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Raouf Ben Abdelali,
Vahid Asnafi,
Thibaut Leguay,
Nicolas Boissel,
Agnès Buzyn,
Patrice Chevallier,
Xavier Thomas,
Stephane Lepretre,
Françoise Huguet,
Norbert Vey, [......],
Nathalie Fegueux,
Pascal Turlure,
Philippe Rousselot,
Jean-Yves Cahn,
Veronique Lheritier,
Yves Chalandon,
Marie-Christine Béné,
Elizabeth Macintyre,
Hervé Dombret,
Norbert Ifrah
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ABSTRACT: Despite recent progress in the understanding of acute lymphoblastic leukemia (T-ALL) oncogenesis, few markers are sufficiently frequent in large subgroups to allow their use in therapeutic stratification. Low ERG and BAALC expression (E/B(low)) and NOTCH1/FBXW7 (N/F) mutations have been proposed as powerful prognostic markers in large cohorts of adult T-ALL. We therefore compared the predictive prognostic value of N/F mutations versus E/B(low) in 232 adult T-ALLs enrolled in the LALA-94 and Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocols. The outcome of T-ALLs treated in the pediatric-inspired GRAALL trials was significantly superior to the LALA-94 trial. Overall, 43% and 69% of adult T-ALL patients were classified as E/B(low) and N/F mutated, respectively. Strikingly, the good prognosis of N/F mutated patients was stronger in more intensively treated, pediatric-inspired GRAALL patients. The E/B expression level did not influence the prognosis in any subgroup. N/F mutation status and the GRAALL trial were the only 2 independent factors that correlated with longer overall survival by multivariate analysis. This study demonstrates that the N/F mutational status and treatment protocol are major outcome determinants for adults with T-ALL, the benefit of pediatric inspired protocols being essentially restricted to the N/F mutated subgroup.
Blood 08/2011; 118(19):5099-107. · 9.90 Impact Factor
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Virginie Nerich,
Bruno Lioure,
Maryline Rave,
Christian Recher,
Arnaud Pigneux,
Brigitte Witz, Martine Escoffre-Barbe,
Marie-Pierre Moles,
Eric Jourdan,
Jean Yves Cahn,
Marie-Christine Woronoff-Lemsi
[show abstract]
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ABSTRACT: The economic profile of acute myeloid leukaemia (AML) is badly known. The few studies published on this disease are now relatively old and include small numbers of patients. The purpose of this retrospective study was to evaluate the induction-related cost of 500 patients included in the AML 2001 trial, and to determine the explanatory factors of cost.
"Induction" patient's hospital stay from admission for "induction" to discharge after induction.
The study was performed from the French Public Health insurance perspective, restrictive to hospital institution costs. The average management of a hospital stay for "induction" was evaluated according to the analytical accounting of Besançon University Teaching Hospital and the French public Diagnosis-Related Group database. Multiple linear regression was used to search for explanatory factors.
Only direct medical costs were included: treatment and hospitalisation.
Mean induction-related direct medical cost was estimated at €41,852 ± 6,037, with a mean length of hospital stay estimated at 36.2 ± 10.7 days. After adjustment for age, sex and performance status, only two explanatory factors were found: an additional induction course and salvage course increased induction-related cost by 38% (± 4) and 15% (± 1) respectively, in comparison to one induction. These explanatory factors were associated with a significant increase in the mean length of hospital stay: 45.8 ± 11.6 days for 2 inductions and 38.5 ± 15.5 if the patient had a salvage course, in comparison to 32.9 ± 7.7 for one induction (P < 10⁻⁴). This result is robust and was confirmed by sensitivity analysis.
Consideration of economic constraints in health care is now a reality. Only the control of length of hospital stay may lead to a decrease in induction-related cost for patients with AML.
International journal of clinical pharmacy. 04/2011; 33(2):191-9.
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Sophie Park,
Charikleia Kelaidi,
Rosa Sapena,
Dominique Vassilieff,
Odile Beyne-Rauzy,
Valérie Coiteux,
Norbert Vey,
Christophe Ravoet,
Stéphane Cheze,
Christian Rose,
Laurence Legros,
Aspasia Stamatoullas, Martine Escoffre-Barbe,
Agnès Guerci,
Marie-Pierre Chaury,
Pierre Fenaux,
François Dreyfus
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ABSTRACT: ESAs are increasingly used to treat anemia of lower risk MDS, even before RBC transfusion requirement. From a previously published patient cohort treated with ESAs, we selected 112 patients with de novo low or int-1 IPSS MDS with Hb<10 g/dl, serum EPO<500 UI/l and who had never been transfused. Erythroid response rate at 12 weeks was 63.1% (IWG 2006). In multivariate analysis, an interval between diagnosis and ESA onset<6 months, Hb level>9 g/dl, and serum EPO<100 UI/l predicted better response to ESA while shorter interval between diagnosis and ESA onset (p=0.01), lower serum EPO (p=0.04) and WHO diagnosis of RCMD-RS (p=0.03) were associated with longer response. Median interval from diagnosis to transfusion dependency was 80 months and 35 months, respectively, in patients with onset of ESA < 6 months and ≥ 6 months from diagnosis (p=0.007). Those results support early onset of ESA in lower risk MDS, to better avoid the consequences of anemia. Early introduction of ESA may also delay the need for RBC transfusions, hypothetically by slowing the disease course, but prospective studies are required to further assess this point.
Leukemia research 11/2010; 34(11):1430-6. · 2.36 Impact Factor
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Mathilde Hunault-Berger,
Thibaut Leguay,
Xavier Thomas,
Ollivier Legrand,
Françoise Huguet,
Caroline Bonmati, Martine Escoffre-Barbe,
Laurence Legros,
Pascal Turlure,
Patrice Chevallier,
Fabrice Larosa,
Frederic Garban,
Oumedaly Reman,
Philippe Rousselot,
Nathalie Dhédin,
André Delannoy,
Marina Lafage-Pochitaloff,
Marie Christine Béné,
Norbert Ifrah,
Hervé Dombret
[show abstract]
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ABSTRACT: The prognosis of acute lymphoblastic leukemia in the elderly is poor. The GRAALL-SA1 phase II, randomized trial compared the efficacy and toxicity of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in patients 55 years or older with Philadelphia chromosome-negative acute lymphoblastic leukemia.
Sixty patients received either continuous-infusion doxorubicin (12 mg/m(2)/day) and continuous-infusion vincristine (0.4 mg/day) on days 1-4 or pegylated liposomal doxorubicin (40 mg/m(2)) and standard vincristine (2 mg) on day 1, accompanied by dexamethasone, followed at day 28 by a second cycle, reinforced by cyclophosphamide. End-points were safety, outcome and prognostic factors.
Myelosuppression was reduced in the pegylated liposomal doxorubicin arm with shorter severe neutropenia (P=0.05), shorter severe thrombocytopenia (P=0.03), and fewer red blood cell transfusions (P=0.04). Grade 3/4 infections and Gram-negative bacteremia were reduced in the pegylated liposomal doxorubicin arm (P=0.04 and P=0.02, respectively). There was a trend towards fewer cardiac events among the patients who received pegylated liposomal doxorubicin (1/29 versus 6/31). The complete remission rate was 82% and, with a median follow-up of 4 years, median event-free survival and overall survival were 9 and 10 months, respectively. Despite the better tolerance of pegylated liposomal doxorubicin, no differences in survival were observed between the two arms, due to trends towards more induction refractoriness (17 versus 3%, P=0.10) and a higher cumulative incidence of relapse (52% versus 32% at 2 years, P=0.20) in the pegylated liposomal doxorubicin arm.
With the drug schedules used in this study, pegylated liposomal doxorubicin did not improve the outcome of elderly patients with acute lymphoblastic leukemia despite reduced toxicities.
Haematologica 10/2010; 96(2):245-52. · 6.42 Impact Factor
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Arnaud Pigneux,
Jean-Luc Harousseau,
Francis Witz,
Mathieu Sauvezie,
Marie-Christine Bene,
Isabelle Luquet,
Mathilde Hunault-Berger,
Christian Recher,
Bruno Lioure,
Chantal Himberlin, Martine Escoffre-Barbe,
Christian Berthou,
Severine Lissandre,
Nathalie Fegueux,
Jean-Yves Cahn,
Eric Jourdan,
François Dreyfus,
Josy Reiffers,
Noël Milpied,
Norbert Ifrah
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ABSTRACT: No significant improvement in treatment outcome has been seen in elderly patients with acute myeloid leukemia (AML) over the past 20 years. This retrospective analysis investigated the prognostic factors for complete remission (CR) and survival in older patients with AML.
The study involved 847 patients older than 60 years enrolled onto three trials carried out in France between 1995 and 2005. Induction therapy consisted of idarubicin (8 mg/m(2), days 1 through 5) and cytarabine (100 mg/m(2), days 1 through 7; group I, 339 patients) or the same drugs plus lomustine (200 mg/m(2) orally on day 1; group II, 508 patients). Consolidation therapy consisted of anthracycline and cytarabine courses at lower doses, preceded or not by a first course of intermediate-dose cytarabine.
The rate of CR was significantly higher in patients in group II compared with group I (68% v 58%; P = .002). The rate of toxic death was similar in the two groups. In multivariate analysis, two prognostic factors were linked to CR: nonadverse cytogenetic (P < .003) and addition of lomustine to induction chemotherapy (P = .002). Median overall survival was significantly improved in patients treated with lomustine (median and SE, 12.7 +/- 2.2 months v 8.7 +/- 2.7 months; P = .004). In multivariate analysis, five prognostic factors positively affected overall survival: addition of lomustine (P = .002), age < or = 69 years (P < .001), Eastern Cooperative Oncology Group performance status lower than 2 (P = .002), French-American-British subgroup 1/2 (P = .02), and nonadverse cytogenetic (P < .001).
Lomustine improves the rate of CR and survival in elderly patients with de novo AML when added to standard induction therapy.
Journal of Clinical Oncology 06/2010; 28(18):3028-34. · 18.37 Impact Factor
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Valerie Ugo,
Sylvie Tondeur,
Marie-Laurence Menot,
Nadine Bonnin,
Gerald Le Gac,
Carole Tonetti,
Veronique Mansat-De Mas,
Lydie Lecucq,
Jean-Jacques Kiladjian,
Christine Chomienne,
Christine Dosquet,
Nathalie Parquet,
Luc Darnige,
Marc Porneuf, Martine Escoffre-Barbe,
Stephane Giraudier,
Eric Delabesse,
Bruno Cassinat
[show abstract]
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ABSTRACT: Myeloproliferative disorders are characterized by clonal expansion of normal mature blood cells. Acquired mutations giving rise to constitutive activation of the JAK2 tyrosine kinase has been shown to be present in the majority of patients. Since the demonstration that the V617F mutation in the exon 14 of the JAK2 gene is present in about 90% of patients with Polycythemia Vera (PV), the detection of this mutation has become a key tool for the diagnosis of these patients. More recently, additional mutations in the exon 12 of the JAK2 gene have been described in 5 to 10% of the patients with erythrocytosis. According to the updated WHO criteria the presence of these mutations should be looked for in PV patients with no JAK2 V617F mutation. Reliable and accurate methods dedicated to the detection of these highly variable mutations are therefore necessary.
For these reasons we have defined the conditions of a High Resolution DNA Melting curve analysis (HRM) method able to detect JAK2 exon 12 mutations. After having validated that the method was able to detect mutated patients, we have verified that it gave reproducible results in repeated experiments, on DNA extracted from either total blood or purified granulocytes. This HRM assay was further validated using 8 samples bearing different mutant sequences in 4 different laboratories, on 3 different instruments.
The assay we have developed is thus a valid method, adapted to routine detection of JAK2 exon 12 mutations with highly reproducible results.
PLoS ONE 01/2010; 5(1):e8893. · 4.09 Impact Factor
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Bruno Cassinat,
Stéphane de Botton,
Charikleia Kelaidi,
Lionel Ades,
Fabien Zassadowski,
Isabelle Guillemot,
Marie-Helene Schlageter,
Emmanuel Raffoux,
Jean-Luc Harousseau,
Olivier Legrand, [......],
Jean Yves Cahn,
Denis Guyotat,
Didier Bouscary,
Anne Parry,
Philippe Rousselot,
Andre Baruchel,
Hervé Dombret,
Sylvie Chevret,
Pierre Fenaux,
Christine Chomienne
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ABSTRACT: 10-20% of APL patients relapse and the challenge remains to early identify these patients to improve survival rate. We report PML-RARalpha transcript detection by RQ-PCR in 260 consecutive APL patients (n = 970 samples). 223 patients with samples of sufficient RNA quality to demonstrate they reached molecular remission were monitored for MRD. During follow-up, 38 of these patients were tested positive for PML-RARalpha mRNA. 13 out of the 38 patients (34%) effectively developed hematological relapse. In the first positive sample, specific PML-RARalpha NCN thresholds over which, or under which, patients could effectively be predicted to relapse or not, were identified and subsequently validated in a second cohort.
Leukemia research 02/2009; 33(9):1178-82. · 2.36 Impact Factor
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Sophie Park,
Sophie Grabar,
Charikleia Kelaidi,
Odile Beyne-Rauzy,
Françoise Picard,
Valérie Bardet,
Valérie Coiteux,
Geneviève Leroux,
Pascale Lepelley,
Marie-Thérèse Daniel, [......],
Lionel Adès,
Norbert Vey,
Lina Aljassem,
Aspasia Stamatoullas,
Lionel Mannone,
Hervé Dombret,
Keith Bourgeois,
Peter Greenberg,
Pierre Fenaux,
François Dreyfus
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ABSTRACT: We analyzed prognostic factors of response, response duration, and possible impact on survival of epoetin alpha, epoetin beta, or darbepoetin alpha (DAR) with or without granulocyte colony-stimulating factor in 403 myelodysplastic syndrome (MDS) patients. Sixty-two percent (40% major and 22% minor) and 50% erythroid responses were seen, and median response duration was 20 and 24 months according to IWG 2000 and 2006 criteria, respectively. Significantly higher response rates were observed with less than 10% blasts, low and int-1 International Prognostic Scoring System (IPSS), red blood cell transfusion independence, serum EPO level less than 200 IU/L, and, with IWG 2006 criteria only, shorter interval between diagnosis and treatment. Significantly longer response duration was associated with major response (IWG 2000 criteria), IPSS low to INT-1, blasts less than 5%, and absence of multilineage dysplasia. Minor responses according to IWG 2000 were reclassified as "nonresponders" or "responders" according to IWG 2006 criteria. However, among those IWG 2000 minor responders, response duration did not differ between IWG 2006 responders and nonresponders. Multivariate adjusted comparisons of survival between our cohort and the untreated MDS cohort used to design IPSS showed similar rate of progression to acute myeloid leukemia in both cohorts, but significantly better overall survival in our cohort, suggesting that epoetin or DAR treatment may have a favorable survival impact in MDS.
Blood 02/2008; 111(2):574-82. · 9.90 Impact Factor
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ABSTRACT: Laboratory detection of spontaneous growth of colony-forming unit-megacaryocytes (CFU-MK), allowing us to distinguish essential thrombocythemia (ET) from reactive thrombocytosis, is therefore useful for the diagnostic of this myeloproliferative disorder. Whether CFU-MK assays allow us to discriminate at least partly between ET and other myeloproliferative disorders such as polycythemia vera (PV) remains, however, to be established. To gain insights about this point, we have performed CFU-MK cultures from bone marrow cells of patients diagnosed with ET (n = 42) or PV (n = 50) using a standardized collagen-based serum-free method. Spontaneous growth of CFU-MK was similarly detected in both 40/42 patients with ET and 47/50 patients with PV. These data suggest clearly that the CFU-MK assay is useful to detect not only ET, but also PV, but fails to discriminate, even partly, between these two myeloproliferative disorders.
American Journal of Hematology 08/2006; 81(7):554-6. · 4.67 Impact Factor
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Eric Deconinck,
Charles Foussard,
Noel Milpied,
Philippe Bertrand,
Patrick Michenet,
Pascale Cornillet-LeFebvre, Martine Escoffre-Barbe,
Herve Maisonneuve,
Vincent Delwail,
Remy Gressin, [......],
Jean-Pierre Vilque,
Bernard Desablens,
Jerome Jaubert,
Jean-François Ramee,
Arash Jenabian,
Antoine Thyss,
Annick Le Pourhiet-Le Mevel,
Philippe Travade,
Roselyne Delepine,
Philippe Colombat
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ABSTRACT: Doxorubicin-based immunochemotherapy, with interferon, has been shown to improve survival in patients with advanced follicular lymphoma. High-dose chemotherapy with stem-cell support is effective in follicular lymphoma in relapse but remains controversial as a first-line therapy. In a randomized study using a purged autologous stem-cell support, we compared these 2 approaches in patients with advanced follicular lymphoma. Newly diagnosed advanced follicular lymphoma patients (172 patients) were randomly assigned either to an immunochemotherapy regimen (cyclophosphamide, doxorubicin, teniposide, prednisone, and interferon) or to a high-dose therapy followed by purged autologous stem-cell transplantation. Compared with the patients who received chemotherapy and interferon, patients treated with high-dose therapy had a higher response rate (69% vs 81%, P = .045) and a longer median event-free survival (not reached vs 45 months). This did not translate into a better survival rate due to an excess of secondary malignancies after transplantation. The Follicular Lymphoma Prognostic Index identified a subgroup of patients with a significantly higher event-free survival rate after high-dose therapy. Autologous stem-cell transplantation cannot be considered as the standard first-line treatment of follicular lymphoma for patients younger than 60 years old with a high tumor burden.
Blood 06/2005; 105(10):3817-23. · 9.90 Impact Factor
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Malika Djeridane,
Stéphane Oudard, Martine Escoffre-Barbe,
Laurence Lacotte-Thierry,
Bernard Desablens,
Jean Briére,
Mamoun Dib,
Philippe Cassasus,
Christiane Ghandour,
Thierry Lamy,
Françoise Lejeune,
Marc Simon,
Catherine Traullé,
Magda Vigier,
Henri Maisonneuve,
Josette Briére,
Pierre Colonna,
Jean-Marie Andrieu
[show abstract]
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ABSTRACT: This Phase II study was performed in patients with advanced or bulky Hodgkin disease (HD) to evaluate the results of a 7-drug chemotherapy (CT) regimen that was administered over 12 weeks according to 2 randomized modalities followed by high-dose lymph node irradiation.
From 1990 to 1996, 162 patients with HD at clinical stages (CS) I-III with bulky disease (mediastinal mass ratio >or= 0.45 and/or unilateral or bilateral pelvic plus lumboaortic disease; 86 patients) or CS IV (76 patients) were randomized to receive the same cumulated dose of a CT regimen consisting of epirubicin (240 mg/m(2)), bleomycin (60 mg/m(2)), vinblastine (20 mg/m(2)), vincristine (4 mg/m(2)), cyclophosphamide (4000 mg/m(2)), etoposide (900 mg/m(2)), and methotrexate (180 mg/m(2)) plus methylprednisolone (1500 mg/m(2)) over 12 weeks either every 4 weeks (Arm Y, 79 patients) or every 3 weeks (Arm Z, 83 patients). Patients with disease in complete remission (CR) or partial remission after CT received extended-field lymph node irradiation (involved areas, 40 grays [Gy]; noninvolved areas, 30 Gy).
Forty-two percent of patients achieved a post-CT CR, and 86% of patients achieved a CR after the completion of irradiation (there was no difference between Arm Y and Arm Z). Thirty-five patients developed recurrent disease; most of those patients were in post-CT partial remission. The 10-year freedom from first progression rate was 63.9% (there was no difference between Arm Y and Arm Z). Thirty-eight patients died: 24 patients from HD, 3 patients from CT-related early sepsis, 1 patient from radiation-induced pneumonitis, 6 patients from a second malignancy, and 4 patients from causes unrelated to treatment. The overall 10-year survival rate was 76.7%. Survival was slightly higher among patients in Arm Y (83.3%) compared with patients in Arm Z (70.2%; P = 0.12).
No differences were found when the same amount of CT was delivered in three courses or in four courses. In 1997, because most recurrences of the H90-A/B trial occurred in patients who achieved a post-CT partial remission, the authors decided to reinforce the intensity of the initial CT and designed a new randomized study comparing two modalities of more intensive CT plus consolidative radiotherapy (H97-LM trial).
Cancer 11/2002; 95(10):2169-79. · 4.77 Impact Factor
