ABSTRACT
OBJECTIVES: To compare the efficacy of venetoclax-azacitidine (VEN-AZA) with AZA in the real-life for patients with first relapsed or refractory acute myeloid leukaemia (R/R AML). METHODS: We retrospectively analysed R/R AML patients treated with VEN-AZA at the Institut Paoli Calmettes between September 2020 and February 2022. We compared them to a historical cohort of patients treated with AZA between 2010 and 2021. RESULTS: Thirty-five patients treated with VEN-AZA were compared with 140 patients treated with AZA. There were more favourable cytogenetics (25.7% vs. 8.6%; p = 0.01) and less FLT3-ITD mutated AML (8.8% vs. 25.5%; p = .049) in the VEN-AZA group. The overall 30-day mortality rate was 7.4% and the overall 90-day mortality was 20%, with no difference between the groups. The complete remission rate was 48.6% in the VEN-AZA group versus 15% (p < .0001). The composite complete response rate was 65.7% in the VEN-AZA group versus 23.6% (p < .0001). OS was 12.8 months in the VEN-AZA group versus 7.3 months (p = 0.059). Patients with primary refractory AML, poor-risk cytogenetics, prior hematopoietic stem-cell transplantation (HSCT) and FLT3-ITD mutated AML had lower response and survival rates. CONCLUSION: VEN-AZA was associated with a better response rate and a longer survival than AZA monotherapy in AML patients who relapsed after or were refractory to intensive chemotherapy.
Subject(s)
Azacitidine , Bridged Bicyclo Compounds, Heterocyclic , Leukemia, Myeloid, Acute , Sulfonamides , Humans , Azacitidine/therapeutic use , Salvage Therapy , Retrospective Studies , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
Although complete remission (CR) is achieved in 50 to 70% of older fit patients with acute myeloid leukemia (AML), consolidation therapy in this age group remains challenging. In this retrospective study, we aimed to compare outcome in elderly patients treated with different post-remission modalities, including allogenic and autologous hematopoietic stem cell transplantation (HSCT), intensive chemotherapy, and standard-dose chemotherapy (repeated 1 + 5 regimen). We collected data of 441 patients ≥ 60 years in first CR from a single institution. Median age was 67 years. Sixty-one (14%) patients received allo-HSCT, 51 (12%) auto-HSCT, 70 (16%) intensive chemotherapy with intermediate- or high-dose cytarabine (I/HDAC), and 190 (43%) 1 + 5 regimen. Median follow-up was 6.5 years. In multivariate analysis, allo-HSCT, cytogenetics, and PS had a significant impact on OS and LFS. In spite of a more favorable-risk profile, the patients who received I/HDAC had no significantly better LFS as compared with patients treated with 1 + 5 (median LFS 8.8 months vs 10.6 months, p = 0.96). In transplanted patients, median LFS was 13.3 months for auto-HSCT and 25.8 months for allo-HSCT. Pre-transplant chemotherapy with I/HDAC had no effect on the outcome. Toxicity was significantly increased for both transplanted and non-transplanted patients treated with I/HDAC, with more units of blood and platelet transfusion and more time spent in hospitalization, but no higher non-relapse mortality. This study shows that post-remission chemotherapy intensification is not associated with significantly better outcome as compared with standard-dose chemotherapy in elderly patients for whom, overall results remain disappointing.
Subject(s)
Consolidation Chemotherapy , Leukemia, Myeloid, Acute/drug therapy , Aged , Aged, 80 and over , Allografts , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Blood Component Transfusion , Combined Modality Therapy , Cytarabine/administration & dosage , Cytarabine/adverse effects , Daunorubicin/administration & dosage , Daunorubicin/adverse effects , Disease-Free Survival , Female , Follow-Up Studies , Hematopoietic Stem Cell Transplantation , Humans , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute/therapy , Male , Middle Aged , Remission Induction , Retrospective Studies , Transplantation, Autologous , Treatment OutcomeSubject(s)
Leukemia, Erythroblastic, Acute , Mutation , Aged , Disease-Free Survival , Female , Humans , Leukemia, Erythroblastic, Acute/blood , Leukemia, Erythroblastic, Acute/classification , Leukemia, Erythroblastic, Acute/genetics , Leukemia, Erythroblastic, Acute/mortality , Male , Middle Aged , Survival Rate , World Health OrganizationSubject(s)
Biomarkers, Tumor/genetics , Chromosome Aberrations , High-Throughput Nucleotide Sequencing/methods , Leukemia, Erythroblastic, Acute/genetics , Mutation/genetics , Female , Humans , Leukemia, Erythroblastic, Acute/mortality , Leukemia, Erythroblastic, Acute/pathology , Male , Middle Aged , Neoplasm Staging , Prognosis , Survival RateSubject(s)
Adaptor Proteins, Signal Transducing/genetics , DNA Mutational Analysis , Leukemia, Myelomonocytic, Chronic/genetics , Phosphoproteins/genetics , Adult , Aged , Aged, 80 and over , Animals , Bone Marrow Cells/cytology , Cohort Studies , DNA-Binding Proteins/genetics , Down-Regulation , Exons , Female , Heterozygote , Humans , Male , Mice , Middle Aged , Mutation , Point Mutation , Protein Structure, Tertiary , RNA-Binding Proteins/genetics , Signal TransductionABSTRACT
The impact of ten-eleven-translocation 2 (TET2) mutations on response to azacitidine (AZA) in MDS has not been reported. We sequenced the TET2 gene in 86 MDS and acute myeloid leukemia (AML) with 20-30% blasts treated by AZA, that is disease categories wherein this drug is approved by Food and Drug Administration (FDA). Thirteen patients (15%) carried TET2 mutations. Patients with mutated and wild-type (WT) TET2 had mostly comparable pretreatment characteristics, except for lower hemoglobin, better cytogenetic risk and longer MDS duration before AZA in TET2 mutated patients (P=0.03, P=0.047 and P=0.048, respectively). The response rate (including hematological improvement) was 82% in MUT versus 45% in WT patients (P=0.007). Mutated TET2 (P=0.04) and favorable cytogenetic risk (intermediate risk: P=0.04, poor risk: P=0.048 compared with good risk) independently predicted a higher response rate. Response duration and overall survival were, however, comparable in the MUT and WT groups. In higher risk MDS and AML with low blast count, TET2 status may be a genetic predictor of response to AZA, independently of karyotype.
Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Azacitidine/therapeutic use , DNA-Binding Proteins/genetics , Leukemia, Myeloid, Acute/genetics , Mutation , Myelodysplastic Syndromes/genetics , Neoplasm Proteins/genetics , Proto-Oncogene Proteins/genetics , Aged , Aged, 80 and over , DNA Methylation/drug effects , DNA, Neoplasm/genetics , DNA-Binding Proteins/physiology , Dioxygenases , Disease-Free Survival , Female , Hemoglobins/analysis , Humans , Kaplan-Meier Estimate , Karyotyping , Leukemia, Myeloid, Acute/blood , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Leukocyte Count , Male , Middle Aged , Myelodysplastic Syndromes/blood , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/pathology , Neoplasm Proteins/physiology , Proto-Oncogene Proteins/physiology , Sequence Analysis, DNA , Treatment OutcomeSubject(s)
Isocitrate Dehydrogenase/genetics , Mutation/genetics , Myelodysplastic Syndromes/genetics , Myeloproliferative Disorders/genetics , Aged , Aged, 80 and over , Base Sequence , DNA-Binding Proteins/genetics , Dioxygenases , Humans , Janus Kinase 2/genetics , Middle Aged , Molecular Sequence Data , Myelodysplastic Syndromes/pathology , Myeloproliferative Disorders/pathology , Proto-Oncogene Proteins/geneticsSubject(s)
Myelodysplastic Syndromes/genetics , Chromosomes, Human, Pair 5 , DNA-Binding Proteins/genetics , Dioxygenases , Genes, p16 , Histone Demethylases , Humans , Mutation , Myelodysplastic Syndromes/etiology , Nuclear Proteins/genetics , Proto-Oncogene Proteins/genetics , Repressor Proteins/geneticsSubject(s)
Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Mutation/genetics , Nuclear Proteins/genetics , Repressor Proteins/genetics , Adult , Aged , Aged, 80 and over , Comparative Genomic Hybridization , Female , Humans , Karyotyping , Male , Middle Aged , Nucleophosmin , Oligonucleotide Array Sequence Analysis , Polymorphism, Genetic , Prognosis , Young Adult , fms-Like Tyrosine Kinase 3/genetics , ras Proteins/geneticsSubject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Mutation, Missense , NFI Transcription Factors/genetics , Neoplasm Proteins/genetics , Point Mutation , Polycythemia Vera/genetics , Sequence Deletion , Amino Acid Substitution , Base Sequence , Chromosomes, Human, Pair 1/genetics , Diagnostic Errors , Disease Progression , Female , Genes, Tumor Suppressor , Humans , Janus Kinase 2/genetics , Leukemia, Monocytic, Acute/genetics , Male , Middle Aged , Molecular Sequence Data , NFI Transcription Factors/chemistry , Neoplasm Proteins/chemistry , Polycythemia Vera/diagnosis , Protein Structure, Tertiary/genetics , Thrombocythemia, Essential/diagnosisSubject(s)
Gene Expression Profiling , Gene Expression Regulation, Leukemic/genetics , Leukemia, Myelomonocytic, Chronic/diagnosis , Leukemia, Myelomonocytic, Chronic/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Leukocytes/cytology , Male , Middle Aged , Models, Genetic , Mutation , Oligonucleotide Array Sequence AnalysisABSTRACT
OBJECTIVES: Myelodysplastic syndromes (MDS) are a group of clonal hematologic disorder, which combine ineffective hematopoiesis and evolution to acute myeloid leukemia. Significant progress has been made in the understanding of the disease pathogenesis, diagnostics and classification. Promising new agents and innovative therapeutic strategies are currently used. In this article we will review these achievements and their impact on the treatment of MDS. CURRENT KNOWLEDGE AND KEY POINTS: The pathogenesis of MDS involves abnormalities of the MDS clone itself such as abnormal apoptosis, signalling or epigenetic regulation and abnormalities of the microenvironment such as immune deregulation or increased angiogenesis, which represent potential therapeutic targets. There is currently no standard treatment for MDS and allogeneic stem cell transplantation remains the only curative strategy. However, besides conventional chemotherapy and growth factors, new agents including hypomethylating agents, antiangiogenic drugs, immune modulatory agents have proved effective. FUTURE PROSPECTS AND PROJECTS: The interesting results achieved with these new agents show that it is necessary to continue investigation in order to improve therapeutic strategies in MDS.