Noel Milpied

Publications of Noel Milpied

• Definitive set-up of clinical-scale procedure for ex-vivo expansion of cord blood hematopoietic cells for transplantation.

  Authors: Pascale Duchez, Jean Chevaleyre, Marija Vlaski, Bernard Dazey, Noel Milpied, Jean-Michel Boiron, Zoran Ivanovic

  Cell transplantation. 03/2012;

  We recently developed a clinical grade ex vivo cord blood expansion procedure enabling a massive amplification of hematopoietic progenitors without any loss of stem cell potential. This procedure,We recently developed a clinical grade ex vivo cord blood expansion procedure enabling a massive amplification of hematopoietic progenitors without any loss of stem cell potential. This procedure, based on Day 14 liquid cultures of cord blood CD34+ cells, in medium Macopharma HP01 and in presence of Stem Cell Factor - SCF (100 ng/ml), fms-Related Tyrosine Kinase 3 - Ligand - FLT3-ligand (100ng/ml), Megakaryocyte Growth and Developmental Factor - MGDF (100 Ng/ml) and Granulocyte - Colony Stimulating Factor -G-CSF (10 Ng/ml) had to be modified due to the commercially unavailability of clinical grade MGDF molecule. So, MGDF was replaced by Thrombopoietin - TPO in five fold lower dose (20 ng/ml) and culture time was reduced to 12 days. That way, a mean expansion fold of 400, 80, and 150 was obtained for total cells, CD34+ cells and Colony Forming Cells - CFC, respectively. This amplification was associated with a slight enhancing effect on stem cells (Scid Repopulating Cells - SRC). These are the ultimate pre-clinical modifications of a clinical grade expansion protocol which is already employed in an ongoing clinical trial.

• Phase II prospective study of treosulfan-based reduced-intensity conditioning in allogeneic HSCT for hematological malignancies from 10/10 HLA-identical unrelated donor.

  Authors: Mauricette Michallet, Mohamad Sobh, Noel Milpied, Jacques-Olivier Bay, Sabine Fürst, Jean-Luc Harousseau, Mohamad Mohty, Franck E Nicolini, Hélène Labussière, Nathalie Tedone, Stéphane Morisset, Stéphane Vigouroux, Joachim Baumgart, Reza Tabrizi, Didier Blaise

  Annals of hematology. 02/2012;

  Different RIC regimens were evaluated prior to allo-HSCT in different hematological malignancies. We conducted this prospective study in adult patients with various hematological malignancies inDifferent RIC regimens were evaluated prior to allo-HSCT in different hematological malignancies. We conducted this prospective study in adult patients with various hematological malignancies in order to evaluate the toxicity and efficacy of treosulfan-based conditioning, followed by allo-HSCT from 10/10 HLA-identical unrelated donors. Conditioning included treosulfan 12 g/m(2)/day i.v. (day -6 to day -4), fludarabine 30 mg/m(2)/day i.v. (day -6 to day -2), and ATG 2.5 mg/kg/day (day -2 to day -1). PBSC were used as HSC source. We included 56 patients (29 AML, 9 MM, 8 MDS, 6 CLL, 3 ALL, and 1 CML) with a median age of 57 years (18-65.5). Fifty-four (96%) patients engrafted; the cumulative incidence of aGVHD grade ≥II at 3 months reached 31%. The cumulative incidence of cGVHD at 18 months was 34% limited and 8% extensive. The median overall survival (OS) was not reached with a 3-year probability of 52%. The cumulative incidence of relapse at 3 years was 25%, and the cumulative incidence of transplant-related mortality (TRM) at 12 and 24 months was 20% and 23%, respectively. Treosulfan appears to be a good alternative for conditioning of MUD transplant patients with promising results in terms of OS, relapse, and TRM.

• Growth factor-associated graft-versus-host disease and mortality 10 years after allogeneic bone marrow transplantation.

  Authors: Olle Ringdén, Myriam Labopin, Norbert-Claude Gorin, Liisa Volin, Giovanni F Torelli, Michel Attal, Jean P Jouet, Noel Milpied, Gerard Socié, Catherine Cordonnier, Mauricette Michallet, Arturo I Atienza, Olivier Hermine, Mohamad Mohty

  British journal of haematology. 02/2012;

  This study analysed the effects of growth factor on outcome after haematopoietic stem-cell transplantation (HSCT) with >9 years follow-up. Of 1887 adult patients with acute leukaemia who receivedThis study analysed the effects of growth factor on outcome after haematopoietic stem-cell transplantation (HSCT) with >9 years follow-up. Of 1887 adult patients with acute leukaemia who received bone marrow from human leucocyte antigen (HLA)-identical siblings and were treated with myeloablative conditioning, 459 (24%) were treated with growth factor. Growth factor hastened engraftment of neutrophils (P < 0·0001), but reduced platelet counts (P = 0·0002). Graft-versus-host disease (GVHD)-free survival (no acute GVHD grade II-IV or chronic GVHD) at 10 years was 12 ± 2% (±SE) in the growth factor group, as opposed to 17 ± 2% in the controls [hazard ratio (HR) 0·81, P = 0·001]. Similar differences in GVHD-free survival were seen in patients with or without conditioning with total body irradiation (TBI). Non-relapse mortality (NRM) was higher in the growth factor group irrespective of whether or not TBI conditioning was included [HR = 1·48; 95% confidence interval (CI): 1·15-1·9; P = 0·002; HR = 1·59; 95% CI: 1·07-2·37; P = 0·02, respectively]. Both groups had similar probabilities of leukaemic relapse (HR = 0·96; 95% CI: 0·78-1·18; P = 0·71). Leukaemia-free survival (LFS) at 10 years was 35 ± 2% in those receiving growth factor prophylaxis, as opposed to 44 ± 1% in the controls (HR = 0·70; 95% CI: 0·60-0·82; P = 0·00001). Prophylaxis with growth factor increases the risk of GVHD, does not affect relapse, increases NRM and reduces LFS > 10 years after HSCT, regardless of conditioning with TBI.

• CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group.

  Authors: Michael Pfreundschuh, Evelyn Kuhnt, Lorenz Trümper, Anders Osterborg, Marek Trneny, Lois Shepherd, Devinder S Gill, Jan Walewski, Ruth Pettengell, Ulrich Jaeger [......] Ofer Shpilberg, Stein Kvaloy, Peter de Nully Brown, Rolf Stahel, Noel Milpied, Armando López-Guillermo, Viola Poeschel, Sandra Grass, Markus Loeffler, Niels Murawski

  The lancet oncology. 09/2011; 12(11):1013-22.

  The MInT study was the first to show improved 3-year outcomes with the addition of rituximab to a CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen in young patients withThe MInT study was the first to show improved 3-year outcomes with the addition of rituximab to a CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen in young patients with good-prognosis diffuse large-B-cell lymphoma. Extended follow-up was needed to establish long-term effects. In the randomised open-label MInT study, patients from 18 countries (aged 18-60 years with none or one risk factor according to the age-adjusted International Prognostic Index [IPI], stage II-IV disease or stage I disease with bulk) were randomly assigned to receive six cycles of a CHOP-like chemotherapy with or without rituximab. Bulky and extranodal sites received additional radiotherapy. Randomisation was done centrally with a computer-based tool and was stratified by centre, bulky disease, age-adjusted IPI, and chemotherapy regimen by use of a modified minimisation algorithm that incorporated a stochastic component. Patients and investigators were not masked to treatment allocation. The primary endpoint was event-free survival. Analyses were by intention to treat. This observational study is a follow-up of the MInT trial, which was stopped in 2003, and is registered at ClinicalTrials.gov, number NCT00400907. The intention-to-treat population included 410 patients assigned to chemotherapy alone and 413 assigned to chemotherapy plus rituximab. After a median follow-up of 72 months (range 0·03-119), 6-year event-free survival was 55·8% (95% CI 50·4-60·9; 166 events) for patients assigned to chemotherapy alone and 74·3% (69·3-78·6; 98 events) for those assigned to chemotherapy plus rituximab (difference between groups 18·5%, 11·5-25·4, log-rank p<0·0001). Multivariable analyses showed that event-free survival was affected by treatment group, presence of bulky disease, and age-adjusted IPI and that overall survival was affected by treatment group and presence of bulky disease only. After chemotherapy and rituximab, a favourable subgroup (IPI=0, no bulk) could be defined from a less favourable subgroup (IPI=1 or bulk, or both; event-free survival 84·3% [95% CI 74·2-90·7] vs 71·0% [65·1-76·1], log-rank p=0·005). 18 (4·4%, 95% CI 2·6-6·9) second malignancies occurred in the chemotherapy-alone group and 16 (3·9%, 2·2-6·2) in the chemotherapy and rituximab group (Fisher's exact p=0·730). Rituximab added to six cycles of CHOP-like chemotherapy improved long-term outcomes for young patients with good-prognosis diffuse large-B-cell lymphoma. The definition of two prognostic subgroups allows a more refined therapeutic approach to these patients than does assessment by IPI alone. Hoffmann-La Roche.

• Allogeneic haematopoietic stem cell transplantation for myelofibrosis: a report of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

  Authors: Marie Robin, Reza Tabrizi, Mohamad Mohty, Sabine Furst, Mauricette Michallet, Jacques-Olivier Bay, Jean-Yves Cahn, Eric De Coninck, Nathalie Dhedin, Marc Bernard, Bernard Rio, Agnès Buzyn, Anne Huynh, Karin Bilger, Pierre Bordigoni, Nathalie Contentin, Raphaël Porcher, Gérard Socié, Noel Milpied

  British journal of haematology. 02/2011; 152(3):331-9.

  Allogeneic haematopoietic stem-cell transplantation (HSCT) is the only curative treatment for myelofibrosis. We report an analysis of the Société Française de Greffe de Moelle et de ThérapieAllogeneic haematopoietic stem-cell transplantation (HSCT) is the only curative treatment for myelofibrosis. We report an analysis of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) registry including patients with myelofibrosis transplanted between 1997 and 2008. Potential risk factors affecting engraftment, non-relapse mortality (NRM), overall survival (OS) and progression-free survival (PFS) were analysed. One hundred and forty-seven patients, aged 20-68 (median 53) years, diagnosed with primary (53%) or secondary myelofibrosis underwent HSCT; 59% of patients were transplanted from a matched sibling donor. The conditioning regimen was myeloablative in 31% of patients. Ninety percent of the patients engrafted. Factors affecting favourably engraftment were splenectomy before HSCT, human leucocyte antigen (HLA) matched sibling donor, peripheral stem cell use as source of stem cells and absence of pre-transplant thrombocytopenia. Four-year OS, PFS and NRM survival were 39% (95%confidence interval [CI]: 31-50), 32% (95%CI: 24-43) and 39% (95%CI 30-48), respectively. Multivariate analysis indicated that HLA-identical sibling donor, chronic phase disease and splenectomy in men had favourable impact on OS.

• Lenalidomide induces remission and mixed quantitative chimerism fluctuations in refractory and relapsed myeloid malignancy with del (5).

  Authors: Pierre-Yves Dumas, Arnaud Pigneux, Reza Tabrizi, Noel Milpied

  Leukemia research. 11/2010; 34(11):e302-3.

• Higher incidence of relapse in patients with acute myelocytic leukemia infused with higher doses of CD34+ cells from leukapheresis products autografted during the first remission.

  Authors: Norbert-Claude Gorin, Myriam Labopin, Josy Reiffers, Noel Milpied, Didier Blaise, Francis Witz, Theo de Witte, Giovanna Meloni, Michel Attal, Teresa Bernal, Vanderson Rocha

  Blood. 10/2010; 116(17):3157-62.

  The stem cell source for autologous transplantation has shifted from bone marrow to peripheral blood (PB). We previously showed that relapse incidence in patients with acute myelocytic leukemiaThe stem cell source for autologous transplantation has shifted from bone marrow to peripheral blood (PB). We previously showed that relapse incidence in patients with acute myelocytic leukemia autografted in first remission (CR1) was greater with PB than bone marrow, and a poorer outcome was associated with a shorter CR1 to PB transplantation interval (≤ 80 days). Leukemic and normal progenitors are CD34(+) and can be concomitantly mobilized; we assessed whether an association exists between the infused CD34(+) cell dose and outcome. The infused CD34(+) cell doses were available for 772 patients autografted more than 80 days after CR1 and were categorized by percentiles. We selected the highest quintile (> 7.16 × 10(6)/kg) as the cutoff point. By multivariate analysis, relapse was more probable in patients who received the highest dose (hazard ratio = 1.48; 95% confidence interval, 1.12-1.95; P = .005), and leukemia-free survival was worse (hazard ratio = 0.72; 95% confidence interval, 0.55-0.93; P = .01). In conclusion, in patients autografted in first remission, relapse was higher and leukemia-free survival lower for those who received the highest CD34(+) PB doses.

• Upfront VIP-reinforced-ABVD (VIP-rABVD) is not superior to CHOP/21 in newly diagnosed peripheral T cell lymphoma. Results of the randomized phase III trial GOELAMS-LTP95.

  Authors: Audrey Simon, Michel Peoch, Philippe Casassus, Eric Deconinck, Philippe Colombat, Bernard Desablens, Olivier Tournilhac, Houchingue Eghbali, Charles Foussard, Jerome Jaubert, Jean Pierre Vilque, Jean François Rossi, Virginie Lucas, Vincent Delwail, Antoine Thyss, Frederic Maloisel, Noel Milpied, Steven le Gouill, Thierry Lamy, Rémy Gressin

  British journal of haematology. 10/2010; 151(2):159-66.

  Peripheral T-Cell lymphomas (PTCL) are relatively rare diseases but appear to be highly aggressive and display worse remission and survival rates than B-cell lymphomas. Despite unsatisfactory resultsPeripheral T-Cell lymphomas (PTCL) are relatively rare diseases but appear to be highly aggressive and display worse remission and survival rates than B-cell lymphomas. Despite unsatisfactory results with the cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) regimen, it remains the reference front-line therapy in these diseases, but has not been challenged in phase III trials. The Groupe Ouest Est d'Etude des Leucémies et Autres Maladies du Sang (GOELAMS) devised an alternative therapeutic schedule including etoposide, ifosfamide, cisplatin alternating with doxorubicin, bleomycin, vinblastine, dacarbazine (VIP-reinforced-ABVD; VIP-rABVD) and compared it to CHOP/21 as front-line treatment in non-cutaneous PTCL. All newly diagnosed patients were eligible. The primary objective was to improve the 2-year event-free survival (EFS) rate. Secondary objectives were to compare the response rate, overall survival, and toxicities as well as identify prognostic factors. Eighty-eight patients were identified between 1996 and 2002. Both arms were well balanced for patients' characteristics in terms of histological and clinical presentation. No significant difference was observed between the two arms in terms of 2-year EFS. Anaplastic large cell lymphoma type and Ann Arbor stage I-II were identified as two independent favourable prognostic factors influencing survival. VIP-rABVD was not superior to CHOP/21 in terms of EFS as first-line treatment of PTCL, confirming that CHOP/21 remains the reference regimen in these lymphomas.

• Reduced-intensity conditioning allogeneic stem cell transplant for relapsed or transformed aggressive B-cell non-Hodgkin lymphoma.

  Authors: Aline Clavert, Steven Le Gouill, Eolia Brissot, Viviane Dubruille, Beatrice Mahe, Thomas Gastinne, Nicolas Blin, Patrice Chevallier, Thierry Guillaume, Jacques Delaunay, Sameh Ayari, Beatrice Saulquin, Anne Moreau, Philippe Moreau, Jean-Luc Harousseau, Noel Milpied, Mohamad Mohty

  Leukemia & lymphoma. 08/2010; 51(8):1502-8.

  The role of reduced-intensity conditioning allogeneic stem cell transplant (RIC allo-SCT) in aggressive B-cell non-Hodgkin lymphoma (NHL) remains a matter of debate. This single-center analysis aimedThe role of reduced-intensity conditioning allogeneic stem cell transplant (RIC allo-SCT) in aggressive B-cell non-Hodgkin lymphoma (NHL) remains a matter of debate. This single-center analysis aimed to assess the potential benefit of RIC allo-SCT in 19 consecutive patients with relapsed or transformed aggressive B-cell NHL. Aggressive transformation (primary or secondary) was documented for these patients by pathological examination. In this series, all patients but two (n = 17; 89.5%) could actually receive autologous stem cell transplant (auto-SCT) prior to RIC allo-SCT. At the time of allo-SCT, eight patients (42%) were in first complete remission (CR), six (31.5%) were beyond first CR, and five (26.5%) were in partial remission. With a median follow-up of 32 (range, 3-86) months, nine patients experienced grade 2-4 acute GVHD (47.5%) and 10 patients had extensive chronic GVHD (52.5%). Overall, the incidence of non-relapse mortality was 26% (95% CI, 8-44%). At last follow-up, 12 patients (63%) were in sustained CR. The Kaplan-Meier estimates of progression-free and overall survival rates were 68% and 68%, respectively, at 4 years. We conclude that RIC allo-SCT after auto-SCT is feasible and a potentially efficient therapy for relapsed or transformed aggressive B-cell NHL, warranting further prospective evaluation.

• Front-line high-dose chemotherapy with rituximab showed excellent long-term survival in adults with aggressive large b-cell lymphoma: final results of a Phase II GOELAMS Study.

  Authors: Marie-Sarah Dilhuydy, Thierry Lamy, Charles Foussard, Remy Gressin, Philippe Casassus, Eric Deconninck, Christine Le Maignan, Diane Damotte, Noel Milpied

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 05/2010; 16(5):672-7.

  To evaluate the effect of rituximab in poor-prognosis patients with diffuse large B-cell lymphoma (DLBCL), a multicenter phase II trial combining rituximab with chemotherapy followed by high-doseTo evaluate the effect of rituximab in poor-prognosis patients with diffuse large B-cell lymphoma (DLBCL), a multicenter phase II trial combining rituximab with chemotherapy followed by high-dose therapy (HDT) with autologous stem cell transplant was conducted by the Groupe Ouest-Est des Leucémies et des Autres Maladies du Sang (GOELAMS). Patients were aged 18 to 60 years, with newly diagnosed CD20-expressing DLBCL, and at least 2 adverse risk factors as defined by the age-adjusted International Prognostic Index (aa-IPI). The treatment consisted of 2 courses of high-dose CHOP-like regimen on day 1 and 15 and 1 course of methotrexate and cytarabine on day 36. Four doses of rituximab (375 mg/m(2)) were infused on days 1, 15, 22, and 36. For patients who achieved at least a partial remission (PR), HDT followed by autologous stem cell transplant was performed on day 66. From April 2002 to May 2003, 42 patients were eligible. Half were high aa-IPI risk patients. Thirty-eight patients (90%) completed the treatment. Treatment-related mortality was 7% and no toxic death was related to rituximab. Complete response rate after the end of the full treatment was 67%. With a median follow-up of 66 months, event-free survival and overall survival rates were 55% and 74%, respectively. Median survival was not reached. First-line HDT with rituximab offers promising results for young adults with intermediate high or high aa-IPI high-grade lymphoma. Immediate and late toxicities were low. This treatment is being randomly compared prospectively with CHOP-14-rituximab in young adults with DLBCL (GOELAMS 075 trial).

• High-dose therapy and autologous stem-cell transplantation in Waldenstrom macroglobulinemia: the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation.

  Authors: Charalampia Kyriakou, Carmen Canals, David Sibon, Jean Yves Cahn, Majid Kazmi, William Arcese, Karin Kolbe, Norbert Claude Gorin, Kristy Thomson, Noel Milpied, Dietger Niederwieser, Karel Indrák, Paolo Corradini, Anna Sureda, Norbert Schmitz

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 04/2010; 28(13):2227-32.

  The role of autologous stem-cell transplantation (ASCT) in Waldenström macroglobulinemia (WM) is not defined. The aim of this study was to analyze the results of ASCT in patients with WM and toThe role of autologous stem-cell transplantation (ASCT) in Waldenström macroglobulinemia (WM) is not defined. The aim of this study was to analyze the results of ASCT in patients with WM and to determine the prognostic factors that have a significant impact on outcome. We analyzed 158 adult patients with WM reported to the European Group for Blood and Marrow Transplantation (EBMT) between January 1991 and December 2005. Median time from diagnosis to ASCT was 1.7 years (range, 0.3 to 20.3 years), 32% of the patients experienced treatment failure with at least three lines of therapy, and 93% had sensitive disease at the time of ASCT. Conditioning regimen was total-body irradiation-based in 45 patients. Median follow-up for surviving patients was 4.2 years (range, 0.5 to 14.8 years). Nonrelapse mortality was 3.8% at 1 year. Ten patients developed a secondary malignancy, with a cumulative incidence of 8.4% at 5 years. Relapse rate was 52.1% at 5 years. Progression-free survival (PFS) and overall survival were 39.7% and 68.5%, respectively, at 5 years and were significantly influenced by number of lines of therapy and chemorefractoriness at ASCT. The achievement of a negative immunofixation after ASCT had a positive impact on PFS after ASCT. When used as consolidation at first response, ASCT provided a PFS of 44% at 5 years. ASCT is a feasible procedure in young patients with advanced WM. ASCT should not be offered to patients with chemoresistant disease and to those who received more than three lines of therapy.

• Reply to K. Filanovsky et al.

  Authors: Patrice Chevallier, Jacques Delaunay, Pascal Turlure, Arnaud Pigneux, Mathilde Hunault, Richard Garand, Thierry Guillaume, Herve Avet-Loiseau, Nathalia Dmytruk, Stephane Girault, Noel Milpied, Norbert Ifrah, Mohamad Mohty, Jean-Luc Harousseau

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 01/2010;

• CD34+ cells obtained from "good mobilizers" are more activated and exhibit lower ex vivo expansion efficiency than their counterparts from "poor mobilizers"

  Authors: Zoran Ivanovic, Milica Kovacevic-Filipovic, Michel Jeanne, Leslie Ardilouze, Anne Bertot, Milène Szyporta, Francis Hermitte, Xavier Lafarge, Pascale Duchez, Marija Vlaski, Noel Milpied, Mirjana Pavlovic, Vincent Praloran, Jean-Michel Boiron

  Transfusion. 10/2009;

  BACKGROUND: The classification of patients into "good" or "poor" mobilizers is based on CD34+ cell count in their peripheral blood (PB) after granulocyte-colony-stimulating factor (G-CSF) injection.BACKGROUND: The classification of patients into "good" or "poor" mobilizers is based on CD34+ cell count in their peripheral blood (PB) after granulocyte-colony-stimulating factor (G-CSF) injection. We hypothesized that, apart from their mobilization from marrow to the blood, the response to G-CSF of CD34+ cells also includes activation of proliferation, metabolic activity, and proliferative capacity. STUDY DESIGN AND METHODS: Mobilized PB CD34+ cells purified from samples obtained by cytapheresis of multiple myeloma or non-Hodgkin's lymphoma patients of both good (>50 CD34+ cells/microL) and poor (</=50 CD34+ cells/microL) mobilizers were studied. The initial cell cycle state of CD34+ cells after selection and their kinetics of activation (exit from G(0) phase) during ex vivo culture were analyzed. Their proliferative capacity was estimated on the basis of ex vivo generation of total cells, CD34+ cells, and colony-forming cells (CFCs), in a standardized expansion culture. Indirect insight in metabolic activity was obtained on the basis of their survival (viability and apoptosis follow-up) during the 7-day-long conservation in hypothermia (4 degrees C) in the air or in atmosphere containing 3% O(2)/6% CO(2). RESULTS: CD34+ cells obtained from good mobilizers were in lower proportion in the G(0) phase, their activation in a cytokine-stimulated culture was accelerated, and they exhibited a lower ex vivo expansion efficiency than those from poor mobilizers. The resistance to hypothermia of good immobilizers' CD34+ cells is impaired. CONCLUSION: A good response to G-CSF mobilization treatment is associated with a higher degree of proliferative and metabolic activation of mobilized CD34+ cells with a decrease in their expansion capacity.

• Cost Effectiveness of High-Dose Chemotherapy with Autologous Stem Cell Support as Initial Treatment of Aggressive Non-Hodgkin's Lymphoma.

  Authors: Philippe Fagnoni, Noel Milpied, Samuel Limat, Eric Deconinck, Virginie Nerich, Charles Foussard, Philippe Colombat, Jean-Luc Harousseau, Marie-Christine Woronoff-Lemsi

  PharmacoEconomics. 02/2009; 27(1):55-68.

  The GOELAMS 072 study showed that first-line high-dose chemotherapy (HDT) with peripheral blood stem cell transplant (PBSCT) support was superior to the standard chemotherapy regimenThe GOELAMS 072 study showed that first-line high-dose chemotherapy (HDT) with peripheral blood stem cell transplant (PBSCT) support was superior to the standard chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine and prednisone; CHOP) in adults with aggressive non-Hodgkin's lymphoma (NHL). The aim of the study was to evaluate the pharmacoeconomic profile of HDT with PBSCT support relative to standard CHOP therapy as first-line treatment in adults with aggressive NHL. We performed a cost-effectiveness analysis from the French Public Health Insurance perspective, restricted to hospital costs (euro, year 2008 values). The clinical effectiveness criterion was censured overall survival (OS) difference after a median follow-up of 4 years for the entire cohort. A total of 197 patients were included (CHOP, n = 99; HDT, n = 98). Uncertainty was assessed using non-parametric bootstrap simulations and various scenario analyses. Five-year OS did not differ significantly between groups for the entire cohort. Nevertheless, subgroup analyses appeared to be more relevant for decision making: among patients with a high-intermediate risk according to the age-adjusted International Prognostic Index (IPI), HDT yielded a significantly higher 5-year OS than CHOP (74% vs 44%; p = 0.001). Among these patients, the mean censured OS survival, adjusted for time discounting and quality of life (QOL), increased with HDT by 1.20 years (95% CI 1.19, 1.21). The cost per life-year saved with HDT was estimated as euro34 315 (95% CI 32 683, 35 947) in this subgroup. Results suggested that HDT with PBSCT support might be considered a cost-effective strategy among patients with high-intermediate-risk NHL according to the age-adjusted IPI. Its place and its cost effectiveness potential versus, or in combination with, rituximab still need further research.

• Long-Term Disease-Free Survival After Gemtuzumab, Intermediate-Dose Cytarabine, and Mitoxantrone in Patients With CD33+ Primary Resistant or Relapsed Acute Myeloid Leukemia.

  Authors: Patrice Chevallier, Jacques Delaunay, Pascal Turlure, Arnaud Pigneux, Mathilde Hunault, Richard Garand, Thierry Guillaume, Herve Avet-Loiseau, Nathalia Dmytruk, Stephane Girault, Noel Milpied, Norbert Ifrah, Mohamad Mohty, Jean-Luc Harousseau

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 11/2008;

  PURPOSE: To determine the antitumor activity and safety of a combination of gemtuzumab ozogamicin (GO), intermediate-dose cytarabine, and mitoxantrone (MIDAM) in patients with refractory or relapsedPURPOSE: To determine the antitumor activity and safety of a combination of gemtuzumab ozogamicin (GO), intermediate-dose cytarabine, and mitoxantrone (MIDAM) in patients with refractory or relapsed CD33(+) acute myeloid leukemia (AML). PATIENTS AND METHODS: We treated 62 patients with refractory (n = 18) or relapsed (n = 44) CD33(+) AML. Median age was 55.5 years. Salvage regimen consisted of GO 9 mg/m(2) on day 4, cytarabine 1 g/m(2) every 12 hours on days 1 through 5, and mitoxantrone 12 mg/m(2)/d on days 1 through 3. Median follow-up time was 26.5 months. RESULTS: Thirty-one patients (50%) achieved complete remission (CR), and eight patients (13%) had CR with delayed platelet recovery (CRp); the overall response (OR; CR + CRp) rate was 63%. A significantly higher OR rate was achieved in patients who had relapsed versus refractory AML (73% v 39%, respectively; P = .007) and patients with CD33 expression more than 98% of the blast population versus less than 98% (79% v 52.3%, respectively; P = .03). The overall, event-free, and disease-free survival rates were 41%, 33%, and 53% at 2 years, respectively. Leukocytosis more than 20,000/microL at MIDAM therapy, high-risk cytogenetics, and absence of postremission therapy were adverse prognostic factors. Age, disease status, and/or CD33 expression did not influence survival parameters. Four early toxic deaths occurred; a grade 3 to 4 hyperbilirubinemia rate of 16% was observed, and two patients had veno-occlusive disease (3%). CONCLUSION: The MIDAM regimen seems to be an effective salvage regimen for refractory/relapsed CD33(+) AML patients. These encouraging results support the need for a randomized phase III trial before considering this combination of GO and chemotherapy as superior or the standard of care treatment for refractory/relapsed CD33(+) AML patients.

• High dose therapy followed by autologous purged stem cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: A randomized multicenter study by the GOELAMS. Final results with a median follow-up of nine years.

  Authors: Emmanuel Gyan, Charles Foussard, Philippe Bertrand, Patrick Michenet, Steven Le Gouill, Christian Berthou, Herve Maisonneuve, Vincent Delwail, Remi Gressin, Philippe Quittet [......] Bernard Desablens, Jerome Jaubert, Jean-Francois Ramee, Nina Arakelyan, Antoine Thyss, Cecile Molucon-Chabrot, Roselyne Delepine, Noel Milpied, Philippe Colombat, Eric Deconinck

  Blood. 11/2008;

  The role of autologous stem cell transplantation (ASCT) as first-line therapy for follicular lymphoma (FL) remains controversial. The multicenter 064 study of the GOELAMS, randomized 172 patientsThe role of autologous stem cell transplantation (ASCT) as first-line therapy for follicular lymphoma (FL) remains controversial. The multicenter 064 study of the GOELAMS, randomized 172 patients with untreated FL for either immunochemotherapy or high-dose therapy (HDT) followed by purged ASCT (Blood. 2005;105:3817-3823). Conditioning was performed with total body irradiation (TBI) and cyclophosphamide. With long-term follow-up, the 9-year OS was similar in the HDT and chemotherapy groups (76% and 80%, respectively). The 9-year PFS was higher in the ASCT than the chemotherapy group (64% vs. 39%; p=0.004). A PFS plateau was observed in the HDT group after 7 years. On multivariate analysis, OS and PFS were independently affected by the ECOG performance status score and the number of nodal areas involved. PFS was also affected by treatment group. Secondary malignancies were more frequent in the HDT than in the chemotherapy group (6 secondary MDS/AML and 6 second cancers 12 vs. 1 AML, p=0.01). In conclusion, the occurrence of a PFS plateau suggests that a subgroup of patients might be cured by ASCT. However, the increased rate of secondary malignancies may discourage the use of purged ASCT in combination with TBI as first-line treatment for FL. This trial has been registered with ClinicalTrials.gov under Identifier: NCT00696735.

• Identical outcome after autologous or allogeneic genoidentical hematopoietic stem-cell transplantation in first remission of acute myelocytic leukemia carrying inversion 16 or t(8;21): a retrospective study from the european cooperative group for blood and marrow transplantation.

  Authors: Norbert-Claude Gorin, Myriam Labopin, Francesco Frassoni, Noel Milpied, Michel Attal, Didier Blaise, Giovanna Meloni, Anna P Iori, Mauricette Michallet, Roel Willemze, Eric Deconninck, Jean-Luc Harousseau, Emmanuelle Polge, Vanderson Rocha

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 08/2008; 26(19):3183-8.

  PURPOSE: Patients with acute myelocytic leukemia carrying inversion 16 (inv16) or t(8;21) have a better initial response to high-dose cytarabine than patients without these chromosomal abnormalities.PURPOSE: Patients with acute myelocytic leukemia carrying inversion 16 (inv16) or t(8;21) have a better initial response to high-dose cytarabine than patients without these chromosomal abnormalities. They presently do not undergo transplantation in first remission (CR1), but there is concern about late relapses. PATIENTS AND METHODS: From 1990 to 2004, 325 adult patients received transplantations in CR1 (159 patients with inv16 and 166 patients with t(8;21), including 35 and 60 patients, respectively, with additional chromosomal abnormalities). Genoidentical allografts were performed in 64 patients with inv16 and 81 patients with t(8;21), and autografts were performed in 95 patients with inv16 and 85 patients with t(8;21). RESULTS: In patients with inv16, after allogeneic and autologous transplantation, the 5-year leukemia-free survival (LFS) rates were 59% and 66% (P = .5), the relapse incidence (RI) rates were 27% and 32% (P = .45), and the transplantation-related mortality (TRM) rates were 14% and 2% (P = .003), respectively. Female patients had a lower RI and a higher LFS. Additional chromosomal abnormalities, compared with no additional abnormalities, were associated with lower RI rate (12% v 34%, respectively; P = .01) and higher 5-year LFS rate (78% v 59%, respectively; P = .04). In patients with t(8;21), after allogeneic and autologous transplantation, the 5-year LFS rates were 60% and 66% (P = .69), the RI rates were 15% and 28% (P = .03), and the TRM rates were 24% and 6% (P = .003), respectively. Younger age and a lower WBC count at diagnosis were associated with a lower TRM and a better LFS. The TRM was lower and the RI was higher in patients with autologous transplantations versus allogeneic transplantations. CONCLUSION: Both autologous and allogeneic transplantation resulted in similar outcomes.

• Graft-versus-lymphoma effect for aggressive T-cell lymphomas in adults: a study by the Société Francaise de Greffe de Moëlle et de Thérapie Cellulaire.

  Authors: Steven Le Gouill, Noel Milpied, Agnès Buzyn, Régis Peffault de Latour, Jean-Paul Vernant, Mohamad Mohty, Marie-Pierre Moles, Krimo Bouabdallah, Claude-Eric Bulabois, Jehan Dupuis, Bernard Rio, Nicole Gratecos, Ibrahim Yakoub-Agha, Michel Attal, Olivier Tournilhac, Didier Decaudin, Jean-Henry Bourhis, Didier Blaise, Christelle Volteau, Mauricette Michallet

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 06/2008; 26(14):2264-71.

  PURPOSE: Aggressive T-cell lymphomas (ATCLs) represent 10% to 15% of non-Hodgkin's lymphomas (NHLs) in adults. ATCLs show a worse prognosis than B-cell lymphomas. PATIENTS AND METHODS: On behalf ofPURPOSE: Aggressive T-cell lymphomas (ATCLs) represent 10% to 15% of non-Hodgkin's lymphomas (NHLs) in adults. ATCLs show a worse prognosis than B-cell lymphomas. PATIENTS AND METHODS: On behalf of the Société Française de Greffe de Moëlle et de Thérapie Cellulaire, we conducted a retrospective analysis including 77 ATCL patients who underwent allogeneic stem-cell transplantation (alloSCT). RESULTS: The different diagnosis included anaplastic large-cell lymphoma (ALCL; n = 27), peripheral T-cell lymphoma not otherwise specified (PTCL-NOS; n = 27), angioimmunoblastic T-cell lymphoma (AITL; n = 11), hepatosplenic gamma/delta lymphoma (HSL; n = 3), T-cell granular lymphocytic leukemia (T-GLL; n = 1), nasal natural killer (NK)/T-cell lymphoma (nasal-NK/L; n = 3) or non-nasal NK/T-cell lymphoma (non-nasal-NK/L; n = 2), enteropathy-type T-cell (n = 1), and human T-lymphotropic virus (HTLV)-1 lymphoma (n = 2). Fifty-seven patients received a myeloablative conditioning regimen. Donors were human leukocyte antigen (HLA)-matched in 70 cases and related in 60 cases. Thirty-one patients were in complete remission (CR) at the time of alloSCT, whereas 26 were in partial response (PR). Five-year toxicity-related mortality (TRM) incidence was 33% (95% CI, 24% to 46%). The 5-year overall survival (OS) and event-free survival (EFS) rates were 57% (95% CI, 45% to 68%) and 53% (95% CI, 41% to 64%), respectively. In multivariate analysis, chemoresistant disease (stable, refractory, or progressing disease) at the time of alloSCT and the occurrence of severe grade 3 to 4 acute graft-versus-host disease (aGVHD) were the strongest adverse prognostic factors for OS (P = .03 and .03, respectively). Disease status at transplantation significantly influenced the 5-year EFS (P = .003), and an HLA-mismatched donor increased TRM (P = .04). CONCLUSION: We conclude that alloSCT is a potentially efficient therapy for NK/T lymphomas and is worth further investigation through prospective clinical trials.

• Predictive factors for outcomes after reduced intensity conditioning hematopoietic stem cell transplantation for hematological malignancies: a 10-year retrospective analysis from the Société Française de Greffe de Moelle et de Thérapie Cellulaire.

  Authors: Mauricette Michallet, Quoc-Hung Le, Mohamad Mohty, Thomas Prébet, Franck Nicolini, Jean-Michel Boiron, Hélène Esperou, Michel Attal, Noel Milpied, Bruno Lioure, Pierre Bordigoni, Ibrahim Yakoub-Agha, Jean-Henri Bourhis, Bernard Rio, Eric Deconinck, Marc Renaud, Zina Chir, Didier Blaise

  Experimental hematology. 05/2008; 36(5):535-44.

  This retrospective study analyzed the impact of demographic and transplantation variables on outcomes of 1108 patients who have undergone allogeneic hematopoietic stem cell transplantation afterThis retrospective study analyzed the impact of demographic and transplantation variables on outcomes of 1108 patients who have undergone allogeneic hematopoietic stem cell transplantation after reduced intensity conditioning (RIC HSCT) for hematological malignancies and were reported to the Société Française de Greffe de Moelle et de Thérapie Cellulaire registry between November 1994 and December 2004. Only 442 patients (40%) were in complete remission (CR) at time of transplantation. Peripheral blood stem cells were used in the majority of patients (n = 878; 79%), 255 patients received fludarabine and low-dose total body irradiation, while 465 patients (42%) fludarabine and busulfan with rabbit anti-thymocyte globulins (ATG). The impact of demographic and transplant variables was studied on overall (OS) and event-free survival (EFS) in univariate and multivariate analysis. With a median follow-up of 21 months, 3-year probability of OS and EFS was 42% and 30%, respectively, and treatment-related mortality was 15% at 2 years. The multivariate analysis showed a significant negative impact on OS and EFS of the absence of CR status before transplantation; conditioning regimen, including >10 mg/kg ATG; and minor ABO incompatibility. In conclusion, this study highlights the major impact on RIC HSCT outcome of disease status before transplantation, ATG dose and ABO incompatibility.

• Efficacy and safety of yttrium-90 ibritumomab tiuxetan in patients with relapsed or refractory diffuse large B-cell lymphoma not appropriate for autologous stem-cell transplantation.

  Authors: Franck Morschhauser, Tim Illidge, Damien Huglo, Giovanni Martinelli, Giovanni Paganelli, Pier Luigi Zinzani, Simon Rule, Anna Marina Liberati, Noel Milpied, Georg Hess, Harald Stein, Joachim Kalmus, Robert Marcus

  Blood. 08/2007; 110(1):54-8.

  A prospective, multicenter, nonrandomized phase 2 trial was conducted to evaluate the efficacy and safety of a single dose of yttrium-90 ((90)Y) ibritumomab tiuxetan in elderly patients in firstA prospective, multicenter, nonrandomized phase 2 trial was conducted to evaluate the efficacy and safety of a single dose of yttrium-90 ((90)Y) ibritumomab tiuxetan in elderly patients in first relapsed or primary refractory diffuse large B-cell lymphoma (DLBCL) ineligible for stem-cell transplantation. Patients had been previously treated with chemotherapy (group A, n = 76) or chemotherapy plus rituximab (group B, n = 28). Patients in group A were further divided into patients in whom induction therapy had failed (stratum AI, n = 33) and patients who had relapsed after achieving complete response (CR; stratum AII, n = 43). The overall response rate (ORR) was 52% and 53% in strata AI and AII, respectively, and 19% in group B, with CR/CRu rates of 24%, 39.5%, and 12%, respectively. Median progression-free survival was 5.9 months and 3.5 months in strata AI and AII, respectively, and 1.6 months in group B. Median overall survival was 21.4, 22.4, and 4.6 months in stratum AI, stratum AII, and group B, respectively. Two patients died from thrombocytopenic cerebral bleeding following administration of therapy. Nonhematologic adverse events were mild to moderate. (90)Y-ibritumomab is active in patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL) and its further evaluation in phase 3 studies is ongoing.