RESUMO
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of T cell progenitors, known to be a heterogeneous disease in pediatric and adult patients. Here we attempted to better understand the disease at the molecular level based on the transcriptomic landscape of 707 T-ALL patients (510 pediatric, 190 adult patients, and 7 with unknown age; 599 from published cohorts and 108 newly investigated). Leveraging the information of gene expression enabled us to identify 10 subtypes (G1G10), including the previously undescribed one characterized by GATA3 mutations, with GATA3R276Q capable of affecting lymphocyte development in zebrafish. Through associating with T cell differentiation stages, we found that high expression of LYL1/LMO2/SPI1/HOXA (G1G6) might represent the early T cell progenitor, pro/precortical/cortical stage with a relatively high age of disease onset, and lymphoblasts with TLX3/TLX1 high expression (G7G8) could be blocked at the cortical/postcortical stage, while those with high expression of NKX2-1/TAL1/LMO1 (G9G10) might correspond to cortical/postcortical/mature stages of T cell development. Notably, adult patients harbored more cooperative mutations among epigenetic regulators, and genes involved in JAK-STAT and RAS signaling pathways, with 44% of patients aged 40 y or above in G1 bearing DNMT3A/IDH2 mutations usually seen in acute myeloid leukemia, suggesting the nature of mixed phenotype acute leukemia.
Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras , Transcriptoma , Criança , Humanos , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genéticaRESUMO
Large amounts of azurophilic granules are considered to be a morphological feature of acute promyelocytic leukaemia (APL). However, a small percentage of acute myeloid leukaemia (AML) patients also have a large number of azurophilic granules. A large cohort of 3210 AML patients in our hospital was screened to identify AML patients who had a large number of azurophilic granules. The clinical parameters of these patients were collected and compared with typical AML patients (control Group 1) and APL patients (control Group 2). The incidence of AML with a large number of azurophilic granules was 1.26%. The fibrinogen and D-dimer levels of patients in the study group were more similar to those of patients in control Group 2, as was the incidence of bleeding events. Additionally, patients in the study group had higher FLT3-ITD and NPM1 mutation rates than patients in control Group 1. Finally, patients in the study group had a higher 30-day mortality rate than those in control Group 2 (24.2% vs. 9.09%) and showed a higher 30-day mortality trend than those in control Group 1. Therefore, we should pay more attention to the prevention of coagulation dysfunction and bleeding events for these patients.
RESUMO
Gilteritinib, a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor, was approved for relapsed/refractory (R/R) FLT3-mutated acute myeloid leukaemia (AML) patients but still showed limited efficacy. Here, we retrospectively analysed the efficacy and safety of different gilteritinib-based combination therapies (gilteritinib plus hypomethylating agent and venetoclax, G + HMA + VEN; gilteritinib plus HMA, G + HMA; gilteritinib plus venetoclax, G + VEN) in 33 R/R FLT3-mutated AML patients. The composite complete response (CRc) and modified CRc (mCRc) rates were 66.7% (12/18) and 88.9% (16/18) in patients received G + HMA + VEN, which was higher compared with that in G + HMA (CRc: 18.2%, 2/11; mCRc: 45.5%, 5/11) or G + VEN (CRc: 50.0%, 2/4; mCRc: 50.0%, 2/4). The median overall survival (OS) for G + HMA + VEN, G + HMA and G + VEN treatment was not reached, 160.0 days and 231.0 days. The median duration of remission (DOR) for G + HMA + VEN, G + HMA and G + VEN treatment was not reached, 82.0 days and 77.0 days. Four patients in the G + HMA + VEN group received alloHSCT after remission exhibited prolonged median DOR. The most common grade 3/4 adverse events were cytopenia, febrile neutropenia and pulmonary infection; there were no differences among the three groups. In conclusion, our data demonstrated promising response of G + HMA + VEN combination therapy in R/R FLT3-mutated AML, and it may be considered an effective therapy bridge to transplantation.
Assuntos
Compostos de Anilina , Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Pirazinas , Sulfonamidas , Tirosina Quinase 3 Semelhante a fms , Adulto , Humanos , Estudos RetrospectivosRESUMO
Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy (DAV) has shown safety and efficacy in eligible patients with newly diagnosed acute myeloid leukemia (AML). However, there are no direct comparisons between DAV and 3 + 7 daunorubicin and cytarabine chemotherapy (DA) alone. We performed a propensity score-matched analysis to compare the outcomes of DAV group with historical DA group and identify the clinical and molecular characteristics of patients who might benefit from the DAV regimen. The DAV group had a higher Complete remission (CR) rate than the DA group (90% vs. 55%, p = 0.008). 25 (96%) patients in the DAV group had a higher MRD-negative CRc rate compared with 13 (62%) patients in the DA group (p = 0.006). After a median follow-up duration of 19.15 (IQR 17.13-21.67) months, the DAV group had an improved overall survival (p = 0.001) and event-free survival (p = 0.069), but not disease-free survival (p = 0.136). Collectively, DAV regimen induced high CR rates and deep MRD-negative CRc rates after one cycle of induction therapy, as well as prolonged the overall survival, in young adult patients with AML who were eligible for intensive chemotherapy. The addition of venetoclax to intensive chemotherapy should be considered in the future to achieve better survival advantages in eligible AML patients.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Sulfonamidas , Adulto Jovem , Humanos , Pontuação de Propensão , Leucemia Mieloide Aguda/tratamento farmacológico , Daunorrubicina , Citarabina , Resposta Patológica CompletaRESUMO
As all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are widely accepted in treating acute promyelocytic leukemia (APL), deescalating toxicity becomes a research hotspot. Here, we evaluated whether chemotherapy could be replaced or reduced by ATO in APL patients at different risks. After achieving complete remission with ATRA-ATO-based induction therapy, patients were randomized (1:1) into ATO and non-ATO groups for consolidation: ATRA-ATO versus ATRA-anthracycline for low-/intermediate-risk patients, or ATRA-ATO-anthracycline versus ATRA-anthracycline-cytarabine for high-risk patients. The primary end point was to assess disease-free survival (DFS) at 3 y by a noninferiority margin of -5%; 855 patients were enrolled with a median follow-up of 54.9 mo, and 658 of 755 patients could be evaluated at 3 y. In the ATO group, 96.1% (319/332) achieved 3-y DFS, compared to 92.6% (302/326) in the non-ATO group. The difference was 3.45% (95% CI -0.07 to 6.97), confirming noninferiority (P < 0.001). Using the Kaplan-Meier method, the estimated 7-y DFS was 95.7% (95% CI 93.6 to 97.9) in ATO and 92.6% (95% CI 89.8 to 95.4) in non-ATO groups (P = 0.066). Concerning secondary end points, the 7-y cumulative incidence of relapse (CIR) was significantly lower in ATO (2.2% [95% CI 1.1 to 4.2]) than in non-ATO group (6.1% [95% CI 3.9 to 9.5], P = 0.011). In addition, grade 3 to 4 hematological toxicities were significantly reduced in the ATO group during consolidation. Hence, ATRA-ATO in both chemotherapy-replacing and -reducing settings in consolidation is not inferior to ATRA-chemotherapy (https://www.clinicaltrials.gov/, NCT01987297).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Trióxido de Arsênio/administração & dosagem , Leucemia Promielocítica Aguda/tratamento farmacológico , Tretinoína/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Trióxido de Arsênio/efeitos adversos , Quimioterapia de Consolidação/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Resultado do Tratamento , Tretinoína/efeitos adversosRESUMO
As reported, SETD2 is recurrently mutated in acute myeloid leukaemia (AML), but knowledge about the specifics is limited. We enrolled 530 consecutive newly diagnosed AML patients in our study, and we analysed the distribution pattern and prognostic role of SETD2 mutation in AML. SETD2 mutation was found to affect 6.3% of AML patients, and it frequently co-occurred with IDH2, NRAS and CEBPA mutations. SETD2-mutated patients saw excellent therapeutic responses but failed to gain better survival time than other patients. This could be because of the high recurrence and mortality in SETD2-mutated patients who have additional mutations, such as NRAS mutation.
Assuntos
Leucemia Mieloide Aguda , Nucleofosmina , Humanos , Prognóstico , Mutação , Leucemia Mieloide Aguda/terapiaRESUMO
Minimal residual disease (MRD) is an important independent prognostic factor for relapse and survival in acute lymphoblastic leukaemia (ALL). Compared with adult B-cell ALL, reports of adult T-cell ALL (T-ALL) MRD have been scarce and mostly based on molecular methods. We evaluated the prognostic value of multiparameter flow cytometry (FCM)-based MRD at the end of induction (EOI-MRD). The present retrospective study included 94 adult patients with T-ALL. MRD was detected by six- to eight-colour FCM. Patients who were EOI-MRD positive had a higher cumulative incidence of relapse (CIR) (87·6% vs. 38·8%, P = 0·0020), and a lower relapse-free survival (RFS) (5·4% vs. 61·0%, P = 0·0005) and overall survival (OS) (32·7% vs. 69·7%, P < 0·0001) than those who were EOI-MRD negative. Moreover, for patients who received allogeneic haematopoietic stem cell transplantation (allo-HSCT) at their first remission, EOI-MRD positivity was predictive of post-transplant relapse (2-year CIR: 68·2% vs. 4·0%, P = 0·0003). Multivariate analysis showed that EOI-MRD was an independent prognostic factor for CIR [hazard ratio (HR) 2·139, P = 0·046], RFS (HR 2·125, P = 0·048) and OS (HR 2·987, P = 0·017). In conclusion, EOI-MRD based on FCM was an independent prognostic factor for relapse and survival in adult T-ALL. For patients who underwent HSCT, EOI-MRD could be used to identify patients with a high risk of relapse after allo-HSCT.
Assuntos
Citometria de Fluxo , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Adolescente , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células T Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Estudos Retrospectivos , Medição de Risco , Taxa de SobrevidaRESUMO
The identification of genetic risk subgroups of T-cell acute lymphoblastic leukemia (T-ALL) may provide evidence for risk stratification and individualized treatment. We investigated the characteristics and prognostic value of tumor suppressor gene CDKN2A deletions in 101 patients with T-ALL. The CDKN2A deletion was present in 23% (23/101) of T-ALL by fluorescence in situ hybridization (FISH). The most common type of CDKN2A deletion was homozygous deletion (70%, 16/23). A lower frequency of CDKN2A deletion was found in patients with early T-cell precursor (ETP) ALL than in patients with non-ETP-ALL (10.4% vs 34.0%; P = .008). Deletion of CDKN2A was significantly associated with younger age (P = .001), higher white blood cell (WBC) count (P < .001) and higher lactate dehydrogenase (LDH) level (P = .002). Patients with CDKN2A deletion had lower 2-year overall survival (OS) and event-free survival (EFS) rates than patients without CDKN2A deletion (2-year OS: 18.6% ± 8.9% vs 47.4% ± 6.2%, P = .032; EFS: 16.4 ± 8.3 vs 38.6 ± 5.9%, P = .022). In multivariable analysis, CDKN2A deletion was an independent adverse prognostic factor for OS (P = .016). In conclusion, adult T-ALL patients with CDKN2A deletion had a poor prognosis, and these patients might benefit from intensive chemotherapy or allogeneic hematopoietic stem-cell transplantation.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/deficiência , Deleção de Genes , Genes p16 , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Adolescente , Adulto , Idoso , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , China/epidemiologia , Terapia Combinada , Análise Mutacional de DNA , DNA de Neoplasias/genética , Feminino , Transplante de Células-Tronco Hematopoéticas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Prognóstico , Resultado do Tratamento , Adulto JovemRESUMO
Decitabine and low-dose chemotherapy are common treatments for intermediate and high risk myelodysplastic syndromes (MDS). In this study, we retrospectively assessed the efficacy and toxicity of the two regimens for MDS-refractory anemia with excess blasts (MDS-RAEB) patients. A total of 112 patients with a diagnosis of MDS-RAEB are included. The overall response (OR) and complete remission (CR) rate was comparable between the two groups (OR: 64.1% vs. 66.7%, pâ¯=â¯0.60; CR: 23.4% vs. 31.3%, pâ¯=â¯0.64). The OR rates of 20â¯mg/m2/day and 15â¯mg/m2/day decitabine regimen were comparable (69.0% vs. 60.0%, pâ¯=â¯0.46). Overall survival (OS) did not differ significantly between the groups (20.7 vs. 13.5â¯months, pâ¯=â¯0.17). In a subgroup analysis that included only patients at ≥60â¯years of age, survival benefit of decitabine was apparent (20.6 vs. 10.0â¯months, pâ¯=â¯0.03). In hematological toxicities, the lowest count of platelet in the decitabine group was higher significantly. And, the incidence of Grade 3-4 infection in the decitabine group was lower significantly. Our results demonstrate that both decitabine and low-dose chemotherapy are effective for MDS-RAEB, but decitabine was safer. Decitabine might be a better choice for patients at ≥60â¯years of age.
Assuntos
Anemia Refratária com Excesso de Blastos/tratamento farmacológico , Anemia Refratária com Excesso de Blastos/mortalidade , Antimetabólitos Antineoplásicos/uso terapêutico , Decitabina/uso terapêutico , Adulto , Idoso , Anemia Refratária com Excesso de Blastos/diagnóstico , Anemia Refratária com Excesso de Blastos/etiologia , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Biomarcadores , Decitabina/administração & dosagem , Decitabina/efeitos adversos , Feminino , Testes Genéticos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/mortalidade , Razão de Chances , Prognóstico , Resultado do TratamentoRESUMO
BACKGROUND: Pulmonary computed tomography (CT) scans are commonly used as part of the clinical criteria in diagnostic workup of invasive fungal diseases like invasive aspergillosis, and may identify radiographic abnormalities, such as halo signs or air-crescent signs. We assessed the diagnostic utility of CT assessment in patients with hematologic malignancies or those who had undergone allogeneic hematopoietic stem cell transplantation in whom invasive aspergillosis was suspected. METHODS: This post-hoc analysis assessed data from a prospective, multicenter, international trial of voriconazole (with and without anidulafungin) in patients with suspected invasive aspergillosis (IA; proven, probable, or possible, using 2008 European Organisation for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria) [NCT00531479]. Eligible patients received at least one baseline lung CT scan. RESULTS: Of 395 patients included in this post-hoc analysis, 240 patients (60.8%) had 'confirmed' proven (9/240, 3.8%) or probable (231/240, 96.3%) invasive aspergillosis (cIA) and 155 patients (39.2%) had 'non-confirmed' invasive aspergillosis (all nIA; all possible IA (de Pauw et al., Clin Infect Dis 46:1813-21, 2008)). Mean age was 52.3 and 50.5 years, 56.3 and 60.0% of patients were male, and most patients were white (71.7 and 71.0%) in the cIA and nIA populations, respectively. Median baseline galactomannan was 1.4 (cIA) and 0.2 (nIA), mean Karnofsky score was 65.3 (cIA) and 66.8 (nIA), and mean baseline platelet count was 48.0 (cIA) and 314.1 (nIA). Pulmonary nodules (46.8% of all patients), bilateral lung lesions (37.5%), unilateral lung lesions (28.4%), and consolidation (24.8%) were the most common radiographic abnormalities. Ground-glass attenuation (cIA: 24.2%; nIA: 11.6%; P < 0.01) and pulmonary nodules (cIA: 52.5%; nIA: 38.1%; P < 0.01) were associated with cIA. Other chest CT scan abnormalities (including halo signs and air-crescent signs) at baseline in patients with hematologic malignancy or hematopoietic stem cell transplantation, and suspected IA, were not associated with cIA. CONCLUSIONS: These findings highlight the limitations in the sensitivity of chest CT scans for the diagnosis of IA, and reinforce the importance of incorporating other available clinical data to guide management decisions on individual patients, including whether empirical treatment is reasonable, pending full evaluation. TRIAL REGISTRATION: NCT00531479 (First posted on ClinicalTrials.gov on September 18, 2007).
Assuntos
Neoplasias Hematológicas/microbiologia , Aspergilose Pulmonar Invasiva/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adulto , Anidulafungina/uso terapêutico , Feminino , Galactose/análogos & derivados , Neoplasias Hematológicas/mortalidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Aspergilose Pulmonar Invasiva/mortalidade , Avaliação de Estado de Karnofsky , Pulmão/microbiologia , Pulmão/patologia , Masculino , Mananas/sangue , Pessoa de Meia-Idade , Contagem de Plaquetas , Estudos Prospectivos , Voriconazol/uso terapêuticoAssuntos
Daunorrubicina , Leucemia Mieloide Aguda , Humanos , Idoso , Daunorrubicina/uso terapêutico , Citarabina/uso terapêutico , Estudos Retrospectivos , Leucemia Mieloide Aguda/etiologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Indução de RemissãoRESUMO
Limited data was available for long-term follow-up in newly diagnosed acute promyelocytic leukemia (APL) patients treated with all-trans-retinoic acid (ATRA) plus intravenously arsenic trioxide (ATO)-based front-line therapy. The aim of this work was to retrospectively analyze the long-term survival rate and frequency of therapy-related myeloid neoplasia (t-MN) occurring in a large cohort of APL patients. A total of 760 newly diagnosed patients with APL between January 1999 and May 2016 were evaluated. The early death rate was 9.2% (70/760). Of the remaining 690 patients with complete remission, patients were grouped according to front-line regimens: ATRA plus ATO with or without chemotherapy (ATO group) and ATRA with chemotherapy (non-ATO group). The median duration of follow-up was 7.5 years (1.0-18.3 years). ATO group showed significant superior 10-year estimated relapse-free survival (RFS) up to 90.3% comparing with 65.5% in the non-ATO group (P < 0.0001). In addition, the 10-year estimated overall survival (OS) was 93.9% for patients in the ATO group and 89.1% for those in the non-ATO group (P = 0.03). In the subgroup analysis, the RFS rate was also higher in ATO group comparing with non-ATO group in both low-to-intermediate-risk (94.2% vs 64.6%, P < 0.0001) and high-risk subgroup (89.6% vs 74.7%, P = 0.04). Notably, the 3-year RFS and OS rates in the chemotherapy-free subgroup of the low-to-intermediate-risk patients (n = 88) were 100% and 100%, respectively. In the entire cohort, a total of 10 patients developed secondary malignant neoplasms, including 7 patients with therapy-related myeloid neoplasms (t-MN). The estimated 5-year cumulative incidence risk of t-MN in the ATO and non-ATO groups was 1.0% and 0.4%, respectively (P = 0.34). Thus, our data revealed that the long-term outcome of patients treated with ATRA plus ATO-based regimens was associated with continuing high efficacy in all Sanz risk patients with newly diagnosed APL.
RESUMO
Early death is the main obstacle for the cure of patients with acute promyelocytic leukemia (APL). We have analyzed risk factors of early death from 526 consecutive newly diagnosed APL patients between 2004 and 2016. The overall incidence of early death was 7.2% (38/526). The peak hazard of early death occurred in the first 0-3 days. Multivariate logistic analysis demonstrated white blood cell (WBC) counts [odds ratio (OR) = 1.039; 95% confidence interval (CI): 1.024-1.055; P < 0.001], age (OR = 1.061; 95% CI: 1.025-1.099; P = 0.001) and platelet counts (OR = 0.971; 95% CI: 0.944-0.999; P = 0.038) were independent risk factors for early death. Furthermore, receiver-operator characteristic (ROC) curve analyses revealed a simple WBC/platelet ratio was significantly more accurate in predicting early death [areas under the ROC curve (AUC) = 0.842, 95% CI: 0.807-0.872) than WBC counts (AUC = 0.793; 95% CI: 0.756-0.827) or Sanz score (AUC = 0.746; 95% CI: 0.706-0.783). We stratified APL patients into four risk subgroups: low risk (WBC ≤ 10 × 109/L, platelet >40 × 109/L), intermediate risk (WBC/platelet <0.2 and age ≤ 60, not in low risk), high risk (WBC/platelet ≥0.2 or age > 60, not in low and ultra-high risk) and ultra-high risk (WBC > 50 × 109/L), the early death rates were 0, 0.6, 12.8, and 41.2%, respectively. In conclusion, we proposed a modified Sanz risk model as a useful predictor of early death risk in patients with APL.
Assuntos
Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/mortalidade , Modelos Teóricos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Valor Preditivo dos Testes , Estudos Prospectivos , Estudos Retrospectivos , Fatores de RiscoRESUMO
Clostridium difficile infection (CDI) is increasing in incidence and severity. Clinically, diarrhea frequently occurs, but severe hematochezia is rarely seen with CDI. We describe here a hematopoietic stem cell transplantation (HSCT) recipient who experienced life-threatening gastrointestinal bleeding due to severe CDI. Subsequent stool surveillance and molecular typing observed the patient who had two episodes of recurrence with a new strain of C. difficile distinct from the initial infection. We analyze C. difficile strains obtained from the patient, and also discuss the diagnosis and treatment of this case.
Assuntos
Clostridioides difficile/isolamento & purificação , Infecções por Clostridium/imunologia , Diarreia/imunologia , Hemorragia Gastrointestinal/imunologia , Hospedeiro Imunocomprometido , Clostridioides difficile/genética , Infecções por Clostridium/diagnóstico , Infecções por Clostridium/microbiologia , Diarreia/diagnóstico , Diarreia/microbiologia , Fezes/microbiologia , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/microbiologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Adulto JovemAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia Promielocítica Aguda , Proteínas de Fusão Oncogênica , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Arsenicais/administração & dosagem , Feminino , Seguimentos , Humanos , Leucemia Promielocítica Aguda/sangue , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/sangue , Proteínas de Fusão Oncogênica/genética , Estudos Retrospectivos , Tretinoína/administração & dosagemRESUMO
The aim of the study is to better understand the mechanism of relapse and acquired clinical resistance to arsenic trioxide (ATO) and/or all-trans retinoic acid (ATRA). Thirty relapsed acute promyelocytic leukemia (APL) patients were followed. Fifteen patients experienced two or more relapses; nine patients had clinical resistance to ATO-based therapy. The frequency and clinical significance of promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARA) mutational status using Sanger sequencing were evaluated. Overall, eight different types of mutations in the RARA region (V218D, R272Q, T278A, T291I, N299D, R294W, A300G, and L220_F228delinsP) were identified in 11 patients. Eight missense mutations (L211P, C213R, S214L, A216V, L217F, D219H, S221G, and D241G) were found in the PML portion of PML-RARA in 14 patients, with A216V as the predominant mutation. Eight patients were found to harbor both PML and RARA mutations over the course of the disease. The PML-region mutations were associated with response to ATO-based therapy (P < 0.0001), number of relapses (P = 0.001), and early relapse (P = 0.013). Notably, one case sampled at nine different time points showed alternating clonal dominance over the course of treatment. This study demonstrated frequent mutations of PML-RARA and supported a clonal selection model in relation to APL relapse and ATO resistance.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Arsenicais/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Mutação de Sentido Incorreto , Proteínas de Fusão Oncogênica/genética , Óxidos/administração & dosagem , Adolescente , Adulto , Idoso , Trióxido de Arsênio , Feminino , Seguimentos , Frequência do Gene , Humanos , Leucemia Promielocítica Aguda/epidemiologia , Leucemia Promielocítica Aguda/patologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Recidiva , Adulto JovemAssuntos
Leucemia Promielocítica Aguda , Complexo de Proteínas Formadoras de Poros Nucleares , Proteínas de Fusão Oncogênica , RNA Mensageiro , RNA Neoplásico , Receptor alfa de Ácido Retinoico , Adulto , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Masculino , Complexo de Proteínas Formadoras de Poros Nucleares/biossíntese , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas de Fusão Oncogênica/biossíntese , Proteínas de Fusão Oncogênica/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Receptor alfa de Ácido Retinoico/biossíntese , Receptor alfa de Ácido Retinoico/genéticaRESUMO
We evaluated the efficacy of low-dose all-trans retinoic acid (ATRA) plus minimal chemotherapy for induction in newly diagnosed acute promyelocytic leukaemia (APL). Furthermore, we compared its long-term outcome with or without the addition of intravenous arsenic trioxide (ATO) in post-remission therapy. From January 2004 to September 2011, a total of 109 patients with a median age of 41 years (range 14-73) were enrolled in the study. Two arms were assigned according to post-remission protocols: ATO group cases were subsequently treated with intravenous ATO, standard chemotherapy, and ATRA. No-ATO group cases were subsequently treated with chemotherapy and ATRA only. Patients were monitored of minimal residual disease (MRD) by reverse-transcriptase polymerase chain reaction. The haematologic complete remission (CR) rate was 96.3%. The early death rate was 0.9%. At a median follow-up of 49 months (range 8-102 months), the Kaplan-Meier estimates of 5-year relapse-free survival were significantly better for patients in the ATO group than in the no-ATO group, 94.4% vs 54.8% (p = 0.0001), and the 5-year overall survival rate was 95.7% vs 64.1%, in the two groups (p = 0.003). Our data show that low-dose ATRA plus minimal chemotherapy exhibits efficacy in induction therapy for untreated APL and suggest that the addition of ATO to post-remission therapy significantly improves the long-term outcome.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Trióxido de Arsênio , Arsenicais/administração & dosagem , China , Quimioterapia de Consolidação , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Dexametasona/administração & dosagem , Avaliação de Medicamentos , Feminino , Harringtoninas/administração & dosagem , Mepesuccinato de Omacetaxina , Humanos , Idarubicina/administração & dosagem , Infusões Intravenosas , Estimativa de Kaplan-Meier , Leucemia Promielocítica Aguda/genética , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Neoplasia Residual , Proteínas de Fusão Oncogênica/genética , Óxidos/administração & dosagem , Recidiva , Indução de Remissão , Estudos Retrospectivos , Terapia de Salvação , Resultado do Tratamento , Tretinoína/administração & dosagem , Adulto JovemRESUMO
Arsenic trioxide (ATO) is an effective therapy for relapsed acute promyelocytic leukemia (APL) patients; however, the optimal treatment strategy remains unclear, and knowledge of the prognostic factors is still limited. We retrospectively analyzed the outcomes of 64 consecutive first relapsed APL patients (12 with molecular relapse and 52 with hematologic relapse). Patients received re-induction with intravenous ATO-based regimens. Patients who achieved a CR2 were offered further courses of alternating ATO/conventional chemotherapy with or without stem cell transplantation (SCT). With a median follow-up of 27 months (range, 6-57) in the molecular relapsed subgroup, the 3-year relapse-free survival (RFS) and overall survival (OS) rates were 81.5 % and 100 %, respectively. With a median follow-up of 38 months (range, 0-129) in the hematologic relapse group, the 3-year RFS and OS rates were 57.1 % and 72.1 %, respectively. Furthermore, in the hematologic relapse group, we compared the outcome between relapsed patients after previous ATO therapy (n = 20) with those who did not receive prior ATO therapy (n = 32). The CR2 rate was 80 % (16/20) vs. 93.8 % (30/32), (p = 0.189). However, the relapse rate was 68.8 % (11/16) vs. 33.3 % (10/30), (p = 0.03). The 4-year OS rate was 62.4 % vs. 71.2 %, (p = 0.816), and the 4-year RFS rate was 29.8 % vs. 66.2 % (p = 0.023). The results indicate that, irrespective of frontline therapy with ATO, salvage therapy with an ATO-based regimen remains effective. However, the long-term survival for those patients who received previous ATO-based treatment was inferior compared to those who did not receive prior ATO. In addition, the alternating ATO/chemotherapy strategy can be a post-remission treatment option in a subset of patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Terapia de Salvação , Adolescente , Adulto , Idoso , Trióxido de Arsênio , Arsenicais/administração & dosagem , Terapia Combinada , Avaliação de Medicamentos , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Infusões Intravenosas , Estimativa de Kaplan-Meier , Leucemia Promielocítica Aguda/cirurgia , Masculino , Pessoa de Meia-Idade , Óxidos/administração & dosagem , Prognóstico , Modelos de Riscos Proporcionais , Recidiva , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Homoharringtonine-based induction regimens have been widely used in China for patients with acute myeloid leukaemia. However, their efficacy has not been tested in a multicentre randomised controlled trial in a large population. We assessed the efficacy and safety of homoharringtonine-based induction treatment for management of newly diagnosed acute myeloid leukaemia. METHODS: This open-label, randomised, controlled, phase 3 study was done in 17 institutions in China between September, 2007, and July, 2011. Untreated patients aged 14-59 years with acute myeloid leukaemia were randomly assigned (by a computer-generated allocation schedule without stratification) to receive one of three induction regimens in a 1:1:1 ratio: homoharringtonine 2 mg/m(2) per day on days 1-7, cytarabine 100 mg/m(2) per day on days 1-7, and aclarubicin 20 mg/day on days 1-7 (HAA); homoharringtonine 2 mg/m(2) per day on days 1-7, cytarabine 100 mg/m(2) per day on days 1-7, and daunorubicin 40 mg/m(2) per day on days 1-3 (HAD); or daunorubicin 40-45 mg/m(2) per day on days 1-3 and cytarabine 100 mg/m(2) per day on days 1-7 (DA). Patients in complete remission were offered two cycles of intermediate-dose cytarabine (2 g/m(2) every 12 h on days 1-3). The primary endpoints were the proportion of patients who achieved complete remission after two cycles of induction treatment and event-free survival in the intention-to-treat population. The trial is registered in the Chinese Clinical Trial Register, number ChiCTR-TRC-06000054. FINDINGS: We enrolled 620 patients, of whom 609 were included in the intention-to-treat analysis. 150 of 206 patients (73%) in the HAA group achieved complete remission versus 125 of 205 (61%) in the DA group (p=0.0108); 3-year event-free survival was 35.4% (95% CI 28.6-42.2) versus 23.1% (95% CI 17.4-29.3; p=0.0023). 133 of 198 patients (67%) in the HAD group had complete remission (vs DA, p=0·20) and 3-year event-free survival was 32.7% (95% CI 26.1-39.5; vs DA, p=0.08). Adverse events were much the same in all groups, except that more patients in the HAA (12 of 206 [5.8%]) and HAD (13 of 198 [6.6%]) groups died within 30 days than in the DA group (two of 205 [1%]; p=0.0067 vs HAA; p=0.0030 vs HAD). INTERPRETATION: A regimen of homoharringtonine, cytarabine, and aclarubicin is a treatment option for young, newly diagnosed patients with acute myeloid leukaemia. FUNDING: Chinese National High Tech Programme, Key Special Research Foundation of the Ministry of Science and Technology of China, National Nature Science Foundation of China, National Clinical Key Specialty Construction Project.