.v.), day 1. CHVP cycles comprised cyclophosphamide (750 mg/m2 i.v. infusion), doxorubicin (25 mg/m2 i.v.) and vindesine (3 mg/m2 i.v.) on day 1, and prednisone (50 mg/m2) on days 1–5.

Results: FM therapy resulted in superior remission rates (OR 81% versus 64%, CR 49% versus 17%; P=0.0004). Median FFS for FM patients was 36 months, compared with 19 months for CHVP patients, and has not yet been reached for early CR patients at 53 months. Treatment arm was the major risk factor influencing survival. Both treatments were well tolerated, with only few infectious complications.

Conclusion: FM was more effective than CHVP in achieving OR and CR, and favorably affected the outcome.

Key words: anthrayclines, fludarabine, follicular lymphoma, mitoxantrone, purine analogs


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
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Low-grade non-Hodgkin's lymphomas (Lg-NHLs) generally have an indolent course compared with intermediate and aggressive NHL. Although responses to initial chemotherapy may be high, virtually all patients relapse, and Lg-NHLs are ultimately fatal diseases [1Go, 2Go]. Combination chemotherapies such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) are effective as first-line therapy, but produce few durable responses [1Go]. CHVP, in which vindesine replaces vincristine, may also be used with similar results [3Go, 4Go]. Maintenance therapy with chlorambucil and {alpha}-interferon has been shown to prolong the effects of combination chemotherapy and increase survival after interferon therapy [5Go].

Fludarabine and mitoxantrone have each shown promising results when used as single agents to treat relapsing diseases [6Go, 7Go]. Fludarabine is a purine analog, and mitoxantrone an anthracenedione, similar to doxorubicin, but with milder non-hematological toxicity. These agents have different mechanisms of action and are potentially synergistic. Response rates of 52%–67% and 27%–67% have been reported for fludarabine and mitoxantrone, respectively, in the management of Lg-NHL, although the majority of these responses were partial [6Go, 8Go]. Preliminary studies using a combination of fludarabine, mitoxantrone and dexamethasone have demonstrated synergistic effects [9Go], and fludarabine–mitoxantrone combinations (FM) have been shown to be highly active in relapsed Lg-NHL [10Go–12Go]. Few studies have tested the FM combination as first-line treatment in Lg-NHL [13Go, 14Go]. Although FM was compared directly with standard approaches, such as CHOP, in a recent report including the use of monoclonal antibodies [15Go], there is a need to reassess the efficacy and toxicity of FM in untreated patients, which was the purpose of this randomized trial directly comparing an FM combination with mini-CHVP (CHVP) in previously untreated, elderly patients with Lg-NHL.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
This clinical trial was conducted by the GOELAMS (Groupe Ouest-Est des Leucémies et Autres Maladies du Sang) in 18 French centers. Between November 1995 and December 1999, patients with previously untreated indolent lymphoma [classified according to the Revised European–American Lymphoma (REAL) classification of lymphoid neoplasms] [2Go] were enrolled in this multicenter, open-label, randomized, phase III trial. All participating centers followed the guidelines of good clinical practice in accordance with the Declaration of Helsinki. The protocol and informed-consent forms were approved by the regional institutional review boards; signed informed consent was obtained before treatment. Patients between 60 and 75 years of age presenting with follicular lymphoma, and patients over 55 years of age presenting with other Lg-NHL subtypes (small lymphocytic, marginal zone or monocytoid B-cell lymphomas), were eligible if they exhibited advanced disease: Ann Arbor stage II with a tumor >10 cm, Ann Arbor stage III–IV, and with the presence of at least one adverse risk factor as defined previously by the Groupe d'Etude des Lymphomes Folliculaires (GELF) [5Go] and included: B-symptoms, a single lymph node >7 cm, or involvement of at least three nodal sites larger than 3 cm; massive splenomegaly (costal overflow >5 cm or a scan image of 20 cm along the main axis); elevated lactate dehydrogenase (LDH) level; an Eastern Cooperative Oncology Group performance status 2–3; or the presence of a lymphomatosis leukemic phase. Patients were required to have adequate liver, renal and cardiac function. Patients with mantle cell lymphoma or any clinical or histological evidence of transformation to a higher-grade NHL were excluded, as were HIV-positive patients and those with diabetes, auto-immune hemolytic anemia, an absolute neutrophil count (ANC) <1.5 g/l, a platelet count <100 g/l (except if NHL-related), active systemic infection, malignancy other than non-melanoma skin cancers or in situ carcinoma of the cervix, or a life expectancy <6 months.

Treatment schedule
Patients were randomized to receive FM or CHVP, repeated at 28-day intervals, for six cycles (induction), followed by three bimonthly cycles for 6 months (consolidation). FM consisted of fludarabine (20 mg/m2 15 min i.v. infusion) on days 1–5 plus mitoxantrone (10 mg/m2 15 min i.v. infusion) on day 1. The CHVP cycle consisted of cyclophosphamide (750 mg/m2 30 min i.v. infusion), doxorubicin (25 mg/m2 i.v. bolus) and vindesine (3 mg/m2 i.v. bolus) on day 1, plus prednisone (50 mg/m2 orally) on days 1–5. Hyperhydration was performed to prevent tumor lysis symptoms during the first cycle. In the event of hematological toxicity (severe hemorrhages, infectious complications, ANC <1.5 g/l or platelets <100 g/l on day 28), treatment was postponed for 1 week or until symptoms resolved. For the FM arm, the recommended anti-infectious prophylaxis comprised trimethoprim/sulfamethoxazole or inhaled pentamidine and oral acyclovir.

Staging and monitoring
Pre-treatment staging evaluation included: clinical examination of any superficial adenopathies, splenomegaly and hepatomegaly; lung X-ray; thorax, abdomen and pelvis scan; and one bone marrow biopsy. Immunological assessments included a Coombs' test and quantitative analysis of immunoglobulins. Laboratory tests included full blood counts and assessment of plasma levels of LDH, ß-2-microglobulin, C-reactive protein, aspartate aminotransferase, alanine aminotransferase, bilirubin, {gamma}-glutamyl transferase, alkaline phosphatase, uricemia and calcemia. Herpes virus, cytomegalovirus, hepatitis B virus and HIV serologies were also carried out. Laboratory testing and blood parameter measurements were performed at baseline and before each cycle. Additional assessments of disease response at tumor sites occurred after the third and sixth treatment cycles, and at the end of treatment. Follow-up examinations were performed every 3 months for 2 years, and every 6 months thereafter.

The response and end point assessments conformed to the published International Workshop on Response Criteria [16Go]. Briefly, complete response (CR) was defined as the disappearance of any clinical, biological and radiological symptoms of lymphoma, and normalization of the marrow biopsy when affected at diagnosis. Unconfirmed CR (CRu) was defined as minimal residual, radiographic masses or persistent lymphoid aggregates in the bone marrow without atypical cells, demonstrated to be stable on two consecutive assessments, at least 3 months apart. Partial response (PR) was defined as a ≥50% reduction in the sum of the products of the greatest diameters of bidimensionally measurable disease, irrespective of the marrow response, or by the total disappearance of tumoral masses with persistent lymphatic infiltration of the bone marrow. Any other response (stable disease or progression) was considered as a failure.

Statistical analyses
The primary end point was response to therapy after six cycles (6 months). Secondary end points were responses after nine cycles (1 year) at the end of chemotherapy, failure-free survival (FFS), overall survival (OS) and safety outcome at 6 months and 1 year. FFS was defined as the time from entry into the trial until failure, relapse or death, and was calculated according to the Kaplan–Meier methodology. The original planned sample size was calculated to detect a 15% difference in the CR rates after six cycles of treatment, in favor of the fludarabine group (45% versus 30%), with {alpha}=0.05 and ß=0.2. Analyses were conducted on an intention-to-treat basis. tests or Fisher's exact tests were used to compare responses and survival curves. Prognostic factors regarded as significant in monovariate analysis were entered into a multistep Cox proportional hazards analysis [17Go]. Data collection was closed in June 2003, and results were computed using Statview software (SAS Institute Inc., Cary, NC, USA).


    Results
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 Abstract
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 Patients and methods
 Results
 Discussion
 References
 
Patients
A total of 155 patients were enrolled. Eleven patients were excluded: six incorrect histologies after central pathologic data review, one withdrawal of consent, one refusal of treatment, one ineligibility case, one cardiac event before treatment administration and one lost to follow-up. In total, 144 patients (72 in each arm) received at least one dose of the protocol-specified treatment. Treatment groups had similar baseline characteristics: 60% of patients had follicular lymphoma and 96% had Ann Arbor stage III–IV disease at enrolment (Table 1). Eighty-nine per cent of all treated patients received at least six cycles of the assigned treatment, and the nine scheduled courses were administered to 69% of patients (72% in the FM arm, 66% in the CHVP arm). The reasons for discontinuation of treatments were two early deaths (pneumonia with severe electrolyte disturbances and pulmonary embolism), one transformation to high-grade NHL, 29 progressions or early failures, one biological hemolysis, three cases of sepsis, four severe cytopenias and one concomitant cancer.


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Table 1. Patients' characteristics

 
Responses and survival
After six and nine cycles of treatment, the overall response rates (CR + CRu + PR) were 82% and 72%, respectively. There were significantly higher response rates in the FM group than the CHVP group, and the complete remission rate (CR + CRu) was also higher in the FM group than the CHVP group after six cycles (45% versus 10%) and nine cycles (60% versus 32%) (Table 2). Treatment failure occurred in 95 patients, most of whom received salvage therapy, often including various combinations with fludarabine (for the CHVP-treated patients) or, occasionally, stem cell transplantation (for both groups). The 4-year overall FFS was 26% (median 26 months), with a highly significant difference between the two treatments: 42% for the FM arm (median 36 months) and 10% for the CHVP arm (median 19 months) (P=0.0001). With a median follow-up of 53 months (range 13–100 months) for all patients and 70 months (range 23–100 months) for surviving patients, the 7-year survival rate was 53.5%; no difference was observed between the two treatment arms (P=0.94; Figure 1) nor between patients with follicular or non-follicular histology (P=0.66).


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Table 2. Responses to induction and consolidation therapy

 


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Figure 1. Overall survival in 144 treated patients. CHVP (cyclophosphamide, doxorubicin, vindesine, prednisone); FM, fludarabine–mitoxantrone.

 
Prognostic factors
Univariate analysis of baseline features revealed that an elevated LDH level, more than one extra-nodal disease site and the presence of bulky disease were adverse prognostic factors in terms of FFS (Table 3), while treatment with FM conferred a significantly better FFS (Figure 2). Multivariate analysis in 140 patients confirmed that LDH, two or more extra-nodal sites and bulky disease correlated with reduced FFS, whereas FM correlated with prolonged FFS (Table 4). In the subset of 115 responding patients (CR + CRu + PR), those achieving CR or CRu showed significantly longer survival (median not yet reached) than PR patients (median 25 months) (P=0.04; Figure 3).


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Table 3. Univariate analysis of adverse prognostic factors for failure-free survival

 


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Figure 2. Failure-free survival in 144 patients treated with FM (fludarabine–mitoxantrone) compared with CHVP (cyclophosphamide, doxorubicin, vindesine, prednisone).

 

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Table 4. Multivariate analysis of adverse prognostic factors for failure-free survival

 


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Figure 3. Overall survival in 115 patients, according to response at six cycles: complete response (CR) + unconfirmed CR (CRu) versus partial response (PR).

 
Toxicities
The number of cycles administered was similar in both arms: 569 for the FM arm and 560 for the CHVP arm. The allocated treatment was stopped in seven cases as a result of side-effects: in the FM arm, five cases were observed (one herpes zoster infection, one biologic hemolysis and three sustained grade 4 neutropenias); in the CHVP arm, two cases were recorded (one fungal infection and one tuberculosis). The toxicity of these chemotherapy regimens was mainly hematological (Table 5). Among the 85 patients with grade 3–4 neutropenia or thrombopenia, four cases in the FM arm developed lymphoma progression and subsequent myelodysplasia. Mild hemolysis was also observed in the FM arm only, and herpes zoster infection occurred in eight patients. Other side-effects were rare, and there were two treatment-related deaths. One patient in the CHVP arm died after two treatment courses, probably due to tumor lysis syndrome. A 68-year-old woman with a high tumor burden was enrolled and received one cycle of FM, despite the presence of thrombosis, pulmonary embolism and thrombopenic idiopathic purpura; she died 3 weeks later. Myelodysplasia or infection prevented optimal subsequent salvage therapy in five patients. Finally, 50 patients have died, 25 in each group. In the FM arm, 20 patients died from disease progression, two from myelodysplasia, one from pulmonary embolism, one from prostate cancer and one died a natural death. In the CHVP arm, 21 patients died from progressive lymphoma (one with early transformation to high-grade NHL), one from severe pneumonitis with severe electrolyte disturbances (mimicking a tumor lysis syndrome), one from infection, one from bowel cancer and one died an unrelated accidental death.


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Table 5. Grade 3 and 4 toxicity in patients treated with FM and CHVP (percentage of patients with at least one event in at least one cycle)

 

    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The optimal therapy for patients with advanced Lg-NHL has not yet been defined [1Go, 2Go, 5Go, 18Go–20Go]. Before the era of in vivo monoclonal antibodies, there was a consensus on initial therapeutic strategies in the management of Lg-NHL. Only patients with criteria of a high tumor burden needed to be treated, but the definitions of these criteria fluctuated according to the authors. The initial therapeutic options for these patients varied from observation to single-agent oral therapy or i.v. drug combinations, with or without subsequent autologous stem cell transplantation [1Go, 4Go, 5Go, 20Go–23Go]. Although responses tend to be higher for combination chemotherapy, the overall prognosis remains unchanged irrespective of the treatment, with a median survival of 7–10 years [1Go, 4Go, 20Go, 21Go]. CHOP or CHOP-like regimens have been described as the standard first-line treatment for Lg-NHL. Southwest Oncology Group (SWOG) trials of anthracycline-based regimens have shown long-term results similar to those of less-aggressive therapies without anthracyclines [18Go]. The GOELAMS has previously reported on the use of the CHVP regimen as a standard treatment for a similar population of patients [3Go, 4Go]. This CHVP regimen was very similar to CHOP used for patients with advanced chronic lymphocytic leukemia or follicular lymphoma, so we can consider this CHVP regimen to be one of the referential anthracycline-based chemotherapies [5Go, 24Go].

Single-agent fludarabine therapy has been found to be effective, inducing remissions in 65% (CR in 37%) of previously untreated patients, although this treatment might be inferior to a CHOP-like combination such as CHVP [6Go, 25Go]. With FM regimens, response rates of 69%–94% have been reported, mostly in the setting of relapse, but also in front-line therapy [11Go, 13Go, 14Go]. In a previous study in 78 Lg-NHL patients, with a median follow-up of 5.5 years, 73 patients (94%) attained an objective response, with a CR demonstrated in 34 patients (44%). The median progression-free survival (PFS) was 32 months, with a 4-year PFS rate of 38%; median survival was not reached and 88% of all patients were alive at 4 years [14Go]. Although there are some data in the literature, randomized trials testing FM combinations are scarce. A recent trial randomized patients to FM and CHOP as front-line chemotherapy, with and without sequential mouse/human anti-CD20 antibody. After chemotherapy, the FM arm achieved a CR rate of 68% compared with 42% in the CHOP arm, and the final CR rate was higher in the FM arm (71% compared with 51%). However, with a median follow-up of 19 months, no statistically significant difference was found among the different study arms in terms of PFS and OS. The authors concluded that FM is superior to CHOP for the front-line treatment of follicular lymphoma, and that rituximab is an effective sequential treatment option. However, the authors also confirm that this superiority is unlikely to translate into better survival [15Go]. Our results demonstrate that the FM regimen achieves a very high response rate (82%) in a group of elderly patients with previously untreated, advanced Lg-NHL. In particular, the complete remission rate (CR + CRu) was clearly demonstrated to be significantly higher in the FM arm. The long survival of primary responding patients suggests that an initial complete remission is required to achieve prolonged FFS and survival [18Go, 21Go, 23Go]. However, OS did not differ between the two treatment arms. A plausible explanation for this obvious paradox is the efficacy of second-line treatments [1Go, 21Go, 26Go]. It should be noted that the majority of patients who failed on the CHVP arm were successfully treated with FM and, occasionally, heavy salvage regimens, with evidence of a prolonged second response. OS was probably not the pertinent end point to evaluate the efficacy of front-line therapy in a disease with an indolent course, such as Lg-NHL. The major prognostic factor was the treatment arm, with a clear advantage for the FM patients in terms of FFS. The other factors significantly influencing outcome were, as expected, markers of high tumor burden, such as LDH, bulky disease or the presence of more than one extra-nodal disease site. In our study, given the limitations of an ECOG performance status up to 2 and the fact that all patients had advanced-stage disease, it is to be expected that the classical International Prognostic Index was not a relevant index [4Go, 22Go]. The same applies to the more recently described Follicular Lymphoma International Prognostic Index [22Go], for which some data were not prospectively collected. Similar to FM, fludarabine and cyclophosphamide combinations have also been reported to be highly effective in both indolent lymphoma and chronic lymphocytic leukemia [27Go]. Superior FFS rates are attainable with more aggressive regimens, such as alternating triple therapy, with high complete remission rates [1Go, 12Go]. The use of rituximab in combination with FM or as a maintenance therapy must be questioned, especially in initially good responders, who might expect a major prolongation of their good initial response status [19Go].

In terms of toxicity, low doses of doxorubicin may be given to elderly patients with bone marrow involvement, without prohibitive hematological toxicity [18Go]. Most authors have reported good tolerance with fludarabine combination regimens [28Go]. In our experience, both treatment arms were well tolerated. The main toxicities associated with the FM combination were severe myelosuppression, which, in a few cases when prophylaxis was omitted, was associated with opportunistic infections. The low incidence of secondary myelodysplasia reported here has also classically been observed in this setting with other treatments [6Go, 9Go, 11Go, 18Go].

Autologous stem cell transplantation in the first-line therapy of follicular lymphoma patients with a high tumor burden has yielded encouraging results in young patient populations in phase II trials; however, phase III trials have exhibited controversial results, with no clear evidence of better survival with front-line intensive treatments and increased toxicity [21Go, 29Go, 30Go]. This therapeutic option is inadequate for patients aged >60 years and, if useful, must be reserved for younger patients.

Thus, the FM regimen may be suitable as a first-line treatment for advanced-stage indolent lymphoma in elderly patients. It offers a higher remission rate and a longer freedom from progression than doxorubicin-based regimens or single-agent therapy. However, caution is needed and opportunistic infections require systematic antimicrobial prophylaxis. Furthermore, it remains unclear whether the FM regimen is suitable for young patients who might benefit from stem cell collection. Until curative treatment strategies are developed, no single trial can resolve all the controversies surrounding the therapy of advanced-stage indolent lymphoma. All these results must be re-evaluated in the light of the results of monoclonal antibody therapies, and several protocols are currently investigating the addition of monoclonal antibodies to standard chemotherapy regimens, and intensive treatment with stem cell support. We must bear in mind that, in the absence of an indisputable curative approach, the treatment of these lymphomas requires a thoughtfully planned strategy to allow progressive management of the disease during the lifespan of inexorably recurrent–remitting patients.


    Acknowledgements
 
This study was supported in part by a clinical grant from Schering SA, France.

Participating GOELAMS centers: Dr C. Foussard, Dr S. François, Dr M. Gardembas (Service de Médecine D–Maladies du Sang, CHU Angers); Dr E. Deconinck, Dr A. Brion, Dr L. Voillat, Dr J. Vuillier (Service d'Hématologie, Hôpital J Minjoz, CHU Besançon); Prof. J. F. Abgrall, Prof. C. Berthou, Dr M. Escoffre-Barbe (Service d'Hématologie, Hôpital Morvan, CHU Brest); Prof. J. M. Andrieu, Dr C. Le Maignan (Unité d'Oncologie Médicale, Hôpital Laennec, Paris); Dr B. Audhuy (Service d'Onco-Hematologie, CH Louis Pasteur, Colmar); Prof. P. Casassus (Unité d'Hématologie, Hôpital Avicenne, CHU Bobigny); Prof. P. Colombat, Dr G. Cartron, Dr M. Delain (Service d'Onco-Hématologie, Hôpital Bretonneau, CHU Tours); Prof. B. Desablens (Service des Maladie du Sang, Hôpital SUD, CHU Amiens); Dr J. Dugay (Service de Médecine, CHR Le Mans); Dr C. Ghandour (Médecine Interne-Maladies du Sang, Rennes); Prof. F. Guilhot, Dr V. Delwail (Service d'Hématologie, Hôpital Jean Bernard, CHU Poitiers); Dr J. Jaubert (Service d'Hématologie, Hôpital Nord, CHU Saint-Etienne); Dr A. Le Mevel (Centre Rene Gauducheau, Nantes); Prof. T. Lamy, Dr C. Dauriac, Dr M. Bernard (Hôpital Pontchaillou, CHU Rennes); Dr H. Maisonneuve (Service Médecine-Hématologie, CH La Roche Sur Yon); Prof. N. Milpied, Dr B. Mahe (Service d'Hématologie, Hôtel Dieu, CHU Nantes); Prof. J. F. Rossi, Dr P. Quittet (Service d'Hématologie, CHU Montpellier); Dr B. Pignon, Dr J. P. Vilque, Dr A. M. Blaise, Dr C. Himberlin (Unité d'Hématologie Clinique, Hôpital Robert Debre, CHU Reims).

Received for publication September 26, 2004. Accepted for publication October 27, 2004.


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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