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1.
N Engl J Med ; 382(2): 140-151, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31914241

RESUMO

BACKGROUND: Patients with anemia and lower-risk myelodysplastic syndromes in whom erythropoiesis-stimulating agent therapy is not effective generally become dependent on red-cell transfusions. Luspatercept, a recombinant fusion protein that binds transforming growth factor ß superfamily ligands to reduce SMAD2 and SMAD3 signaling, showed promising results in a phase 2 study. METHODS: In a double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients with very-low-risk, low-risk, or intermediate-risk myelodysplastic syndromes (defined according to the Revised International Prognostic Scoring System) with ring sideroblasts who had been receiving regular red-cell transfusions to receive either luspatercept (at a dose of 1.0 up to 1.75 mg per kilogram of body weight) or placebo, administered subcutaneously every 3 weeks. The primary end point was transfusion independence for 8 weeks or longer during weeks 1 through 24, and the key secondary end point was transfusion independence for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48. RESULTS: Of the 229 patients enrolled, 153 were randomly assigned to receive luspatercept and 76 to receive placebo; the baseline characteristics of the patients were balanced. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in the luspatercept group, as compared with 13% of those in the placebo group (P<0.001). A higher percentage of patients in the luspatercept group than in the placebo group met the key secondary end point (28% vs. 8% for weeks 1 through 24, and 33% vs. 12% for weeks 1 through 48; P<0.001 for both comparisons). The most common luspatercept-associated adverse events (of any grade) included fatigue, diarrhea, asthenia, nausea, and dizziness. The incidence of adverse events decreased over time. CONCLUSIONS: Luspatercept reduced the severity of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts who had been receiving regular red-cell transfusions and who had disease that was refractory to or unlikely to respond to erythropoiesis-stimulating agents or who had discontinued such agents owing to an adverse event. (Funded by Celgene and Acceleron Pharma; MEDALIST ClinicalTrials.gov number, NCT02631070; EudraCT number, 2015-003454-41.).


Assuntos
Receptores de Activinas Tipo II/uso terapêutico , Anemia Sideroblástica/tratamento farmacológico , Transfusão de Eritrócitos , Hematínicos/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Receptores de Activinas Tipo II/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Sideroblástica/terapia , Método Duplo-Cego , Feminino , Hematínicos/efeitos adversos , Hemoglobinas/análise , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Infusões Subcutâneas , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Proteínas Recombinantes de Fusão/efeitos adversos
3.
Ann Hematol ; 99(1): 7-19, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31650290

RESUMO

Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies associated with an erythroid maturation defect, resulting in anemia. Treatments for MDS include erythropoiesis-stimulating agents (ESAs). The identification of prognostic markers is important to help predict response and improve outcomes. Various scoring systems have been developed to help predict response to ESAs. Despite limitations in its assessment, serum erythropoietin (sEPO) level is an important predictor of hematologic response to ESAs in patients with lower-risk MDS. Numerous studies have reported significantly lower sEPO levels among responders versus non-responders. Furthermore, treatment response is significantly more likely among those with sEPO levels below versus those above various cutoffs. Other prognostic indicators for response to ESAs include lower transfusion requirement, fewer bone marrow blasts, higher hemoglobin, lower serum ferritin, lower-risk MDS, and more normal cytogenetics. Studies of other MDS therapies (e.g., lenalidomide and luspatercept) have also reported that lower sEPO levels are indicative of hematologic response. In addition, lower sEPO levels (up to 500 IU/L) have been included in treatment algorithms for patients with lower-risk MDS to define whether ESAs are indicated. Lower sEPO levels are predictive of hematologic response-particularly to ESAs. Further, clinical trials should use sEPO thresholds to ensure more homogeneous cohorts.


Assuntos
Receptores de Activinas Tipo II/uso terapêutico , Eritropoetina/sangue , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Lenalidomida/uso terapêutico , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Feminino , Ferritinas/sangue , Hemoglobinas/metabolismo , Humanos , Masculino , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/patologia , Prognóstico , Fatores de Risco
4.
Zhonghua Nei Ke Za Zhi ; 58(12): 908-910, 2019 Dec 01.
Artigo em Chinês | MEDLINE | ID: mdl-31775455

RESUMO

To retrospectively analyze the safety and efficacy of low dose subcutaneous decitabine combined with arsenic trioxide in patients with intermediate or high-risk myelodysplastic syndrome (MDS). Three of the total 11 MDS patients achieved complete remission (CR) and 6 achieved hematological improvement (HI), 1 stable disease (SD), and 1 progressive disease (PD). One patient was treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). The median follow-up time was 413(90-1 275) d. Nine patients were still alive. Low dose subcutaneous decitabine combined with arsenic trioxide can be an alternative regimen for intermediate or high-risk MDS patients.


Assuntos
Trióxido de Arsênio/uso terapêutico , Decitabina/administração & dosagem , Síndromes Mielodisplásicas/tratamento farmacológico , Trióxido de Arsênio/administração & dosagem , Decitabina/uso terapêutico , Humanos , Estudos Retrospectivos , Resultado do Tratamento
5.
Zhonghua Nei Ke Za Zhi ; 58(12): 933-936, 2019 Dec 01.
Artigo em Chinês | MEDLINE | ID: mdl-31775462

RESUMO

A 54-year-old man was admitted to respiratory department with chief complaints of recurrent cough and dyspnea. Chest imaging showed multiple patchy shadows and interstitial changes. Evidence of infectious diseases was not definite, and antibiotic treatments were not effective. In the meantime, myelodysplasia syndrome was diagnosed with pancytopenia. The pathologic findings of transbronchoscopic lung biopsyshowed chronic inflammatory interstitial changes, suggesting a clinical diagnosis of organizing pneumonia. After glucocorticoids treatment, his condition aggravated. The second percutaneous lung biopsy showed the infiltration of a large number of neutrophils. Therefore, the final diagnosis of myelodysplasia syndrome with Sweet syndrome was made. Then glucocorticoids and supportive treatment were given This case may improve physicians' understanding of myelodysplasia syndrome complicated with Sweet syndrome.


Assuntos
Doenças Pulmonares Intersticiais/diagnóstico por imagem , Pulmão/patologia , Síndromes Mielodisplásicas/diagnóstico , Neutrófilos/patologia , Síndrome de Sweet/diagnóstico , Broncoscopia , Tosse/etiologia , Dispneia/etiologia , Glucocorticoides/uso terapêutico , Humanos , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/tratamento farmacológico , Pancitopenia/diagnóstico , Pneumonia , Síndrome de Sweet/complicações , Síndrome de Sweet/tratamento farmacológico , Resultado do Tratamento
6.
Ann Hematol ; 98(11): 2523-2531, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31637485

RESUMO

The use of hypomethylating agents (HMAs) prior to hematopoietic stem cell transplantation (HSCT) in patients with myelodysplastic syndromes (MDS) was still controversial. Therefore, we sought to evaluate the impact of hypomethylation therapy before HSCT, with a special focus on long-term outcome. Databases, including PubMed, Embase Ovid, and the Cochrane Library, were searched for studies published up to 4 November 2018. Overall survival (OS) was selected as the primary endpoint, and relapse-free survival (RFS) was the secondary endpoint. A total of 6 cohort studies were included in the final meta-analysis. Our results showed that the outcome of patients with MDS using HMAs prior to HSCT was similar compared to those who did not with OS (HR = 0.81, 95% CI 0.63-1.04, p = 0.104) and RFS (HR = 0.96, 95% CI 0.72-1.26, p = 0.749). The pooled HR of OS in the older patients was 0.75 (95% CI 0.57-0.98, p = 0.035). No evidence showed that patients with MDS will benefit from using HMAs before HSCT in long-term survival (OS and RFS) compared to chemotherapy or best supportive therapy, though older patients were more likely to benefit from pre-transplantation HMAs treatment in terms of long-term survival. Our conclusions await further validation by prospective studies with larger sample size and randomized-controlled design. Particularly, to clarify whether the older patients who are candidates for HSCT could benefit from this bridging treatment will be of great interest.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Decitabina/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Síndromes Mielodisplásicas/tratamento farmacológico , Aloenxertos , Antimetabólitos Antineoplásicos/farmacologia , Azacitidina/farmacologia , Decitabina/farmacologia , Intervalo Livre de Doença , Humanos , Síndromes Mielodisplásicas/terapia , Pré-Medicação , Análise de Sobrevida , Resultado do Tratamento
7.
Drugs Today (Barc) ; 55(9): 545-562, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31584572

RESUMO

On November 21, 2018, the U.S. Food and Drug Administration (FDA) approved glasdegib in combination with low-dose cytarabine (LDAC), for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients > 75 years old or who have comorbidities that would be prohibitive of intensive induction chemotherapy. Glasdegib is a small-molecule inhibitor of a component of the hedgehog (HH) pathway, an upregulated pathway in leukemia and leukemia stem cells that is associated with relapse, drug resistance and poor survival. Preclinical studies suggested that glasdegib could sensitize AML cells to chemotherapy. FDA approval was based on a randomized, placebo-controlled, phase II trial in elderly or infirmed adults with new AML, unable to receive intensive induction chemotherapy, in whom the addition of glasdegib to LDAC nearly doubled the median overall survival compared with LDAC alone. In this report, we examine the preclinical development of glasdegib, its pharmacology and the clinical investigation that demonstrated its safety and efficacy, resulting in its approval. Additionally, we highlight ongoing investigation and future applications of this therapy.


Assuntos
Benzimidazóis/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Ensaios Clínicos Fase II como Assunto , Citarabina , Aprovação de Drogas , Humanos , Quimioterapia de Indução , Ensaios Clínicos Controlados Aleatórios como Assunto , Estados Unidos , United States Food and Drug Administration
8.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1568-1573, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607313

RESUMO

OBJECTIVE: To investigate the clinical efficacy and safety of low-dose decitabine (DAC) alone for treatment of myelodysplastic syndrome (MDS) Methods: Fifty-one patients with meddle- and high-risk MDS were selected, and were randomly divided into A, B and C groups according to the drug regimens: the therapeutic regimen in A group consisted of low dose DAC 10 mg/(m2·d)×7 d; the therapeutic regimen in B group: normal dose DAC 20 mg/(m2·d) ×5 d; the therapeutic regimen in C group: low dose DAC+CAG DAC 10 mg/(m2·d) d 1-5,cytarabine 10 mg/(m2·d) q12h d 1-7, aclaromycin 10 mg/d d 1-4,G-CSF 200 µg/(m2·d), d 1-7. All patients in 3 groups were treated for 4 circles. The efficacy and response were compared among 3 groups. RESULTS: The complete remission rates (CR%) in A, B and C groups were 18.75%, 22.22% and 23.53% respectively, and the overall response rate (ORR%) in A, B and C groups were 56.25%, 61.11% and 58.82% respectively, without statistical difference among 3 groups (P>0.05).After 1 year of follow-up, the survival rate was not significantly different among 3 groups, the blood cell accounts were higher than the basic value. After 1 course of treatment, the inhibition rate of III-IV grade myelosuppression was statistically significantly different among the 3 groups (P<0.05), and the infection rate among 3 groups also was statistically different, The incidence of myelosuppression and infection in A group was significantly lower than that in B and C groups. The per capita blood transfusion during the four-month treatment was not statistically different among 3 groups. however, that in the A group was lesser than B and C groups. CONCLUSION: The therapeutic efficacy of low dose decitabine alone for treatment of MDS is equal to routine dose decitabine and decitabine plus CAG, but the low dose group shows less myelosuppressive and more safe effects.


Assuntos
Decitabina/uso terapêutico , Síndromes Mielodisplásicas , Protocolos de Quimioterapia Combinada Antineoplásica , Citarabina , Humanos , Síndromes Mielodisplásicas/tratamento farmacológico , Resultado do Tratamento
9.
J Cancer Res Clin Oncol ; 145(11): 2835-2843, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31506740

RESUMO

PURPOSE: Molecular mechanisms of response to hypomethylating agents in patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) still remain largely unknown. Therefore, the effects of 5-Azacytidine (Aza) on clonal architecture and DNA methylation were investigated in this study. METHODS: Using next-generation sequencing (NGS), 30 myeloid leukemia-associated genes were analyzed in 15 MDS/CMML patients with excellent response to Aza. Effects on methylation levels were analyzed by quantitative methylation analysis using pyrosequencing for the global methylation marker LINE-1 in patients and myeloid cell lines. Various myeloid cell lines and a healthy cohort were screened for methylation levels in 23 genes. Selected targets were verified on the MDS/CMML cohort. RESULTS: The study presented here showed a stable variant allele frequency and stable global methylation levels in responding patients. A significant demethylation of EZH2 and NOTCH1 was revealed in patients with Aza response. CONCLUSIONS: A response to Aza is not associated with eradication of malignant clones, but rather with a stabilization of the clonal architecture. We suggest changes in CpG methylation levels of EZH2 and NOTCH1 as potential targets of epigenetic response to Aza treatment which may also serve as useful biomarkers after clinical evaluation.


Assuntos
Azacitidina/farmacologia , Biomarcadores Tumorais/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Leucemia Mielomonocítica Crônica/genética , Síndromes Mielodisplásicas/genética , Receptor Notch1/genética , Idoso , Antimetabólitos Antineoplásicos/farmacologia , Estudos de Casos e Controles , Ilhas de CpG , Metilação de DNA , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Leucemia Mielomonocítica Crônica/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/patologia , Prognóstico , Receptor Notch1/metabolismo , Células Tumorais Cultivadas
10.
Clinics (Sao Paulo) ; 74: e771, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31508719

RESUMO

OBJECTIVES: To evaluate the effects of epoetin (EPO) alfa treatment on overall survival, event-free survival and response duration in patients with myelodysplastic syndrome (MDS) who were treated at a haematological referral centre in northeastern Brazil. METHODS: This was a retrospective cohort study of 36 patients diagnosed with MDS and treated with EPO alfa at 30,000 to 60,000 IU per week. Clinical data were collected from medical records. The events assessed were non-response to treatment and progression to acute myeloid leukaemia (AML). Statistical analyses were performed using GraphPad Prism 7 and SPSS 24 software. RESULTS: The overall survival of patients who received EPO alfa treatment was 51.64%, with a median of 65 months of treatment, and the overall survival of this group was 100% during the first 24 months. We detected a 43.5-month median event-free survival, with a response rate of 80.5%. We observed responses from 25 to 175 months. Patients with transfusion dependence and those with a high-risk stratification, as determined by the International Prognostic Scoring System (IPSS), the Revised International Prognostic Scoring System (IPSS-R), the WHO classification-based Prognostic Scoring System (WPSS) and the WHO 2016, had a lower event-free survival than other patients. CONCLUSIONS: Despite the wide use of EPO alfa in the treatment of anaemia in patients with MDS, the median response duration is approximately only 24 months. Our data provide encouraging results concerning the benefits of using EPO alfa for the improvement of the quality of life, as patients treated with EPO showed higher overall survival, event-free survival rates and longer response durations than have been previously described in the literature.


Assuntos
Epoetina alfa/uso terapêutico , Hematínicos/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/mortalidade , Idoso , Idoso de 80 Anos ou mais , Transfusão de Sangue , Brasil , Progressão da Doença , Feminino , Hemoglobinas/análise , Humanos , Estimativa de Kaplan-Meier , Cariótipo , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Intervalo Livre de Progressão , Valores de Referência , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
11.
Expert Opin Investig Drugs ; 28(10): 835-849, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31510809

RESUMO

Introduction: The incidence of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) is increasing with the aging population. Prognosis and overall survival (OS) remain poor in elderly patients and in those not eligible for intensive treatment. Hypomethylating agents (HMAs) have played an important role in this group of patients but their efficacy is limited. Areas covered: This article reviews the mechanism of action, pharmacology, safety profile and clinical efficacy of subcutaneous guadecitabine, a second-generation DNA methylation inhibitor in development for the treatment of AML and MDS. Expert opinion: Although guadecitabine did not yield improved complete remission (CR) rates and OS compared to the control arm in patients with treatment-naïve AML who were ineligible for intensive chemotherapy, subgroup analysis in patients who received ≥4 cycles of therapy demonstrated superior outcomes in favor of guadecitabine. Given its stability, ease of administration, safety profile and prolonged exposure time, guadecitabine would be the more appropriate HMA, replacing azacitidine and decitabine, to be used combination treatment regimens in patients with myeloid malignancies.


Assuntos
Azacitidina/análogos & derivados , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Idoso , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Azacitidina/farmacologia , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Humanos , Leucemia Mieloide Aguda/patologia , Síndromes Mielodisplásicas/patologia , Prognóstico , Taxa de Sobrevida , Fatores de Tempo
12.
J Cancer Res Clin Oncol ; 145(12): 3089-3097, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31559495

RESUMO

PURPOSE: Myelodysplastic syndromes (MDSs) refractory or relapsed after hypomethylating agents (HMAs) remain a therapeutic challenge. The CHG regimen has been demonstrated to be effective in initially treating higher risk MDS. The current study evaluated the efficacy and toxicity of the CHG regimen in patients who were resistant to decitabine. METHODS: Patients with higher risk MDS relapsed or refractory to decitabine were enrolled in this study. Each patient received the CHG regimen (cytarabine (25 mg/day, days 1-14) and homoharringtonine (1 mg/day, days 1-14) intravenously with G-CSF (300 µg/day) subcutaneously from day 0 until neutrophil count recovery to 2.0 × 109 cells/L). Next gene sequencing with a 31-gene panel was carried out in patients. RESULTS: Thirty-three patients were enrolled, including 12 relapsed and 21 refractory cases. The overall response rate (ORR) was 39.4% (13 of 33), with 9 (27.3%) achieving complete remission (CR), 2 having marrow CR (mCR), and 2 achieving partial remission (PR). The CR rate was higher in patients harboring fewer gene mutations (0-1) (55.6%) than in those with more gene mutations (> 1) (12.5%) (p = 0.021). The median overall survival (OS) of the 33 patients was 7.0 months. Patients who achieved a response had significantly longer survival times than were found in those without a response (21.0 M vs. 4.0 M, p < 0.0001). The regimen was endurable for most of the patients. CONCLUSIONS: The CHG priming regimen provided a safe and effective salvage regimen for higher risk MDS patients who were resistant to decitabine. Further studies involving larger samples will be needed. Clinical trial No. ChiCTR-ONC-11001501.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/uso terapêutico , Decitabina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Mepesuccinato de Omacetaxina/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Idoso , Citarabina/efeitos adversos , Feminino , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Mepesuccinato de Omacetaxina/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/efeitos dos fármacos , Indução de Remissão/métodos , Terapia de Salvação/métodos , Resultado do Tratamento
13.
Lancet Haematol ; 6(9): e480-e488, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400961

RESUMO

BACKGROUND: Outcomes for younger patients with acute myeloid leukaemia have moderately improved over the past two decades owing to better supportive care and recent introduction of novel targeted agents. Blocking PD-1 and its ligand's pathways enhances antileukaemia responses by enabling T cells in murine models. We aimed to assess the addition of nivolumab to frontline therapy with idarubicin and cytarabine in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome. METHODS: This single-arm, phase 2 part of the phase 1-2 study of nivolumab in combination with idarubicin and cytarabine was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible patients were aged 18-60 years (or >60 years if suitable for intensive chemotherapy), and had newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, and an Eastern Cooperative Oncology Group performance status of 0-2. Induction included cytarabine 1·5 g/m2 by 24-h continuous infusion daily on days 1-4 (3 days in patients >60 years) and idarubicin 12 mg/m2 daily on days 1-3. Nivolumab 3 mg/kg was started on day 24 (range 22-26) and continued every 2 weeks for up to a year in responders. Responders received either up to five consolidation cycles of attenuated doses of idarubicin and cytarabine, or allogeneic stem cell transplantation if eligible. The primary endpoint was event-free survival. Efficacy and safety analyses were done in all patients who received at least one dose of study treatment. Secondary endpoints were relapse-free survival and overall survival. This ongoing trial is registered with ClinicalTrials.gov, number NCT02464657. FINDINGS: Between Aug 7, 2015, and June 2, 2018, 44 patients were enrolled of whom 22 (50%) had adverse genetic risk by European Leukaemia Network classification. All patients were evaluable for safety and efficacy. At a median follow-up of 17·25 months (IQR 0·50-30·40), median event-free survival was not reached (95% CI 7·93-NR). Median relapse-free survival of responders was 18·54 months (95% CI 8·20-23·22). The median overall survival was 18·54 months (95% CI 10·81-28·81). Six patients had seven grade 3-4 immune-related adverse events with two cases of rash, two of colitis, and one each of transaminitis, pancreatitis, and cholecystitis. 19 (43%) of 44 patients achieved a response and proceeded to allogeneic stem cell transplantation, with grade 3-4 graft-versus-host disease observed in five (26%). No treatment related deaths were attributed to nivolumab. INTERPRETATION: Addition of nivolumab to induction chemotherapy with idarubicin and cytarabine is feasible in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome. Post-transplant severe graft-versus-host disease could be improved, and earlier initiation of checkpoint inhibitor therapy is warranted in future studies. FUNDING: The MD Anderson Cancer Center Support Grant CA016672, and the MD Anderson Cancer Center Leukaemia SPORE CA100632 from the National Cancer Institute, Bristol Myers Squibb.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/administração & dosagem , Idarubicina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Nivolumabe/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Colite/etiologia , Citarabina/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Exantema/etiologia , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Idarubicina/efeitos adversos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Nivolumabe/efeitos adversos , Taxa de Sobrevida , Resultado do Tratamento
14.
Int J Mol Sci ; 20(16)2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31394818

RESUMO

During the last decade, substantial advances have been made in the understanding of the complex molecular, immunological and cellular disturbances involved in the initiation as well as evolution of myelodysplastic syndromes (MDS). In 85% of the mainly frail and older patient population, anemia is present at the time of diagnosis and is thus a major therapeutic challenge. High rates of primary resistance to erythropoiesis-stimulating agents (ESAs), the currently only approved standard therapy to treat anemia in lower-risk MDS, demand the development of novel and efficient drugs with a good safety profile. Luspatercept, a ligand trap of activin receptor II, is able to promote late stage erythropoiesis even in patients failing prior ESA treatment. The presence of ring sideroblastic phenotype defines a subgroup of patients with higher response rates. Additionally, recent developments in clinical research using HIF-1 or telomerase modulation by roxadustat or imetelstat are promising. Other areas of translational research involve targeting the inflammasome by anti-inflammatory drugs in order to improve anemia. These efforts will hopefully pave the way for new targeted treatment options for anemic low-risk MDS patients.


Assuntos
Resistência a Medicamentos , Hematínicos/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Animais , Terapia Combinada , Gerenciamento Clínico , Hematínicos/administração & dosagem , Hematínicos/efeitos adversos , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/metabolismo , Resultado do Tratamento
15.
Medicine (Baltimore) ; 98(35): e16742, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31464903

RESUMO

RATIONALE: Cases of coexistence of 2 cancers, such as colorectal cancer and diffuse large B-cell lymphoma (DLBCL), colorectal cancer and myelodysplastic syndrome (MDS), and DLBCL with MDS, have been reported, whereas the coexistence of 3 different cancers in a patient is extremely rare. Here we report a case of co-occurrence of colon adenocarcinoma, DLBCL, and MDS in a 78-year-old Chinese man. PATIENT CONCERNS: He presented to our hospital with palpable lumps in the abdomen without any of the following symptoms including abdominal pain, fever, contact pain, tenesmus, changes in bowel habits and shape, nausea, and vomiting. DIAGNOSES: The patient was first diagnosed with sigmoid colon adenocarcinoma and DLBCL in the right ascending colon using enhanced computed tomography, colonoscopy, and immunohistochemistry. After resection of the sigmoid adenocarcinoma and DLBCL, MDS was diagnosed according to the results of routine blood tests, bone marrow aspiration smear, and flow cytometry. INTERVENTIONS: Overall, the patient was treated with surgical resection of the sigmoid adenocarcinoma and DLBCL of the colon, combined with 4 cycles of chemotherapies targeting MDS. OUTCOMES: Blood test results and follow-up indicated that the treatment regimen showed promising outcomes. LESSONS: In conclusion, a case of synchronous existence of colon cancer, DLBCL, and MDS is reported, which suggests that careful attention should be paid clinically to checking the state of bone marrow for elderly cancer patients. Efforts are also needed to establish an effective system for distinguishing the origin of multi-existent cancers and to develop effective therapeutic regimens for multi-existent cancers with fewer side effects.


Assuntos
Adenocarcinoma/diagnóstico por imagem , Colo Ascendente/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Síndromes Mielodisplásicas/diagnóstico , Neoplasias do Colo Sigmoide/diagnóstico por imagem , Adenocarcinoma/cirurgia , Idoso , Biópsia , Medula Óssea , China , Colo Ascendente/patologia , Colonoscopia , Tratamento Farmacológico , Humanos , Linfoma Difuso de Grandes Células B/cirurgia , Masculino , Síndromes Mielodisplásicas/tratamento farmacológico , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Primárias Múltiplas/terapia , Neoplasias do Colo Sigmoide/cirurgia , Tomografia Computadorizada por Raios X , Resultado do Tratamento
16.
Crit Rev Oncol Hematol ; 142: 51-57, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31376677

RESUMO

The biological milieu and clinical picture of myelodysplastic syndromes (MDS) is characterised by a variety of immune mechanisms and manifestations, including an increased frequency of autoimmune disorders. The present review will try to shed some light on the potential clinical and pathogenetic implications of these immune processes in MDS by focusing on the beneficial effects exerted by some MDS-modifying therapies on autoimmune manifestations.


Assuntos
Doenças Autoimunes/terapia , Autoimunidade , Síndromes Mielodisplásicas/terapia , Doenças Autoimunes/tratamento farmacológico , Humanos , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/imunologia
17.
Int J Clin Oncol ; 24(11): 1449-1458, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31300904

RESUMO

BACKGROUND: The prevention of invasive fungal infections is important in patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) receiving cytoreductive chemotherapy. However, the role of oral voriconazole (VRCZ) in such patients has not been established. This study aimed to investigate the effectiveness of oral VRCZ compared to that of first-generation azoles prescribed within 7 days after the onset of chemotherapy in adult patients with AML/MDS using the Japanese administrative database. METHODS: This nationwide retrospective cohort study was conducted using the Diagnosis Procedure Combination/Per-Diem Payment System. The primary outcome was the proportion of patients who switched to intravenous antifungal agents. Analyses using the instrumental variable method were performed to address unmeasured confounding. RESULTS: In total, data on 5517 inpatients from 142 hospitals were analyzed. An oral VRCZ prescription was significantly associated with a reduction in the proportion of patients switching to intravenous antifungal agents compared to first-generation azole prescription (21.0% (95% confidence interval [CI] - 33.4 to - 8.6)). The impact of oral VRCZ in reducing the proportion of patients switching to intravenous antifungal agents was stronger in patients aged < 65 years than in those aged ≥ 65 years (- 40.6%, 95% CI - 63.2 to - 17.9; - 21.9%, 95% CI - 35.8 to - 8.1, respectively) and in patients prescribed oral azole within 3 days from the onset of chemotherapy than in those prescribed the same later (- 32.9%, 95% CI - 46.7 to - 19.2; - 9.0%, 95% CI - 33.7 to 15.7, respectively). CONCLUSION: Oral VRCZ administration may benefit adult patients with AML/MDS undergoing chemotherapy.


Assuntos
Antifúngicos/administração & dosagem , Infecções Fúngicas Invasivas/prevenção & controle , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Voriconazol/administração & dosagem , Administração Intravenosa , Administração Oral , Idoso , Feminino , Mortalidade Hospitalar , Humanos , Infecções Fúngicas Invasivas/mortalidade , Japão/epidemiologia , Tempo de Internação/estatística & dados numéricos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/mortalidade , Estudos Retrospectivos
18.
Drugs ; 79(12): 1305-1319, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31292909

RESUMO

Eltrombopag is an orally available thrombopoietin receptor agonist indicated for the treatment of immune thrombocytopenia (ITP). Beyond the effect on megakaryopoiesis, the drug also showed a stimulating effect on the hematopoietic stem cell with consistent clinical efficacy in aplastic anemia (AA) and myelodysplastic syndromes (MDS). Eltrombopag is highly effective in ITP and less so in AA and MDS. This observation underlines the importance of residual normal hematopoiesis, which is maximal in ITP, minimal/absent in AA, and dysregulated in MDS. In ITP, the drug at 50-75 mg daily induced up to 85% responses both in clinical trials and real-life studies, with the possibility of tapering and discontinuation. In AA, eltrombopag at 150 mg daily was effective in about 40% of cases relapsed/refractory to standard immunosuppression or ineligible for bone marrow transplant. In MDS, the drug seems less effective, with responses in about a quarter of patients at various schedules. The efficacy of eltrombopag in ITP, AA, and MDS suggests the existence of common immune-pathological mechanisms in these diseases, including autoimmunity against peripheral blood cells and bone marrow precursors, as well as a possible evolution of one condition into the other. Additional mechanisms of action emerging from the clinical use of eltrombopag include modulation of T-regulatory cells, restoration of Fc-γ receptor balance in phagocytes, and an iron-mobilizing effect. In this review, we analyzed the most recent literature on eltrombopag use and efficacy in patients with ITP, AA, and MDS, exploring the basis for different dosing, combined treatments, and discontinuation in each context.


Assuntos
Anemia Aplástica/tratamento farmacológico , Benzoatos/uso terapêutico , Hidrazinas/uso terapêutico , Megacariócitos/imunologia , Síndromes Mielodisplásicas/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/uso terapêutico , Benzoatos/administração & dosagem , Benzoatos/efeitos adversos , Humanos , Hidrazinas/administração & dosagem , Hidrazinas/efeitos adversos , Imunomodulação , Imunossupressão , Púrpura Trombocitopênica Idiopática/imunologia , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Receptores de Trombopoetina/agonistas
19.
Ann Hematol ; 98(9): 2063-2072, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31312928

RESUMO

Rigosertib is a novel multi-kinase inhibitor, which has clinical activity towards leukemic progenitor cells of patients with high-risk myelodysplastic syndromes (MDS) after failure or progression on hypomethylating agents. Since the bone marrow microenvironment plays an important role in MDS pathogenesis, we investigated the impact of rigosertib on cellular compartments within the osteo-hematopoietic niche. Healthy C57BL/6J mice treated with rigosertib for 3 weeks showed a mild suppression of hematopoiesis (hemoglobin and red blood cells, both - 16%, p < 0.01; white blood cells, - 34%, p < 0.05; platelets, - 38%, p < 0.05), whereas there was no difference in the number of hematopoietic stem cells in the bone marrow. Trabecular bone mass of the spine was reduced by rigosertib (- 16%, p = 0.05). This was accompanied by a lower trabecular number and thickness (- 6% and - 10%, respectively, p < 0.05), partly explained by the increase in osteoclast number and surface (p < 0.01). Milder effects of rigosertib on bone mass were detected in an MDS mouse model system (NHD13). However, rigosertib did not further aggravate MDS-associated cytopenia in NHD13 mice. Finally, we tested the effects of rigosertib on human mesenchymal stromal cells (MSC) in vitro and demonstrated reduced cell viability at nanomolar concentrations. Deterioration of the hematopoietic supportive capacity of MDS-MSC after rigosertib pretreatment demonstrated by decreased number of colony-forming units, especially in the monocytic lineage, further supports the idea of disturbed crosstalk within the osteo-hematopoietic niche mediated by rigosertib. Thus, rigosertib exerts inhibitory effects on the stromal components of the osteo-hematopoietic niche which may explain the dissociation between anti-leukemic activity and the absence of hematological improvement.


Assuntos
Glicina/análogos & derivados , Hematopoese/efeitos dos fármacos , Células-Tronco Hematopoéticas , Células-Tronco Mesenquimais , Síndromes Mielodisplásicas , Nicho de Células-Tronco/efeitos dos fármacos , Sulfonas/farmacologia , Animais , Glicina/farmacologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Transgênicos , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia
20.
Chin J Integr Med ; 25(7): 497-501, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31278627

RESUMO

OBJECTIVE: To investigate the relation of blood arsenic concentration (BAC) with clinical effect and safety of arsenic-containing Qinghuang Powder (, QHP) in patients with myelodysplastic syndrome (MDS). METHODS: Totally 163 patients with MDS were orally treated with QHP for 2 courses of treatment, 3 months as 1 course. The BACs of patients were detected by atomic fluorescence spectrophotometry at 1, 3, and 6 months during the treatment, and the effective rate, hematological improvement and safety in patients after treatment with QHP were analyzed. RESULTS: After 2 courses of treatment, the total effective rate was 89.6% (146/163), with 31.3% (51/163) of hematological improvement and 58.3% (95/163) of stable disease. The hemoglobin increased from 73.48 ± 19.30 g/L to 80.39 ± 26.56 g/L (P<0.05), the absolute neutrophil count increased from 0.81 ± 0.48 × 109/L to 1.08 ± 0.62 × 109/L (P<0.05), and no significant changes were observed in platelet counts (P>0.05). Among 46 patients previously depended on blood transfusion, 28.3% (13/46) completely got rid of blood transfusion and 21.7% (10/46) reduced the volume of blood transfusion by more than 50% after treatment. The BACs were significantly increased in patients treated for 1 month with 32.17 ± 18.04 µ g/L (P<0.05), 3 months with 33.56 ± 15.28 µ g/L (P<0.05), and 6 months with 36.78 ± 11.92 µ g/L (P<0.05), respectively, as compared with those before treatment (4.08 ± 2.11 µ g/L). There were no significant differences of BACs among the patients treated for 1, 3 and 6 months (P>0.05). The adverse reactions of digestive tract during the treatment were mild abdominal pain and diarrhea in 14 cases (8.6%), and no patients discontinued the treatment. The BACs of patients with gastrointestinal adverse reactions were significantly lower than those without gastrointestinal adverse reactions (22.39 ± 10.38 vs. 37.89 ± 11.84, µ g/L, P<0.05). The BACs of patients with clinical effect were significantly higher than those failed to treatment (40.41 ± 11.69 vs. 23.84 ± 12.03, µ g/L, P<0.05). CONCLUSION: QHP was effective and safe in the treatment of patients with MDS and the effect was associated with BACs of patients.


Assuntos
Arsênico/sangue , Arsenicais/efeitos adversos , Arsenicais/uso terapêutico , Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/uso terapêutico , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/tratamento farmacológico , Contagem de Células Sanguíneas , Transfusão de Sangue , Humanos , Cariótipo , Pós , Fatores de Risco
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