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1.
Leukemia ; 21(3): 453-61, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17252021

ABSTRACT

In a multicenter trial, 259 young adults (15-49 years) with newly diagnosed acute myeloid leukemia (AML) were first randomized to receive a timed-sequential induction regimen given either alone (135 patients) or concomitantly with granulocyte-macrophage colony-stimulating factor (GM-CSF) (124 patients). Patients reaching complete remission (CR) were then randomized to compare a timed-sequential consolidation to a postremission chemotherapy including four cycles of high-dose cytarabine followed by maintenance courses. In the appropriate arm, GM-CSF was given concurrently with chemotherapy during all cycles of consolidation. CR rates were significantly better in the GM-CSF arm (88 vs 78%, P<0.04), but did not differ after salvage. Patients receiving GM-CSF had a higher 3-year event-free survival (EFS) estimate (42 vs 34%), but GM-CSF did not impact on overall survival. Patients with intermediate-risk cytogenetics benefited more from GM-CSF therapy (P=0.05) in terms of EFS than patients with other cytogenetics. This was also confirmed when considering only patients following the second randomization, or subgroups defined by a prognostic index based on cytogenetics and the number of courses required for achieving CR. Priming of leukemic cells with hematopoietic growth factors is a means of enhancing the efficacy of chemotherapy in younger adults with AML.


Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Leukemia, Myeloid/drug therapy , Premedication , Acute Disease , Adolescent , Adult , Amsacrine/administration & dosage , Amsacrine/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Division/drug effects , Combined Modality Therapy , Cytarabine/administration & dosage , Cytarabine/adverse effects , Daunorubicin/administration & dosage , Daunorubicin/adverse effects , Disease-Free Survival , Drug Administration Schedule , Female , Granulocyte-Macrophage Colony-Stimulating Factor/administration & dosage , Hematopoietic Stem Cell Transplantation , Humans , Kaplan-Meier Estimate , Leukemia, Myeloid/genetics , Leukemia, Myeloid/pathology , Leukemia, Myeloid/surgery , Male , Middle Aged , Mitoxantrone/administration & dosage , Mitoxantrone/adverse effects , Neoplastic Stem Cells/drug effects , Proportional Hazards Models , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacology , Risk , Salvage Therapy , Stimulation, Chemical , Transplantation, Homologous , Treatment Outcome
2.
Leuk Lymphoma ; 46(7): 1007-16, 2005 Jul.
Article in English | MEDLINE | ID: mdl-16019551

ABSTRACT

Post-remission options were compared in a population of 262 relapsing and refractory acute myeloid leukemia patients achieving complete remission (CR) after the same re-induction according to etoposide - mitoxantrone - cytarabine (EMA) trials. The selection of post-remission therapy depended on trial recommendations, age, performance status, and availability of an HLA-identical sibling. One hundred and thirty patients received chemotherapy consolidation courses, 50 received autologous stem cell transplantation (SCT), and 43 underwent allogeneic bone marrow transplantation (BMT), while 39 did not receive any additional therapy. The preliminary analysis identified 3 favorable prognostic factors correlated with event-free survival (EFS): M3 subtype, previous CR duration > 1 year, and transplantation. Three year EFS was 68 vs. 23% with autologous SCT and allogeneic BMT in M3 patients and, respectively, 41 vs. 20% in non-M3 patients. Three year probabilities of treatment-related mortality were 11 and 47%, respectively. A statistical model was conceived with adjustment on prognostic factors and post-remission option. In the multivariate analysis, autologous SCT appeared significantly better than allogeneic BMT (P < 0.01) or chemotherapy (P = 0.001), while allogeneic BMT was not statistically different than chemotherapy. This indicates a high treatment-related toxicity with allogeneic BMT in patients re-induced by highly intensive chemotherapy, and therefore a tendency for a better outcome with autologous SCT as post-remission treatment in those patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid/drug therapy , Neoplasm Recurrence, Local/therapy , Salvage Therapy , Stem Cell Transplantation , Acute Disease , Adolescent , Adult , Aged , Combined Modality Therapy , Cytarabine/administration & dosage , Etoposide/administration & dosage , Female , Humans , Leukemia, Myeloid/mortality , Male , Middle Aged , Mitoxantrone/administration & dosage , Neoplasm Recurrence, Local/mortality , Remission Induction , Survival Rate , Transplantation, Autologous , Transplantation, Homologous , Treatment Outcome
3.
Leukemia ; 26(6): 1247-54, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22289988

ABSTRACT

Recently, DNA methyltransferase 3A (DNMT3A) mutations have been identified in acute myeloid leukemia (AML), the highest frequency being found within cytogenetically normal (CN) AML. In this study, diagnostic samples from 123 adults younger than 60 years with primary CN-AML homogeneously treated in the Acute Leukemia French Association-9801 and -9802 trials were screened for mutations in DNMT3A-conserved domains by direct sequencing. Patients were also assessed for the presence of FLT3 (fms-like tyrosine kinase receptor-3), NPM1 (nucleophosmin), CEBPA, WT1 (Wilms tumor 1), IDH1 (isocitrate dehydrogenase 1) and IDH2 mutations. Thirty-eight mutations were detected in 36 patients (29%): 36 nucleotide substitutions, mostly affecting amino-acid residue R882 and two frameshift deletions. DNMT3A mutations were significantly associated with the French-American-British subtypes M4/M5 and the presence of NPM1 mutations. In the whole cohort, DNMT3A mutated patients had a shorter event-free survival (5-year EFS: 13% vs 32%, P = 0.02) and overall survival (5-year OS: 23% vs 45%, P = 0.02) compared with DNMT3A wild-type patients. In multivariate analysis including age, white blood cell count, NPM1/FLT3-internal tandem duplication/CEBPA risk group and DNMT3A mutational status, the presence of a DNMT3A mutation remained an independent adverse prognostic factor for EFS and OS, suggesting that testing for DNMT3A mutations could help further improve risk stratification in CN-AML.


Subject(s)
Biomarkers, Tumor/genetics , Cytogenetic Analysis , DNA (Cytosine-5-)-Methyltransferases/genetics , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Mutation/genetics , Adolescent , Adult , DNA Methyltransferase 3A , DNA, Neoplasm/genetics , Female , Follow-Up Studies , Humans , Leukemia, Myeloid, Acute/classification , Male , Middle Aged , Nucleophosmin , Polymerase Chain Reaction , Prognosis , Prospective Studies , Retrospective Studies , Risk Factors , Survival Rate , Young Adult , fms-Like Tyrosine Kinase 3/genetics
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