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
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Abstract |
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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 15, 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 15.
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
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Introduction |
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Fludarabine and mitoxantrone have each shown promising results when used as single agents to treat relapsing diseases [6, 7
]. 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 [6
, 8
]. Preliminary studies using a combination of fludarabine, mitoxantrone and dexamethasone have demonstrated synergistic effects [9
], and fludarabinemitoxantrone combinations (FM) have been shown to be highly active in relapsed Lg-NHL [10
12
]. Few studies have tested the FM combination as first-line treatment in Lg-NHL [13
, 14
]. Although FM was compared directly with standard approaches, such as CHOP, in a recent report including the use of monoclonal antibodies [15
], 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.
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Patients and methods |
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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 15 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 15. 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, -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 [16]. 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 KaplanMeier 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 =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 [17
]. Data collection was closed in June 2003, and results were computed using Statview software (SAS Institute Inc., Cary, NC, USA).
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Results |
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Discussion |
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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 [6, 25
]. With FM regimens, response rates of 69%94% have been reported, mostly in the setting of relapse, but also in front-line therapy [11
, 13
, 14
]. 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 [14
]. 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 [15
]. 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 [18
, 21
, 23
]. However, OS did not differ between the two treatment arms. A plausible explanation for this obvious paradox is the efficacy of second-line treatments [1
, 21
, 26
]. 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 [4
, 22
]. The same applies to the more recently described Follicular Lymphoma International Prognostic Index [22
], 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 [27
]. Superior FFS rates are attainable with more aggressive regimens, such as alternating triple therapy, with high complete remission rates [1
, 12
]. 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 [19
].
In terms of toxicity, low doses of doxorubicin may be given to elderly patients with bone marrow involvement, without prohibitive hematological toxicity [18]. Most authors have reported good tolerance with fludarabine combination regimens [28
]. 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 [6
, 9
, 11
, 18
].
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 [21, 29
, 30
]. 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 recurrentremitting patients.
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Acknowledgements |
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Participating GOELAMS centers: Dr C. Foussard, Dr S. François, Dr M. Gardembas (Service de Médecine DMaladies 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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