Arnaud Pigneux

Publications of Arnaud Pigneux

• Early matched sibling hematopoietic cell transplantation for adult AML in first remission using an age-adapted strategy: long-term results of a prospective GOELAMS study.

  Authors: Bruno Lioure, Marie C Béné, Arnaud Pigneux, Anne Huynh, Patrice Chevallier, Nathalie Fegueux, Didier Blaise, Brigitte Witz, Martine Delain, Jérôme Cornillon [......] Fabrice Larosa, Thierry Lamy, Edouard Randriamalala, Mario Ojeda-Uribe, Christian Berthou, Luc Fornecker, Jean-Luc Harousseau, Didier Bouscary, Norbert Ifrah, Jean-Yves Cahn

  Blood. 02/2012; 119(12):2943-2948.

  The LAM2001 phase 3 trial, involving 832 patients with acute myeloid leukemia (AML; median: 46 years) proposed HLA-identical sibling allograft HSCT for all patients with an identified donor. TheThe LAM2001 phase 3 trial, involving 832 patients with acute myeloid leukemia (AML; median: 46 years) proposed HLA-identical sibling allograft HSCT for all patients with an identified donor. The trial compared reduced-intensity conditioning (RIC) for patients older than 50 years of age (N = 47) and myeloablative conditioning for younger patients (N = 117). BM HSCT was performed in the younger patients, while the older ones received a consolidation course, followed by peripheral blood allo-HSCT using RIC. The incidence of grade II-IV acute GVHD, was 51.9% (95% confidence interval [CI]: 42.1-61.8) and 11.3% (1.6-21.2) after myeloablative or RIC, respectively (P < .0001) and that of chronic GVHD 45.8% (95% CI: 34.8-56.7) and 41.7% (24.7-58.6; NS). Cumulative incidence of nonrelapse mortality at 108 months was 15.8% (95% CI: 9.8-23.2) for myeloablative, and 6.5% (0.2-16.2) for RIC (NS). CI of relapse at 108 months was 21.7% (95% CI: 13.9-28.6) and 28.6% (16.5-43.4; NS). Overall survival at 108 months was 63.4% (95% CI: 54.6-72.2) and 65.8% (52.2-72.2), respectively, after myeloablative or RIC (NS). RIC peripheral blood stem cell allo-HSCT is prospectively feasible for patients between the ages of 51 and 60 years without excess of relapse or nonrelapse mortality, and compares favorably with myeloablative marrow allo-HSCT proposed to younger patients. This study was registered at clinicaltrials.gov as no. NCT01015196.

• Rituximab for the treatment of adult relapsed/refractory CD20 positive B-ALL patients: a pilot series.

  Authors: Patrice Chevallier, Arnaud Pigneux, Nelly Robillard, Sameh Ayari, Thierry Guillaume, Jacques Delaunay, Marion Eveillard, Pierre-Yves Dumas, Eric Lippert, Mohamad Mohty, Thibaut Leguay

  Leukemia research. 12/2011; 36(3):311-5.

  No series have reported the results of the use of the therapeutic anti-CD20 monoclonal antibody (Rituximab) in the setting of adult refractory/relapsed B-ALL. We report here the outcomes of such nineNo series have reported the results of the use of the therapeutic anti-CD20 monoclonal antibody (Rituximab) in the setting of adult refractory/relapsed B-ALL. We report here the outcomes of such nine patients treated at two french institutions by a combination of Rituximab+chemotherapy. We showed that four patients could achieve complete response while four other patients were documented with blast clearance superior to 50% from the baseline in bone marrow. We conclude that our results suggested some efficacy for the use of Rituximab in combination with chemotherapy in the setting of refractory/relapsed adult B-ALL. Larger series within prospective trials are needed to confirm these results.

• Comparable outcome after related or unrelated allogeneic stem cell transplant following reduced conditioning with fludarabine, busulfan and antithymocyte globulin.

  Authors: Stéphane Vigouroux, Reza Tabrizi, Cyril Melot, Joëlle Coiffard, Xavier Lafarge, Gérald Marit, Krimo Bouabdallah, Arnaud Pigneux, Thibaut Leguay, Marie-Sarah Dilhuydy, Anna Schmitt, Jean-Michel Boiron, Noël Milpied

  Leukemia & lymphoma. 08/2011; 53(1):162-5.

• Dismal prognostic value of monosomal karyotype in elderly patients with acute myeloid leukemia: a GOELAMS study of 186 patients with unfavorable cytogenetic abnormalities.

  Authors: Aurore Perrot, Isabelle Luquet, Arnaud Pigneux, Francine Mugneret, Jacques Delaunay, Jean-Luc Harousseau, Carole Barin, Jean-Yves Cahn, Philippe Guardiola, Chantal Himberlin, Christian Recher, Norbert Vey, Bruno Lioure, Mario Ojeda-Uribe, Nathalie Fegueux, Christian Berthou, Edouard Randriamalala, Marie C Béné, Norbert Ifrah, Francis Witz

  Blood. 05/2011; 118(3):679-85.

  The prognosis of acute myeloid leukemia (AML) is very poor in elderly patients, especially in those classically defined as having unfavorable cytogenetics. The recent monosomal karyotype (MK) entity,The prognosis of acute myeloid leukemia (AML) is very poor in elderly patients, especially in those classically defined as having unfavorable cytogenetics. The recent monosomal karyotype (MK) entity, defined as 2 or more autosomal monosomies or combination of 1 monosomy with structural abnormalities, has been reported to be associated with a worse outcome than the traditional complex karyotype (CK). In this retrospective study of 186 AML patients older than 60 years, the prognostic influence of MK was used to further stratify elderly patients with unfavorable cytogenetics. CK was observed in 129 patients (69%), and 110 exhibited abnormalities according to the definition of MK (59%). MK(+) patients had a complete response rate significantly lower than MK(-) patients: 37% vs 64% (P = .0008), and their 2-year overall survival was also decreased at 7% vs 22% (P < .0001). In multivariate analysis, MK appeared as the major independent prognostic factor related to complete remission achievement (odds ratio = 2.3; 95% confidence interval, 1-5.4, P = .05) and survival (hazard ratio = 1.7; 95% confidence interval, 1.1-2.5, P = .008). In the subgroup of 129 CK(+) patients, survival was dramatically decreased for MK(+) patients (8% vs 28% at P = .03). These results demonstrate that MK is a major independent factor of very poor prognosis in elderly AML.

• Induction-related cost of patients with acute myeloid leukaemia in France.

  Authors: 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

  International journal of clinical pharmacy. 04/2011; 33(2):191-9.

  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 thisThe 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.

• Methotrexate Reduces the Incidence of Severe Acute Graft-versus-Host Disease without Increasing the Risk of Relapse after Reduced-Intensity Allogeneic Stem Cell Transplantation from Unrelated Donors.

  Authors: Stéphane Vigouroux, Reza Tabrizi, Cyril Melot, Joelle Coiffard, Xavier Lafarge, Gérald Marit, Krimo Bouabdallah, Arnaud Pigneux, Thibaut Leguay, Marie-Sarah Dilhuydy, Anna Schmitt, Jean-Michel Boiron, Noël Milpied

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 01/2011; 17(1):93-100.

  Optimized prophylaxis against graft-versus-host disease (GVHD) after unrelated reduced-intensity allogeneic transplantation when preceded by a conditioning regimen utilizing antithymocyte globulinOptimized prophylaxis against graft-versus-host disease (GVHD) after unrelated reduced-intensity allogeneic transplantation when preceded by a conditioning regimen utilizing antithymocyte globulin (ATG) is poorly defined. To investigate the effects of methotrexate (MTX) in this treatment setting, we conducted a retrospective analysis. Sixty-three patients were selected based on the administration of a total dose of 5 mg/kg of ATG in the conditioning regimen and then separated into either group M+ (n = 39), which received MTX or group M- (n = 24), which did not. All patients received cyclosporine. In the M- and M+ groups, cumulative incidences (CI) of grade III-IV acute GVHD (aGVHD) were 43% and 10%, respectively (P = .002). Multivariate analysis indicated that grade III-IV aGVHD was favored by both the absence of MTX and the provision of a female donor for a male recipient. At 2 years, the M+ and M- groups exhibited, respectively: overall survival of 69% and 40% (P = .06), disease-free survival of 57% and 43% (P = .2), nonrelapse mortality of 20% and 44% (P = .1), and incidence of relapse of 27% and 35% (P = .6). These data suggest that MTX reduces the incidence of severe aGVHD without increasing the risk of relapse but with an accompanying trend toward improved survival after unrelated reduced-intensity transplantation with ATG in the conditioning regimen.

• 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.

• Addition of lomustine to idarubicin and cytarabine improves the outcome of elderly patients with de novo acute myeloid leukemia: a report from the GOELAMS.

  Authors: 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

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 06/2010; 28(18):3028-34.

  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 prognosticNo 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.

• 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;

• Single-Agent Laromustine, A Novel Alkylating Agent, Has Significant Activity in Older Patients With Previously Untreated Poor-Risk Acute Myeloid Leukemia.

  Authors: Gary J Schiller, Susan M O'Brien, Arnaud Pigneux, Daniel J Deangelo, Norbert Vey, Jonathan Kell, Scott Solomon, Robert K Stuart, Verena Karsten, Ann L Cahill, Maher X Albitar, Francis J Giles

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 12/2009;

  PURPOSE: An international phase II study of laromustine (VNP40101M), a sulfonylhydrazine alkylating agent, was conducted in patients age 60 years or older with previously untreated poor-risk acutePURPOSE: An international phase II study of laromustine (VNP40101M), a sulfonylhydrazine alkylating agent, was conducted in patients age 60 years or older with previously untreated poor-risk acute myeloid leukemia (AML). PATIENTS AND METHODS: Laromustine 600 mg/m(2) was administered as a single 60-minute intravenous infusion. Patients were age 70 years or older or 60 years or older with at least one additional risk factor-unfavorable AML karyotype, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2, and/or cardiac, pulmonary, or hepatic comorbidities. RESULTS: Eighty-five patients (median age, 72 years; range, 60 to 87 years) were treated. Poor-risk features included age 70 years or older, 78%; adverse karyotype, 47%; PS of 2, 41%; pulmonary disease, 77%; cardiac disease, 73%; and hepatic disease, 3%. Ninety-six percent of patients had at least two risk factors, and 39% had at least four risk factors. The overall response rate (ORR) was 32%, with 20 patients (23%) achieving complete response (CR) and seven (8%) achieving CR with incomplete platelet recovery (CRp). ORR was 20% in patients with adverse cytogenetics; 32% in those age 70 years or older; 32% in those with PS of 2; 32% in patients with baseline pulmonary dysfunction; 34% in patients with baseline cardiac dysfunction; and 27% in 33 patients with at least four risk factors. Twelve (14%) patients died within 30 days of receiving laromustine therapy. Median overall survival was 3.2 months, with a 1-year survival of 21%; the median duration of survival for those who achieved CR/CRp was 12.4 months, with a 1-year survival of 52%. CONCLUSION: Laromustine has significant single-agent activity in elderly patients with poor-risk AML. Adverse events are predominantly myelosuppressive or respiratory. Response rates are consistent across a spectrum of poor-risk features.

• Phase III randomized, placebo-controlled, double-blind study of high dose continuous infusion cytarabine alone or with laromustine (VNP40101M) in patients with acute myeloid leukemia in first relapse.

  Authors: Francis Giles, Norbert Vey, Daniel DeAngelo, Karen Seiter, Wendy Stock, Robert Stuart, Darinka Boskovic, Arnaud Pigneux, Martin Tallman, Joseph Brandwein, Jonathan Kell, Tadeusz Robak, Peter Staib, Xavier Thomas, Ann Cahill, Maher Albitar, Susan O'Brien

  Blood. 09/2009;

  Laromustine is a sulfonylhdrazine alkylator with significant anti-leukemia activity. An international, randomized (2:1), double-blind, placebo-controlled study was conducted to compare completeLaromustine is a sulfonylhdrazine alkylator with significant anti-leukemia activity. An international, randomized (2:1), double-blind, placebo-controlled study was conducted to compare complete remission (CR) rates and overall survival (OS) in patients with first relapse acute myeloid leukemia (AML) treated with laromustine and high-dose cytarabine (HDAC) versus HDAC/placebo. Patients received 1.5 g/m(2)/day cytarabine continuous infusion for 3 days and laromustine 600 mg/m(2) (N=177) or placebo (N=86) on day 2. Patients in CR received consolidation with laromustine/HDAC or HDAC/placebo as per initial randomization. Following interim analysis at 50% enrollment, the Data Safety Monitoring Board (DSMB) expressed concern that any advantage in CR would be compromised by the observed on-study mortality, and enrollment was held. The CR rate was significantly higher for the laromustine/HDAC group (35% versus 19%, P=0.005). However the 30 day mortality rate, and median progression-free survival were significantly worse in this group compared to HDAC/placebo (11% versus 2%, P=0.016) 54 days versus 34, P=0.002). OS and median response durations were similar in both groups. Laromustine/HDAC induced significantly more CR than HDAC/placebo but OS was not improved due to mortality associated with myelosuppression and its sequelae. The DSMB subsequently approved a revised protocol with laromustine dose reduction and recombinant growth factor support. The study was registered as NCT00112554 at www.clinicaltrials.gov.

• Acute Myeloid Leukemia With Translocation (8;21) or Inversion (16) in Elderly Patients Treated With Conventional Chemotherapy: A Collaborative Study of the French CBF-AML Intergroup.

  Authors: Thomas Prébet, Nicolas Boissel, Sarah Reutenauer, Xavier Thomas, Jacques Delaunay, Jean-Yves Cahn, Arnaud Pigneux, Bruno Quesnel, Francis Witz, Sylvain Thépot, Valérie Ugo, Christine Terre, Christian Recher, Emmanuelle Tavernier, Mathilde Hunault, Benjamin Esterni, Sylvie Castaigne, François Guilhot, Hervé Dombret, Norbert Vey

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 09/2009;

  PURPOSE: Acute myeloid leukemia (AML) with translocation (t) (8;21) or inversion (inv) (16) is associated with a favorable prognosis when treated with intensive chemotherapy. In elderly patients,PURPOSE: Acute myeloid leukemia (AML) with translocation (t) (8;21) or inversion (inv) (16) is associated with a favorable prognosis when treated with intensive chemotherapy. In elderly patients, these AML types are rare, and intensive treatments are much less tolerated. We conducted a retrospective study to evaluate the characteristics and outcome of AML with t(8;21) or inv(16) in the elderly. PATIENTS AND METHODS: Patients with t(8;21) or inv(16) AML who were age 60 years or older and who received at least one course of induction chemotherapy were included. Postremission therapy consisted of low-dose maintenance chemotherapy (n = 72) or intensive consolidation (n = 56). RESULTS: A total of 147 patients were analyzed. The median age was 67 years. Sixty patients had t(8;21), and 87 patients had inv(16). A total of 129 patients achieved complete response (CR) after one or two induction courses (ie, 88% CR rate), and 15 patients (10%) died early (ie, during the 8 weeks after induction). During a median follow-up of 48 months, the 5-year probabilities of overall survival (OS) and leukemia-free survival (LFS) were 31% and 27%, respectively. Multivariate analysis showed a negative impact of high WBC, impaired performance status, and deletion (9q) on OS and LFS. Administration of intensive consolidation was associated with better LFS only in patients with t(8;21). In addition, the need for critical care during induction independently predicted lower LFS. CONCLUSION: Because of a high CR rate, induction chemotherapy should be considered systematically for elderly patients who have AML with t(8;21) or inv(16). The high risk of relapse suggests that alternative strategies of postremission therapy are warranted.

• Computer tomography in pulmonary invasive aspergillosis in hematological patients with neutropenia: An useful tool for diagnosis and assessment of outcome in clinical trials.

  Authors: Denis Caillot, Valérie Latrabe, Anne Thiébaut, Raoul Herbrecht, Stéphane de Botton, Arnaud Pigneux, Françoise Monchecourt, Lamine Mahi, Serge Alfandari, Jean-François Couaillier

  European journal of radiology. 08/2009;

  BACKGROUND AND OBJECTIVE: The exact timing of the evolution of lesion volumes of invasive pulmonary aspergillosis (IPA) on CT scan images could be helpful in the management of hematological patientsBACKGROUND AND OBJECTIVE: The exact timing of the evolution of lesion volumes of invasive pulmonary aspergillosis (IPA) on CT scan images could be helpful in the management of hematological patients but has never been evaluated in a prospective study. We analyzed the CT scan data from the prospective Combistrat trial. DESIGN AND METHODS: Volumes of aspergillosis lesions from 30 patients (including 24 acute myeloid leukaemia) with probable (n=26) or proven (n=4) IPA according to the EORTC-MSG modified criteria, were measured prospectively on the thoracic CT scans at the enrolment in the study on day 0 (D0), D7, D14 and end of treatment (EOT). RESULTS: For the overall population, the volume of pulmonary aspergillosis lesions increased significantly from D0 to D7 (1.6 fold; p=0.003). Then this volume decreased significantly from D7 to D14 (1.36 fold at D14 with p=0.003 for D14 vs. D7, but with p=0.56 for D14 vs. D0). At EOT (= D17, median value), the volume of lesions was significantly lower than D14 (0.76 fold the initial volume; p<0.001) but it was not significantly different when compared to D0 (p=0.11). CONCLUSIONS: The results of this prospective study suggest that the sequential analysis of CT scan in neutropenic patients with IPA depicts more precisely the evolution of lesion volumes than comparison to baseline images. Moreover, the systematic use of chest CT appears to be a useful tool for diagnosis and outcome evaluation of IPA in clinical trials.

• Improved Outcome of Acute Promyelocytic Leukemia With High WBC Counts Over the Last 15 Years: The European APL Group Experience.

  Authors: Charikleia Kelaidi, Sylvie Chevret, Stéphane de Botton, Emmanuel Raffoux, Agnès Guerci, Xavier Thomas, Arnaud Pigneux, Thierry Lamy, Françoise Rigal-Huguet, Sandrine Meyer-Monard, Patrice Chevallier, Frédéric Maloisel, Erick Deconinck, Augustin Ferrant, Nathalie Fegueux, Norbert Ifrah, Miguel Sanz, Hervé Dombret, Pierre Fenaux, Lionel Adès

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 06/2009;

  PURPOSE: Acute promyelocytic leukemia (APL) with pretreatment WBC counts greater than 10,000/microL is still considered to carry a poorer prognosis than APL with WBC lower than 10,000/mL. WePURPOSE: Acute promyelocytic leukemia (APL) with pretreatment WBC counts greater than 10,000/microL is still considered to carry a poorer prognosis than APL with WBC lower than 10,000/mL. We evaluated outcome improvement in such patients in recent years. PATIENTS AND METHODS: Nine hundred two patients with APL, including 173 patients (19.1%) and 59 patients (6.5%) with WBC counts more than 10,000/microL and more than 50,000/microL, respectively, were enrolled between 1993 and 2005 in two successive randomized trials of the European APL group (APL 93 and APL 2000) that tested, in particular, the modalities of combination of all-trans retinoic acid (ATRA) and chemotherapy, maintenance treatment, escalating doses of cytarabine, early administration of dexamethasone, and CNS prophylaxis. RESULTS: Between the APL 93 and 2000 trials, the complete response (CR) rate increased from 89.6% to 93%, and the 5-year cumulative incidence of relapse (CIR) decreased from 40% to 9.5% in patients with WBC counts of 10,000 to 50,000/microL. In patients with WBC counts more than 50,000/microL, the CR rate increased from 82% to 91%, and 5-year CIR decreased from 59% to 24%. Whereas in the APL 93 trial, increased WBC counts were significantly associated with higher CIR and shorter survival, this was not the case in the APL 2000 trial. In patients with increased WBC counts, enrollment onto the APL 2000 trial (v APL 93) and combined maintenance with ATRA and chemotherapy were associated with significantly lower CIR and better survival. CONCLUSION: Outcome of APL with high WBC count has markedly improved over the years as a result of fewer early deaths and fewer relapses. Better initial supportive care and combined maintenance treatment have contributed to this improvement.

• Laromustine, a sulfonyl hydrolyzing alkylating prodrug for cancer therapy.

  Authors: Arnaud Pigneux

  IDrugs : the investigational drugs journal. 02/2009; 12(1):39-53.

  Laromustine (Onrigin), under development by Vion Pharmaceuticals Inc, belongs to the sulfonylhydrazine class of alkylating agents and is in clinical development for the treatment of malignancies.Laromustine (Onrigin), under development by Vion Pharmaceuticals Inc, belongs to the sulfonylhydrazine class of alkylating agents and is in clinical development for the treatment of malignancies. Laromustine is a prodrug that yields a chloroethylating compound (VNP-4090-CE) and a carbamoylating compound (methyl isocyanate). The antineoplastic effect of laromustine is attributed primarily to the chloroethylating species, which causes the preferential alkylation of DNA at the O6 position of guanine, a lesion that results in interstrand crosslinks and, eventually, cell death. The carbamoylating species contributes to antitumor activity by inhibiting the DNA repair protein O6-alkylguanine transferase. Early phase I clinical trials in patients with solid tumors indicated that laromustine was associated with myelosuppression; few extramedullary toxicities were observed, indicating potential efficacy for the treatment of hematological malignancies. Phase II trials have been completed in patients with previously untreated acute myelogenous leukemia (AML), high-risk myelodysplastic syndrome (MDS) and relapsed AML. The most encouraging results were observed in patients over 60 years of age with poor-risk de novo AML for which no standard treatment exists. Laromustine is currently in phase II/III trials for AML and phase II trials for MDS and solid tumors. Laromustine appears to be a promising agent that will add to the armamentarium of drugs available to treat patients who do not respond to, or are not fit for, intensive chemotherapy, such as elderly individuals.

• 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.

• Triptolide cooperates with chemotherapy to induce apoptosis in acute myeloid leukemia cells.

  Authors: Arnaud Pigneux, François-Xavier Mahon, Maialene Uhalde, Marie Jeanneteau, Francis Lacombe, Noël Milpied, Josy Reiffers, Francis Belloc

  Experimental hematology. 11/2008;

  OBJECTIVE: Triptolide has shown antitumor activity in a broad range of solid tumors and on leukemic cells in vitro. MATERIALS AND METHODS: The THP1 cell line and primary acute myeloid leukemia (AML)OBJECTIVE: Triptolide has shown antitumor activity in a broad range of solid tumors and on leukemic cells in vitro. MATERIALS AND METHODS: The THP1 cell line and primary acute myeloid leukemia (AML) cells were cultured with triptolide alone or in association with AraC or idarubicin in increasing concentrations. Apoptosis was measured by flow cytometry using DiOC6(3) for the cell line and fluorescein isothiocyanateAnnexin-V and CD45 labeling for fresh blast cells. Protein expression was measured by Western blot. Cell cycle distribution of apoptotic cells was measured by flow cytometry. RESULTS: A synergistic effect was observed when triptolide was added to idarubicin or to AraC to induce apoptosis of THP-1 leukemic cells. The triptolide/AraC association was also investigated in vitro on primary blast cells from 25 AML patients. This combination induced significantly higher percentages of apoptosis vs treatment with each drug separately (p<0.005). The IkappaB and X-linked inhibitor of apoptosis protein contents, which were altered by triptolide in idarubicin-treated cells, were not modified in AraC-treated cells. The association of AraC with triptolide increased the number of cells blocked in the S phase and most underwent apoptosis. CONCLUSION: These results suggest that, by modifying the cell cycle kinetics, AraC sensitizes AML cells to apoptosis induced by low concentration triptolide. The in vitro proapoptotic effect of triptolide associated with the antiproliferative activity of AraC warrants further clinical investigation for treatment of AML patients, especially elderly patients for whom low-dose AraC treatment could be improved by the addition of triptolide.

• Central nervous system involvement in adult acute lymphoblastic leukemia at diagnosis and/or at first relapse: Results from the GET-LALA group.

  Authors: Oumedaly Reman, Arnaud Pigneux, Françoise Huguet, Norbert Vey, André Delannoy, Nathalie Fegueux, Stéphane de Botton, Aspasia Stamatoullas, Olivier Tournilhac, Agnès Buzyn, Christiane Charrin, Claude Boucheix, Jean Gabert, Véronique Lhéritier, Jean-Paul Vernant, Denis Fière, Hervé Dombret, Xavier Thomas

  Leukemia research. 06/2008;

  Outcome of adult acute lymphoblastic leukemia (ALL) with central nervous system (CNS) involvement is not clearly defined. We studied 104 patients presenting with CNS involvement at diagnosis amongOutcome of adult acute lymphoblastic leukemia (ALL) with central nervous system (CNS) involvement is not clearly defined. We studied 104 patients presenting with CNS involvement at diagnosis among 1493 patients (7%) included into the LALA trials, and 109 patients presenting CNS disease at the time of first relapse among the 709 relapsing patients (15%). Eighty-seven patients (84%) with CNS leukemia at diagnosis achieved complete remission (CR). Fifty-three patients underwent stem cell transplantation (SCT): 25 allogeneic SCT, 28 autologous SCT, while 34 continued with chemotherapy alone. Seven-year overall survival (OS) and disease-free survival (DFS) were 34% and 35%, respectively. There were no significant differences in terms of CR, OS and DFS among patients with CNS involvement at diagnosis and those without CNS disease. There were also no differences among the two groups regarding T lineage ALL, B lineage ALL, and among those who underwent SCT. After a first relapse, 38 patients with CNS recurrence (35%) achieved a second CR. The median OS was 6.3 months. Outcome was similar to that of relapsing patients without CNS disease. CNS leukemia in adult ALL is uncommon at diagnosis as well as at the time of first relapse. With intensification therapy, patients with CNS leukemia at diagnosis have a similar outcome than those who did not present with CNS involvement. CNS leukemia at first relapse remains of similar poor prognosis than all other adult ALL in first relapse.

• Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results.

  Authors: Lionel Adès, Miguel A Sanz, Sylvie Chevret, Pau Montesinos, Patrice Chevallier, Emmanuel Raffoux, Edo Vellenga, Agnès Guerci, Arnaud Pigneux, Francoise Huguet [......] Juan Bergua, Thierry Lamy, Anne Vekhoff, Silvia Negri, Norbert Ifrah, Hervé Dombret, Augustin Ferrant, Dominique Bron, Laurent Degos, Pierre Fenaux

  Blood. 03/2008; 111(3):1078-84.

  All-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC)All-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC) remains disputed. We performed a joint analysis of patients younger than 65 years included in Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) LPA 99 trial, where patients received no AraC in addition to ATRA, high cumulative dose idarubicin, and mitoxantrone, and APL 2000 trial, where patients received AraC in addition to ATRA and lower cumulative dose daunorubicin. In patients with white blood cell (WBC) count less than 10 x 10(9)/L, complete remission (CR) rates were similar, but 3-year cumulative incidence of relapse (CIR) was significantly lower in LPA 99 trial: 4.2% versus 14.3% (P = .03), although 3-year survival was similar in both trials. This suggested that AraC is not required in APL with WBC count less than 10 x 10(9)/L, at least in trials with high-dose anthracycline and maintenance treatment. In patients with WBC of 10 x 10(9)/L or more, however, the CR rate (95.1% vs 83.6% P = .018) and 3-year survival (91.5% vs 80.8%, P = .026) were significantly higher in APL 2000 trial, and there was a trend for lower 3-year CIR (9.9% vs 18.5%, P = .12), suggesting a beneficial role for AraC in those patients.

• Liposomal amphotericin B in combination with caspofungin for invasive aspergillosis in patients with hematologic malignancies: a randomized pilot study (Combistrat trial).

  Authors: Denis Caillot, Anne Thiébaut, Raoul Herbrecht, Stéphane de Botton, Arnaud Pigneux, Frédéric Bernard, Jérôme Larché, Françoise Monchecourt, Serge Alfandari, Lamine Mahi

  Cancer. 01/2008; 110(12):2740-6.

  BACKGROUND: Invasive aspergillosis (IA) has a poor prognosis in immunocompromised patients. Combinations of drugs that act on different targets are expected to improve the clinical efficacy ofBACKGROUND: Invasive aspergillosis (IA) has a poor prognosis in immunocompromised patients. Combinations of drugs that act on different targets are expected to improve the clinical efficacy of separate compounds. METHODS: Patients with proven or probable IA were randomized in a prospective, open pilot study to receive either a combination of liposomal amphotericin B (AmB) at the standard dose (3 mg/kg daily) and caspofungin at the standard dose or monotherapy with a high-dose AmB regimen (10 mg/kg daily). RESULTS: Thirty patients (21 men and 9 women) with hematologic malignancies were analyzed, and there were 15 patients in each arm. The median duration of treatment was 18 days for the combination group and 17 days for the high-dose monotherapy group. At the end of treatment, there were significantly more favorable overall responses (partial or complete responses; P = .028) in the combination group (10 of 15 patients; 67%) compared with the high-dose monotherapy group (4 of 15 patients; 27%). Survival rates at 12 weeks after inclusion were 100% and 80%, respectively. Infusion-related reactions occurred in 3 patients in the high-dose monotherapy group. A 2-fold increase in serum creatinine occurred in 4 of 17 patients (23%) who received high-dose monotherapy and 1 of 15 patient (7%) who received combination therapy; hypokalemia <3 mmol/L occurred in 3 patients and 2 patients, respectively. CONCLUSIONS: The combination of liposomal AmB and caspofungin was promising as therapy for IA compared with monotherapy. A trial that includes more patients will be required next to confirm the results of this pilot study.