Assuntos
Glicina , Síndromes Mielodisplásicas , Piridinas , Humanos , Síndromes Mielodisplásicas/tratamento farmacológico , Piridinas/uso terapêutico , Piridinas/farmacologia , Glicina/análogos & derivados , Glicina/uso terapêutico , Glicina/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacosAssuntos
Citometria de Fluxo , Mutação , Síndromes Mielodisplásicas , Humanos , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/tratamento farmacológico , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Células Precursoras Eritroides/patologia , Células Precursoras Eritroides/metabolismo , Hematínicos/uso terapêutico , Idoso de 80 Anos ou mais , AdultoRESUMO
Myeloid sarcoma (MS) occurs in patients with acute myeloid leukemia (AML). In rare cases, MS can represent a form of blast transformation in patients with myeloproliferative neoplasms (MPN), myelodysplastic neoplasms (MDS), or MDS/MPN. The most frequent chromosomal alterations in MS are t(8;21) or inv(16), with other alterations being reported. Cases of MS in Janus kinase 2 (JAK2)-positive MDS with fibrosis are exceedingly rare. Here, we describe such a case. To the best of our knowledge, this is the first report of a JAK2 V617F mutation-positive MDS case occurring concurrently with MS involving the posterior aspect of the left seventh rib. No clear association has been previously demonstrated between the intramedullary AML cytogenetics and extramedullary disease occurrence. Interestingly, samples from the intramedullary MDS and extramedullary mass in this patient presented the same JAK2 V617F mutation. Following a treatment regimen of azacitidine and venetoclax, the patient achieved complete remission. The chest CT scan showed that the seventh posterior rib mass disappeared. This case provides valuable information for the potential future treatment of this disease.
Assuntos
Janus Quinase 2 , Síndromes Mielodisplásicas , Sarcoma Mieloide , Humanos , Janus Quinase 2/genética , Sarcoma Mieloide/patologia , Sarcoma Mieloide/genética , Sarcoma Mieloide/tratamento farmacológico , Sarcoma Mieloide/diagnóstico , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/diagnóstico , Masculino , Mutação , Pessoa de Meia-Idade , Idoso , Fibrose , FemininoRESUMO
We describe a case of erythema induratum of Bazin (EIB) that presented recurrently on the extremities during treatment with anti-tuberculosis medications. The anti-tuberculosis medications were effective, so they were continued despite the occurrence of the EIB lesions, and those lesions disappeared 5 months after first appearing. EIB is currently considered a multifactorial disorder with many different causes, with tuberculosis being an example, and it is thought to be a hypersensitive immune response to Mycobacterium tuberculosis. The clinical manifestations may fluctuate depending on the immune response of the host. Our patient was affected with myelodysplastic syndrome, and we believe that this was a major factor that interfered with a normal immune response. This case illustrates the importance of providing intensive anti-tuberculosis treatment from the start, and in cases where EIB co-presents, to continue this treatment until the end, in order to prevent relapse.
Assuntos
Antituberculosos , Eritema Endurado , Síndromes Mielodisplásicas , Humanos , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/tratamento farmacológico , Eritema Endurado/tratamento farmacológico , Eritema Endurado/patologia , Antituberculosos/uso terapêutico , Recidiva , Masculino , Idoso , FemininoRESUMO
RATIONAL: Patients with gastric cancer show a relatively low incidence of developing secondary myelodysplastic syndrome (MDS). PATIENT CONCERNS: A 60-year-old man was admitted because of pain and discomfort in the upper abdomen and intermittent abdominal pain. DIAGNOSES: Ulcerative moderately poorly differentiated adenocarcinoma (pT2N2M0G3, stage IIB) and MDS. INTERVENTIONS: The patient underwent chemotherapy with oxaliplatin (OXP, intravenously guttae on day 1) plus capecitabine (CAP, bis in die orally on day 1-14). The patient developed degree III myelosuppression after OXP plus CAP chemotherapy and MDS was subsequently confirmed by diagnosis of the bone marrow biopsy. Temporary but significant hematological improvements were observed after the patient received corresponding treatment, which helped achieve remission and improve pancytopenia. OUTCOMES: The patient presented partial remission after corresponding treatment and no other complications have been recorded. LESSONS: Acute MDS is an unusual adverse effect induced by OXP plus CAP chemotherapy. It is urgent to suggest implementing a supplementary assessment or examination for patients receiving these therapies in future cases.
Assuntos
Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Capecitabina , Síndromes Mielodisplásicas , Oxaliplatina , Neoplasias Gástricas , Humanos , Síndromes Mielodisplásicas/induzido quimicamente , Síndromes Mielodisplásicas/tratamento farmacológico , Capecitabina/efeitos adversos , Capecitabina/administração & dosagem , Capecitabina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/tratamento farmacológico , Oxaliplatina/efeitos adversos , Oxaliplatina/uso terapêutico , Oxaliplatina/administração & dosagem , Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/uso terapêutico , Compostos Organoplatínicos/administração & dosagemRESUMO
BACKGROUND: Mouse double minute-2 homolog (MDM2) plays a key role in downregulating p53 activity in hematologic malignancies, and its overexpression is associated with poor outcomes. METHODS: This phase 1 study assessed the safety and efficacy of different dosing regimens of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine (AZA) in patients with relapsed or refractory acute myeloid leukemia or high-risk myelodysplastic syndromes. RESULTS: Seventy-four patients (monotherapy, n = 57; milademetan-AZA combination, n = 17) were treated. The maximum tolerated dose of milademetan was 160 mg once daily given for the first 14-21 days of 28-day cycles as monotherapy and on Days 5-14 in combination with AZA. Dose-limiting toxicities were gastrointestinal, fatigue, or renal/electrolyte abnormalities. Treatment-emergent adverse events related to milademetan occurred in 82.5% and 64.7% of participants in the monotherapy and AZA combination arms, respectively. Two participants (4.2%) in the monotherapy arm achieved complete remission (CR), and 1 (2.1%) achieved CR with incomplete blood count recovery (CRi). Two participants (13.3%) achieved CRi in the combination arm. New TP53 mutations, detected only during milademetan monotherapy, were found pre-existing below standard detection frequency by droplet digital polymerase chain reaction. INTERPRETATION: Milademetan was relatively well tolerated in this population; however, despite signals of activity, clinical efficacy was minimal.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Leucemia Mieloide Aguda , Dose Máxima Tolerável , Síndromes Mielodisplásicas , Proteínas Proto-Oncogênicas c-mdm2 , Humanos , Masculino , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Azacitidina/uso terapêutico , Feminino , Idoso , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso de 80 Anos ou mais , Síndromes Mielodisplásicas/tratamento farmacológico , Adulto , Resultado do Tratamento , Carbolinas , Compostos Heterocíclicos de 4 ou mais AnéisRESUMO
Etiological factors involved in myelodysplastic syndrome (MDS) include immunologic, oxidative stress and inflammatory factors, among others, and these are targets for microRNAs (miRNs). Here, we evaluated whether some miRNs may affect tumor development comparing untreated and 5-azacitidine (5-AZA) MDS-treated patients. Peripheral blood samples were collected from 20 controls and 24 MDS patients, and selected miRNs related to redox balance and inflammation (inflamma-miRs), including miR-18a, miR-21, miR-34a and miR-146a, were isolated and measured by quantitative real-time polymerase chain reaction (qRTPCR). A differential expression profile of miRNs was detected in untreated MDS patients and the 5-AZA group. Inflammation increases miRNs and, specifically, miR-18a, miR-21 and miR-34a were significantly overexpressed in untreated MDS, compared to controls. However, we did not observe any miRN profile alteration during the progression of the disease. On the other hand, 5-AZA treatment tends to restore miRN expression levels. Relating to prognostic risk factors, high-risk MDS groups (high Revised International Prognostic Scoring System (IPSS-R), high cytogenetic risk, high molecular risk (HMR) mutations) tended to be related with higher expression levels of miR-18a and miR-34a. Higher miRN expression is correlated with lower glutathione peroxidase activity, while they are related with a higher profile of pro-inflammatory cytokines (IL-2, IL-6, IL-8, TNF-α). Although our study was limited by the low number of MDS patients included, we identified miRN deregulation involved in MDS development that could regulate redox sensors and inflammatory responses. Finally, 5-AZA treatment is related with lower miRN expression levels in MDS patients.
Assuntos
Inflamação , MicroRNAs , Síndromes Mielodisplásicas , Humanos , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/tratamento farmacológico , MicroRNAs/genética , MicroRNAs/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Inflamação/genética , Azacitidina/farmacologia , Adulto , Idoso de 80 Anos ou mais , Estresse Oxidativo , Estudos de Casos e Controles , PrognósticoRESUMO
VEXAS syndrome is a recently described autoinflammatory syndrome caused by the somatic acquisition of UBA1 mutations in myeloid precursors and is frequently associated with hematologic malignancies, chiefly myelodysplastic syndromes. Disease presentation can mimic several rheumatologic disorders, delaying the diagnosis. We describe a case of atypical presentation resembling late-onset axial spondylarthritis, later progressing to a systemic inflammatory syndrome with chondritis, cutaneous vasculitis, and transfusion-dependent anemia, requiring high doses of steroids. Ruxolitinib was used as the first steroid-sparing strategy without response. However, azacitidine showed activity in controlling both inflammation and the mutant clone. This case raises the question of whether azacitidine's anti-inflammatory effects are dependent on or independent of clonal control. We discuss the potential relevance of molecular remission in VEXAS syndrome and highlight the importance of a multidisciplinary team for the care of such complex patients.
Assuntos
Azacitidina , Sacroileíte , Enzimas Ativadoras de Ubiquitina , Humanos , Azacitidina/uso terapêutico , Sacroileíte/tratamento farmacológico , Sacroileíte/diagnóstico , Sacroileíte/genética , Enzimas Ativadoras de Ubiquitina/genética , Mutação , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/diagnósticoRESUMO
BACKGROUND: The aim of this study was to evaluate the therapeutic regimen of a patient with myelodysplastic syndrome (MDS) who developed invasive fungal infections caused by drug-resistant Candida tropicalis after chemotherapy and to investigate the effect of drug treatment. METHODS: We referred to the Diagnostic Criteria and Treatment Principles of invasive fungal diseases in patients with hematological diseases and malignant tumors (2013, fourth revised edition) and the Expert Consensus on Clinical Application of Posaconazole (2022 Edition). In addition, the drug treatment regimens of drug-resistant Candida tropicalis were reviewed. The doctors in charge were involved in the drug treatment process, and the ra-tional drug use was selected according to evidence-based medicine. RESULTS: After 4 months of use, the nodules around the body disappeared, and there was no further fever during follow-up. After 6 months of use, posaconazole was discontinued, and the patient continued to follow-up for 1 month without further fever or nodules. CONCLUSIONS: The combination of posaconazole, amphotericin B liposome, and micafungin is effective in the treatment of fluconazole-resistant Candida tropicalis infection.
Assuntos
Anfotericina B , Antifúngicos , Farmacorresistência Fúngica , Síndromes Mielodisplásicas , Triazóis , Humanos , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/complicações , Antifúngicos/uso terapêutico , Triazóis/uso terapêutico , Triazóis/administração & dosagem , Anfotericina B/uso terapêutico , Candida tropicalis/efeitos dos fármacos , Masculino , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/diagnóstico , Infecções Fúngicas Invasivas/microbiologia , Micafungina/uso terapêutico , Micafungina/administração & dosagem , Idoso , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Myelodysplastic syndrome (MDS) is a heterogeneous spectrum of clonal hematopoietic disorders with varying degrees of cytopenia and morphologic dysplasia. The hemoglobin, albumin, lymphocyte, and platelet (HALP) score is a prognostic marker in several types of malignant tumors. Prognostic value of HALP score remains unclear for MDS. To determine the prognostic value of baseline HALP score in MDS. We retrospectively analyzed data from 130 newly diagnosed MDS patients evaluated and classified under HALP score. By the receiver operating characteristic (ROC) analysis, the optimal cut-off value of HALP was > 67.5 in predicting mortality. Patients were divided into two groups: with low and high HALP scores, and the characteristics were compared between both groups. Patients' median age was 68 (19-84) years, and 79 (60.8%) were male. Higher HALP score was detected in MDS patients with intermediate-risk under IPSS score, and at high and very high risks under IPSS-R score, and those receiving azacitidine (AZA) treatment. The survival rates of those with a HALP score > 67.5 were significantly lower than those with low HALP score at 17.77 ± 3.98 (median ± SE) (p < 0.001). The 3-, 5- and 10-years survival rates of individuals with HALP scores > 67.5 were found as 25, 18, and 11%, respectively. Median overall survival (OS) was also determined as 33.10 (95% CI 16.34-49.88) months by the Kaplan-Meier method. HALP score has shown an ability to be a useful prognostic biomarker in various cancers, including MDS. The meaningful cut-off value of HALP is disease-specific and largely study-specific. High HALP score is associated with unfavorable clinicopathological characteristics. Also, it may be useful in predicting OS and mortality of MDS.
Assuntos
Síndromes Mielodisplásicas , Humanos , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/patologia , Masculino , Idoso , Feminino , Pessoa de Meia-Idade , Prognóstico , Idoso de 80 Anos ou mais , Adulto , Estudos Retrospectivos , Hemoglobinas/análise , Hemoglobinas/metabolismo , Adulto Jovem , Curva ROC , Plaquetas/patologia , Linfócitos/patologia , Contagem de PlaquetasRESUMO
BACKGROUND: As new treatment options for patients with higher-risk myelodysplastic syndromes are emerging, identification of prognostic markers for hypomethylating agent (HMA) treatment and understanding mechanisms of their delayed and short-term responses are essential. Early fetal hemoglobin (HbF) induction has been suggested as a prognostic indicator for decitabine-treated patients. Although epigenetic mechanisms are assumed, responding patients' epigenomes have not been thoroughly examined. We aimed to clarify HbF kinetics and prognostic value for azacytidine treated patients, as well as the epigenetic landscape that might influence HbF re-expression and its clinical relevance. RESULTS: Serial HbF measurements by high-performance liquid chromatography (n = 20) showed induction of HbF only among responders (p = 0.030). Moreover, HbF increase immediately after the first azacytidine cycle demonstrated prognostic value for progression-free survival (PFS) (p = 0.032, HR = 0.19, CI 0.24-1.63). Changes in methylation patterns were revealed with methylated DNA genome-wide sequencing analysis (n = 7) for FOG-1, RCOR-1, ZBTB7A and genes of the NuRD-complex components. Targeted pyrosequencing methodology (n = 28) revealed a strong inverse correlation between the degree of γ-globin gene (HBG2) promoter methylation and baseline HbF levels (p = 0.003, rs = - 0.663). A potential epigenetic mechanism of HbF re-expression in azacytidine responders was enlightened by targeted methylation analysis, through hypomethylation of site -53 of HBG2 promoter (p = 0.039, rs = - 0.504), which corresponds to MBD2-NuRD binding site, and to hypermethylation of the CpG326 island of ZBTB7A (p = 0.05, rs = 0.482), a known HbF repressor. These changes were associated to blast cell clearance (pHBG2 = 0.011, rs = 0.480/pZBTB7A = 0.026, rs = 0.427) and showed prognostic value for PFS (pZBTB7A = 0.037, HR = 1.14, CI 0.34-3.8). CONCLUSIONS: Early HbF induction is featured as an accessible prognostic indicator for HMA treatment and the proposed potential epigenetic mechanism of HbF re-expression in azacytidine responders includes hypomethylation of the γ-globin gene promoter region and hypermethylation of the CpG326 island of ZBTB7A. The association of these methylation patterns with blast clearance and their prognostic value for PFS paves the way to discuss in-depth azacytidine epigenetic mechanism of action.
Assuntos
Azacitidina , Metilação de DNA , Epigênese Genética , Hemoglobina Fetal , Síndromes Mielodisplásicas , Humanos , Hemoglobina Fetal/genética , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Azacitidina/farmacologia , Feminino , Masculino , Idoso , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/genética , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Prognóstico , Idoso de 80 Anos ou mais , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Antimetabólitos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/farmacologiaRESUMO
While myelodysplastic syndromes with del(5q) (del(5q) MDS) comprises a well-defined hematological subgroup, the molecular basis underlying its origin remains unknown. Using single cell RNA-seq (scRNA-seq) on CD34+ progenitors from del(5q) MDS patients, we have identified cells harboring the deletion, characterizing the transcriptional impact of this genetic insult on disease pathogenesis and treatment response. Interestingly, both del(5q) and non-del(5q) cells present similar transcriptional lesions, indicating that all cells, and not only those harboring the deletion, may contribute to aberrant hematopoietic differentiation. However, gene regulatory network (GRN) analyses reveal a group of regulons showing aberrant activity that could trigger altered hematopoiesis exclusively in del(5q) cells, pointing to a more prominent role of these cells in disease phenotype. In del(5q) MDS patients achieving hematological response upon lenalidomide treatment, the drug reverts several transcriptional alterations in both del(5q) and non-del(5q) cells, but other lesions remain, which may be responsible for potential future relapses. Moreover, lack of hematological response is associated with the inability of lenalidomide to reverse transcriptional alterations. Collectively, this study reveals transcriptional alterations that could contribute to the pathogenesis and treatment response of del(5q) MDS.
Assuntos
Antígenos CD34 , Deleção Cromossômica , Cromossomos Humanos Par 5 , Células-Tronco Hematopoéticas , Lenalidomida , Síndromes Mielodisplásicas , Análise de Célula Única , Humanos , Lenalidomida/farmacologia , Lenalidomida/uso terapêutico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/metabolismo , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Antígenos CD34/metabolismo , Cromossomos Humanos Par 5/genética , Masculino , Feminino , Idoso , Redes Reguladoras de Genes/efeitos dos fármacos , Pessoa de Meia-Idade , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Transcriptoma , Idoso de 80 Anos ou mais , RNA-Seq , Perfilação da Expressão GênicaRESUMO
In patients with lower-risk myelodysplastic syndromes/neoplasms (MDS), response to first-line therapy is limited and transient. The MATTERHORN randomized, double-blind, phase 3 trial evaluated roxadustat versus placebo for patients with transfusion-dependent, lower-risk MDS. Eligible patients had very low-, low-, or intermediate-risk MDS with or without prior erythropoiesis-stimulating agent treatment, and a transfusion burden of 1-4 packed red blood cell (pRBC) units every 8 weeks (Q8W). Patients were randomized (3:2) to oral roxadustat (2.5 mg/kg) or placebo, both three times weekly, with best supportive care. Primary efficacy endpoint was transfusion independence (TI) for ≥56 days within 28 weeks (TI responders). MATTERHORN was terminated due to interim analysis outcomes not meeting statistical significance. In total, 272 patients were screened, and 140 patients were enrolled (82, roxadustat, and 58, placebo). At final analysis, 38/80 (47.5%) patients and 19/57 (33.3%) in the roxadustat and placebo arms, respectively, were TI responders (p = .217). A greater percentage of patients in the roxadustat arm with a transfusion burden of ≥2 pRBC units Q4W were TI responders (36.1%; 13/36) compared with the placebo arm (11.5%; 3/26; p-nominal = .047). The seven on-study deaths (4, roxadustat, and 3, placebo) were considered unrelated to treatment. Three roxadustat patients progressed to acute myeloid leukemia. Despite MATTERHORN not meeting its primary endpoint, a numerically higher TI rate was achieved with roxadustat treatment compared with placebo. Further analyses are needed to confirm the MDS patient subgroups deriving clinical benefit from this novel treatment.
Assuntos
Glicina , Isoquinolinas , Síndromes Mielodisplásicas , Humanos , Síndromes Mielodisplásicas/tratamento farmacológico , Idoso , Masculino , Método Duplo-Cego , Feminino , Isoquinolinas/uso terapêutico , Isoquinolinas/administração & dosagem , Pessoa de Meia-Idade , Glicina/análogos & derivados , Glicina/uso terapêutico , Glicina/administração & dosagem , Idoso de 80 Anos ou mais , Resultado do Tratamento , Adulto , Transfusão de EritrócitosRESUMO
DNA methyltransferase inhibitors (DNMTi), most commonly cytidine analogs, are compounds that decrease 5'-cytosine methylation. DNMTi are used clinically based on the hypothesis that cytosine demethylation will lead to re-expression of tumor suppressor genes. 5-Aza-4'-thio-2'-deoxycytidine (Aza-TdCyd or ATC) is a recently described thiol-substituted DNMTi that has been shown to have anti-tumor activity in solid tumor models. In this study, we investigated the therapeutic potential of ATC in a murine transplantation model of myelodysplastic syndrome. ATC treatment led to the transformation of transplanted wild-type bone marrow nucleated cells into lymphoid leukemia, and healthy mice treated with ATC also developed lymphoid leukemia. Whole-exome sequencing revealed 1,000 acquired mutations, almost all of which were C>G transversions in a specific 5'-NCG-3' context. These mutations involved dozens of genes involved in human lymphoid leukemia, such as Notch1, Pten, Pax5, Trp53, and Nf1. Human cells treated in vitro with ATC showed 1,000 acquired C>G transversions in a similar context. Deletion of Dck, the rate-limiting enzyme for the cytidine salvage pathway, eliminated C>G transversions. Taken together, these findings demonstrate a highly penetrant mutagenic and leukemogenic phenotype associated with ATC. Significance: Treatment with a DNA methyltransferase inhibitor generates a distinct mutation signature and triggers leukemic transformation, which has important implications for the research and clinical applications of these inhibitors.
Assuntos
Azacitidina , Leucemia-Linfoma Linfoblástico de Células Precursoras , Animais , Camundongos , Humanos , Azacitidina/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Metilação de DNA/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Decitabina/farmacologia , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Camundongos Endogâmicos C57BLRESUMO
Hypomethylating therapies using decitabine or azacitidine are actively investigated to treat acute myeloid leukemia, myelodysplastic syndromes, as maintenance therapy after allogenic stem cell transplant and hemoglobinopathies. The therapeutic mechanism is to de-repress genes that have been turned off through oncogenesis or development via methylation. The therapy can be non-cytotoxic at low dosage, sparing healthy stem cells and operating on committed precursors. Because the methods of determining maximum tolerated dose are not well suited to this paradigm, and because the mechanism of action, which is depletion of DNA methylase 1 (DNMT1), is complex and dependent on passing through a cell cycle, a pharmacodynamic assay that measures DNMT1 can inform clinical trials aimed at establishing and improving therapy. Herein, we provide an assay that measures DNMT1 relative levels in circulating T cells of peripheral blood.
Assuntos
Azacitidina , DNA (Citosina-5-)-Metiltransferase 1 , Metilação de DNA , Decitabina , Azacitidina/farmacologia , Humanos , Decitabina/farmacologia , Metilação de DNA/efeitos dos fármacos , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/genética , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêutico , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/metabolismoRESUMO
TP53 mutations are found in 5%-10% of de novo myelodysplastic syndrome (MDS) and AML cases. By contrast, in therapy related MDS and AML, mutations in TP53 are found in up to 30%-40% of patients. The majority of inactivating mutations observed in MDS and AML are missense mutations localized in a few prevalent hotspots. TP53 missense mutations together with truncating mutations or chromosomal loss of TP53 determine a loss-of-function effect on normal p53 function. Clonal expansion of TP53-mutant clones is observed under the selection pressure of chemotherapy or MDM2 inhibitor therapy. TP53-mutant clones are resistant to current chemotherapy, and when responses to treatment have been observed, they have correlated poorly with overall survival. The most heavily investigated and targeted agent for patients with TP53-mutant MDS and AML has been APR-246 (eprenetapopt) a p53 reactivator, in combination with azacitidine, but also in triplets with venetoclax. Despite positive results in phase II trials, a phase III trial did not confirm superior response or improved survival. Other agents, like magrolimab (anti-CD47 antibody), failed to demonstrate improved activity in TP53-mutant MDS and AML. Agents whose activity is not dependent on a functional apoptosis system like anti-CD123 antibodies or cellular therapies are in development and may hold promises. Delivering prognostic information in a dismal disease like TP53-mutated MDS and AML is particularly challenging. The physician should balance hope and realism, describing the trajectory of possible treatments and at the same time indicating the poor outcome, together with promoting adaptive coping in patients and elaborating on the nature of the disease.
Assuntos
Leucemia Mieloide Aguda , Mutação , Síndromes Mielodisplásicas , Proteína Supressora de Tumor p53 , Humanos , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Síndromes Mielodisplásicas/tratamento farmacológico , Proteína Supressora de Tumor p53/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/tratamento farmacológico , Terapia de Alvo MolecularRESUMO
Dysfunctional bone marrow (BM) endothelial progenitor cells (EPCs) with high levels of reactive oxygen species (ROS) are responsible for defective hematopoiesis in poor graft function (PGF) patients with acute leukemia or myelodysplastic neoplasms post-allotransplant. However, the underlying mechanism by which BM EPCs regulate their intracellular ROS levels and the capacity to support hematopoiesis have not been well clarified. Herein, we demonstrated decreased levels of peroxisome proliferator-activated receptor delta (PPARδ), a lipid-activated nuclear receptor, in BM EPCs of PGF patients compared with those with good graft function (GGF). In vitro assays further identified that PPARδ knockdown contributed to reduced and dysfunctional BM EPCs, characterized by the impaired ability to support hematopoiesis, which were restored by PPARδ overexpression. Moreover, GW501516, an agonist of PPARδ, repaired the damaged BM EPCs triggered by 5-fluorouracil (5FU) in vitro and in vivo. Clinically, activation of PPARδ by GW501516 benefited the damaged BM EPCs from PGF patients or acute leukemia patients in complete remission (CR) post-chemotherapy. Mechanistically, we found that increased expression of NADPH oxidases (NOXs), the main ROS-generating enzymes, may lead to elevated ROS level in BM EPCs, and insufficient PPARδ may trigger BM EPC damage via ROS/p53 pathway. Collectively, we found that defective PPARδ contributes to BM EPC dysfunction, whereas activation of PPARδ in BM EPCs improves their hematopoiesis-supporting ability after myelosuppressive therapy, which may provide a potential therapeutic target not only for patients with leukemia but also for those with other cancers.
Assuntos
Células Progenitoras Endoteliais , Hematopoese , PPAR delta , Espécies Reativas de Oxigênio , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Adulto Jovem , Células da Medula Óssea/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Células Progenitoras Endoteliais/metabolismo , Células Progenitoras Endoteliais/efeitos dos fármacos , Fluoruracila/farmacologia , Hematopoese/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/tratamento farmacológico , NADPH Oxidases/metabolismo , PPAR delta/metabolismo , PPAR delta/genética , Espécies Reativas de Oxigênio/metabolismo , Tiazóis/farmacologia , Proteína Supressora de Tumor p53/metabolismoRESUMO
OPINION STATEMENT: A majority of patients with lower-risk myelodysplastic syndrome (MDS) will present with or develop anemia. Anemia in MDS is associated with decreased quality of life and may correlate with decreased progression-free survival and overall survival. In this state of the art review we summarize current risk stratification approaches to identify lower-risk MDS (LR-MDS), the natural history of the disease, and meaningful clinical endpoints. The treatment landscape of LR-MDS with anemia is also rapidly evolving; we review the role of supportive care, erythropoietin stimulating agents, lenalidomide, luspatercept, hypomethylating agents (HMAs), and immunosuppressive therapy (IST) in the management of LR-MDS with anemia. In patients with deletion 5q (del5q) syndrome lenalidomide has both efficacy and durability of response. For patients without del5q who need treatment, the management approach is impacted by serum erythropoietin (EPO) level, SF3B1 mutation status, and ring sideroblast status. Given the data from the Phase III COMMANDS trial, we utilize luspatercept in those with SF3B1 mutation or ring sideroblasts that have an EPO level < 500 U/L; in patients without an SF3B1 mutation or ring sideroblasts there is equipoise between luspatercept and use of an erythropoietin stimulating agent (ESA). For patients who have an EPO level ≥ 500 U/L or have been previously treated there is not a clear standard of care. For those without previous luspatercept exposure it can be considered particularly if there is an SF3B1 mutation or the presence of ring sideroblasts. Other options include HMAs or IST; the Phase III IMERGE trial supports the efficacy of the telomerase inhibitor imetelstat in this setting and this may become a standard option in the future as well.
Assuntos
Anemia , Gerenciamento Clínico , Síndromes Mielodisplásicas , Humanos , Síndromes Mielodisplásicas/terapia , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/tratamento farmacológico , Anemia/etiologia , Anemia/diagnóstico , Anemia/terapia , Anemia/tratamento farmacológico , Resultado do Tratamento , Suscetibilidade a Doenças , Fatores de RiscoAssuntos
Anemia Aplástica , Soro Antilinfocitário , Triazóis , Humanos , Soro Antilinfocitário/uso terapêutico , Anemia Aplástica/tratamento farmacológico , Triazóis/uso terapêutico , Masculino , Feminino , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/complicações , Adulto , Pessoa de Meia-Idade , Antifúngicos/uso terapêutico , IdosoRESUMO
Objective: This study aimed to evaluate the efficacy and safety of venetoclax (VEN) combined with hypomethylating agents (HMA) in the treatment of higher-risk myelodysplastic syndromes (HR-MDS) and analyze the factors influencing their therapeutic effect. Methods: The clinical data of 83 patients with HR-MDS who were diagnosed at the First Affiliated Hospital of Zhengzhou University between November 2019 and May 2023 were retrospectively analyzed. All patients were treated with VEN combined with HMA. The Kaplan-Meier method was used to depict the survival curves, and the log-rank test was used to compare survival between the groups. Results: The median age was 57 (15-82) years old, and 51 patients (61.4%) were male. Forty-five patients (54.2%) were initially treated with HMA, 23 (27.7%) received ≤4 cycles of HMA, and 15 (18.1%) demonstrated HMA failure. At the median follow-up of 10.3 (0.6-34.4) months, the overall response rate (ORR) was 62.7% (52/83), including 18 patients (21.7%) with a complete response (CR), 14 (16.9%) with a bone marrow CR (mCR) with hematological improvement, and 20 (24.1%) with a mCR. The ORR of patients with initial treatment, ≤4 HMA cycles, and HMA failure were 66.7%, 60.9%, and 53.3%, respectively (P=0.641). The median overall survival time was 14.6 (95% CI 7.2-22.0) months, and the median progression-free survival time was 8.9 (95% CI 6.7-11.1) months. The multivariate analysis showed that serum alkaline phosphatase (ALP) ≥90 U/L (OR=14.574, 95% CI 3.036-69.951, P=0.001), TP53 mutation (OR=13.052, 95% CI 1.982-85.932, P=0.008), and U2AF1 mutation (OR=7.720, 95% CI 1.540-38.698, P=0.013) were independent risk factors for poor efficacy of VEN combined with HMA. Hematological toxicity occurred in all patients, and the incidence of treatment-induced grade 3-4 leukopenia was 48.2% (40/83). Infection was the most common non-hematological adverse event, mainly pulmonary infection (31.3%) . Conclusion: VEN combined with HMA had a high response rate in patients with HR-MDS, both at initial treatment and with HMA failure. ALP ≥ 90 U/L, TP53 mutation, and U2AF1 mutation were independent risk factors for non-response to treatment.