RESUMO
BACKGROUND: Patients with relapsed or refractory acute myeloid leukemia (R/R AML) and FLT3-internal tandem duplication (FLT3-ITD) respond infrequently to salvage chemotherapy. OBJECTIVE: To investigate the efficacy of sorafenib plus triplet therapy with venetoclax, azacitidine, and homoharringtonine (VAH) as a salvage therapy in this population. METHODS: This multicenter, single-arm, phase 2 study was conducted at 12 hospitals across China. Eligible patients had R/R AML with FLT3-ITD (aged 18-65 years) who were treated with VAH. The primary endpoint was composite complete remission (CRc) after two cycles. Secondary outcomes included the overall response rate (ORR), safety, and survival. RESULTS: Between July 9, 2020, and March 19, 2022, 58 patients were assessed for eligibility, 51 of whom were enrolled. The median patient age was 47 years (interquartile range [IQR] 31-57). CRc was 76.5% with ORR of 82.4%. At a median follow-up of 17.7 months (IQR, 8.7-24.7), the median duration of CRc was not reached (NR), overall survival was 18.1 months (95% confidence interval [CI], 11.8-NR) and event-free survival was 11.4 months (95% CI, 5.6-NR). Grade 3 or 4 adverse events occurring in ≥10% of patients included neutropenia in 47 (92.2%), thrombocytopenia in 41 (80.4%), anemia in 35 (68.6%), febrile neutropenia in 29 (56.9%), pneumonia in 13 (25.5%), and sepsis in 6 (11.8%) patients. Treatment-related death occurred in two (3.9%) patients. CONCLUSIONS: The sorafenib plus VAH regimen was well tolerated and highly active against R/R AML with FLT3-ITD. This regimen may be a suitable therapeutic option for this population, but larger population trials are needed to be explored. TRIAL REGISTRATION: Clinical Trials Registry: NCT04424147.
Assuntos
Azacitidina , Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Azacitidina/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/uso terapêutico , Mepesuccinato de Omacetaxina/uso terapêutico , Leucemia Mieloide Aguda/terapia , Resposta Patológica Completa , Sorafenibe/efeitos adversos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , IdosoRESUMO
BACKGROUND: Circular RNAs (circRNA) are pivotal in hematological diseases. Previous study showed that circ_0014614 (circDAP3) was significantly underexpressed in bone marrow-derived exosomes from essential thrombocythemia (ET) patients, affecting the differentiation of bone marrow lineage cells into megakaryocytes. METHODS: Fluorescence in situ hybridization (FISH) was used to display circ_0014614's primary cytoplasmic location in K562 cells. Cytoscape software was used to predict the circRNA-miRNA-mRNA networks, and their expression at the cellular level was detected by Quantitative reverse transcription-polymerase chain reaction (qRT-PCR). qRT-PCR was utilized to detect the expression levels of circ_0014614ï¼miR-138-5p and caspase3 mRNA. Western blot was used to determine the protein levels of GATA-1, RUNX-1, NF-E2, CD41 and caspase3. The proliferation of K562 cells was assessed using the Cell Counting Kit-8 (CCK-8) Assay. Furthermore, the interplay between miR-138-5p and circ_0014614 or caspase3 was elucidated through a Dual-luciferase reporter assay. RESULTS: FISH assay indicated circ_0014614's primary cytoplasmic location in K562 cells. In ET bone marrow and K562 cells, circ_0014614 and caspase3 were down-regulated, whereas miR-138-5p saw a significant surge. Overexpressing circ_0014614 curtailed K562 cells' proliferation and differentiation. Further, circ_0014614 targeted miR-138-5p, with heightened miR-138-5p levels counteracting circ_0014614's inhibition. MiR-138-5p further targeted caspase3, and caspase3 silencing neutralized suppressed miR-138-5p's effects on K562 cell differentiation. CONCLUSION: Circ_0014614 was down-regulated in ET bone marrow and bone marrow lineage cells, and upregulating circ_0014614 can inhibit bone marrow lineage cells' proliferation and differentiation into megakaryocytes. Mechanistically, circ_0014614 functioned as ceRNA via sponging miR-138-5p and alleviated the inhibitory effect of miR-138-5p on its target caspase3, which potentially deters tumor activity in ET.
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Caspase 3 , Diferenciação Celular , Megacariócitos , MicroRNAs , RNA Circular , Trombocitemia Essencial , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Megacariócitos/metabolismo , Megacariócitos/patologia , RNA Circular/genética , Caspase 3/metabolismo , Trombocitemia Essencial/genética , Trombocitemia Essencial/patologia , Trombocitemia Essencial/metabolismo , Células K562 , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Feminino , Masculino , Pessoa de Meia-IdadeRESUMO
Biallelic mutations of the CEBPA gene (CEBPAbi) are generally associated with favorable prognosis in patients with acute myeloid leukemia (AML). Monoallelic mutations of the CEBPA gene in carboxy-terminal DNA-binding region (CEBPAsmbZIP) and amino-terminal transactivation domains (CEBPAsmTAD) indicate distinct clinical characteristics and therapeutic outcomes. However, further investigation is required to fully understand these differences. In this retrospective study, we enrolled 77 AML patients with CEBPA mutations, including 53 with CEBPAbi, 12 with CEBPAsmbZIP and 12 with CEBPAsmTAD. The clinical characteristics of the three CEBPAmut groups presented significant differences in age, FAB classification, hemoglobin level and platelet count at diagnosis. The CEBPAsmTAD group exhibited shorter 2-year overall survival (OS) and relapse-free survival (RFS) compared to the CEBPAbi group and CEBPAsmbZIP group in AML patients. The most common co-mutations observed in CEBPAmut AML patients were TET2 and GATA2, which had no effect on prognosis. 2-year RFS of 27 CEBPAmut AML patients who underwent allo-HSCT was better than those who did not. MRD3 positive was identified as an influencing factor for 2-year OS and RFS. Allo-HSCT was found to improve the prognosis of CEPBAmut AML patients with positive MRD3 and adverse co-mutations.
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Proteínas Estimuladoras de Ligação a CCAAT , Leucemia Mieloide Aguda , Mutação , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/diagnóstico , Proteínas Estimuladoras de Ligação a CCAAT/genética , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , Idoso , Transplante de Células-Tronco Hematopoéticas , Resultado do Tratamento , Adulto Jovem , Adolescente , Intervalo Livre de Doença , Prognóstico , Fator de Transcrição GATA2/genética , Taxa de SobrevidaRESUMO
BACKGROUND: The heterogeneity of relapsed or refractory (R/R) acute myeloid leukemia (AML) leads to no response to venetoclax (VEN)-based therapy in more than half of the patients. Genetic characteristics are considered important predictors for response to treatment in adults with AML. However, the association of genetic characteristics with outcomes receiving VEN-based therapy is incompletely understood in R/R AML. OBJECTIVE: To evaluate the efficacy of VEN combined with hypomethylating agents (HMA) and identify the potential genetic predictors of response in R/R AML. METHODS: A total of 150 R/R AML patients treated with VEN combined with HMA were enrolled in this retrospective study. Outcomes of the response and overall survival (OS) were analyzed. The predictors of response and OS were analyzed by logistic regression or Cox proportional hazards model. RESULTS: With a median of two (range, 1-4) cycles of therapy, the overall response rate was 56.2%, including 22.0% complete remission (CR), 21.3% CR with incomplete hematologic recovery, 2.0% morphologic leukemia-free state, and 10.7% partial remission, in which 25 patients achieved measurable residual disease (MRD)-negative response. With a median follow-up of 11.2 [95% confidence interval (CI), 7.2-14.8] months, 1- and 2-year OS were 46.9% (95% CI, 37.8%-58.1%) and 38.9% (95% CI, 28.7%-52.9%), respectively. Adverse cytogenetics and European Leukemia Net (ELN) risk predicted inferior response to VEN-based therapy. Mutations in IDH1/2, NPM1, ASXL1, and chromatin-cohesin genes predicted superior response to VEN-based therapy, whereas mutations in active signaling genes such as FLT3-ITD and K/NRAS predicted inferior response. CONCLUSION: VEN combined with HMA was effective with R/R AML patients, and the response to treatment was associated with genetic characteristics.
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Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Adulto , Humanos , Estudos Retrospectivos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Strategies to overcome resistance to FMS-like tyrosine kinase 3 (FLT3)-targeted therapy in acute myeloid leukemia (AML) are urgently needed. We identified autophagy as one of the resistance mechanisms, induced by hypoxia and the bone marrow microenvironment via activation of Bruton tyrosine kinase (BTK). Suppressing autophagy/BTK sensitized FLT3- mutated AML to FLT3 inhibitor-induced apoptosis. Furthermore, co-targeting FLT3/BTK/aurora kinases with a novel multikinase inhibitor CG-806 (luxeptinib) induced profound apoptosis in FLT3-mutated AML by co-suppressing FLT3/BTK, antagonizing autophagy, and causing leukemia cell death in FLT3-wildtype AML by aurora kinase-mediated G2/M arrest and polyploidy, in addition to FLT3 inhibition. Thus, CG-806 exerted profound anti-leukemia activity against AML regardless of FLT3 mutation status. CG-806 also significantly reduced AML burden and extended survival in an in vivo patient-derived xenograft leukemia murine model of FLT3 inhibitor-resistant FLT3-ITD/TKD double-mutant primary AML. Taken together, these findings indicate that CG-806 has a unique mechanistic action and pre-clinical activity, which is presently undergoing clinical evaluation in both FLT3 wildtype and mutant AML.
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Leucemia Mieloide Aguda , Tirosina Quinase 3 Semelhante a fms , Humanos , Animais , Camundongos , Tirosina Quinase da Agamaglobulinemia/genética , Tirosina Quinase 3 Semelhante a fms/genética , Apoptose , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo Celular , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Autofagia , Microambiente TumoralRESUMO
Venetoclax (VEN)-based regimens are the standard of care for elderly or unfit patients with newly diagnosed (ND) acute myeloid leukemia (AML). Some single-arm studies have implied that hypomethylating agents (HMAs) plus priming regimens may potentially provide an alternative therapeutic approach, owing to encouraging efficacy seen. However, no comparative data exists yet regarding these two treatment approaches. In this retrospective multi-center cohort study, we enrolled 294 ND AML patients, allocating 167 to the HMA + priming group and 127 to the VEN-based group. Treatment response and overall survival (OS) were compared between groups. Molecular subgroup analyses were also conducted. With a median of two cycles for HMA + priming group, the overall response (ORR) was 65.3%, including 55.1% complete remission (CR), 9.6% CR with incomplete hematologic recovery (CRi) and 0.6% morphologic leukemia-free state (MLFS). With a median of two cycles for VEN-based group, the ORR was 70.9%, including 46.5% CR, 18.9% CRi, and 5.5% MLFS. Response differences (ORR or CR/CRi) between groups were not significant (p > 0.05). With a median follow-up of 10.1 months, median OSs were similar between groups (20.9 vs 16.3 months, p = 0.41). However, VEN regimens demonstrated superior CR/CRi for patients with mutations in FLT3, IDH1/2, and NPM1 compared to HMA + priming (80.0% vs 35.0%, p = 0.01; 90.9% vs 65.5%, p = 0.02; 90.9% and 65.5%, p = 0.02, respectively). In conclusion, HMAs plus modified priming regimens might be a potential alternative therapeutic approach for patients with ND AML, but VEN-based regimens presented predominance in specific molecular subgroups. Molecular characteristics contribute to guiding choice of treatment.
Assuntos
Leucemia Mieloide Aguda , Humanos , Idoso , Estudos de Coortes , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Sulfonamidas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos RetrospectivosRESUMO
BACKGROUND: Patients with refractory central nervous system leukemia (CNSL) have a dismal prognosis and lack effective therapy. Case reports have shown that sorafenib is effective against brain metastases, including leukemia. METHODS: To explore the efficacy of sorafenib combined with conventional therapies for refractory CNSL, a phase 2 study was conducted. The primary end point was the complete remission rate (CRR) within 8 weeks of treatment. Secondary end points included the overall response rate (ORR), event-free survival (EFS), overall survival (OS), and adverse events (AEs). RESULTS: Twenty-six patients with refractory CNSL were enrolled; they included 17 with isolated CNSL, 7 with hematological relapse, and 2 with another extramedullary relapse. After 8 weeks of treatment, 21 patients achieved complete remission, 2 achieved partial remission, and 3 achieved no remission for a CRR of 80.8% (95% CI, 62.1%-91.5%) and an ORR of 88.5% (95% CI, 71.0%-96.0%). Twenty patients survived, and 6 died. The 2-year EFS and OS rates were 75.0% (95% CI, 54.5%-88.3%) and 76.9% (95% CI, 54.2%-90.4%), respectively. Six patients experienced grade 3 or 4 treatment-related AEs, including moderate chronic graft-vs-host disease (n = 3), grade 3 or 4 acute graft-vs-host disease (n = 2), and grade 3 skin rash (n = 1). No treatment-related deaths occurred during the therapy of refractory CNSL. CONCLUSIONS: Sorafenib combined with conventional therapies is effective and safe for refractory CNSL. LAY SUMMARY: Sorafenib combined with conventional therapies is effective and safe for refractory central nervous system leukemia.
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Neoplasias do Sistema Nervoso Central , Doença Enxerto-Hospedeiro , Leucemia , Sistema Nervoso Central , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Humanos , Recidiva , Estudos Retrospectivos , SorafenibeRESUMO
BACKGROUND: Autophagy plays a critical role in drug resistance in acute myeloid leukemia (AML), including the subtype with FLT3-ITD mutation. Yet how autophagy is activated and mediates resistance to FLT3 inhibitors in FLT3-ITD-positive AML remains unsure. METHODS: We detected the expression of autophagy markers in FLT3-ITD-positive leukemic cells after vs. before acquired resistance to FLT3 inhibitors; tested the stimulative effect of acquired D835Y mutation and bone marrow micro-environment (BME) on autophagy; explored the mechanism of autophagy mediating FLT3 inhibitor resistance. RESULTS: Sorafenib-resistant cells markedly overpresented autophagy markers in comparison with sorafenib-sensitive cells or the cells before sorafenib treatment. Both acquired D835Y mutation and BME activated cytoprotective autophagy to mediate FLT3 inhibitor resistance. Autophagy activation decreased the suppression efficacy of FLT3 inhibitors on FLT3 downstream signaling and then weakened their anti-leukemia effect. Inhibition of autophagy with CQ significantly enhanced the suppressive effect of FLT3 inhibitor on FLT3 downstream signaling, in the end overcame resistance to FLT3 inhibitors. CONCLUSIONS: Autophagy might be stimulated by acquired mutation or BME, and bypass activate FLT3 downstream signaling to mediate FLT3 inhibitor resistance in FLT3-ITD-positive AML. Targeting autophagy could be a promising strategy to overcome resistance.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda , Autofagia/genética , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Mutação/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Microambiente Tumoral , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/farmacologia , Tirosina Quinase 3 Semelhante a fms/uso terapêuticoRESUMO
BACKGROUND: Cidofovir (CDV) is a nucleotide analogue with broad antiviral activities. It remains unclear about the CDV administration for anti-cytomegalovirus (CMV) treatment in patients with haploidentical hematopoietic stem cell transplantation (haplo-HSCT). PATIENTS AND METHODS: In this study, 31 out of 101 haplo-HSCT recipients who suffered CMV infection in the CT group (conventional treatment) were enrolled into the CDV-ST group (CDV second-line treatment). These patients were treated with CDV as they failed conventional treatment or they were unavailable to the preemptive antiviral therapy. Nine patients with CMV infection were enrolled into the CDV-FT group (CDV-frontline treatment) and received CDV preemptive therapy. RESULTS: In the CDV-ST group, 23 of 28 (82.1%) patients were observed treatment response with a median time of 9 (2-23) days, and 20 (71.8%) among these patients obtained complete response (CR). In the CDV-FT group, six of eight (75.0%) patients acquired CR with a median of 6 (4-25) days. The treatment response in CDV-treated groups was comparable with those in CT groups. Besides, there was no statistical difference in CMV-related mortality between the three groups (p > .05). During the follow-up period (median follow-up:10 [1-28] months), a total of 8 of 22 (36.4%) patients experienced CMV reactivation in the CDV-ST group versus 23 of 62 (37.1%) in the CT group (p > .05). CDV-related toxicities occurred in 13 of 40 (32.5%) patients, including six (15%) reversible nephrotoxicity. CONCLUSION: Our study suggests that CDV is potentially an option for the salvage treatment of CMV infection in the haplo-HSCT patients.
Assuntos
Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Antivirais , Cidofovir/uso terapêutico , Citomegalovirus , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estudos Retrospectivos , Terapia de SalvaçãoRESUMO
BACKGROUND: Epigenetic dysregulation plays important roles in leukemogenesis and the progression of acute myeloid leukemia (AML). Histone acetyltransferases (HATs) and histone deacetylases (HDACs) reciprocally regulate the acetylation and deacetylation of nuclear histones. Aberrant activation of HDACs results in uncontrolled proliferation and blockade of differentiation, and HDAC inhibition has been investigated as epigenetic therapeutic strategy against AML. METHODS: Cell growth was assessed with CCK-8 assay, and apoptosis was evaluated by flow cytometry in AML cell lines and CD45 + and CD34 + CD38- cells from patient samples after staining with Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI). EZH2 was silenced with short hairpin RNA (shRNA) or overexpressed by lentiviral transfection. Changes in signaling pathways were detected by western blotting. The effect of chidamide or EZH2-specific shRNA (shEZH2) in combination with adriamycin was studied in vivo in leukemia-bearing nude mouse models. RESULTS: In this study, we investigated the antileukemia effects of HDAC inhibitor chidamide and its combinatorial activity with cytotoxic agent adriamycin in AML cells. We demonstrated that chidamide suppressed the levels of EZH2, H3K27me3 and DNMT3A, exerted potential antileukemia activity and increased the sensitivity to adriamycin through disruption of Smo/Gli-1 pathway and downstream signaling target p-AKT in AML cells and stem/progenitor cells. In addition to decreasing the levels of H3K27me3 and DNMT3A, inhibition of EZH2 either pharmacologically by chidamide or genetically by shEZH2 suppressed the activity of Smo/Gli-1 pathway and increased the antileukemia activity of adriamycin against AML in vitro and in vivo. CONCLUSIONS: Inhibition of EZH2 by chidamide has antileukemia activity and increases the chemosensitivity to adriamycin through Smo/Gli-1 pathway in AML cells (Fig. 5). These findings support the rational combination of HDAC inhibitors and chemotherapy for the treatment of AML.
Assuntos
Aminopiridinas , Leucemia Mieloide Aguda , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Animais , Apoptose , Benzamidas , Linhagem Celular Tumoral , Proliferação de Células , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Camundongos , Receptor SmoothenedRESUMO
Circular RNAs (circRNA) are closely associated with the pathogenesis of various hematological diseases. However, little is known about the potential functions of circRNAs in essential thrombocythemia (ET) development. The circRNA profile alterations in the bone marrow of ET patients were mainly investigated in this study. The sizes of exosomes derived from human bone marrow tissues were validated by the nanoparticle tracking analysis (NTA) method. CD63 and TSG101 expressions in exosomes were analyzed by western blot analysis. The profiles and differential expression of circRNAs in bone-derived exosomes were characterized by high-throughput sequencing. Herein, circular structures and expression of circRNAs were verified by Sanger sequencing and real-time polymerase chain reaction, respectively. The circRNA-miRNA-mRNA networks were predicted using the Cytoscape software. And we detected the effect of circ_0014614 on the transformation of K562 cells into megakaryocytes. Exosomes derived from the bone marrow of ET patients and healthy volunteers showed a diameter between 70 and 140 nm and expressed high CD63 and TSG101. Meanwhile, the circRNA profiles were significantly altered in bone marrow-derived exosomes from ET patients, among which circDAP3, circASXL1, and circRUNX1 were significantly downregulated in ET patients, thus conferring a new insight into the role of circRNAs in the pathogenesis of ET. Besides this, circRNA-encoding genes and miRNA-mRNA networks targeted by this three circRNA were involved in various biological processes and signaling pathways. And circ_0014614 could inhibit K562 cells' differentiation into megakaryocytes. The predictions of the potential function of these three differentially expressed circRNAs along with their interaction with specific miRNAs could provide a basis for circRNA-based ET diagnosis and treatment.
Assuntos
Medula Óssea , Exossomos/metabolismo , RNA Circular/metabolismo , Trombocitemia Essencial , Medula Óssea/metabolismo , Medula Óssea/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Humanos , Trombocitemia Essencial/metabolismo , Trombocitemia Essencial/patologiaRESUMO
BACKGROUND: Identification of biomarkers for acute myeloid leukemia (AML) is important for treating this malignancy. Recent studies have reported that microRNAs (miRNAs) are stably detectable in the blood/plasma and can be used as biomarkers for various types of cancer including AML. The aim of this study was to analyze miR-223 level in serum as a potential indicator for AML diagnosis and prognosis prediction. METHODS: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect the levels of miR-223 in the serum samples from 131 patients and 70 healthy individuals. RESULTS: The results revealed that serum miR-223 was underexpressed in AML patients, particularly those in intermediate and unfavorable cytogenetic risk groups. Further analysis revealed that serum miR-223 could yield a receiver operating characteristic (ROC) area under the curve (AUC) of 0.849 with 83.2% sensitivity and 81.4% specificity. Moreover, a significant increase in serum miR-223 level was observed in AML subjects after their treatment. Reduced serum miR-223 level was highly associated with aggressive clinical variables and shorter survival of patients. Furthermore, miR-223 expression was identified to be an independent prognostic predictor of worse overall survival. CONCLUSION: In conclusion, miR-223 may be a reliable diagnostic and prognostic biomarker for AML.
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Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/genética , MicroRNAs/sangue , MicroRNAs/genética , Adulto , Regulação para Baixo/genética , Feminino , Humanos , Leucemia Mieloide Aguda/cirurgia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Prognóstico , Curva ROC , Análise de Sobrevida , Resultado do TratamentoRESUMO
Accumulating evidence indicates that enhancer of zeste homolog 2 (EZH2) promotes the metastatic ability of solid tumors, but the role of EZH2 in extramedullary infiltration (EMI) in acute myeloid leukemia (AML) has not been thoroughly explored. In the present study, we investigated the possible association between EZH2 and EMI. We found that the messenger RNA (mRNA) and protein expression levels of EZH2 in AML patients were both significantly higher than in idiopathic thrombocytopenic purpura (ITP) patients. Furthermore, a positive correlation between EZH2 mRNA expression and percentage of peripheral blood blasts wa s found in AML patients (r = 0.404, p = 0.009). The migratory capacities of Kasumi-1 and HL-60, which both show a high level of EZH2 expression, were markedly higher than those of U937 and KG-1α. In contrast, silencing of EZH2 resulted in reduction in proliferation and migration ability and an increase in apoptosis. The latter observation was accompanied by reduced expression of associated proteins p-ERK, p-cmyc, and matrix metalloproteinase 2 (MMP-2) and an increase in epithelial cadherin (E-cadherin). These data suggest that higher expression of EZH2 may be associated with extramedullary infiltration in acute myeloid leukemia and affect pathogenesis via activation of the p-ERK/p-cmyc/MMP-2 and E-cadherin signaling pathways.
Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/biossíntese , Leucemia Mieloide Aguda/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Movimento Celular/fisiologia , Criança , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Leucemia Mieloide Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Transdução de Sinais/fisiologia , Adulto JovemRESUMO
Despite the development of several Fms-like tyrosine kinase 3 (FLT3) inhibitors that have improved outcomes in patients with FLT3-mutant acute myeloid leukemia (AML), drug resistance is frequently observed, which may be associated with the activation of additional pro-survival pathways, such as those regulated by BTK, aurora kinases (AuroK), and potentially others, in addition to acquired tyrosine kinase domain (TKD) mutations of FLT3 gene. FLT3 may not always be a driver mutation. We evaluated the anti-leukemia efficacy of the novel multi-kinase inhibitor CG-806, which targets FLT3 and other kinases, to circumvent drug resistance and target FLT3 wild-type (WT) cells. The anti-leukemia activity of CG-806 was investigated by measuring apoptosis induction and analyzing the cell cycle using flow cytometry in vitro. CG-806 demonstrated superior anti-leukemia efficacy compared to commercially available FLT3 inhibitors, both in vitro and in vivo, regardless of FLT3 mutational status. The mechanism of action of CG-806 may involve its broad inhibitory profile against FLT3, BTK, and AuroK. In FLT3 mutant cells, CG-806 induced G1 phase blockage, whereas in FLT3 WT cells, it resulted in G2/M phase arrest. Targeting FLT3 and Bcl-2 and/or Mcl-1 simultaneously results in a synergistic pro-apoptotic effect in FLT3 mutant leukemia cells. The results of this study suggest that CG-806 is a promising multi-kinase inhibitor with anti-leukemic efficacy regardless of FLT3 mutational status. A phase 1 clinical trial of CG-806 for the treatment of AML has been initiated (NCT04477291).Key pointsThe multi-kinase inhibitor CG-806 exerts superior anti-leukemic activity in AML, regardless of its FLT3 status.CG-806 triggered G1 arrest in FLT3 mutated cells and G2/M arrest in FLT3 WT cells through the suppression of FLT3/BTK and aurora kinases.Concomitantly targeting FLT3 and Bcl-2 and/or Mcl-1 exerted synergistic pro-apoptotic effects on both FLT3 WT and mutated AML cells.
RESUMO
PURPOSE: T(8;21)(q22;q22.1)/AML1-ETO positive acute myeloid leukemia (AE-AML) is sensitive to conventional chemotherapy with a favorable prognosis. However, recent small case reports suggest the limited effectiveness of venetoclax (VEN) and hypomethylating agents (HMA) in treating AE-AML. The aim of this retrospective study was to evaluate the effectiveness of VEN plus AZA (VA) in AE-AML and explore whether adding homoharringtonine (HHT) to VA (VAH) could improve the response. METHODS: Patients who received VEN plus AZA and HHT (VAH) or VEN plus AZA (VA) regimens were included in this retrospective study. The endpoints of this study were to evaluate the rate of composite complete remission (CRc), measurable residual disease (MRD), event-free survival (EFS), overall survival (OS), and relapse between VAH and VA groups. RESULTS: A total of 32 AE-AML patients who underwent VA or VAH treatments (newly diagnosed with VA, ND-VA, n = 8; relapsed/refractory with VA, R/R-VA, n = 10; relapsed/refractory with VAH, R/R-VAH, n = 14) were included. The CR (complete remission) /CRi (CR with incomplete count recovery) rate of ND-VA, R/R-VA and R/R-VAH were 25%, 10%, and 64.3%, respectively. Measurable residual disease (MRD) negative was observed in 66.7% of R/R-VAH and none of VA-R/R patients. Co-occurring methylation mutations are associated with poor outcomes with VA but exhibit a more favorable response with VAH treatment. Additionally, patients with c-kit mutation presented inferior outcomes with both VEN-based regimens. All regimens were tolerated well by all patients. CONCLUSION: Our data confirmed the poor response of VA in AE-AML, whether used as frontline or salvage therapy. Adding HHT to VA may improve outcomes and enhance the efficacy of VEN in this population.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Compostos Bicíclicos Heterocíclicos com Pontes , Subunidade alfa 2 de Fator de Ligação ao Core , Mepesuccinato de Omacetaxina , Leucemia Mieloide Aguda , Proteína 1 Parceira de Translocação de RUNX1 , Sulfonamidas , Humanos , Mepesuccinato de Omacetaxina/administração & dosagem , Mepesuccinato de Omacetaxina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Feminino , Estudos Retrospectivos , Azacitidina/administração & dosagem , Sulfonamidas/administração & dosagem , Idoso , Adulto , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Proteína 1 Parceira de Translocação de RUNX1/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Fusão Oncogênica/genética , Adulto JovemRESUMO
BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous disease, and its heterogeneity is associated with treatment response. Despite the demonstrated success of venetoclax (VEN)-based therapy for AML, the effect of FLT3 mutations on the efficacy of the therapy is poorly understood. We aimed to compare the efficacy of VEN-based therapy between FLT3-mutated (FLT3mut ) and FLT3 wild-type (FLT3wt ) patients and identify the predictors of efficacy in FLT3mut patients. METHODS: A total of 266 AML patients (127 newly diagnosed [ND] and 139 refractory/relapsed [R/R]) receiving VEN-based regimens were enrolled in this study. A retrospective analysis was performed, and the treatment responses and overall survival (OS) of FLT3mut and FLT3wt patients were compared. Logistic regression and Cox proportional hazards model were applied to examine the clinical and genetic predictors of outcomes. RESULTS: With a median of two cycles of VEN-based therapy, for the ND AML cohort, the FLT3mut group had a comparable composite complete remission (CRc) rate with the FLT3wt group (79.3% vs. 61.2%, p = 0.072). For the R/R AML cohort, the FLT3mut group exhibited a lower CRc rate than the FLT3wt group. With a median follow-up of 8.6 months (95% confidence interval [CI], 8.0-10), the median OS observed in the FLT3mut and FLT3wt groups for both cohorts were close (14.0 vs. 19.9 months, p = 0.356; 10.0 vs. 11.9 months, p = 0.680). For the ND AML cohort, in FLT3mut patients, MRD-positive and RNA-splicing mutation predicted inferior survival (hazard ratio [HR], 10.3; 95% CI: 2.0-53.8; p = 0.006; HR 11.3; 95% CI: 1.2-109.3; p = 0.036, respectively). For the R/R AML cohort, in FLT3mut patients, adverse ELN risk was associated with an inferior response (odds ratio [OR], 0.2; 95% CI: 0.1-0.8; p = 0.025), whereas NPM1 co-mutation was associated with a superior response (57.1%; OR, 6.7; 95% CI: 1.5-30.1; p = 0.014). CR/CRi predicted a better survival (HR 0.2; 95% CI: 0.1-0.8; p = 0.029), while DNMT3A mutation predicted an inferior survival (HR, 4.6; 95% CI: 1.4-14.9; p = 0.011). CONCLUSIONS: FLT3 mutations may influence response to VEN-based therapy in R/R AML patients but not in ND AML patients. Furthermore, clinical and genetic characteristics could predict outcomes of FLT3mut patients receiving VEN-based therapy.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Nucleofosmina , Sulfonamidas , Humanos , Estudos Retrospectivos , Mutação , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
BACKGROUND: The post-remission therapy (PRT) choices for adult t(8;21) acute myeloid leukemia (AML) in first complete remission (CR1) need to be further explored. AIMS: We aimed to investigate the impact of measurable residual disease (MRD) combined with CD19 on PRT choices for adult t(8;21) AML in CR1. METHODS: A total of 150 t(8;21) AML patients were enrolled, including 67 underwent chemotherapy (CMT) and 83 allogeneic hematopoietic stem cell transplantation (allo-SCT) as PRT in CR1. Subgroup analyses were performed according to MRD level after three cycles of chemotherapy combined with CD19 expression. RESULTS: Multivariate analysis indicated MRDhigh after three courses of treatment (HR, 0.14 [95% CI, 0.03-0.66]; p = 0.013) and CD19 negativity (HR, 0.14 [95% CI, 0.02-0.96]; p = 0.045) were risk factors for relapse, while allo-SCT was protective factor for relapse (HR, 0.34 [95% CI, 0.15-0.75]; p = 0.008). Grouped by MRD after three courses of chemotherapy, allo-SCT had lower CIR (p < 0.001) and better OS (p = 0.003) than CMT for MRDhigh patients, CMT showed a higher CIR (35.99% vs. 15.34%, p = 0.100) but comparable OS (p = 0.588) than allo-SCT for MRDlow patients. Grouped by CD19 expression, allo-SCT demonstrated lower CIR (p < 0.001) and better OS (p = 0.002) than CMT for CD19- patients. CMT had a higher CIR (41.37% vs. 10.48%, p = 0.007) but comparable OS (p = 0.147) than allo-SCT for CD19+ patients. Grouped by MRD combined with CD19, MRDhigh /CD19+ subsets were identified out of CD19+ patients benefiting from allo-SCT with lower CIR (p = 0.002) and superior OS (p = 0.020) than CMT. CMT preserved comparable CIR (p = 0.939) and OS (p = 0.658) with allo-SCT for MRDlow /CD19+ patients. MRDlow /CD19- subsets were also identified from MRDlow patients requiring allo-SCT with lower CIR (p < 0.001) and superior OS (p = 0.008) than CMT. Allo-SCT maintained lower CIR (p < 0.001) and superior OS (p = 0.008) than CMT for MRDhigh /CD19- patients. CONCLUSIONS: MRD combined with CD19 might optimize PRT choices for adult t(8;21) AML patients in CR1.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Adulto , Humanos , Transplante Homólogo , Transplante de Células-Tronco , Recidiva , Resposta Patológica Completa , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/metabolismo , Neoplasia Residual , Estudos Retrospectivos , PrognósticoRESUMO
Immunotherapy elicits a systemic antitumour immune response in peripheral circulating T cells. However, the T cell trafficking circuit between organs and their contributions to antitumour immunity remain largely unknown. Here we show in multiple mouse leukaemia models that high infiltration of leukaemic cells in bone marrow (BM) stimulates the transition of CD8+CD44+CD62L+ central memory T cells into CD8+CD44-CD62L- T cells, designated as inter-organ migratory T cells (TIM cells). TIM cells move from the BM to the intestine by upregulating integrin ß7 and downregulating C-X-C motif chemokine receptor 3 during leukaemogenesis. Upon immunogenic chemotherapy, these BM-derived TIM cells return from the intestine to the BM through integrin α4-vascular cell adhesion molecule 1 interaction. Blocking C-X-C motif chemokine receptor 3 function boosts the immune response against leukaemia by enhancing T cell trafficking. This phenomenon can also be observed in patients with leukaemia. In summary, we identify an unrecognized intestine-BM trafficking circuit of T cells that contributes to the antitumour effects of immunogenic chemotherapy.
Assuntos
Linfócitos T CD8-Positivos , Movimento Celular , Camundongos Endogâmicos C57BL , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Humanos , Receptores CXCR3/metabolismo , Cadeias beta de Integrinas/metabolismo , Medula Óssea/imunologia , Medula Óssea/patologia , Medula Óssea/metabolismo , Intestinos/imunologia , Intestinos/patologia , Camundongos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Mucosa Intestinal/metabolismo , Linhagem Celular Tumoral , Camundongos KnockoutRESUMO
It is known that leukemia patients with extramedullary infiltration (EMI) have a worse prognosis than patients without it. Recent data indicate that the amyloid precursor protein (APP) is involved in cell adhesion, motility, and proliferation. The expression of APP and its prognostic significance in acute myeloid leukemia (AML) have not been studied. Our study shows that AML/ETO(+) leukemia patients that overexpress APP easily get EMI and that their long-term survival rate is lower than patients without overexpression of APP. In an in vitro study, we knocked down APP in Kasumi-1 cells using small interfering RNA (siRNA). Transwell data show that siRNA/APP substantially impairs cell migration, but it does not inhibit cell proliferation. Furthermore, by quantitative real-time polymerase chain reaction and Western blot, we found that siRNA/APP decreases MMP-2 expression in vitro. Our study provides a novel clue that APP is involved in the extramedullary infiltration of leukemia by MMP-2.
Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Movimento Celular , Leucemia Mieloide Aguda/patologia , Infiltração Leucêmica/patologia , Metaloproteinase 2 da Matriz/metabolismo , Adulto , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Precursor de Proteína beta-Amiloide/genética , Western Blotting , Adesão Celular , Proliferação de Células , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Masculino , Metaloproteinase 2 da Matriz/genética , Invasividade Neoplásica , Proteínas de Fusão Oncogênica/genética , Prognóstico , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Proteína 1 Parceira de Translocação de RUNX1 , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Adulto JovemRESUMO
Knowledge concerning the clinical and biological characteristics of acute leukemia of ambiguous lineage (ALAL) is limited so that there has been a lack of uniformity in treatment. In this report, we retrospectively investigated the effect of intensified conditioning on adult ALAL undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 59 patients with ALAL (male in 37 cases and female in 22 cases) were consecutively enrolled in the data analyses. Twenty-four patients received the standard conditioning (total body irradiation (TBI) + cyclophosphamide (CY) or busulfan + CY protocol) and 35 received the intensified conditioning (TBI + CY + etoposide or fludarabine + cytarabine plus TBI + CY + etoposide protocol). Five-year transplant-related mortality was 17.6 ± 9.6 % and 25.5 ± 8.0 %, the 5-year overall survival (OS) post-transplantation was 23.8 ± 8.9 % and 64.0 ± 8.4 %, disease-free survival was 16.7 ± 7.6 % and 55.8 ± 9.4 %, the 5-year cumulative incidence of relapse was 80.8 ± 8.5 % and 28.8 ± 9.9 %, respectively, in the standard and the intensified group (P = 0.380, P = 0.029, P = 0.005, and P < 0.001). Both univariate and multivariate analysis indicated that the intensified conditioning regimen and acute graft-versus-host disease were favorable factors to reduce the relapse. The younger patients, patients with CR at the time of transplantation, and the intensified conditioning regimen were favorable factors to elevate the survival. In conclusion, intensified conditioning regimens followed by allo-HSCT might improve long-term survival and decrease relapse of leukemia in adult ALAL compared to the standard conditioning regimens.