... Ivosidenib + azacitidin, nový standard v léčbě AML s mutací IDH1 u pacientů nevhodných k intenzivní terapii ... ... -- Výsledky s ivosidenibem + azacitidinem potvrzeny v reálné praxi -- Přínos IVO + HMA v závislosti ...
- Keywords
- refrakterní akutní myeloidní leukémie, Ivosidenib,
- MeSH
- Leukemia, Myeloid, Acute * diagnosis drug therapy MeSH
- Anemia, Aplastic etiology MeSH
- Azacitidine pharmacology therapeutic use MeSH
- Transplantation, Homologous adverse effects MeSH
- Remission Induction MeSH
- Isocitrate Dehydrogenase * antagonists & inhibitors therapeutic use MeSH
- Drug Therapy, Combination MeSH
- Middle Aged MeSH
- Humans MeSH
- Mutation genetics drug effects MeSH
- Bone Marrow Examination methods MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
The backbone of therapy for elderly patients with myelodysplastic syndromes and acute myeloid leukemia consists of hypomethylating agents 5-aza-2'-deoxycytidine (DAC) and 5-azacytidine (AZA). However, resistance frequently emerges during treatment. To investigate the mechanisms of resistance, we generated DAC-resistant variants of the acute myeloid leukemia cell lines, MOLM-13 and SKM-1, through their prolonged cultivation in increasing concentrations of DAC. The resistant cell variants, MOLM-13/DAC and SKM-1/DAC, exhibited cross-resistance to cytarabine and gemcitabine, but remained sensitive to AZA. Existing studies have suggested that the loss of deoxycytidine kinase (DCK) may play an important role in DAC resistance. DCK is critical for DAC activation, but the precise mechanisms of its downregulation remain incompletely understood. We identified a novel point mutation (A180P) in DCK, which results in acquired DAC resistance. Although the DCK mRNA was actively transcribed, the mutant protein was not detected in DAC-resistant cells. The transfection of HEK293 cells with the mutant DCK, combined with proteasomal inhibition, revealed rapid proteasomal degradation, establishing a mechanistic link between the A180P mutation and DCK loss, not previously described. This highlights the importance of also evaluating DCK at the protein and/or enzymatic activity levels in patients. The loss of functional DCK impairs the phosphorylation of deoxynucleosides, conferring resistance to DAC, gemcitabine, and cytarabine, but AZA, phosphorylated by uridine-cytidine kinase, remains effective and may represent a therapeutic alternative for patients with acquired DAC resistance.
- MeSH
- Leukemia, Myeloid, Acute * genetics drug therapy MeSH
- Azacitidine * pharmacology analogs & derivatives MeSH
- Drug Resistance, Neoplasm * genetics drug effects MeSH
- Cytarabine pharmacology MeSH
- Decitabine * pharmacology MeSH
- Deoxycytidine analogs & derivatives pharmacology MeSH
- Deoxycytidine Kinase * genetics metabolism MeSH
- HEK293 Cells MeSH
- Humans MeSH
- Mutation MeSH
- Cell Line, Tumor MeSH
- Antimetabolites, Antineoplastic * pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Leukemia, Myeloid, Acute * drug therapy MeSH
- Azacitidine therapeutic use MeSH
- Molecular Targeted Therapy * methods MeSH
- Isocitrate Dehydrogenase antagonists & inhibitors MeSH
- Clinical Trials, Phase III as Topic MeSH
- Congresses as Topic MeSH
- Humans MeSH
- Antineoplastic Agents therapeutic use MeSH
- Antineoplastic Combined Chemotherapy Protocols therapeutic use MeSH
- Pyridines therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Newspaper Article MeSH
- News MeSH
Myelodysplastic syndromes (MDS) are myeloid malignancies with heterogeneous genotypes and phenotypes, characterized by ineffective haematopoiesis and a high risk of progression towards acute myeloid leukaemia (AML). Prognosis for patients treated with hypomethylating agents (HMAs), as is azacytidine, the main drug used as frontline therapy for MDS is mostly based on cytogenetics and next generation sequencing (NGS) of the initial myeloid clone. Although the critical influence of the epigenetic landscape upon cancer cells survival and development as well on tumour environment establishment is currently recognized and approached within current clinical practice in MDS, the heterogenous response of the patients to epigenetic therapy is suggesting a more complex mechanism of action, as is the case of RNA methylation. In this sense, the newly emerging field of epitranscriptomics could provide a more comprehensive perspective upon the modulation of gene expression in malignancies, as is the proof-of-concept of MDS. We initially did RNA methylation sequencing on MDS patients (n = 6) treated with azacytidine and compared responders with non-responders. Afterwards, the genes identified were assessed in vitro and afterwards validated on a larger cohort of MDS patients treated with azacytidine (n = 58). Our data show that a more accurate prognosis could be based on analysing the methylome and thus we used methylation sequencing to differentially split high-grade MDS patients with identical demographical and cytogenetic features, between azacytidine responders and non-responders.
- MeSH
- Azacitidine * pharmacology therapeutic use MeSH
- Epigenesis, Genetic drug effects MeSH
- Middle Aged MeSH
- Humans MeSH
- RNA Methylation MeSH
- DNA Methylation * drug effects MeSH
- Myelodysplastic Syndromes * genetics drug therapy pathology MeSH
- Prognosis MeSH
- Antimetabolites, Antineoplastic therapeutic use pharmacology MeSH
- Sequence Analysis, RNA MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Gene Expression Profiling MeSH
- Transcriptome genetics drug effects MeSH
- High-Throughput Nucleotide Sequencing MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Our observational study analysed fungal infection frequency within cohorts with versus without antifungal prophylaxis (AFP) among newly diagnosed first-line venetoclax and azacitidine (VEN + AZA)-treated acute myeloid leukaemias in Czech, Austrian and Slovak haematology centres. Among 186 patients, 85 (46%) received antifungal prophylaxis, while 101 (54%) received no prophylaxis. Fungal infections occurred in 1/85 patients with prophylaxis (1%) and 5/101 patients without prophylaxis (5%) (p = 0.222). No significant difference was recorded between cohorts with and without AFP in terms of death rate (p = 0.296) and overall survival (p = 0.844). In conclusion, most infections were not severe, developing during the first treatment-cycle and did not affect patients' overall outcome.
- MeSH
- Leukemia, Myeloid, Acute * drug therapy complications MeSH
- Antifungal Agents * therapeutic use administration & dosage MeSH
- Azacitidine * administration & dosage therapeutic use MeSH
- Bridged Bicyclo Compounds, Heterocyclic * administration & dosage therapeutic use MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Mycoses * prevention & control etiology MeSH
- Antineoplastic Combined Chemotherapy Protocols * adverse effects therapeutic use administration & dosage MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Sulfonamides * administration & dosage therapeutic use MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Observational Study MeSH
- MeSH
- Leukemia, Myeloid, Acute * diagnosis drug therapy MeSH
- Anthracyclines therapeutic use MeSH
- Azacitidine therapeutic use MeSH
- Cytarabine therapeutic use MeSH
- Induction Chemotherapy methods MeSH
- Humans MeSH
- Antibodies, Monoclonal therapeutic use MeSH
- Antineoplastic Agents therapeutic use MeSH
- Antineoplastic Combined Chemotherapy Protocols therapeutic use MeSH
- Recurrence MeSH
- Maintenance Chemotherapy methods MeSH
- Check Tag
- Humans MeSH
- Keywords
- ivosidenib, azacitidine,
- MeSH
- Leukemia, Myeloid, Acute * diagnosis drug therapy genetics MeSH
- Molecular Diagnostic Techniques methods MeSH
- Genetic Testing MeSH
- Enzyme Inhibitors pharmacology therapeutic use MeSH
- Humans MeSH
- Antineoplastic Combined Chemotherapy Protocols MeSH
- Randomized Controlled Trials as Topic MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
Akutní myeloidní leukemie je nejčastějším typem akutní leukemie u dospělých. Dlouhodobé výsledky terapie zůstávají u většiny nemocných neuspokojivé. Pokračující výzkum procesu maligní transformace hematopoetické kmenové buňky poodhalil nové mutace, které představují atraktivní cíle pro moderní léky. Ivosidenib, inhibitor mutované izocitrátdehydrogenázy 1 (IDH1), prokázal v kombinaci s azacitidinem povzbudivé výsledky u nemocných s dříve neléčenou akutní myeloidní leukemií s IDH1 mutací. Přehledový článek diskutuje aktuální možnosti použití ivosidenibu u nemocných s akutní myeloidní leukemií v České republice.
Acute myeloid leukemia is the most common type of acute leukemia in adults. The long-term treatment results remain unsatisfactory for the majority of patients. Ongoing research into the process of malignant transformation of the hematopoietic stem cells has revealed new mutations that represent attractive targets for modern drugs. Ivosidenib, an inhibitor of mutated isocitrate dehydrogenase 1 (IDH1), has shown encouraging results in combination with azacitidine in patients with previously untreated acute myeloid leukemia with an IDH1 mutation. The review discusses the current possibilities of using ivosidenib in patients with acute myeloid leukemia in the Czech Republic.
- Keywords
- ivosidenib,
- MeSH
- Leukemia, Myeloid, Acute * drug therapy MeSH
- Enzyme Inhibitors pharmacology therapeutic use MeSH
- Humans MeSH
- Antineoplastic Agents pharmacology therapeutic use MeSH
- Antineoplastic Combined Chemotherapy Protocols MeSH
- Randomized Controlled Trials as Topic MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
Venetoclax-azacitidine is approved for treatment of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy based on the interim overall survival (OS) analysis of the VIALE-A study (NCT02993523). Here, long-term follow-up is presented to address survival benefit and long-term outcomes with venetoclax-azacitidine. Patients with newly diagnosed AML who were ineligible for intensive chemotherapy were randomized 2:1 to receive venetoclax-azacitidine or placebo-azacitidine. OS was the primary endpoint; complete remission with/without blood count recovery (CR/CRi) was a key secondary endpoint. This final analysis was conducted when 100% of the predefined 360 OS events occurred. In VIALE-A, 431 patients were enrolled to venetoclax-azacitidine (n = 286) or placebo-azacitidine (n = 145). At 43.2 months median follow-up, median OS was 14.7 months (95% confidence interval [CI], 12.1-18.7) with venetoclax-azacitidine, and 9.6 months (95% CI, 7.4-12.7) with placebo-azacitidine (hazard ratio, 0.58 [95% CI, 0.47-0.72], p < .001); the estimated 24-month OS rate was 37.5% and 16.9%, respectively. Median OS for patients with IDH1/2 mutations and those with measurable residual disease responses was reached in this final analysis. CR/CRi rate was similar to interim analysis. Any-grade hematologic and gastrointestinal adverse events were most common in venetoclax-azacitidine and placebo-azacitidine arms, including thrombocytopenia (47% and 42%) and neutropenia (43% and 29%). No new safety signals were identified. Long-term efficacy and safety confirm venetoclax-azacitidine is an improvement in standard-of-care for patients with AML who are not eligible for intensive chemotherapy because of advanced age or comorbidities.
- MeSH
- Leukemia, Myeloid, Acute * drug therapy MeSH
- Azacitidine adverse effects MeSH
- Bridged Bicyclo Compounds, Heterocyclic * MeSH
- Humans MeSH
- Follow-Up Studies MeSH
- Neutropenia * MeSH
- Antineoplastic Combined Chemotherapy Protocols adverse effects MeSH
- Sulfonamides * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Randomized Controlled Trial MeSH
