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Philippe Solal-Céligny,
Monica Bellei,
Luigi Marcheselli,
Emanuela Anna Pesce,
Stefano Pileri,
Peter McLaughlin,
Stefano Luminari,
Barbara Pro,
Silvia Montoto,
Andrés J M Ferreri,
Eric Deconinck,
Noël Milpied,
Leo I Gordon,
Massimo Federico
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ABSTRACT: PURPOSEPatients with follicular lymphoma (FL) registered in the F2-study and initially managed without treatment were analyzed to describe the presentation and outcome of a watch and wait (W&W) strategy in the rituximab era, to identify parameters for initiating treatment, and to evaluate whether initial W&W could have deleterious effects on treatment efficacy after progression or relapse. PATIENTS AND METHODS
Between 2003 and 2005, 120 patients selected from the 1,093 treatment-naive patients with FL in the F2-study cohort were initially managed expectantly (W&W), and 107 patients were assessed. Most of these patients (80%) had disseminated disease with a low tumor burden according to Groupe d'Etudes des Lymphomes Folliculaires criteria.ResultsAfter a median follow-up of 64 months, treatment was initiated in 54 patients (50%), with a median delay of 55 months for the entire cohort. In a univariate analysis, involvement of more than four nodal areas (hazard ratio [HR], 2.26) and serum albumin less than 3.5 g/dL (HR, 3.51) were predictive of a shorter time to lymphoma treatment initiation. In a multivariate analysis, only involvement of more than four nodal areas remained significant (HR, 2.32). The 4-year freedom from treatment failure (FFTF) rate of W&W patients (79%; 95% CI, 69% to 85%) was not inferior to that of a subgroup of 242 patients from the F2-study cohort with good prognosis characteristics who were initially treated with a rituximab-based regimen (69%; 95% CI, 61% to 76%; P = .103). CONCLUSION
In the rituximab era, patients with FL in a selected prognostically favorable group can still be managed with W&W. W&W does not seem to have detrimental effects on FFTF and overall survival rates after treatment.
Journal of Clinical Oncology 09/2012; · 18.37 Impact Factor
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ABSTRACT: Rituximab has markedly changed the treatment of B-cell malignancies. Despite its widespread use, however, its precise mode of action and the impact of host- and tumor-related factors on rituximab-activated biological pathways were only recently clarified. Biological mechanisms resulting in complete resistance to rituximab may exist at both the cellular and subcellular level; however, their frequency and their impact on clinical response are unclear. The identification of Fcγ receptor polymorphisms that can influence anti-CD20 antibody activity has resulted in the development of third-generation anti-CD20 antibodies. However, it is also now appreciated that pharmacokinetic variability is a major factor affecting clinical response to anti-CD20 antibodies. The concept of antigenic mass, which takes into account the total tumor load and the expression levels of the target antigen CD20, is able to explain the correlation between rituximab plasma concentrations and treatment responses. Thus, it can be hypothesized that dosing regimens that take this information into account will help to improve response rates.
Clinical Cancer Research 01/2011; 17(1):19-30. · 7.74 Impact Factor
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Tadeusz Robak,
Anna Dmoszynska, Philippe Solal-Céligny,
Krzysztof Warzocha,
Javier Loscertales,
John Catalano,
Boris V Afanasiev,
Loree Larratt,
Christian H Geisler,
Marco Montillo,
Ilya Zyuzgin,
Peter S Ganly,
Caroline Dartigeas,
András Rosta,
Jörg Maurer,
Myriam Mendila,
M Wayne Saville,
Nancy Valente,
Michael K Wenger,
Sergey I Moiseev
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ABSTRACT: Rituximab, a monoclonal antibody that targets the CD20 cell surface antigen, has clinical activity in patients with non-Hodgkin's lymphoma and other B-lymphocyte disorders when administered alone or in combination with chemotherapy. Promising results have previously been reported in nonrandomized studies in patients with chronic lymphocytic leukemia (CLL). This trial was designed to compare chemoimmunotherapy with chemotherapy alone in patients with previously treated CLL.
This international, multicenter, randomized trial compared six cycles of rituximab plus fludarabine and cyclophosphamide (R-FC) with six cycles of fludarabine and cyclophosphamide alone (FC) in patients with previously treated CLL. A total of 552 patients with Binet stage A (1%), B (59%), or C (31%) disease entered the study and were randomly assigned to receive R-FC (n = 276) or FC (n = 276).
After a median follow-up time of 25 months, rituximab significantly improved progression-free survival in patients with previously treated CLL (hazard ratio = 0.65; P < .001; median, 30.6 months for R-FC v 20.6 months for FC). Event-free survival, response rate, complete response rate, duration of response, and time to new CLL treatment or death were also significantly improved. Although the rates of adverse events, grade 3 or 4 events, and serious adverse events were slightly higher in the R-FC arm, R-FC was generally well tolerated, with no new safety findings and no detrimental effect on quality of life.
R-FC significantly improved the outcome of patients with previously treated CLL.
Journal of Clinical Oncology 03/2010; 28(10):1756-65. · 18.37 Impact Factor
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Massimo Federico,
Monica Bellei,
Luigi Marcheselli,
Stefano Luminari,
Armando Lopez-Guillermo,
Umberto Vitolo,
Barbara Pro,
Stefano Pileri,
Alessandro Pulsoni,
Pierre Soubeyran,
Sergio Cortelazzo,
Giovanni Martinelli,
Maurizio Martelli,
Luigi Rigacci,
Luca Arcaini,
Francesco Di Raimondo,
Francesco Merli,
Elena Sabattini,
Peter McLaughlin, Philippe Solal-Céligny
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ABSTRACT: The aim of the F2 study was to verify whether a prospective collection of data would enable the development of a more accurate prognostic index for follicular lymphoma (FL) by using parameters which could not be retrospectively studied before, and by choosing progression-free survival (PFS) as principal end point.
Between January 2003 and May 2005, 1,093 patients with a newly diagnosed FL were registered and 942 individuals receiving antilymphoma therapy were selected as the study population. The variables we used for score definition were selected by means of bootstrap resampling procedures on 832 patients with complete data. Procedures to select the model that would minimize errors were also performed.
After a median follow-up of 38 months, 261 events for PFS evaluation were recorded. beta2-microglobulin higher than the upper limit of normal, longest diameter of the largest involved node longer than 6 cm, bone marrow involvement, hemoglobin level lower than 12 g/dL, and age older than 60 years were factors independently predictive for PFS. Using these variables, a prognostic model was devised to identify three groups at different levels of risk. The 3-year PFS rate was 91%, 69%, and 51% for patients at low, intermediate, and high risk, respectively (log-rank = 64.6; P < .00001). The 3-year survival rate was 99%, 96%, and 84% for patients at low, intermediate, and high risk, respectively (P < .0001).
Follicular Lymphoma International Prognostic Index 2 is a simple prognostic index based on easily available clinical data and may represent a promising new tool for the identification of patients with FL at different risk in the era of immunochemotherapy.
Journal of Clinical Oncology 09/2009; 27(27):4555-62. · 18.37 Impact Factor
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Catherine Sebban,
Pauline Brice,
Richard Delarue,
Corinne Haioun,
Bertrand Souleau,
Nicolas Mounier,
Nicole Brousse,
Pierre Feugier,
Hervé Tilly, Philippe Solal-Céligny,
Bertrand Coiffier
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ABSTRACT: The treatment of patients with follicular lymphoma has changed with the introduction of high-dose therapy (HDT) with autologous stem-cell transplant then with rituximab. The effect of these two strategies on the outcome of relapsing patients with follicular lymphoma has never been compared.
We analyzed two cohorts of patients treated in two successive randomized studies with the same treatment, cyclophosphamide, doxorubicin, teniposide, and prednisolone plus interferon, to evaluate the role of rituximab and HDT in salvage therapy after first disease progression or relapse.
Of the 364 patients included in these two studies, 254 progressed or relapsed and constitute the population of this analysis. Among them, 98 had been treated with HDT, including 33 of them after rituximab-containing salvage regimen, and 69 with rituximab alone or combined with chemotherapy but without HDT. Patients' characteristics at diagnosis were similar in all subgroups. If event-free survival was identical for patients treated within Groupe d'Etude des Lymphomes Folliculaires (GELF) -86 or GELF-94 studies, overall survival was longer in GELF-94 study. HDT was associated with a statistically significant benefit in terms of event-free survival from relapse and survival after relapse (SAR). Rituximab was associated with a greater benefit than HDT for these two end points. When both treatments were combined, patients treated with rituximab-containing salvage regimen followed by HDT had 5-year SAR more than 90%.
In follicular lymphoma, for patients treated with first-line chemotherapy the combination of a salvage regimen containing rituximab with or without HDT leads to a dramatic improvement of long-term outcome.
Journal of Clinical Oncology 08/2008; 26(21):3614-20. · 18.37 Impact Factor
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ABSTRACT: The introduction of rituximab (MabThera, Rituxan) maintenance treatment has initiated a new era in the management of low-grade non-Hodgkin's lymphomas.
Five randomized trials have recently reported on rituximab maintenance in the treatment of indolent non-Hodgkin's lymphomas. These trials enrolled patients with follicular, mantle cell and small lymphocytic non-Hodgkin's lymphomas, mostly in relapse. Patients responding to either rituximab monotherapy, chemotherapy alone or rituximab associated with chemotherapy were randomly assigned between observation and rituximab maintenance. Maintenance treatment significantly improved progression-free survival and response duration, and resulted in increased overall survival in two patients. In one trial, rituximab maintenance therapy produced significantly longer progression-free survival compared with rituximab retreatment at disease progression.
Rituximab maintenance therapy has demonstrated an impact on survival in patients with follicular lymphoma. These data justify recommending rituximab maintenance for patients with relapsed follicular lymphoma. Further trials are needed to determine its efficacy in first-line follicular lymphoma and other histological subtypes. The optimal schedule of maintenance therapy has not been established. Although these trials did not report severe adverse drug reactions, information concerning long-term toxicity is scarce, and careful monitoring of patients is therefore recommended.
Current Opinion in Oncology 10/2007; 19(5):425-32. · 4.10 Impact Factor
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Philippe Solal-Céligny
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ABSTRACT: The human/mouse chimeric monoclonal antibody rituximab has been used extensively in treatment of hematologic malignancies, and its efficacy and safety are well established, both as single-agent therapy and when used in combination with chemotherapy. Mild-to-moderate, transient infusion-related reactions are the most common adverse event, and rituximab does not add significantly to the toxicity of chemotherapy. Rituximab maintenance therapy has now emerged as an effective treatment for follicular lymphoma. Patients on rituximab maintenance therapy receive regular doses of rituximab for periods up to 2 years after initial induction therapy and are completely depleted of B-cells throughout this time, although B-cells eventually recover when maintenance treatment is stopped. In randomized trials of rituximab maintenance therapy versus observation after induction with single-agent rituximab, standard chemotherapy or rituximab plus chemotherapy, patients receiving rituximab maintenance therapy did not experience significantly greater toxicity than those in the observation arms, and no cumulative or unexpected toxicities were observed. Findings to date thus indicate that rituximab maintenance therapy is well tolerated, but further assessment of the long-term effects of prolonged B-cell depletion is still required.
Leukemia Research 04/2006; 30 Suppl 1:S16-21. · 2.92 Impact Factor
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Philippe Solal-Céligny,
Pascal Roy,
Philippe Colombat,
Josephine White,
Jim O Armitage,
Reyes Arranz-Saez,
Wing Y Au,
Monica Bellei,
Pauline Brice,
Dolores Caballero, [......],
Nicolas Mounier,
Stephen J Proctor,
Ama Rohatiner,
Paul Smith,
Pierre Soubeyran,
Hervé Tilly,
Umberto Vitolo,
Pier-Luigi Zinzani,
Emanuele Zucca,
Emili Montserrat
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ABSTRACT: The prognosis of follicular lymphomas (FL) is heterogeneous and numerous treatments may be proposed. A validated prognostic index (PI) would help in evaluating and choosing these treatments. Characteristics at diagnosis were collected from 4167 patients with FL diagnosed between 1985 and 1992. Univariate and multivariate analyses were used to propose a PI. This index was then tested on 919 patients. Five adverse prognostic factors were selected: age (> 60 years vs < or = 60 years), Ann Arbor stage (III-IV vs I-II), hemoglobin level (< 120 g/L vs > or = 120 g/L), number of nodal areas (> 4 vs < or = 4), and serum LDH level (above normal vs normal or below). Three risk groups were defined: low risk (0-1 adverse factor, 36% of patients), intermediate risk (2 factors, 37% of patients, hazard ratio [HR] of 2.3), and poor risk (> or = 3 adverse factors, 27% of patients, HR = 4.3). This Follicular Lymphoma International Prognostic Index (FLIPI) appeared more discriminant than the International Prognostic Index proposed for aggressive non-Hodgkin lymphomas. Results were very similar in the confirmation group. The FLIPI may be used for improving treatment choices, comparing clinical trials, and designing studies to evaluate new treatments.
Blood 10/2004; 104(5):1258-65. · 9.90 Impact Factor
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Danielle Canioni,
Pauline Brice,
Eric Lepage,
Myrna Chababi,
Véronique Meignin,
Bruno Salles,
Luc Xerri,
Pierre-Yves Péaud,
Philippe Rousselot,
Michel Peuchmaur, Philippe Solal-Céligny,
Nicole Brousse
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ABSTRACT: The influence of bone marrow biopsy (BMB) histology on prognosis and management of follicular lymphomas (FL) remains controversial. A total of 390 patients with grade 1 or 2 FL were prospectively included in the multicentric Groupe d'Etude des Lymphomes Folliculaires trial and their BMB reviewed in order (i) to quantify the ratio of lymphomatous foci (LFo) area to that of BMB size (LFo/BMB), (ii) to determine the BMB patterns for a practical grading of marrow infiltration, (iii) to assess the intra- and inter-observer reproducibility of this grading and (iv) to analyse this grading on event-free (EFS) and overall survival (OS), using univariate and multivariate analyses. A total of 267 patients (68%) had BMB involvement, with inter- and intra-observer reproducibility for classifying the patterns of involvement of 91 and 96%, respectively. Uni- and multivariate analyses demonstrated the adverse influence of (i) a ratio of LFo/BMB > or = 0.1, i.e. three or four nodules/medullary space or > or = 1 nodule + foci of diffuse involvement on EFS (P = 0.03) and (ii) two different histological patterns in the same BMB on EFS (P = 0.004) and OS (P = 0.001). This latter finding was only significant in patients with a high tumour burden and remained significant in multivariate analysis. These results indicate that BMB histology can predict survival of FL patients with a high tumour burden, and may help in defining their treatment.
British Journal of Haematology 09/2004; 126(3):364-71. · 4.94 Impact Factor
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Danielle Canioni,
Pauline Brice,
Eric Lepage,
Myrna Chababi,
Véronique Meignin,
Bruno Salles,
Luc Xerri,
Pierre-Yves Péaud,
Philippe Rousselot,
Michel Peuchmaur, Philippe Solal-Céligny,
Nicole Brousse,
The Groupe d'Etude des Lymphomes Folliculaires
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ABSTRACT: The influence of bone marrow biopsy (BMB) histology on prognosis and management of follicular lymphomas (FL) remains controversial. A total of 390 patients with grade 1 or 2 FL were prospectively included in the multicentric Groupe d'Etude des Lymphomes Folliculaires trial and their BMB reviewed in order (i) to quantify the ratio of lymphomatous foci (LFo) area to that of BMB size (LFo/BMB), (ii) to determine the BMB patterns for a practical grading of marrow infiltration, (iii) to assess the intra- and inter-observer reproducibility of this grading and (iv) to analyse this grading on event-free (EFS) and overall survival (OS), using univariate and multivariate analyses. A total of 267 patients (68%) had BMB involvement, with inter- and intra-observer reproducibility for classifying the patterns of involvement of 91 and 96%, respectively. Uni- and multivariate analyses demonstrated the adverse influence of (i) a ratio of LFo/BMB ≥0·1, i.e. three or four nodules/medullary space or ≥1 nodule + foci of diffuse involvement on EFS (P = 0·03) and (ii) two different histological patterns in the same BMB on EFS (P = 0·004) and OS (P = 0·001). This latter finding was only significant in patients with a high tumour burden and remained significant in multivariate analysis. These results indicate that BMB histology can predict survival of FL patients with a high tumour burden, and may help in defining their treatment.
British Journal of Haematology 07/2004; 126(3):364 - 371. · 4.94 Impact Factor
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ABSTRACT: Advances in the treatment of follicular lymphoma (FL) have been achieved through the development of newer combination regimens, mostly based upon purine analogs and/ or monoclonal antibodies, as well as recent progress in the area of stem cell transplantation.
These advances have increased the need to obtain consensus regarding treatment priorities from the various options available, ranging from the traditional palliative approach through to the novel regimens available including stem cell transplantation.
The apparent synergism between chemotherapy and rituximab, which facilitates the achievement of complete clinical (CR) and molecular remission (MR), together with the possible feasibility of maintenance and re-treatment with rituximab have increased the interest in the use of this drug as primary treatment for FL. This review summarizes the available literature and deals with the role of rituximab in refractory/relapsed FL as well as in previously untreated FL patients. The improvement in remission rates and response duration associated with immunotherapy are contrasted with the potential risks, such as the development of rituximab resistance, as well as other less recognized complications related to altered humoral immunity.
Despite all the advances reported, treatment might still have to be individualized for patients with FL, until evidence of an important survival advantage for rituximab over chemotherapy is established. The possible role of autotransplantation for FL and the use of rituximab is also reviewed.
Haematologica 08/2003; 88(7):811-23. · 6.42 Impact Factor
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New England Journal of Medicine 07/2003; 348(26):2691-4; discussion 2691-4. · 53.30 Impact Factor
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ABSTRACT: Indolent non-Hodgkin's lymphomas (NHLs) are essentially incurable with current treatments. Rituximab is a specific anti-CD20 chimeric monoclonal antibody against the CD20 antigen, which is stably expressed on most B-cells (from the pre-B-cell stage). Compared with chemotherapy, rituximab has an excellent tolerability profile, making it a good therapeutic option for patients with indolent NHL. In the pivotal study for rituximab, patients with relapsed or refractory indolent or follicular lymphoma (FL) had an overall response rate of 50%. There is evidence that first-line rituximab therapy may be associated with better response rates; in previously untreated FL with a low tumor burden, rituximab monotherapy has produced an overall response rate of 73%. Attempts to improve response rates to rituximab by increasing the dose or frequency of dosing showed that the addition of four extra infusions of rituximab (in addition to the standard treatment schedule) resulted in an overall response rate of 76% in patients with FL. Augmenting rituximab with cytokines is also an option for increasing response rates in patients with indolent NHL. In a trial by the Nordic Lymphoma Study Group in patients with previously untreated or first-relapse indolent NHL, who had stable disease or a partial response after four doses of rituximab, 48% of the patients treated with rituximab plus interferon-alpha2a achieved a complete response. A further option is to combine rituximab with chemotherapy. Interim analyses from the East German Study Group have shown that rituximab plus mitoxantrone, chlorambucil and prednisolone (MCP) resulted in overall response rates of 89% in patients with untreated indolent lymphoma. Rituximab is therefore an excellent treatment option both as first-line and as salvage therapy for patients with indolent NHL.
Anti-Cancer Drugs 12/2002; 13 Suppl 2:S11-7. · 2.41 Impact Factor
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Philippe Solal-Céligny
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ABSTRACT: There is currently no standard first-line treatment for indolent non-Hodgkin's lymphoma (NHL) because there is no curative treatment. In asymptomatic patients, treatment with chemotherapy does not improve survival compared with a "watch and wait" approach. Improved treatment strategies, with curative intent, are thus required for indolent NHL. Rituximab is effective and well tolerated in the treatment of indolent NHL and can be considered for asymptomatic patients, where the side effects of chemotherapy may outweigh the benefits. In addition, rituximab does not compromise the use of subsequent chemotherapy in patients who relapse. A study of rituximab monotherapy in patients with low-tumor-burden follicular lymphoma has shown high rates of both clinical remission and molecular remission (clearance of bcl-2-positive cells from blood and/or bone marrow). After 2 years, half the patients relapsed, indicating that improved strategies are still required. Efforts to improve the efficacy of rituximab have included repeated administrations of the antibody and combined administration with chemotherapy or interferon-alpha2a. The optimal role of rituximab in first-line therapy for indolent NHL will be determined through randomized clinical trials.
Seminars in Oncology 05/2002; 29(2 Suppl 6):2-6. · 3.50 Impact Factor
