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Patricia Pautier,
Clara Locher,
Caroline Robert,
Alain Deroussent,
Caroline Flament,
Axel Le Cesne,
Annie Rey,
Ratislav Bahleda, Vincent Ribrag,
Jean-Charles Soria,
Gilles Vassal,
Alexander Eggermont,
Laurence Zitvogel,
Nathalie Chaput,
Angelo Paci
[show abstract]
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ABSTRACT: Imatinib mesylate (IM) is a small molecule inhibitor of protein tyrosine kinases. In addition to its direct effect on malignant cells, it has been suggested IM may activate of natural killer (NK) cells, hence exerting immunomodulatory functions. In preclinical settings, improved antitumor responses have been observed when IM and interleukin-2 (IL-2), a cytokine that enhances NK cells functions, were combined. The goals of this study were to determine the maximum tolerated dose (MTD) of IL-2 combined with IM at a constant dose of 400 mg, the pharmacokinetics of IM and IL-2, as well as toxicity and clinical efficacy of this immunotherapeutic regimen in patients affected by advanced tumors. The treatment consisted in 50 mg/day cyclophosphamide from 21 d before the initiation of IM throughout the first IM cycle (from D-21 to D14), 400 mg/day IM for 14 d (D1 to D14) combined with escalating doses of IL-2 (3, 6, 9 and 12 MIU/day) from days 10 to 14. This treatment was administered at three week intervals to 17 patients. Common side effects of the combination were mild to moderate, including fever, chills, fatigue, nausea and hepatic enzyme elevation. IL-2 dose level II, 6 MIU/day, was determined as the MTD with the following dose-limiting toxicities: systemic capillary leak syndrome, fatigue and anorexia. Pharmacokinetic studies revealed that the area under the curve and the maximum concentration of IM and its main metabolite CGP74588 increased significantly when IM was concomitantly administered with IL-2. In contrast, IM did not modulate IL-2 pharmacokinetics. No objective responses were observed. The best response obtained was stable disease in 8/17 (median duration: 12 weeks). Finally, IL-2 augmented the impregnation of IM and its metabolite. The combination of IM (400 mg/day) and IL-2 (6 MIU/day) in tumors that express IM targets warrants further investigation.
Oncoimmunology. 02/2013; 2(2):e23079.
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Vincent Ribrag,
Hervé Tilly,
Olivier Casasnovas,
André Bosly,
Reda Bouabdallah,
Richard Delarue,
François Boue,
Dominique Bron,
Pierre Feugier,
Corinne Haioun,
Firtz Offner,
Bertrand Coiffier
[show abstract]
[hide abstract]
ABSTRACT: PURPOSE: Bortezomib has previously demonstrated activity in indolent lymphomas including follicular lymphoma with response rate ranging from 13% to 56%. However, the optimal schedule of bortezomib remains to be investigated in follicular lymphoma. EXPERIMENTAL DESIGN: We conducted a randomised phase II study where patients with follicular lymphoma in relapse or refractory receive either bortezomib 1.5mg/m(2) biweekly on days 1, 4, 8 and 11 of a 21-day cycle (arm A) or 1.6mg/m(2) weekly on days 1, 8, 15 and 22 of a 35-day cycle (arm B). An interim analysis was planned after 15 fully evaluable patients randomised in each treatment arm. If only five subjects or fewer respond, the treatment arm was concluded to be ineffective and was closed to inclusion. RESULTS: Eighty-seven patients were included in the trial. Arm B was closed to inclusion after interim analysis. 15/50 patients (30%) in arm A and 8/37 patients (22%) in arm B achieved a response. Median duration of response was 16 and 15 months for arms A and B, respectively. Most drug-related adverse events (AEs) (all grades, all cycles) were mild. CONCLUSION: This study demonstrates tolerability and durable clinical benefit of bortezomib when given at 1.5mg/m(2) biweekly. Despite a higher response rate in the biweekly arm, no major difference in patient's outcome was observed between the two arms in the final analysis.
European journal of cancer (Oxford, England: 1990) 12/2012; · 4.12 Impact Factor
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Martin Dreyling,
Hanneke C Kluin-Nelemans,
Sílvia Beà,
Wolfram Klapper,
Niclas Vogt,
Marie-Helene Delfau-Larue,
Grit Hutter,
Chan Cheah,
Annalisa Chiappella,
Sergio Cortelazzo,
Christiane Pott,
Georg Hess,
Carlo Visco,
Umberto Vitolo,
Pawel Klener,
Igor Aurer,
Michael Unterhalt, Vincent Ribrag,
Eva Hoster,
Olivier Hermine
[show abstract]
[hide abstract]
ABSTRACT: Abstract Mantle cell lymphoma (MCL) is a distinct subtype of malignant lymphoma characterized by the chromosomal translocation t(11;14)(q13;q32) resulting in constitutional overexpression of cyclin D1 and cell cycle dysregulation in virtually all cases. Clinically, MCL displays an aggressive clinical course with a continuous relapse pattern and a median survival of only 3-7 years. However, a subset of up to 15% long-term survivors has recently been identified with a rather indolent clinical course. In general, conventional chemotherapy is only palliative and median duration of remissions is only 1-2 years. In 2000, the European MCL Network ( http://www.european-mcl.net ) was founded, which consists of 15 national lymphoma study groups supplemented by experts in hematopathology, cytogenetics and molecular genetics. During the last decade, the European consortium has successfully initiated the largest phase III trials in MCL worldwide. In the current study generation, the addition of high dose Ara-C to an R-CHOP like regimen followed by myeloablative consolidation achieved a significant improvement of progression-free survival. Similarly, in elderly patients rituximab maintenance until progression led to a marked prolongation of remission duration. Emerging strategies include proteasome inhibitors, immune modulatory drugs (IMiDs), mTOR inhibitors and others, all based on the dysregulated cell cycle machinery and impairment of several signaling transduction and apoptotic pathways. Future strategies will apply individualized approaches according to the molecular risk profile of the patient. At the annual conference in Lisbon, recent results of molecular pathogenesis, analyses of current clinical trials and new study concepts were discussed.
Leukemia & lymphoma 09/2012; · 2.40 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The characterization of the mantle cell lymphoma (MCL) entity had a major impact on patient management and has played a profound role in improving therapy. Although the prognosis is improving in MCL, there is no definitive proof that the therapies currently available will lead to cure. Few randomized studies have been conducted in MCL patients. In young patients, initial intensive therapy with high-dose cytarabine followed by high-dose chemotherapy and hematopoietic stem cell reinfusion has resulted in prolonged progression-free survival. In elderly subjects, who always represent a more heterogeneous group of patients, there is no consensus concerning which drugs can be used during induction chemotherapy. New drugs have essentially been evaluated in patients with recurrent disease or refractory to first-line regimens. Recently, two of them (bortezomib and temsirolimus) with different modes of action were registered in MCL. Targeted therapies are also being investigated extensively in MCL and are yielding interesting activities.
Expert Review of Anti-infective Therapy 09/2012; 12(9):1205-15. · 2.65 Impact Factor
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Richard Delarue,
Corinne Haioun, Vincent Ribrag,
Pauline Brice,
Alain Delmer,
Herve Tilly,
Gilles Salles,
Achiel Van Hoof,
Olivier Casasnovas,
Nicole Brousse,
Francois Lefrere,
Olivier Hermine
[show abstract]
[hide abstract]
ABSTRACT: Treatment of mantle cell lymphoma (MCL) in younger patients remains a challenge. We report results of a phase II trial using Cytarabine and Rituximab (R) as induction regimen before autologous stem cell transplantation (ASCT). Patients under 66y with stage III-IV, MCL were included. Treatment consisted in three courses of CHOP21 with Rituximab at the third one and three R-DHAP. Responding patients were eligible for ASCT with TAM6 or BEAM. Sixty patients were included. Median age was 57 years. Characteristics of patients were: BM involvement 85%, leukemic disease 48%, gastrointestinal involvement 52%, PS>1 6%, LDH>1N 38%, MIPI (low 55%, intermediate 38%, high 13%). ORR was 93% after (R)-CHOP and 95% after R-DHAP. Whereas CR was uncommon after (R)-CHOP (12%), high proportion of patients (57%) was in CR after R-DHAP. With median follow-up of 67 months, median EFS is 83 months and median OS is not reached. Five-year OS is 75%. Comparison with previous study without Rituximab (Lefrere et al., Haematologica 2007) shows improvement of outcome (median EFS: 51 versus 83 months). No toxic death or unexpected toxicities were observed. This study confirms that induction with Rituximab and Cytarabine-based regimens are safe and effective in MCL patients. This regimen is currently compared with R-CHOP21 induction in a multicentric European protocol.
Blood 06/2012; · 9.90 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Tumor-associated macrophages (TAMs) might be associated with worse outcome in classical Hodgkin lymphoma (cHL). Our aim was to determine whether TAMs correlated with refractoriness in cHL. In a cohort of 18 consecutive primary refractory or early relapsed cases and 41 randomly selected controls (responder patients), high TAM infiltration was significantly associated with refractoriness or early relapse (p = 0.004) and remained independently correlated with outcome in multivariate analysis (odds ratio 8.276, 95% confidence interval 1.214-56.408). This study provides evidence that the marker CD68 might accurately predict early outcome of de novo cHL and could be used in combination with c-kit and TiA1 staining.
Leukemia & lymphoma 06/2012; · 2.40 Impact Factor
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[show abstract]
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ABSTRACT: To propose an alternative approach for treatment of pulmonary marginal zone lymphoma, using a very small radiation dose (2 × 2 Gy) delivered exclusively to tumor sites.
Patients had localized pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma according to the World Health Organization classification. The 6-MV radiation treatments were delivered using tumor-limited fields, except in cases of diffuse bilateral involvement. Two daily fractions of 2 Gy were delivered to tumor-limited fields using a 6-MV linear accelerator.
Ten patients with pulmonary MALT lymphoma entered the study. All but 1 had localized tumor masses. The median follow-up was 56 months (range, 2-103 months). Complete remission or an unconfirmed complete remission was obtained in 60% of patients within the first 2 months, and two additional partial responses were converted into a long-term unconfirmed complete remission. All patients are well and alive, no local progression was observed, and the 5-year progression-free survival rate was 87.5% (95% confidence interval 49%-97%).
Our results suggest that extremely low radiation doses delivered exclusively to tumor sites might be a treatment option in pulmonary MALT lymphoma.
International journal of radiation oncology, biology, physics 03/2012; 83(3):e385-9. · 4.59 Impact Factor
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Martin Dreyling,
Hanneke C. Kluin-Nelemans,
Sílvia Beà,
Elena Hartmann,
Itziar Salaverria,
Grit Hutter,
Patricia Perez-Galan,
Gael Roue,
Christiane Pott,
Steven Le Gouill, [......],
Georg Hess,
Francesco Zaja,
Umberto Vitolo,
Michal Szymczyk,
Jan Walewski, Vincent Ribrag,
Michael Unterhalt,
Olivier Hermine,
Eva Hoster,
for the European Mantle Cell Lymphoma Network
[show abstract]
[hide abstract]
ABSTRACT: Abstract Mantle cell lymphoma (MCL) is a distinct subtype of malignant lymphoma characterized by the chromosomal translocation t(11;14)(q13;q32), resulting in constitutional overexpression of cyclin D1 and cell cycle dysregulation in virtually all cases. Clinically, MCL shows an aggressive clinical course with a continuous relapse pattern and a median survival of only 3–5 years. However, recently a subset of up to 15% long-term survivors has been identified with a rather indolent clinical course. Advanced stage disease is usually apparent already at first clinical manifestation; in general, conventional chemotherapy is only palliative and median duration of remissions is only 1–2 years. In 2000, the European MCL Network (http://www.european-mcl.net) was founded, which consists of 15 national lymphoma study groups supplemented by experts in hematopathology, cytogenetics and molecular genetics. During the last decade, the European consortium has successfully initiated the largest phase III trials in MCL worldwide. In the current study generation, the addition of high-dose Ara-C to a rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP)-like regimen followed by myeloablative consolidation achieved a significant improvement of progression-free survival. Similarly, in elderly patients, rituximab maintenance until progression led to a marked prolongation of remission duration. Emerging strategies include proteasome inhibitors, immune modulatory drugs (IMiDs), mammalian target of rapamycin (mTOR) inhibitors and others, all based on the dysregulated control of cell cycle machinery and impairment of several apoptotic pathways. Combination strategies are currently being investigated in numerous trials, but their introduction into clinical practice and current treatment algorithms remains a challenge. Future strategies will apply individualized approaches according to the molecular risk profile of the patient. At the annual conference in Warsaw, recent results of molecular pathogenesis, analyses of current clinical trials and new study concepts were discussed.
11/2011; 52(12):2226-2236.
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Martin Dreyling,
Hanneke C Kluin-Nelemans,
Sílvia Beà,
Elena Hartmann,
Itziar Salaverria,
Grit Hutter,
Patricia Perez-Galan,
Gael Roue,
Christiane Pott,
Steven Le Gouill, [......],
Simon Rule,
Georg Hess,
Francesco Zaja,
Umberto Vitolo,
Michal Szymczyk,
Jan Walewski, Vincent Ribrag,
Michael Unterhalt,
Olivier Hermine,
Eva Hoster
[show abstract]
[hide abstract]
ABSTRACT: Mantle cell lymphoma (MCL) is a distinct subtype of malignant lymphoma characterized by the chromosomal translocation t(11;14)(q13;q32), resulting in constitutional overexpression of cyclin D1 and cell cycle dysregulation in virtually all cases. Clinically, MCL shows an aggressive clinical course with a continuous relapse pattern and a median survival of only 3-5 years. However, recently a subset of up to 15% long-term survivors has been identified with a rather indolent clinical course. Advanced stage disease is usually apparent already at first clinical manifestation; in general, conventional chemotherapy is only palliative and median duration of remissions is only 1-2 years. In 2000, the European MCL Network ( http://www.european-mcl.net ) was founded, which consists of 15 national lymphoma study groups supplemented by experts in hematopathology, cytogenetics and molecular genetics. During the last decade, the European consortium has successfully initiated the largest phase III trials in MCL worldwide. In the current study generation, the addition of high-dose Ara-C to a rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP)-like regimen followed by myeloablative consolidation achieved a significant improvement of progression-free survival. Similarly, in elderly patients, rituximab maintenance until progression led to a marked prolongation of remission duration. Emerging strategies include proteasome inhibitors, immune modulatory drugs (IMiDs), mammalian target of rapamycin (mTOR) inhibitors and others, all based on the dysregulated control of cell cycle machinery and impairment of several apoptotic pathways. Combination strategies are currently being investigated in numerous trials, but their introduction into clinical practice and current treatment algorithms remains a challenge. Future strategies will apply individualized approaches according to the molecular risk profile of the patient. At the annual conference in Warsaw, recent results of molecular pathogenesis, analyses of current clinical trials and new study concepts were discussed.
Leukemia & lymphoma 08/2011; 52(12):2226-36. · 2.40 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The evaluation of treatment efficacy with RECIST criteria does not take into account tumour growth dynamics. We notably investigated the impact of the pre-treatment tumour growth rate (GR) on the evaluation of treatment response.
Seventy-six patients included in phase I clinical trials had scanographic evaluations before and after starting an experimental treatment. The GR was calculated for the pre-treatment period and for the experimental period (i.e. during the new treatment). Tumour response was evaluated per protocol at week 12 and at week 24 of the experimental period according to RECIST criteria. We studied the relation between pre-treatment and experimental GRs and RECIST tumour response.
On average the tumour GR was decreased by 40% during the experimental period; compared to the pretreatment period (p=0.03). An increased growth rate (acceleration of GR during experimental treatment compared to pretreatment) was observed in 20 (38%) of the 53 patients considered as non-progressive at week 12 according to RECIST. Conversely a decreased GR was observed in 12 out of 23 (53%) patients classified as progressive according to RECIST. The variation in the GR between the pre-treatment and experimental period was not significantly correlated with response evaluated according to RECIST at week 12 or at week 24 (p=0.45 and 0.44, respectively).
RECIST evaluation of tumour response depends on the natural history of the tumours and poorly measures the impact of treatment on the kinetics of tumour growth. Integrating pre-treatment GR evaluations could substantially improve the assessment of treatment efficacy in drug development.
European journal of cancer (Oxford, England: 1990) 07/2011; 47(17):2512-6. · 4.12 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Mantle cell lymphoma (MCL) is an individualized entity that is well characterized at the molecular level and considered to be a disease of elderly patients. However, about half of patients are less than 65 years of age and may benefit from intensive therapies. Although MCL has been considered during the last three decades as an incurable disease with current chemotherapy regimens, in young patients recent intense chemo-immunotherapy (CIT) induction regimens including high-dose cytarabine with consolidation with autologous stem cell transplantation (ASCT) have increased significantly the outcome of patients with the disease; some may experience long-term survival free of disease and may even be cured. In addition, new drugs targeting some pathways, including molecular alterations of the disease, are being progressively incorporated into the therapeutic armamentarium of the disease and will certainly contribute to further improve prognosis. In the near future, more individualized approaches are foreseen that will take into account risk factors present at diagnosis, biomarkers representative of the molecular alterations, as well as quality of the response assessed by molecular residual diseases analysis. In this review, we discuss the current therapeutic approaches with classical CITs, the role of autologous and allogeneic stem cell transplantation, and the main new drugs that target major molecular pathways alterations of the disease, as well as their positioning during induction, consolidation, and maintenance in first-line treatment and in relapsing younger patients with MCL.
Seminars in Hematology 07/2011; 48(3):194-207. · 3.99 Impact Factor
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Didier Decaudin,
Nicolas Mounier,
Hervé Tilly, Vincent Ribrag,
Hervé Ghesquières,
Krimo Bouabdallah,
Franck Morschhauser,
Bertrand Coiffier,
Steven Le Gouill,
Serge Bologna,
Richard Delarue,
Anne Huynh,
André Bosly,
Josette Brière,
Christian Gisselbrecht
[show abstract]
[hide abstract]
ABSTRACT: This study was designed to evaluate the safety and efficacy of a conventional dose of yttrium-90 ((90)Y) ibritumomab tiuxetan combined with the etoposide rabinoside acytarabine melphalan (BEAM) regimen before autologous stem cell transplantation (ASCT) in chemosensitive relapsed or refractory low-grade B-cell lymphomas.
From March 2005 to August 2006, 77 prospective patients were included, 69 (90%) with follicular lymphomas.
The last salvage chemotherapy regimen included rituximab for 74 patients and ASCT for 75 patients. Before ASCT, rates of complete response/unconfirmed response (CR/CRu) and partial response were 77% and 23%, respectively. After zevaline-BEAM (Z-BEAM), time to >1 × 10(9)/L neutrophils was 12 days (range, 9-35 days), and time to >20 × 10(9)/L platelets was 12 days (range, 3-42 days). No other significant extrahematologic toxicity was observed. Three months after ASCT, 68 patients (88%) were in CR/CRu. After a median follow-up of 28 months, 2-year event-free survival (EFS) and overall survival were 63% and 97%, respectively, but EFS for first-relapsed patients was 72%. When using patients as their own controls, 2-year EFS was superior after ASCT and compared favorably with the duration of response of last chemotherapy (62% vs. 37%, P = .007) (Point 1.10).
Z-BEAM appears safe and needs to be further evaluated in a randomized trial.
Clinical lymphoma, myeloma & leukemia 04/2011; 11(2):212-8.
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Leukemia & lymphoma 03/2011; 52(3):521-4. · 2.40 Impact Factor
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Sophie Viaud,
Caroline Flament,
Mustapha Zoubir,
Patricia Pautier,
Axel LeCesne, Vincent Ribrag,
Jean-Charles Soria,
Virginie Marty,
Philippe Vielh,
Caroline Robert,
Nathalie Chaput,
Laurence Zitvogel
[show abstract]
[hide abstract]
ABSTRACT: Low doses of the alkylating agent cyclophosphamide (CTX) mediate antiangiogenic and immunostimulatory effects, leading to potent tumoricidal activity in association with various immunotherapeutic strategies. Here, we show in rodents and cancer patients that CTX markedly promotes the differentiation of CD4(+) T helper 17 (Th17) cells that can be recovered in both blood and tumor beds. However, CTX does not convert regulatory T cells into Th17 cells. Because Th17 are potent inducers of tissue inflammation and autoimmunity, these results suggest impact on the clinical management of various types of malignancies treated with alkylating agents and a potential need to optimize CTX-based immunotherapy in patients.
Cancer Research 02/2011; 71(3):661-5. · 7.86 Impact Factor
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Martin Dreyling,
Eva Hoster,
Silvia Bea,
Elena Hartmann,
Heike Horn,
Grit Hutter,
Itziar Salaverria,
Christiane Pott,
Marek Trneny,
Steven Le Gouill,
Sergio Cortelazzo,
Michal Szymczyk,
Wojciech Jurczak,
Ofer Shpilberg, Vincent Ribrag,
Olivier Hermine
[show abstract]
[hide abstract]
ABSTRACT: Mantle cell lymphoma (MCL) is a distinct subtype of malignant lymphoma which is characterized by the chromosomal translocation t(11;14)(q13;q32), resulting in constitutional overexpression of cyclin D1 and cell cycle dysregulation in virtually all cases. Clinically, MCL shows an aggressive clinical course with a continuous relapse pattern and a median survival of only 3-5 years. However, recently a subset of 15% long-term survivors has been identified with a rather indolent clinical course, even after conventional treatment strategies only. Advanced stage disease is usually apparent already at first clinical manifestation; thus, conventional chemotherapy is only palliative, and the median duration of remissions is only 1-2 years. Emerging strategies including proteasome inhibitors, immune modulatory drugs (IMiDs), mTOR inhibitors, and others are based on the dysregulated control of cell cycle machinery and impaired apoptotic pathways. Monotherapy of these compounds achieves efficacy comparable to conventional chemotherapy in relapsed MCL, and combination strategies are currently being investigated in numerous trials; however, their introduction into clinical practice and current treatment algorithms remain a challenge. In 2000 the European MCL Network ( http://www.european-mcl.net ) was founded, consisting of 15 national lymphoma study groups supplemented by experts in histopathology and molecular genetics. During the past decade, the European consortium has successfully initiated the largest phase III trials in MCL worldwide, with a current annual recruitment of almost 200 patients per year in first-line studies. In detail, in prospective randomized studies, the addition of a B-lymphocyte specific antibody doubled the median progression-free survival from 14 to 28 months, and a dose-intensified consolidation with high-dose radiochemotherapy and subsequent autologous stem cell transplant resulted in superior response duration (3.7 vs. 1.6 years) and even improved overall survival in a recent analysis. Future strategies will apply individualized approaches according to the molecular risk profile of the patient. At the recent annual conference in Jerusalem, recent results of molecular pathogenesis, analyses of current clinical trials, and new study concepts were discussed.
Leukemia & lymphoma 09/2010; 51(9):1612-22. · 2.40 Impact Factor
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Christiane Pott,
Eva Hoster,
Marie-Helene Delfau-Larue,
Kheira Beldjord,
Sebastian Böttcher,
Vahid Asnafi,
Anne Plonquet,
Reiner Siebert,
Evelyne Callet-Bauchu,
Niels Andersen, [......],
Marek Trneny,
Jan Walewski,
Peter Dreger,
Michael Unterhalt,
Wolfgang Hiddemann,
Michael Kneba,
Hanneke C Kluin-Nelemans,
Olivier Hermine,
Elizabeth Macintyre,
Martin Dreyling
[show abstract]
[hide abstract]
ABSTRACT: The prognostic impact of minimal residual disease (MRD) was analyzed in 259 patients with mantle cell lymphoma (MCL) treated within 2 randomized trials of the European MCL Network (MCL Younger and MCL Elderly trial). After rituximab-based induction treatment, 106 of 190 evaluable patients (56%) achieved a molecular remission (MR) based on blood and/or bone marrow (BM) analysis. MR resulted in a significantly improved response duration (RD; 87% vs 61% patients in remission at 2 years, P = .004) and emerged to be an independent prognostic factor for RD (hazard ratio = 0.4, 95% confidence interval, 0.1-0.9, P = .028). MR was highly predictive for prolonged RD independent of clinical response (complete response [CR], complete response unconfirmed [CRu], partial response [PR]; RD at 2 years: 94% in BM MRD-negative CR/CRu and 100% in BM MRD-negative PR, compared with 71% in BM MRD-positive CR/CRu and 51% in BM MRD-positive PR, P = .002). Sustained MR during the postinduction period was predictive for outcome in MCL Younger after autologous stem cell transplantation (ASCT; RD at 2 years 100% vs 65%, P = .001) and during maintenance in MCL Elderly (RD at 2 years: 76% vs 36%, P = .015). ASCT increased the proportion of patients in MR from 55% before high-dose therapy to 72% thereafter. Sequential MRD monitoring is a powerful predictor for treatment outcome in MCL. These trials are registered at www.clinicaltrials.gov as #NCT00209222 and #NCT00209209.
Blood 04/2010; 115(16):3215-23. · 9.90 Impact Factor
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Delphine Rolland, Vincent Ribrag,
Corinne Haioun,
Herve Ghesquieres,
Fabrice Jardin,
Reda Bouabdallah,
Patricia Franchi,
Josette Briere,
Eric De Kerviler,
Catherine Chassagne-Clement,
Mitch Raponi,
Remi Houlgatte,
Jean-Philippe Jais,
Catherine Thieblemont
[show abstract]
[hide abstract]
ABSTRACT: Farnesyltransferase (Ftase) was identified by gene-expression profiling and by preclinical evaluation in in vitro and in vivo mantle cell lymphoma (MCL) models as a rational therapeutic target in MCL, one of the most refractory B-cell lymphomas. We conducted a multicenter phase II study of a potent Ftase inhibitor, tipifarnib, in patients with relapsed or refractory MCL.
Tipifarnib was administered at 300 mg orally twice daily for the first 21 days of each 28-day cycle for 4 cycles, and in case of response for 6 cycles. Study endpoints were objective response at 4 and 6 cycles, progression free survival (PFS), overall survival, and toxicity. Prediction of response was retrospectively evaluated in the initial tumor biopsy by the RASGRP1/APTX gene expression ratio, and the AKAP13 expression level.
Eleven patients (median age, 71 years) were enrolled. Patients received a median number of three prior therapies (range 1-11). Nine patients completed at least 3 cycles of tipifarnib. No grade III-IV hematological toxicities were recorded. One patient presented a complete response (CR) after 4 and a persistent CR at 6 cycles (ORR = 9%). Median PFS was 3 months (range 0.7-14.2). The RASGRP1/APTX gene expression ratio was higher in the responder (n = 1) while the AKAP13 expression was higher in the non-responders (n = 2). This corresponds to the expected result for predicting response to tipifarnib.
Treatment with tipifarnib relapsed or refractory MCL is associated with low response rates. Limited gene expression studies suggest that response may be associated with molecular targets.
Cancer Chemotherapy and Pharmacology 12/2009; 65(4):781-90. · 2.83 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The mammalian target of rapamycin (mTOR) pathway regulates translation of key proteins that contribute to the pathogenesis of advanced hematologic malignancies. Inhibitors of mTOR (temsirolimus, everolimus, and deforolimus) constitute a new class of antitumor agents, with potential for treatment of relapsed and/or refractory hematologic malignancies. Mantle cell lymphoma (MCL) was the first hematologic malignancy in which mTOR inhibition was explored as a treatment strategy, owing to its characteristic overexpression of cyclin D1, a G1 cyclin regulated by mTOR signaling. Temsirolimus and everolimus exhibited antitumor activity against relapsed, refractory disease in phase II studies. In a randomized phase III trial, once-weekly intravenous temsirolimus 175 mg for 3 weeks followed by 75 mg once weekly was recently shown to improve progression-free survival (p=0.0009) and objective response rate (p=0.0019) versus investigator's choice of therapy in relapsed or refractory MCL. Evidence of antitumor activity seen in early clinical trials for other non-Hodgkin lymphoma subtypes, multiple myeloma, and myeloid leukemias supports further studies of mTOR inhibitors, alone or in combination strategies, in these diseases. Overall, the clinical findings to date strengthen mTOR inhibition as a novel and promising strategy for the treatment of certain hematologic malignancies, particularly for MCL.
Leukemia & lymphoma 09/2009; 50(12):1916-30. · 2.40 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Bortezomib demonstrated promising activity in lymphomas. The authors conducted a randomized phase 2 trial of frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with the addition of bortezomib in patients with B-cell lymphoma.
Patients were randomized between 2 schedules of bortezomib, Arm A (Days 1, 4, 8, and 11) and Arm B (Days 1 and 8), combined with 6 cycles of R-CHOP. For the first patients (Step 1), bortezomib was given at a dose of 1 mg/m(2) in Arm A and 1.3 mg/m(2) in Arm B. For the next patients (Step 2), doses were increased to 1.3 mg/m(2) and 1.6 mg/m(2) in Arms A and B, respectively. The primary endpoint was the rate of complete response (CR) and unconfirmed CR (CR/CRu) after 6 cycles.
Forty-nine patients were included in the study, and 41 patients (84%) achieved a CR/CRu, ie, 18 of 20 patients (90%) in Arm A and 23 of 29 patients (79%) in Arm B. There were 6 partial responses and 2 patients with progressive disease. Neurologic toxicity occurred in 21 patients (43%) and was grade 2 in 11 patients (7 patients in Step 2) and grade 3 in 10 patients (9 patients in Step 2). Other grade 3 and 4 toxicities included constipation (n = 1), infections (n = 3), and cardiac events (n = 2). Grade 3 and 4 thrombocytopenia and leucopenia occurred in 14% and 41% of cycles, respectively.
R-CHOP + bortezomib was an effective regimen and produced an 84% CR rate. However, the dose-limiting neurotoxicity should be kept in mind for further trials with vinca alkaloids or other potentially neurotoxic drugs combination therapies.
Cancer 08/2009; 115(19):4540-6. · 4.77 Impact Factor
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Didier Decaudin,
Jacques Bosq,
Jean-Nicolas Munck,
Chantal Bayle,
Serge Koscielny,
Sabah Boudjemaa,
Annelise Bennaceur,
Anne-Marie Venuat,
Philippe Naccache,
Belguendouz Bendahmane, Vincent Ribrag,
Patrice Carde,
José Luis Pico,
Marcel Hayat
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ABSTRACT: We reviewed 77 cases considered as lymphocytic lymphomas of intermediate differentiation or diffuse centrocytic lymphomas. Forty-five cases were diagnosed as mantle cell lymphoma (MCL). The architectural pattern was diffuse in 95%, 8 cases presented large blastoid cells and CD5 positivity was observed in 28/34 cases. Of 20 cases studied, 8 presented a t(11;14)(q13;q32). Patient characteristics were: median age 59 years, B symptoms in 38%, 87% stages 111-IV, bone marrow involvement in 67% with peripheral leukemic cells in 24%. Forty-four patients were treated with chemotherapy and 7 received radiotherapy. The complete response (CR) rate was 58%. Of the 26 CR, 19 relapsed at a median of 15 months. Disease-free survival was 42% and overall survival was 73% at 3 years. In a univariate analysis, overall survival was related to liver and bone marrow involvement, the presence of peripheral lymphomatous cells and achieving a complete response.
06/2009; 26(5-6):539-550.
