阿拓莫兰对成人急性髓样白血病化疗患者肝功能损伤的预防作用观察

目的 观察阿拓莫兰对成人急性髓样白血病化疗患者肝功能损伤的预防作用。方法 选取我院2013年1月至2015年3月期间收治的急性髓样白血病患者103例,采用随机数字表法将纳入的患者分为观察组52例和对照组51例。给予对照组患者柔红霉素和阿糖胞苷（DA）方案化疗,观察组在对照组基础上给予阿拓莫兰,检测并分析两组患者在化疗前和化疗后不同时间肝功能指标的变化。结果 化疗后,观察组患者血清ALT水平为（41.67±5.02）U/L,显著低于对照组（52.68±5.41）U/L,差异有显著性（P<0.05）,观察组AST水平为（37.50±4.22）U/L,低于对照组（43.27±4.31）U/L,差异有显著性（P<0.05）,观察组血清TBiL水平为（20.05±2.22）μmol/L,低于对照组的（25.96±3.30）μmol/L,差异具有显著性（P<0.05）;化疗后,观察组患者肝损伤为9.62%,显著低于对照组的29.41%,差异具有显著性（P<0.05）;治疗后,两组患者外周血白细胞计数显著下降、红细胞显著上升、血小板显著下降,但组间比较差异无显著性（P>0.05）。结论 阿拓莫兰可显著降低成人急性髓样白血病化疗患者肝损伤发生率和损伤程度。     

Outcomes and charges of elderly patients with acute myeloid leukemia

A retrospective database analysis was conducted to evaluate hospitalization outcomes and charges among elderly acute myeloid leukemia (AML) patients. The data source was a longitudinal (2000-2003) inpatient database from 28 US hospitals. Data on 275 AML patients aged 60 and older were analyzed for demographic and treatment characteristics, hospital mortality, length of stay (LOS), overall days of stay (DOS), and charges across multiple admissions. Multivariate modeling was performed to determine factors that influenced outcomes. Overall, 115 (41.8%) patients received inpatient chemotherapy (CT); most (90.4%) received it on the first admission. Of all initial CT regimens 40.9% consisted of a single agent. The mean LOS for initial hospitalization was 23.0 (SD 21.8) days for patients who received CT and 6.7 (SD 7.5) days for those who did not. One quarter (25.3%) of initial hospitalizations resulted in death. On initial hospitalization, mean total charges were $113,118 (SD $220,417) for patients who received CT and $43,999 (SD $190,533) for those who did not; for both groups mean charges were higher than respective subsequent admission charges. Overall, in-hospital mortality did not differ significantly between on-CT and off-CT groups (43.5 and 38.8%, respectively). In multivariate modeling, CT was significantly associated (P < 0.0001) with increased charges and LOS. Elderly patients with AML incurred substantial hospital charges and inpatient mortality. The highest charges and a substantial number of deaths occurred during first admission. Although treatment with CT was associated with increased charges and days in-hospital, inpatient mortality in the two groups was found to be similar.     

Long-term outcome of high risk patients with myelodysplastic syndromes or secondary acute myeloid leukemia receiving intensive chemotherapy

Intensive chemotherapy (IC) used to be a common treatment approach for patients with higher-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia after MDS (sAML). We conducted a retrospective analysis of 299 patients, including a matched pair analysis comparing 96 patients receiving IC with 96 patients not undergoing IC, in order to evaluate the impact of IC on overall survival (OS) and to identify factors that influence remission rates and OS. Complete remission (CR) after first induction chemotherapy was reached in 50% of patients. Parameters influencing the probability of achieving CR were blast count in the bone marrow (<?30%), age <?65 years, presence of Auer rods, duration of antecedent MDS shorter than 6 months, and timing of IC in relation to first diagnosis. The difference in survival time was not significantly better for patients receiving IC (median OS 12.7 months vs. 7 months). Parameters favorably influencing survival were the presence of Auer rods, age below 60 years, blast count below 30%, IC given shortly after first diagnosis, and achievement of CR. On multivariate analysis, achieving CR, presence of Auer rods, and percentage of blasts below or above 30% significantly influenced median survival. Relapse occurred in 63% of patients after a median of 9.9 months with a median survival of 7.6 months. Considering the high relapse rate and short survival, we conclude that intensive chemotherapy is not promising for high-risk MDS or sAML.     

Role of induction and consolidation chemotherapy in elderly acute myeloid leukemia patients

The present study sought to elucidate the role of induction and consolidation therapy in elderly patients. We retrospectively collected data of 477 patients who were aged over 60 years at the time of acute myeloid leukemia (AML) diagnosis. The median overall survival (OS) was 339 days in the induction group (n = 266) and 86 days in the best supportive care group (n = 211) (P < 0.001). In the induction group, the complete remission (CR) rate was 58.3 %, and treatment-related death was 15.4 %. Successful induction was related to good performance [Eastern Cooperative Oncology Group (ECOG <2)] [hazard ratio (HR) 3.215; P = 0.002]. Mortality correlated with failure to achieve CR (HR 4.059; P < 0.001) and poor performance status (ECOG >2) (HR 2.731; P = 0.035). In CR patients, poor karyotype and absence of consolidation (HR 2.313; P = 0.003) correlated with mortality. More than one cycle of consolidation was associated with better OS (P < 0.001). Lack of salvage therapy was associated with mortality in patients who did not achieve CR (HR 3.223; P = 0.005). Intensive induction in patients with good performance and >1 cycle of consolidation after CR may be the best strategy for improving OS in elderly AML patients.     

Hemophagocytic syndrome in patients with acute myeloid leukemia undergoing intensive chemotherapy

Hemophagocytic lymphohistiocytosis is a condition of immune dysregulation characterized by severe organ damage induced by a hyperinflammatory response and uncontrolled T-cell and macrophage activation. Secondary hemophagocytic lymphohistiocytosis typically occurs in association with severe infections or malignancies. Patients with acute myeloid leukemia may be prone to develop hemophagocytic lymphohistiocytosis because of an impaired immune response and a high susceptibility to severe infections. In a series of 343 patients treated by intensive chemotherapy over a 5-year period in our center, we identified 32 patients (9.3%) with fever, very high ferritin levels, and marrow hemophagocytosis (i.e. patients with hemophagocytic lymphohistiocytosis). Compared to patients without hemophagocytic lymphohistiocytosis, these 32 patients had hepatomegaly, pulmonary or neurological symptoms, liver abnormalities, lower platelet count and higher levels of C-reactive protein as well as prolonged pancytopenia. A microbial etiology for the hemophagocytosis was documented in 24 patients: 14 bacterial infections, 9 Herpesviridae infections and 11 fungal infections. The treatment of hemophagocytic lymphohistiocytosis consisted of corticosteroids and/or intravenous immunoglobulins along with adapted antimicrobial therapy. Patients with hemophagocytic lymphohistiocytosis had a median overall survival of 14.9 months, which was significantly shorter than that of patients without hemophagocytic lymphohistiocytosis (22.1 months) (P=0.0016). Hemophagocytic lymphohistiocytosis was significantly associated with a higher rate of induction failure, mainly due to deaths in aplasia. Hemophagocytic lymphohistiocytosis can be diagnosed in up to 10% of patients with acute myeloid leukemia undergoing intensive chemotherapy and is associated with early mortality. Fever, very high ferritin levels and marrow hemophagocytosis represent the cornerstone of the diagnosis. Further biological studies are needed to better characterize and recognize this syndrome in patients with acute myeloid leukemia.     

Choosing induction chemotherapy in therapy-related acute myeloid leukemia

Patients with AML that develops after cytotoxic therapy (tAML) have overall inferior outcomes relative to de novo AML due to both patient-related factors and the intrinsic biology of the disease. Treatment of patients with tAML is challenging. The key initial clinical decision is whether a patient is a candidate for or likely to benefit from intensive induction chemotherapy, a determination which we argue should not be predicated on chronologic age alone. For those determined likely to tolerate intensive induction chemotherapy, CPX-351 is likely superior to conventional induction with cytarabine and daunorubicin. For those deemed inappropriate for intensive induction, hypomethylating agents have the strongest evidence base in elderly adults with AML, and are an attractive option in tAML. This is particularly true in patients with TP53 mutations who are less likely to respond to conventional induction chemotherapy. Exciting options on the therapeutic horizon for tAML include combination therapies incorporating BCL2 inhibitors, Hedgehog pathway inhibitors, and isocitrate dehydrogenase inhibitors.     

Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy

Granulocyte colony-stimulating factor (G-CSF) has had a major impact on management of "severe chronic neutropenia," a collective term referring to congenital, idiopathic, or cyclic neutropenia. Almost all patients respond to G-CSF with increased neutrophils, reduced infections, and improved survival. Some responders with congenital neutropenia have developed myelodysplastic syndrome and acute myeloblastic leukemia (MDS/AML), which raises the question of the role of G-CSF in pathogenesis. The Severe Chronic Neutropenia International Registry (SCNIR), Seattle, WA, has data on 696 neutropenic patients, including 352 patients with congenital neutropenia, treated with G-CSF from 1987 to present. Treatment and patient demographic data were analyzed. The 352 congenital patients were observed for a mean of 6 years (range, 0.1-11 years) while being treated. Of these patients, 31 developed MDS/AML, for a crude rate of malignant transformation of nearly 9%. None of the 344 patients with idiopathic or cyclic neutropenia developed MDS/AML. Transformation was associated with acquired marrow cytogenetic clonal changes: 18 patients developed a partial or complete loss of chromosome 7, and 9 patients manifested abnormalities of chromosome 21 (usually trisomy 21). For each yearly treatment interval, the annual rate of MDS/AML development was less than 2%. No significant relationships between age at onset of MDS/AML and patient gender, G-CSF dose, or treatment duration were found (P >.15). In addition to the 31 patients who developed MDS/AML, the SCNIR also has data on 9 additional neutropenic patients whose bone marrow studies show cytogenetic clonal changes but the patients are without transformation to MDS/AML. Although our data does not support a cause-and-effect relationship between development of MDS/AML and G-CSF therapy or other patient demographics, we cannot exclude a direct contribution of G-CSF in the pathogenesis of MDS/AML. This issue is unclear because MDS/AML was not seen in cyclic or idiopathic neutropenia. Improved survival of congenital neutropenia patients receiving G-CSF therapy may allow time for the expression of the leukemic predisposition that characterizes the natural history of these disorders. However, other factors related to G-CSF may also be operative in the setting of congenital neutropenia. (Blood. 2000;96:429-436)     

Tailored temozolomide therapy according to MGMT methylation status for elderly patients with acute myeloid leukemia

Temozolomide sensitivity is determined by methylation of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter. This study assessed whether the temozolomide dose can be tailored by MGMT promoter status and whether protracted, low-dose temozolomide can "prime" blasts in patients with unmethylated MGMT (unMGMT). Elderly patients with high-risk AML were stratified by MGMT methylation. Patients with methylated MGMT (mMGMT) received temozolomide 200 mg/m(2) orally for 7 days every 4 weeks, while patients with unMGMT received temozolomide 100 mg/m(2) orally for 14 days followed by 200 mg/m(2) orally for 7 days every 6weeks. Of 36 patients (median age, 75 years), 31 (86%) had an unMGMT promoter. Overall response rate for the entire cohort was 36%. Patients with mMGMT and unMGMT had similar response rates (40% vs. 29%). Median duration of response and overall survival (OS) among responders were 29 and 35 weeks, respectively. Induction deaths (ID) occurred in 25% of patients, mostly caused by disease progression. Hematological toxicities were the most common adverse event. Toxicities were similar between patients on conventional versus protracted schedules. High HCT-CI scores were predictive of lower CR rate, higher ID, and shorter OS, while bone marrow blast count <50% at screening predicted for improved responses. Temozolomide, dosed according to MGMT methylation status, demonstrated modest clinical activity in elderly patients with AML, especially in those presenting with fewer comorbidities and low disease burden. The trial was registered on www.ClinicalTrials.gov as #NCT00611247.     

Triptolide cooperates with chemotherapy to induce apoptosis in acute myeloid leukemia cells

OBJECTIVE: Triptolide has shown antitumor activity in a broad range of solid tumors and on leukemic cells in vitro. MATERIALS AND METHODS: The THP1 cell line and primary acute myeloid leukemia (AML) cells were cultured with triptolide alone or in association with AraC or idarubicin in increasing concentrations. Apoptosis was measured by flow cytometry using DiOC6(3) for the cell line and fluorescein isothiocyanateAnnexin-V and CD45 labeling for fresh blast cells. Protein expression was measured by Western blot. Cell cycle distribution of apoptotic cells was measured by flow cytometry. RESULTS: A synergistic effect was observed when triptolide was added to idarubicin or to AraC to induce apoptosis of THP-1 leukemic cells. The triptolide/AraC association was also investigated in vitro on primary blast cells from 25 AML patients. This combination induced significantly higher percentages of apoptosis vs treatment with each drug separately (p<0.005). The IkappaB and X-linked inhibitor of apoptosis protein contents, which were altered by triptolide in idarubicin-treated cells, were not modified in AraC-treated cells. The association of AraC with triptolide increased the number of cells blocked in the S phase and most underwent apoptosis. CONCLUSION: These results suggest that, by modifying the cell cycle kinetics, AraC sensitizes AML cells to apoptosis induced by low concentration triptolide. The in vitro proapoptotic effect of triptolide associated with the antiproliferative activity of AraC warrants further clinical investigation for treatment of AML patients, especially elderly patients for whom low-dose AraC treatment could be improved by the addition of triptolide.     

Comparison of conventional chemotherapy and short-term intensive chemotherapy in adult acute myeloid leukemia

We designed a short term intensive chemotherapy (DCMP-85 regimen) that completed 4 courses of postremission therapy without maintenance therapy in an effort to improve remission durations for adult patients with AML. Twenty six patients aged 14-65 yr were entered into this study. The rate of complete remission is 76.9%. A Kaplan-Meier analysis of patients entering remission predicts that 56% of patients will remain in remission at 3 years (median follow-up is 12 mo). Comparison three different conventional chemotherapies (DC(M)P, DCMP Two Step and BH-AC DMP), DCMP-85 has achieved higher CR rate and 3-year leukemia-free survival rate, so far. Therefore, we conclude short term intensive chemotherapy is getting better results.     

High-dose chemotherapy and autologous bone marrow transplantation in acute myeloid leukemia

For younger patients with acute myeloid leukemia (AML), an allogeneic transplant from a matched sibling may afford the best chance of cure. In patients who are older or without a matched sibling donor, dose intensification can be achieved with an autologous bone marrow transplant (ABMT). We report here the results of a high-dose chemotherapy regime with nonpurged ABMT in 82 adult patients in first remission of AML with a median follow-up of 31 months. The median age was 40 years (range 16 to 57 years). The median interval between remission and ABMT was 5 months (range 1 to 12 months). Twenty-eight of these patients received a second course of the same high-dose chemotherapy and ABMT. The procedure related mortality rate was 6%. The projected leukemia-free survival (LFS) at 5 years is 48% for all 82 patients and 50% for the 76 patients with no known preceding myelodysplastic syndrome. For those patients with primary AML who received a double ABMT the projected LFS is 67%. The interval between remission and ABMT did not predict for either relapse or LFS. ABMT using a multidrug chemotherapy protocol is less toxic than allogeneic BMT yet results in a similar LFS.     

Feasibility of outpatient consolidation chemotherapy in older versus younger patients with acute myeloid leukemia

Intensive consolidation chemotherapy for acute myeloid leukemia (AML) patients in complete remission is being increasingly administered on an outpatient basis. Although this approach has been found to be safe and feasible in younger patients, its safety in older patients remains unknown. We therefore undertook an evaluation of outpatient-based consolidation chemotherapy in older AML patients, and compared results to younger patients treated at the same institution over the same time period. The overall rate of readmission was ~50%, mostly for infections, with mean admission duration of 2 weeks. The overall mortality rate was 2.2%. Readmission rates and duration of readmission were somewhat higher in older patients, but infection rate, intensive care (ICU) admissions, and mortality rates were comparable to those in the younger patient cohort. However, we also observed that rates of febrile neutropenia, bacteremia, ICU admission, and death were significantly higher during the second consolidation, as compared with the first, in both younger and older patients. We conclude that outpatient-based consolidation therapy can be safely undertaken in a substantial proportion of fit older patients with AML.     

Low-dose combination chemotherapy for acute myeloid leukemia in elderly patients: A novel approach

Eighteen patients aged 60-84 years with acute myeloid leukemia were treated with low-dose combination chemotherapy comprising cytarabine, etoposide, and mitozantrone or 6-thioguanine; seven of these patients had a pre-existing myelodysplastic syndrome. Nine patients achieved a complete remission, and five had a partial remission. The duration of survival in these 14 responding patients has ranged from 2+ to 19+ months. Myelotoxicity occurred regularly, with time to recovery (neutrophils ≥0.5 × 10⁹/L, platelets ≥50 × 10⁹/L) from nadir being 10-14 days in 12 of the 14 patients. This novel approach with an overall response rate of 78% appears to be a simple and effective form of therapy for elderly patients. Am. J. Hematol. 55:115-117, 1997. © 1997 Wiley-Liss, Inc.     

Standard induction chemotherapy followed by attenuated consolidation in elderly patients with acute myeloid leukemia

The benefits of intensive post-remission chemotherapy have not been verified in elderly patients with acute myeloid leukemia (AML). To reduce fatal complications caused by intensive post-remission therapy, we performed a prospective phase II multicenter trial of standard induction chemotherapy (‘7+3’ of cytarabine plus daunorubicin), followed by two cycles of attenuated consolidation therapy (‘5+1’ of cytarabine plus daunorubicin) for elderly patients with AML, excluding those with M3. Of the 41 patients enrolled in the study, 24 (58.5%) attained CR. Of these 24, 17 (70.8%) completed both planned cycles of consolidation therapy. After a median follow-up of 566 days (range, 63–1190 days) among surviving patients, 15 relapsed, with an actuarial 3-year disease-free survival rate of 22.5%. There were no fatal complications during consolidation therapy. Actuarial 3-year overall survival was 17.0%. These findings suggest that, when compared with previous findings using more intensive consolidation therapy, attenuated consolidation therapy does not compromise outcomes in elderly AML patients.     

Gender modulates the relationship between body weight and plasma glucose in overweight or obese subjects

Obesity and weight increase during adult life are strong predictors of type 2 diabetes. Whether fasting plasma glucose (FPG) is likewise related to body weight as well as with its increase during the adult life in obese-overweight people and whether this relationship is different between the genders is the question asked by the present study. We measured FPG in 1063 overweight-obese subjects (395M/668F) with BMI > or =25 kgm(-2) and classified with no history of diabetes and with a FPG< 7 mmol/l, who consequently came to the Outpatient Clinic of our Diabetes Unit to obtain dietetic advice. Weight increase was determined as the difference between actual weight and weight at 18 years (weight-diff), including only patients with weight-diff> 0. By univariate analysis age, BMI, waist circumference and weight change were loosely related to FPG in both sexes, even if the relation between plasma glucose and anthropometric variables was more consistent in females. By multivariate regression analysis, after adjusting for age, waist circumference, menopausal status and smoking habit, FPG was significantly related to both waist circumference and weight-diff only in women. Odds Ratio for fasting hyperglycaemia (FPG> 6.11 mmol/l), for each S.D. unit increase in weight-diff, after adjusting for age, waist circumference, smoking habit and menopausal status was 1.272; 95% CI: 0.863-1.901 (p=ns) for males and 1.800; 95% CI: 1.239-2.652 (p=0.002) for women. In conclusion our findings suggest that in non-diabetic overweight-obese people, after controlling for main cofounders, anthropometric variables and in particular waist circumference and weight change after 18 years are linearly related to FPG in women, independently predicting the risk of fasting hyperglycaemia only in these latter.