ABSTRACT
Enhanced expression of ecotropic viral integration site 1 (EVI-1) occurs in â¼10% of acute myeloid leukemia (AML) patients and is associated with a very poor disease outcome. Patients with EVI-1-positive AML have poor initial responses to chemotherapy and high relapse rates, indicating an urgent need for alternative treatment strategies improving clinical outcome for these patients. Because treatment of acute promyelocytic patients with all-trans retinoic acid (ATRA) has improved the survival of these patients substantially, we investigated whether ATRA might also be effective for the subgroup of AML patients with EVI-1 overexpression. Here, we show that a substantial part of the EVI-1-positive AML cases respond to ATRA by induction of differentiation and decreased clonogenic capacity of myeloid blasts. Most importantly, we demonstrate that in vivo treatment of primary EVI-1-positive AML with ATRA leads to a significant reduction in leukemic engraftment. Altogether, our results show that a considerable part of the EVI-1-positive primary AML cases are sensitive to ATRA, suggesting that combining ATRA with the currently used conventional chemotherapy might be a promising treatment strategy decreasing relapse rates and enhancing complete remissions in this poor prognostic subgroup of AML patients.
Subject(s)
Antineoplastic Agents/pharmacology , DNA-Binding Proteins/genetics , Leukemia, Myeloid, Acute/drug therapy , Proto-Oncogenes/genetics , Transcription Factors/genetics , Tretinoin/pharmacology , Animals , Cell Differentiation/drug effects , DNA-Binding Proteins/analysis , Female , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , MDS1 and EVI1 Complex Locus Protein , Male , Mice, SCID , Myeloid Cells/cytology , Myeloid Cells/drug effects , Myeloid Cells/metabolism , Myeloid Cells/pathology , Transcription Factors/analysis , Tumor Cells, Cultured , Up-RegulationSubject(s)
Antineoplastic Agents/therapeutic use , Aphasia/etiology , Ataxia/etiology , Blast Crisis/diagnosis , Confusion/etiology , Hearing Loss/etiology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Benzamides , Blast Crisis/etiology , Blast Crisis/pathology , Blast Crisis/therapy , Cytarabine/administration & dosage , Cytarabine/therapeutic use , Diagnosis, Differential , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications , Male , Middle Aged , Piperazines/administration & dosage , Piperazines/adverse effects , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Stem Cell Transplantation , Treatment OutcomeABSTRACT
BACKGROUND: About 70-80 percent of patients with acute myeloid leukemia enter complete remission, but at least half of these patients who achieve remission go on to relapse. Improved treatment is likely to come from increasing the time to relapse, especially for younger patients. With the vastly increasing number of targeted therapies there is a strong need for short-term end-points to efficiently test such therapies for further pursuance. Minimal residual disease assessment may offer such an end-point since it is a strong independent prognostic factor. As proof of principle we examined this concept for FLT3-ITD status at diagnosis. DESIGN AND METHODS: We determined FLT3-ITD status in bone marrow samples from 196 patients with newly diagnosed acute myeloid leukemia. The frequencies of residual leukemic cells of these 196 patients were assessed in 267 follow-up bone marrow samples using immunophenotypic assessment of minimal residual disease. RESULTS: The median frequency of residual leukemic cells after the first cycle of chemotherapy was 8.5-fold higher in patients with FLT3-ITD than in those with wild type FLT3. Such a difference translates into differences in survival, even if other potentially outcome-modulating mutations, such as NPM1, KIT, NRAS, KRAS, FLT3-exon 20 and PTPN11 are included in the analysis. CONCLUSIONS: This study shows that it could be possible to study the efficacy of FLT3 inhibitors using the level of minimal residual disease as a short-term end-point.
