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151. Post-Induction Minimal Residual Disease (MRD) Defines a Large Subset of Adults with Favorable Ph-Negative Acute Lymphoblastic Leukemia (ALL), Who Do Not Benefit From Allogeneic Stem Cell Transplantation (SCT) in First Complete Remission: A GRAALL Study.

Author

Beldjord, Kheira, primary, Lhéritier, Véronique, additional, Boulland, Marie-Laure, additional, Grardel, Nathalie, additional, Cayuela, Jean-Michel, additional, Cavé, Hélène, additional, Schäfer, Beat, additional, Bakkus, Marleen, additional, Garrido, Marlène, additional, Dhédin, Nathalie, additional, Huynh, Anne, additional, Leguay, Thibaut, additional, Gardin, Claude, additional, Thomas, Xavier, additional, Chalandon, Yves, additional, Huguet, Françoise, additional, Vernant, Jean-Paul, additional, Fest, Thierry, additional, Ifrah, Norbert, additional, Macintyre, Elizabeth, additional, and Dombret, Hervé, additional

Published
2009
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152. Azacytidine (AZA) in MDS (including RAEB-t and CMML) in Patients (pts) ≥ 80 Years: Results of the French ATU Program.

Author

Itzykson, Raphael, primary, Thépot, Sylvain, additional, Achour, Bechir, additional, Quesnel, Bruno, additional, Dreyfus, Francois, additional, Turlure, Pascal, additional, Taksin, Anne-Laure, additional, Vey, Norbert, additional, Koka, Anne Marfaing, additional, de Botton, Stephane, additional, Wattel, Eric, additional, Isnard, Francoise, additional, Plantier, Isabelle, additional, Dartigeas, Caroline, additional, Zerhouni, Chahinez, additional, Gardin, Claude, additional, Ades, Lionel, additional, Beyne-Rauzy, Odile, additional, and Fenaux, Pierre, additional

Published
2009
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153. Abnormal Expression and Function of the Lnk Adaptor Protein in Myeloproliferative Neoplasms (MPN).

Author

Kiladjian, Jean-Jacques, primary, Baran-Marszak, Fanny, additional, Desterke, Christophe, additional, Cassinat, Bruno, additional, Magdoud, Hajer, additional, Mazoyer, Elisabeth, additional, Fenaux, Pierre, additional, Gardin, Claude, additional, Cymbalista, Florence, additional, Le Bousse-Kerdiles, Marie-Caroline, additional, Varin-Blank, Nadine, additional, and Velazquez, Laura, additional

Published
2009
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154. Azacytidine (AZA) as First Line Therapy in AML: Results of the French ATU Program.

Author

Thépot, Sylvain, primary, Itzykson, Raphael, additional, Seegers, Valerie, additional, Recher, Christian, additional, Quesnel, Bruno, additional, Delaunay, Jacques, additional, Cluzeau, Thomas, additional, Koka, Anne Marfaing, additional, Stamatoullas, Aspasia, additional, Chaury, MP, additional, Dartigeas, Caroline, additional, Cheze, Stéphane, additional, Salanoubat, Celia, additional, Morel, Pierre, additional, Plantier, Isabelle, additional, Taksin, Anne-Laure, additional, Marolleau, Jean Pierre, additional, Pautas, Cecile, additional, Wattel, Eric, additional, Isnard, Francoise, additional, Sanhes, Laurence, additional, Harel, Stephanie, additional, de Botton, Stephane, additional, Chait, Yasmine, additional, Uzunov, Madalina, additional, Guerci, Agnes, additional, Dahoun, Mehdi, additional, Vey, Norbert, additional, Dombret, Herve, additional, Dreyfus, Francois, additional, Ades, Lionel, additional, Fenaux, Pierre, additional, and Gardin, Claude, additional

Published
2009
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155. Azacytidine in Refractory or Relapsed AML After Intensive Chemotherapy (IC): Results of the French ATU Program.

Author

Itzykson, Raphael, primary, Thépot, Sylvain, additional, Recher, Christian, additional, Delaunay, Jacques, additional, Quesnel, Bruno, additional, Dreyfus, Francois, additional, Koka, Anne Marfaing, additional, Vey, Norbert, additional, Stamatoullas, Aspasia, additional, Gyan, Emmanuel, additional, Cluzeau, Thomas, additional, Rousselot, Philippe, additional, Reman, Oumedaly, additional, Plantier, Isabelle, additional, Marolleau, Jean Pierre, additional, Morel, Pierre, additional, Wattel, Eric, additional, Visanica, Sorin, additional, Zerhouni, Chahinez, additional, Bordessoule, Dominique, additional, Ades, Lionel, additional, Fenaux, Pierre, additional, and Gardin, Claude, additional

Published
2009
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157. Very Long Term Outcome of Acute Promyelocytic Leukemia After Treatment with All Trans Retinoic Acid and Chemotherapy: The European APL Group Experience.

Author

Ades, Lionel, primary, Guerci, Agnes, additional, Raffoux, Emmanuel, additional, Sanz, Miguel, additional, Chevallier, Patrice, additional, Lapusan, Simona, additional, Recher, Christian, additional, Thomas, Xavier, additional, Rayon, Chelo, additional, Castaigne, Sylvie, additional, Tournilhac, Olivier, additional, Botton, Stephane de, additional, Ifrah, Norbert, additional, Cahn, Jean-Yves, additional, Solary, Eric, additional, Gardin, Claude, additional, Fegeux, Nathalie, additional, Bordessoule, Dominique, additional, Ferrant, Augustin, additional, Meyer, Sandrine, additional, Vey, Norbert, additional, Dombret, Herve, additional, Degos, Laurent, additional, Chevret, Sylvie, additional, and Fenaux, Pierre, additional

Published
2009
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159. Which AML Subsets Benefit from Leukemic Cell Priming during Chemotherapy? Long-Term Analysis of the ALFA-9802 GM-CSF Study

Author

Thomas, Xavier, primary, Raffoux, Emmanuel, additional, Renneville, Aline, additional, Pautas, Cécile, additional, de Botton, Stephane, additional, de Revel, Thierry, additional, Reman, Oumedaly, additional, Terre, Christine, additional, Gardin, Claude, additional, Le, Quoc-Hung, additional, Philippe, Nathalie, additional, Cordonnier, Catherine, additional, Bourhis, Jean-Henri, additional, Elhamri, Mohamed, additional, Hayette, Sandrine, additional, Parmentier, Christine, additional, Fenaux, Pierre, additional, Castaigne, Sylvie, additional, Preudhomme, Claude, additional, and Dombret, Hervé, additional

Published
2008
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160. Epigenetic Therapy with 5-Azacitidine, Valproic Acid, and ATRA in Patients with High-Risk AML or MDS: Results of the French VIVEDEP Phase II Study

Author

Raffoux, Emmanuel, primary, de Labarthe, Adrienne, additional, Cras, Audrey, additional, Recher, Christian, additional, Turlure, Pascal, additional, Marolleau, Jean-Pierre, additional, Reman, Oumedaly, additional, Gardin, Claude, additional, Maury, Sebastien, additional, Rousselot, Philippe, additional, Malfuson, Jean-Valère, additional, Maarek, Odile, additional, Degos, Laurent, additional, Chomienne, Christine, additional, and Dombret, Hervé, additional

Published
2008
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161. Response to Azacytidine (AZA) in MDS or AML with Del 5q : Current Results of the French ATU Program

Author

Itzykson, Raphael, primary, Thépot, Sylvain, primary, Fabre, Claire, primary, Dreyfus, Francois, primary, Quesnel, Bruno, primary, Wattel, Eric, primary, de Botton, Stephane, primary, Pilorge, Sylvain, primary, Dartigeas, Caroline, primary, Stamatoullas, Aspasia, primary, Prebet, Thomas, primary, Ojeda-Uribe, Mario, primary, Cheze, Stéphane, primary, Tournilhac, Olivier, primary, Solary, Eric, primary, Damaj, Gandhi, primary, Tertian, Gerard, primary, Himberlin, Chantal, primary, Mbida, Rose-Marie, primary, Beve, Blandine, primary, Adès, Lionel, primary, Gardin, Claude, primary, and Fenaux, Pierre, primary

Published
2008
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162. Impact of ATRA Duration during the Induction Treatment of Newly Diagnosed APL

Author

Thepot, Sylvain, primary, Gardin, Claude, primary, Chevret, Sylvie, primary, de Botton, Stephane, primary, Raffoux, Emmanuel, primary, Guerci, Agnes, primary, Thomas, Xavier, primary, Pigneux, Arnaud, primary, Vey, Norbert, primary, Lamy, Thierry, primary, Huguet, Francoise, primary, Vekhoff, Anne, primary, Meyer, Sandrine, primary, Rayon, Chelo, primary, Pabst, Thomas, primary, Chevalier, Patrice, primary, Maloisel, Frederic, primary, Deconinck, Eric, primary, Ferrant, Augustin, primary, Bron, Dominique, primary, Dombret, Herve, primary, Fegueux, Nathalie, primary, de la Serna, Javier, primary, Cahn, jean-Yves, primary, Ifrah, Norbert, primary, Sanz, Miguel A, primary, Fenaux, Pierre, primary, and Ades, Lionel, primary

Published
2008
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163. Impact of Post-Remission Treatments in Patients Aged 65–70 Years with De Novo AML: A Comparison of Two Concomitant Randomized ALFA Trials with Overlapping Age Inclusion Criteria

Author

Itzykson, Raphael, primary, Gardin, Claude, primary, Pautas, Cécile, primary, Thomas, Xavier, primary, Turlure, Pascal, primary, Raffoux, Emmanuel, primary, Terré, Christine, primary, Castaigne, Sylvie, primary, Dombret, Hervé, primary, and Boissel, Nicolas, primary

Published
2008
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164. Long-Term Survival Analysis in Older Patients with AML Treated Intensively: Positive Impact of Idarubicin in a Cure Fraction Estimation Model.

Author

Dombret, Hervé, primary, Gardin, Claude, additional, Chevret, Sylvie, additional, Pautas, Cecile, additional, Turlure, Pascal, additional, Thomas, Xavier, additional, Quesnel, Bruno, additional, de Revel, Thierry, additional, Terré, Christine, additional, Fenaux, Pierre, additional, Bordessoule, Dominique, additional, and Castaigne, Sylvie, additional

Published
2008
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167. Treatment of AML with Azacytidine (AZA): Current Results of the French ATU Program.

Author

Fabre, Claire, primary, Gardin, Claude, primary, Mbida, Rose-Marie, primary, Quesnel, Bruno, primary, Dreyfus, François, primary, Isnard, Françoise, primary, Mannone, Lionel, primary, Legros, Laurence, primary, Prebet, Thomas, primary, Vey, Norbert, primary, Beyne-Rauzy, Odile, primary, Dalbies, Florence, primary, Cheze, Stéphane, primary, Delaunay, Jacques, primary, Fruchart, Christophe, primary, Marfaing-Koka, Anne, primary, Stamatoullas, Aspasia, primary, Bordessoule, Dominique, primary, Cambier, Nathalie, primary, Cornillon, Jérôme, primary, Dartigeas, Caroline, primary, Delmas-Marsalet, Béatrice, primary, and Fenaux, Pierre, primary

Published
2007
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169. Decision Criteria for the Futility of Intensive Chemotherapy in Older Patients with Acute Myeloid Leukemia (AML).

Author

Dombret, Hervé, primary, Malfuson, Jean-Valère, additional, Etienne, Anne, additional, Turlure, Pascal, additional, de Revel, Thierry, additional, Thomas, Xavier, additional, Contentin, Nathalie, additional, Terré, Christine, additional, Michallet, Mauricette, additional, Castaigne, Sylvie, additional, Bordessoule, Dominique, additional, Vey, Norbert, additional, and Gardin, Claude, additional

Published
2007
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170. The EGFR-Inhibitor Erlotinib Induces Differentiation, Cell Cycle Arrest and Apoptosis in EGFR-Negative Cells of MDS and AML.

Author

Boehrer, Simone, primary, Ades, Lionel, additional, Braun, Thorsten, additional, Galluzzi, Lorenzo, additional, Grosjean, Jennifer, additional, Fabre, Claire, additional, Le Roux, Genevieve, additional, Gardin, Claude, additional, Martin, Antoine, additional, de Botton, Stephane, additional, Fenaux, Pierre, additional, and Kroemer, Guido, additional

Published
2007
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171. Randomized Comparison of Standard Induction with Daunorubicin (DNR) for 3 Days vs Idarubicin (IDA) for 3 or 4 Days in AML pts Aged 50 to 70 and of Maintenance with Interleukin 2. Final Analysis of the ALFA 9801 Study.

Author

Pautas, Cecile, primary, Thomas, Xavier, primary, Merabet, Fatiha, primary, Raffoux, Emmanuel, primary, Bourhis, Jean Henri, primary, de Botton, Stephane, primary, Reman, Oumedaly, primary, Turlure, Pascal, primary, Gardin, Claude, primary, Contentin, Nathalie, primary, de Revel, Thierry, primary, Plantier, Isabelle, primary, Rousselot, Philippe, primary, Preudhomme, Claude, primary, Fenaux, Pierre, primary, Janvier, Maud, primary, Terre, Christine, primary, Dombret, Herve, primary, Michallet, Mauricette, primary, Chevret, Sylvie, primary, and Castaigne, Sylvie, primary

Published
2007
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173. Prognostic Impact of Cytogenetic Abnormalities in Elderly Patients with Acute Myeloid Leukemia (AML) Enrolled in the ALFA-9803 Trial.

Author

Terré, Christine, primary, Gardin, Claude, additional, Gachard, Nathalie, additional, Tigaud, Isabelle, additional, Désangles, François, additional, Bastard, Christian, additional, Maarek, Odile, additional, Lai, Jean-Luc, additional, Bernheim, Alain, additional, Perot, Christine, additional, Nguyen-Khac, Florence, additional, Eclache, Virginie, additional, Plessis, Ghislaine, additional, Turlure, Pascal, additional, Thomas, Xavier, additional, de Revel, Thierry, additional, Fenaux, Pierre, additional, and Dombret, Hervé, additional

Published
2007
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174. Postremission treatment of elderly patients with acute myeloid leukemia in first complete remission after intensive induction chemotherapy:results of the multicenter randomized Acute Leukemia French Association (ALFA) 9803 trial

Author

Gardin, Claude, primary, Turlure, Pascal, additional, Fagot, Thierry, additional, Thomas, Xavier, additional, Terre, Christine, additional, Contentin, Nathalie, additional, Raffoux, Emmanuel, additional, de Botton, Stephane, additional, Pautas, Cecile, additional, Reman, Oumedaly, additional, Bourhis, Jean-Henri, additional, Fenaux, Pierre, additional, Castaigne, Sylvie, additional, Michallet, Mauricette, additional, Preudhomme, Claude, additional, de Revel, Thierry, additional, Bordessoule, Dominique, additional, and Dombret, Herve, additional

Published
2007
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175. Impact of Post-Remission Therapy on Survival of Older Patients with AML Treated with Intensive Chemotherapy: Results of the Multicenter ALFA-9803 Trial.

Author

Turlure, Pascal, primary, Gardin, Claude, primary, Malfuson, Jean-Valere, primary, Thomas, Xavier, primary, Terre, Christine, primary, Contentin, Nathalie, primary, Raffoux, Emmanuel, primary, de Botton, Stephane, primary, Pautas, Cecile, primary, Reman, Oumedaly, primary, Bourhis, Jean-Henri, primary, Dhedin, Nathalie, primary, Janvier, Maud, primary, Fenaux, Pierre, primary, Castaigne, Sylvie, primary, Michallet, Mauricette, primary, Preudhomme, Claude, primary, de Revel, Thierry, primary, Bordessoule, Dominique, primary, and Dombret, Herve, primary

Published
2006
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176. Effect of Priming with Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) in Younger Adults with Newly Diagnosed Acute Myeloid Leukemia (AML): A Trial by the Acute Leukemia French Association (ALFA) Group.

Author

Thomas, Xavier, primary, Raffoux, Emmanuel, additional, De Botton, Stephane, additional, Pautas, Cecile, additional, Arnaud, Philippe, additional, De Revel, Thierry, additional, Reman, Oumedaly, additional, Terre, Christine, additional, Corront, Bernadette, additional, Gardin, Claude, additional, Plantier, Isabelle, additional, Le, Quoc-Hung, additional, Quesnel, Bruno, additional, Cordonnier, Catherine, additional, Bourhis, Jean-Henri, additional, Elhamri, Mohamed, additional, Fenaux, Pierre, additional, Preudhomme, Claude, additional, Michallet, Mauricette, additional, Castaigne, Sylvie, additional, and Dombret, Herve, additional

Published
2005
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177. ALFA-9000 Trial - An Analysis of Cytogenetic Subsets: Significant Long-Term Benefit of Early Induction Reinforcement Is Observed in CBF-AML Only.

Author

Gardin, Claude, primary, Chevret, Sylvie, additional, Charrin, Christiane, additional, Thomas, Xavier, additional, Bastard, Christian, additional, Lai, Jean-Luc, additional, Maarek, Odile, additional, de Botton, Stephane, additional, Bordessoule, Dominique, additional, Tilly, Herve, additional, de Revel, Thierry, additional, Terre, Christine, additional, Preudhomme, Claude, additional, Bauters, Francis, additional, Michallet, Mauricette, additional, Fiere, Denis, additional, Castaigne, Sylvie, additional, Fenaux, Pierre, additional, and Dombret, Herve, additional

Published
2005
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178. Secondary or Concomitant Neoplasms among Adults Diagnosed with Acute Lymphoblastic Leukemia (ALL) and Treated According to the LALA-87 and LALA-94 Trials.

Author

Tavernier, Emmanuelle, primary, de Botton, Stephane, primary, Dhedin, Nathalie, primary, Bulabois, Claude-Eric, primary, Reman, Oumedaly, primary, Vey, Norbert, primary, Garban, Frederic, primary, Boiron, Jean-Michel, primary, Gardin, Claude, primary, Fegueux, Nathalie, primary, Witz, Francis, primary, Lioure, Bruno, primary, Gratecos, Nicole, primary, Isnard, Francoise, primary, Delannoy, Andre, primary, Vernant, Jean-Paul, primary, Dombret, Herve, primary, Lheritier, Veronique, primary, Fiere, Denis, primary, and Thomas, Xavier, primary

Published
2005
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179. Analysis of JAK2 Mutation in Essential Thrombocythemia (ET) Patients with Monoclonal and Polyclonal X-Chromosome Inactivation Patterns (XCIPs).

Author

Kiladjian, Jean-Jacques, primary, Elkassar, Nahed, primary, Hetet, Gilles, primary, Balitrand, Nicole, primary, Conejero, Carole, primary, Giraudier, Stephane, primary, Cassinat, Bruno, primary, Gardin, Claude, primary, Fenaux, Pierre, primary, Chomienne, Christine, primary, and Grandchamp, Bernard, primary

Published
2005
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181. Rescue therapy combining intermediate-dose cytarabine with amsacrine and etoposide in relapsed adult acute lymphoblastic leukemia

Author

Reman, Oumedaly, primary, Buzyn, Agnes, additional, Lhéritier, Veronique, additional, Huguet, Francoise, additional, Kuentz, Mathieu, additional, Stamatoullas, Aspasia, additional, Delannoy, Andre, additional, Fegueux, Nathalie, additional, Micléa, Jean-Michel, additional, Boiron, Jean-Michel, additional, Vernant, Jean Paul, additional, Gardin, Claude, additional, Hacini, Maurice, additional, Georges, Michel, additional, Fière, Denis, additional, and Thomas, Xavier, additional

Published
2004
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184. Hepatic Manifestations of Hemophagocytic Syndrome: A Study of 30 Cases.

Author

De Kerguenec, Caroline, Hillaire, Sophie, Molinié, Vincent, Gardin, Claude, Degott, Claude, Erlinger, Serge, and Valla, Dominique

Subjects
MACROPHAGES, BONE marrow, LYMPH nodes, HYPERTRIGLYCERIDEMIA, JAUNDICE
Abstract

OBJECTIVE: Hemophagocytic syndrome has been defined as the combination of a proliferation of cytologically benign, actively phagocytic macrophages in bone marrow, spleen, or lymph nodes in association with fever, cytopenia, splenomegaly, and hypertriglyceridemia. Hepatic dysfunction is often present but the nature of the hepatic lesions and related manifestations have not been fully characterized. The aim of this study was to ascertain the features of hepatic involvement in hemophagocytic syndrome. METHODS: Thirty patients with hemophagocytic syndrome were retrospectively studied. Inclusion criteria included: 1) bone marrow with hemophagocytic histiocytosis, 2) clinical or biological signs of hepatic involvement, and 3) available liver specimen. RESULTS: The association of fever, jaundice, and hepatomegaly or splenomegaly was present in 50% of the patients. Median value for serum alanine transaminase activity was five times the upper limit of normal values (range, 0.3-125), for serum alkaline phosphatase activity 2.7 upper limit of normal values (range, 0.2-47.7), for total bilirubin 136 µmol/L (range, 4-681 µmol/L), and for factor V 70% (range, 19-145%). Sinusoidal dilatation with hemophagocytic histiocytosis were found in the biopsy specimen in all patients. An underlying condition potentially responsible for altered immune function (lymphoma, leukemia, liver transplantation) was identified in 29 patients. Liver biopsy was diagnostic for the underlying condition in 15 patients (including eight cases with nonspecific bone marrow biopsy findings). High serum bilirubin, elevated serum alkaline phosphatase activity, low factor V level, and lack of treatment for the underlying disease were associated with a poor prognosis. CONCLUSIONS: Hemophagocytic syndrome should be suspected in immunodeficient patients with fever, jaundice, and hepatosplenomegaly. Hepatic lesions are characterized by nonspecific sinusoidal dilatation with hemophagocytic histiocytosis and in 50% of the patients by alterations specific to the underlying condition. Liver biopsy is a useful diagnostic procedure in patients with this clinical presentation. [ABSTRACT FROM AUTHOR]

Published
2001
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185. Comparison of a Combination of Vosaroxin (VOS) and Intermediate-Dose Cytarabine (IDAC) with Idac for the Consolidation Therapy of Younger Patients with Favorable- and Intermediate-Risk Acute Myeloid Leukemia (AML) in First Complete Remission (CR): Preliminary Results of a Randomized Phase 2 R4-VOS Study of the French ALFA-Filo AML Intergroup

Author

Vey, Norbert, Orvain, Corentin, Recher, Christian, Pigneux, Arnaud, Bernard, Marc, Banos, Anne, Peterlin, Pierre, Chantepie, Sylvain, Thomas, Xavier, Pautas, Cecile, Gardin, Claude, Lemasle, Emilie, Raffoux, Emmanuel, Guieze, Romain, Himberlin, Chantal, Loiseau, Clémence, Belhabri, Amine, Luquet, Isabelle, Terré, Christine, Carre, Martin, Preudhomme, Claude, Delabesse, Eric, Celli-Lebras, Karine, Mineur, Ariane C, Brasme, Jean-Francois, Hamel, Jean Francois, Dombret, Hervé, and Hunault, Mathilde

Abstract

In spite of CR rates of 75-80% currently achieved with anthracycline-cytarabine regimens in younger patients with favorable and intermediate-risk AML, relapse remains a major issue. The French AML intergroup launched the BIG-1 trial in 2015 in order to test different strategies aiming at reducing relapse rate and improving survival. All patients with previously untreated non-APL and non-CBF AML aged 18-60 years are eligible for trial participation which is still ongoing. The trial design includes several randomizations (R): Idarubicin vs daunorubicin for induction (R1), HDAC vs IDAC for consolidation (R2), post-transplant GVHD prophylaxis modalities (R3). R4 consists of nested randomized phase 2-3 trials testing the addition of new drugs to the IDAC or HDAC backbones during the consolidation phase. The protocol was designed to allow the sequential evaluation of several new agents over the trial period. Vosaroxin (VOS) has shown antileukemic activity (Advani, Clin Cancer Res 2010). The combination of VOS and IDAC showed higher CR rate and a non-significant OS benefit as compared to a placebo-IDAC arm in a large phase 3 trial in patients with refractory/relapsed AML (Ravandi Lancet Oncol 2015). We hypothesized that the addition of VOS to IDAC would improve LFS as compared to IDAC alone when given during the consolidation phase.

Published
2020
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186. Very Long Term Follow up a Phase II Study of Post-Remission Subcutaneous (SC) Azacitidine (AZA) in Patients with AML Post-MDS or Higher-Risk (HR) MDS

Author

Cherait, Amina, Braun, Thorsten, Bouabdallah, Krimo, Caillot, Denis, Guerci, Agnès, Raffoux, Emmanuel, Marolleau, Jean Pierre, Pautas, Cecile, Banos, Anne, Himberlin, Chantal, Taksin, Anne Laure, Pigneux, Arnaud, Thomas, Xavier, Vey, Norbert, Chevret, Sylvie, Dombret, Herve, Chermat, Fatiha, Ades, Lionel, Gardin, Claude, and Fenaux, Pierre

Abstract

Background:Results of the phase III QUAZAR trial suggest that post-remission treatment with an oral form (CC-486) of azacitidine (AZA) can prolong CR duration and overall survival(OS) in AML patients reaching at least PR with intensive chemotherapy (IC) (Wei et al, ASH 2019). Maintenance treatment with subcutaneous (SC) AZA was recently shown to improve DFS in elderly AML (Huls et al, Blood 2019, a study that also included 10% MDS). We report very long term results of a study evaluating SC AZA as post-remission treatment in patients with AML post-MDS or high-risk MDS (HR-MDS) who achieved at least PR after IC, a population known to have short responses with IC.

Published
2020
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187. Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial

Author

Braun, Thorsten, Itzykson, Raphael, Renneville, Aline, de Renzis, Benoit, Dreyfus, François, Laribi, Kamel, Bouabdallah, Krimo, Vey, Norbert, Toma, Andrea, Recher, Christian, Royer, Bruno, Joly, Bertrand, Vekhoff, Anne, Lafon, Ingrid, Sanhes, Laurence, Meurice, Guillaume, Oréar, Cédric, Preudhomme, Claude, Gardin, Claude, Ades, Lionel, Fontenay, Michaela, Fenaux, Pierre, Droin, Nathalie, and Solary, Eric

Abstract

Hydroxyurea is the standard therapy of chronic myelomonocytic leukemia (CMML) presenting with advanced myeloproliferative and/or myelodysplastic features. Response to hypomethylating agents has been reported in heterogeneous series of CMML. We conducted a phase 2 trial of decitabine (DAC) in 39 patients with advanced CMML defined according to a previous trial. Median number of DAC cycles was 10 (range, 1-24). Overall response rate was 38% with 4 complete responses (10%), 8 marrow responses (21%), and 3 stable diseases with hematologic improvement (8%). Eighteen patients (46%) demonstrated stable disease without hematologic improvement, and 6 (15%) progressed to acute leukemia. With a median follow-up of 23 months, overall survival was 48% at 2 years. Mutations in ASXL1, TET2, AML1, NRAS, KRAS, CBL, FLT3, and janus kinase 2 (JAK2) genes, and hypermethylation of the promoter of the tumor suppressor gene TIF1γ, did not predict response or survival on DAC therapy. Lower CJUN and CMYB gene expression levels independently predicted improved overall survival. This trial confirmed DAC efficacy in approximately 40% of CMML patients with advanced myeloproliferative or myelodysplastic features and suggested that CJUN and CMYB expression could be potential biomarkers in this setting. This trial is registered at EudraCT (eudract.ema.europa.eu) as #2008-000470-21 and www.clinicaltrials.gov as #NCT01098084.

Published
2011
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188. Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine

Author

Itzykson, Raphael, Thépot, Sylvain, Quesnel, Bruno, Dreyfus, Francois, Beyne-Rauzy, Odile, Turlure, Pascal, Vey, Norbert, Recher, Christian, Dartigeas, Caroline, Legros, Laurence, Delaunay, Jacques, Salanoubat, Célia, Visanica, Sorin, Stamatoullas, Aspasia, Isnard, Francoise, Marfaing-Koka, Anne, de Botton, Stephane, Chelghoum, Youcef, Taksin, Anne-Laure, Plantier, Isabelle, Ame, Shanti, Boehrer, Simone, Gardin, Claude, Beach, C. L., Adès, Lionel, and Fenaux, Pierre

Abstract

Prognostic factors for response and survival in higher-risk myelodysplastic syndrome patients treated with azacitidine (AZA) remain largely unknown. Two hundred eighty-two consecutive high or intermediate-2 risk myelodysplastic syndrome patients received AZA in a compassionate, patient-named program. Diagnosis was RA/RARS/RCMD in 4%, RAEB-1 in 20%, RAEB-2 in 54%, and RAEB-t (AML with 21%-30% marrow blasts) in 22%. Cytogenetic risk was good in 31%, intermediate in 17%, and poor in 47%. Patients received AZA for a median of 6 cycles (1-52). Previous low-dose cytosine arabinoside treatment (P = .009), bone marrow blasts > 15% (P = .004), and abnormal karyotype (P = .03) independently predicted lower response rates. Complex karyotype predicted shorter responses (P = .0003). Performance status ≥ 2, intermediate- and poor-risk cytogenetics, presence of circulating blasts, and red blood cell transfusion dependency ≥ 4 units/8 weeks (all P < 10−4) independently predicted poorer overall survival (OS). A prognostic score based on those factors discriminated 3 risk groups with median OS not reached, 15.0 and 6.1 months, respectively (P < 10−4). This prognostic score was validated in an independent set of patients receiving AZA in the AZA-001 trial (P = .003). Achievement of hematological improvement in patients who did not obtain complete or partial remission was associated with improved OS (P < 10−4). In conclusion, routine tests can identify subgroups of patients with distinct prognosis with AZA treatment.

Published
2011
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189. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience

Author

Adès, Lionel, Guerci, Agnes, Raffoux, Emmanuel, Sanz, Miguel, Chevallier, Patrice, Lapusan, Simona, Recher, Christian, Thomas, Xavier, Rayon, Consuelo, Castaigne, Sylvie, Tournilhac, Olivier, de Botton, Stephane, Ifrah, Norbert, Cahn, Jean-Yves, Solary, Eric, Gardin, Claude, Fegeux, Nathalie, Bordessoule, Dominique, Ferrant, Augustin, Meyer-Monard, Sandrine, Vey, Norbert, Dombret, Herve, Degos, Laurent, Chevret, Sylvie, and Fenaux, Pierre

Abstract

Acute promyelocytic leukemia (APL) is highly curable with the combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy (CT), but very long-term results of this treatment, when CT should be added to ATRA and the role of maintenance treatment, remain uncertain. In our APL93 trial that included 576 newly diagnosed APL patients, with a median follow-up of 10 years, 10-year survival was 77%. Maintenance treatment significantly reduced 10-year cumulative incidence of relapses, from 43.2% to 33%, 23.4%, and 13.4% with no maintenance, maintenance using intermittent ATRA, continuous 6 mercaptopurine plus methotrexate, and both treatments, respectively (P < .001). Maintenance particularly benefited patients with white blood cell (WBC) count higher than 5 × 109/L (5000/μL). Early addition of CT to ATRA significantly improved 10-year event-free survival (EFS), but without significant effect on overall survival (OS). The 10-year cumulative incidence of deaths in complete response (CR), resulting mainly from myelosuppression, was 5.7%, 15.4%, and 21.7% in patients younger than 55, 55 to 65, and older than 65 years, respectively, supporting the need for less myelosuppressive treatments, particularly for consolidation therapy. This study is registered at http://clinicaltrials.gov as NCT00599937.

Published
2010
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190. Very long-term outcome of acute promyelocytic leukemia after treatment with all-transretinoic acid and chemotherapy: the European APL Group experience

Author

Adès, Lionel, Guerci, Agnes, Raffoux, Emmanuel, Sanz, Miguel, Chevallier, Patrice, Lapusan, Simona, Recher, Christian, Thomas, Xavier, Rayon, Consuelo, Castaigne, Sylvie, Tournilhac, Olivier, de Botton, Stephane, Ifrah, Norbert, Cahn, Jean-Yves, Solary, Eric, Gardin, Claude, Fegeux, Nathalie, Bordessoule, Dominique, Ferrant, Augustin, Meyer-Monard, Sandrine, Vey, Norbert, Dombret, Herve, Degos, Laurent, Chevret, Sylvie, Fenaux, Pierre, and Group, for the European APL

Abstract

Acute promyelocytic leukemia (APL) is highly curable with the combination of all-transretinoic acid (ATRA) and anthracycline-based chemotherapy (CT), but very long-term results of this treatment, when CT should be added to ATRA and the role of maintenance treatment, remain uncertain. In our APL93 trial that included 576 newly diagnosed APL patients, with a median follow-up of 10 years, 10-year survival was 77%. Maintenance treatment significantly reduced 10-year cumulative incidence of relapses, from 43.2% to 33%, 23.4%, and 13.4% with no maintenance, maintenance using intermittent ATRA, continuous 6 mercaptopurine plus methotrexate, and both treatments, respectively (P< .001). Maintenance particularly benefited patients with white blood cell (WBC) count higher than 5 × 109/L (5000/μL). Early addition of CT to ATRA significantly improved 10-year event-free survival (EFS), but without significant effect on overall survival (OS). The 10-year cumulative incidence of deaths in complete response (CR), resulting mainly from myelosuppression, was 5.7%, 15.4%, and 21.7% in patients younger than 55, 55 to 65, and older than 65 years, respectively, supporting the need for less myelosuppressive treatments, particularly for consolidation therapy. This study is registered at http://clinicaltrials.govas NCT00599937.

Published
2010
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191. Efficacy and safety of lenalidomide in intermediate-2 or high-risk myelodysplastic syndromes with 5q deletion: results of a phase 2 study

Author

Adès, Lionel, Boehrer, Simone, Prebet, Thomas, Beyne-Rauzy, Odile, Legros, Laurence, Ravoet, Christophe, Dreyfus, François, Stamatoullas, Aspasia, Pierre Chaury, Marie, Delaunay, Jacques, Laurent, Guy, Vey, Norbert, Burcheri, Sara, Mbida, Rose-Marie, Hoarau, Natacha, Gardin, Claude, and Fenaux, Pierre

Abstract

Higher-risk MDS with del5q carry a poor prognosis. In this phase 2 trial, 47 patients with higher-risk MDS received lenalidomide 10 mg/day. International Prognostic Scoring System was high in 60%, intermediate-2 risk in 40%. del 5q was isolated, with one additional and more than one additional abnormality in 19%, 23%, and 58% patients, respectively. Thirteen (27%) patients achieved hematologic response, including 7 hematologic complete remission (CR) (with complete [4] or partial [3] cytogenetic response), 2 marrow CR and 4 hematologic improvement erythroid, and 12 became red blood cell (RBC) transfusion independent, for a median duration of 6.5 months. Median CR duration was 11.5 months. Six of 9 (67%) patients with isolated del 5q achieved CR, versus 1 of 11 and none of 27 patients with one or more than one additional abnormality, respectively (P < .001). Seven of 20 (35%) with initial platelets more than 100 000/mm3 obtained CR, compared with none of the 27 with lower platelet counts less than 100 000/mm3 (P = .001). Our data support a potential role of lenalidomide in higher-risk MDS with isolated del 5q. This trial was registered at www.clinicaltrials.gov as NCT00424229.

Published
2009
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192. Prognostic Significance of DDX41Germline Mutations in Intensively Treated AML Patients: An ALFA-Filo Study

Author

Duployez, Nicolas, Duchmann, Matthieu, Largeaud, Laetitia, Lambert, Juliette, Bidet, Audrey, Clappier, Emmanuelle, Thomas, Xavier, de Botton, Stephane, Gardin, Claude, Recher, Christian, Pigneux, Arnaud, Itzykson, Raphael, Preudhomme, Claude, Dombret, Hervé, Delabesse, Eric, and Sebert, Marie

Abstract

Background:The WHO 2016 classification identifies myeloid malignancies with germline predisposition as a distinct subgroup (Arber DA et al., Blood 2016). We and other reported mutations of the DEAD-box RNA helicase 41 gene (g DDX41m) as the most common predisposition to MDS/AML (Sébert et al., Blood 2019). Relatively good outcomes have been suggested in small cohorts receiving heterogeneous treatment, but the prognostic significance of g DDX41m in AML patients (pts) treated with intensive chemotherapy (IC) has never been reported. Here, we analyzed the prognostic impact of g DDX41m in a large cohort of newly diagnosed AML pts treated with IC in 5 prospective ALFA (Acute Leukemia French Association) and FILO (French Innovative Leukemia Organization) trials.

Published
2021
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193. Fractionated Inotuzumab Ozogamicin Combined with Low-Intensity Chemotherapy Provides Very Good Outcome in Older Patients with Newly Diagnosed CD22+ Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia: First Results from the EWALL-INO Study

Author

Chevallier, Patrice, Leguay, Thibault, Doubek, Michael, Huguet, Francoise, Salek, Cyril, Cabannes, Aurélie, Wartiovaara-Kautto, Ulla, Saillard, Colombe, Raffoux, Emmanuel, Cluzeau, Thomas, Leprêtre, Stéphane, Balsat, Marie, Berceanu, Anna, Boissel, Nicolas, Clappier, Emmanuelle, Morisset, Laure, Gardin, Claude, Dombret, Hervé, and Rousselot, Philippe

Abstract

On behalf of the GRAALL group, the Czech Republic ALL group, the Finland ALL group and the EWALL group.

Published
2021
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194. Replacing the Anthracycline By Gemtuzumab Ozogamicin in Older Patients with De Novo Standard-Risk Acute Myeloid Leukemia Treated Intensively - Results of the Randomized ALFA1401-Mylofrance 4 Study

Author

Lambert, Juliette, Lambert, Jérôme, Lemasle, Emilie, Joris, Magalie, Chantepie, Sylvain, Pautas, Cecile, Thomas, Xavier, Malfuson, Jean Valere, Gastaud, Lauris, Caillot, Denis, Tavernier, Emmanuelle, Turlure, Pascal, Carp, Diana, Berthon, Celine, Legrand, Olivier, Marçais, Ambroise, Vaida, Iona, Barbieux, Sarah, Rousselot, Philippe, Gardin, Claude, Terré, Christine, Duployez, Nicolas, Preudhomme, Claude, Celli-Lebras, Karine, Castaigne, Sylvie, and Dombret, Herve

Published
2021
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195. Prognostic Significance of DDX41 Germline Mutations in Intensively Treated AML Patients: An ALFA-Filo Study

Author

Duployez, Nicolas, Duchmann, Matthieu, Largeaud, Laetitia, Lambert, Juliette, Bidet, Audrey, Clappier, Emmanuelle, Thomas, Xavier, de Botton, Stephane, Gardin, Claude, Recher, Christian, Pigneux, Arnaud, Itzykson, Raphael, Preudhomme, Claude, Dombret, Hervé, Delabesse, Eric, and Sebert, Marie

Abstract

Lambert: ASTELLAS: Consultancy; CELGENE/BMS: Consultancy. de Botton: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Honoraria, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syros: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Other; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. Recher: Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MaatPharma: Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Delabesse: Astellas: Consultancy; Novartis: Consultancy. Sebert: Abbvie: Consultancy; BMS: Consultancy.

Published
2021
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196. The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases

Author

Kiladjian, Jean-Jacques, Cervantes, Francisco, Leebeek, Franck W. G., Marzac, Christophe, Cassinat, Bruno, Chevret, Sylvie, Cazals-Hatem, Dominique, Plessier, Aurélie, Garcia-Pagan, Juan-Carlos, Murad, Sarwa Darwish, Raffa, Sebastian, Janssen, Harry L. A., Gardin, Claude, Cereja, Sophie, Tonetti, Carole, Giraudier, Stéphane, Condat, Bertrand, Casadevall, Nicole, Fenaux, Pierre, and Valla, Dominique C.

Abstract

Myeloproliferative diseases (MPDs) represent the commonest cause of splanchnic vein thrombosis (SVT), including Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT), but their diagnosis is hampered by changes secondary to portal hypertension, while their influence in the outcome of SVT remains unclear. We assessed the diagnostic and prognostic value of JAK2 and MPL515 mutations in 241 SVT patients (104 BCS, 137 PVT). JAK2V617F was found in 45% of BCS and 34% of PVT, while JAK2 exon 12 and MPL515 mutations were not detected. JAK2V617F was found in 96.5% of patients with bone marrow (BM) changes specific for MPD and endogenous erythoid colonies, but also in 58% of those with only one feature and in 7% of those with neither feature. Stratifying MPD diagnosis first on JAK2V617F detection would have avoided BM investigations in 40% of the patients. In BCS, presence of MPD carried significantly poorer baseline prognostic features, required hepatic decompression procedures earlier, but had no impact on 5-year survival. Our results suggest that JAK2V617F testing should replace BM investigations as initial test for MPD in patients with SVT. Underlying MPD is associated with severe forms of BCS, but current therapy appears to offset deleterious effects of MPD on the medium-term outcome.

Published
2008
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197. Erlotinib exhibits antineoplastic off-target effects in AML and MDS: a preclinical study

Author

Boehrer, Simone, Adès, Lionel, Braun, Thorsten, Galluzzi, Lorenzo, Grosjean, Jennifer, Fabre, Claire, Le Roux, Génèviève, Gardin, Claude, Martin, Antoine, de Botton, Stéphane, Fenaux, Pierre, and Kroemer, Guido

Abstract

Erlotinib, an inhibitor of the epidermal growth factor receptor (EGFR), induces differentiation, cell-cycle arrest, and apoptosis of EGFR-negative myeloblasts of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), as well as in EGFR-negative cell lines representing these diseases (P39, KG-1, and HL 60). This off-target effect can be explained by inhibitory effects on JAK2. Apoptosis induction coupled to mitochondrial membrane permeabilization occurred independently from phenotypic differentiation. In apoptosis-sensitive AML cells, erlotinib caused a rapid (within less than 1 hour) nucleocytoplasmic translocation of nucleophosmin-1 (NPM-1) and p14ARF. Apoptosis-insensitive myeloblasts failed to manifest this translocation yet became sensitive to apoptosis induction by erlotinib when NPM-1 was depleted by RNA interference. Moreover, erlotinib reduced the growth of xenografted human AML cells in vivo. Erlotinib also killed CD34+ bone marrow blasts from MDS and AML patients while sparing normal CD34+ progenitors. This ex vivo therapeutic effect was once more associated with the nucleocytoplasmic translocation of NPM-1 and p14ARF. One patient afflicted with both MDS and non–small cell lung cancer manifested hematologic improvement in response to erlotinib. In summary, we here provide novel evidence in vitro, ex vivo, and in vivo for the potential therapeutic efficacy of erlotinib in the treatment of high-risk MDS and AML.

Published
2008
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198. Outcome of acute myeloid leukaemia following myelodysplastic syndrome after azacitidine treatment failure.

Author

Prébet, Thomas, Gore, Steven D., Thépot, Sylvain, Esterni, Benjamin, Quesnel, Bruno, Beyne Rauzy, Odile, Dreyfus, François, Gardin, Claude, Fenaux, Pierre, and Vey, Norbert

Subjects
LEUKEMIA, DISEASE complications, DYSPLASIA, CELL transformation, CELLULAR pathology
Abstract

The article presents information on a study which showed that the outcome of high risk myelodysplastic syndrome (MDS) after azacitidine (AZA) failure. The study the outcome of 74 patients with secondary acute myeloid leukaemia (AML) after AZA treatment failure, collected from two Johns Hopkins University trials and the French AZA compassionate programme.

Published
2012
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199. An Old AML Drug Revisited.

Author

Dombret, Hervé and Gardin, Claude

Subjects
*CLINICAL trials, *ACUTE myeloid leukemia, *ONCOLOGY, *OLD age
Abstract

The article highlights the long-term results of two large, randomized trials on managing acute myeloid leukemia (AML) conducted by investigators from the Eastern Cooperative Oncology Group (ECOG) in the U.S. and a collaborative group of European investigators from the Netherlands, Belgium, Germany and Switzerland. Among the factors that negatively influence the outcome of patients with AML are older age, poor performance status and high white-cell count. Both studies have concluded that the 90-milligram (mg) dose of daunorubicin, as compared with the standard 45-mg dose, appear to be similar. According to the authors, high-dose daunorubicin does not benefit the majority of older patients with AML.

Published
2009
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200. A Randomized Comparison of All Transretinoic Acid (ATRA) Followed by Chemotherapy and ATRA Plus Chemotherapy and the Role of Maintenance Therapy in Newly Diagnosed Acute Promyelocytic Leukemia

Author

Fenaux, Pierre, Chastang, Claude, Chevret, Sylvie, Sanz, Miguel, Dombret, Herve´, Archimbaud, Eric, Fey, Martin, Rayon, Consuelo, Huguet, Franc¸oise, Sotto, Jean-Jacques, Gardin, Claude, Makhoul, Pascale Cony, Travade, Philippe, Solary, Eric, Fegueux, Nathalie, Bordessoule, Dominique, Miguel, Jesus San, Link, Harmut, Desablens, Bernard, Stamatoullas, Aspasia, Deconinck, E., Maloisel, Fre´deric, Castaigne, Sylvie, Preudhomme, Claude, and Degos, Laurent

Abstract

All transretinoic acid (ATRA) followed by daunorubicin (DNR)-AraC chemotherapy (CT) has improved the outcome of acute promyelocytic leukemia (APL) by comparison to CT alone. In a randomized trial, (1) we compared 2 induction schedules (ATRA followed by CT [ATRA?CT] and ATRA plus CT [ATRA+CT, with CT added on day 3 of ATRA treatment]) and (2) we assessed the role of maintenance treatment. Four hundred thirteen patients =75 years of age and with newly diagnosed APL were included. Induction treatment was stratified on white blood cell (WBC) count and age: patients =65 years of age and with an initial WBC count of =5,000/µL (n = 208) were randomized between ATRA?CT and ATRA+CT (initially randomized patients); patients with a WBC count greater than (high WBC count group, n = 163) and patients 66 to 75 years of age with a WBC count greater than 5,000/µL (elderly group, n = 42) were not initially randomized and received ATRA+CT from day 1 and ATRA ?CT, respectively. All patients achieving CR received 2 additional DNR-AraC courses (only 1 in patients 66 to 75 years of age) and were then randomized for maintenance between no treatment, intermittent ATRA (15 days every 3 months) for 2 years, continuous low-dose CT (6 mercaptopurine + methotrexate) for 2 years, or both, using a 2-by-2 factorial design. Overall, 381 (92%) of the patients achieved complete remission (CR), 31 (7%) suffered an early death, and only 1 patient had leukemic resistance. ATRA syndrome occurred in 64 patients (15%) and was fatal in 5 cases. The CR rate was similar in all induction treatment groups. Event-free survival (EFS) was significantly lower in the high WBC group (P = .0002) and close to significance in the elderly group (P = .086) as compared with initially randomized patients. Relapse at 2 years was estimated at 6% in the ATRA+CT group, versus 16% in the ATRA?CT group (P = .04, relative risk [RR] = .41). EFS at 2 years was estimated at 84% in the ATRA+CT group, versus 77% in the ATRA?CT group (P = .1, RR = .62). Two hundred eighty-nine patients were randomized for maintenance. The 2-year relapse rate was 11% in patients randomized to continuous maintenance CT and 27% in patients randomized to no CT (P = .0002) and 13% in patients randomized to intermittent ATRA and 25% in patients randomized to no ATRA (P= .02). An additive effect of continuous maintenance CT and intermittent ATRA was seen, and only 6 of the 74 patients who received both maintenance treatments had relapsed. Overall survival was improved in patients who received maintenance CT (P = .01), and there was a trend for better survival in patients who received maintenance ATRA (P = .22). Our findings strongly suggest that early addition of chemotherapy to ATRA and maintenance therapy combining continuous CT and intermittent ATRA can reduce the incidence of relapse in APL. This effect already translates into significantly better survival for maintenance treatment with continuous CT.

Published
1999
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