MicroRNA-181b-5p insufficiency predicts treatment response failure risk and unfavorable event-free survival as well as overall survival in acute myeloid leukemia patients

The present study aimed to explore the correlation of microRNA (miR)-181b-5p expression with treatment response and long-term prognosis in acute myeloid leukemia (AML) patients. miR-181b-5p was detected in the bone marrow of 84 AML patients before therapy. After induction therapy, the patients exhibiting complete remission (CR) were recorded. Next, event-free survival (EFS) and overall survival (OS) were calculated. miR-181b-5p had excellent potential to discriminate AML patients from healthy donors [area under the curve (AUC): 0.922, 95% confidence interval (CI): 0.873-0.971)]. In addition, miR-181b-5p expression was decreased in AML patients with the FLT3-ITD mutation (P=0.032) or WT1 mutation (P=0.017) when compared to AML patients without these genetic mutations. Meanwhile, miR-181b-5p expression was negatively correlated with the National Comprehensive Cancer Network (NCCN) risk classification of AML (P=0.036). Furthermore, miR-181b-5p expression was elevated in CR AML patients compared to non-CR AML patients (P=0.030). Moreover, higher miR-181b-5p expression was associated with favorable accumulating EFS (P=0.001) and OS (P=0.024). In addition, higher miR-181b-5p expression was independently associated with better EFS (hazard ratio: 0.698, P=0.012). In conclusion, miR-181b-5p insufficiency is associated with induction therapy response failure, unfavorable accumulating EFS and OS in AML patients.     

Treatment outcome in older patients with childhood acute myeloid leukemia

BACKGROUND.

Older age has historically been an adverse prognostic factor in pediatric acute myeloid leukemia (AML). To the authors' knowledge, the impact of age relative to that of other prognostic factors on the outcome of patients treated in recent trials is unknown.

METHODS.

Clinical outcome and causes of treatment failure of 351 patients enrolled on 3 consecutive protocols for childhood AML between 1991 and 2008 were analyzed according to age and protocol.

RESULTS.

The more recent protocol (AML02) produced improved outcomes for patients aged 10 years to 21 years compared with 2 earlier studies (AML91 and AML97), with 3‐year rates of event‐free survival (EFS), overall survival (OS), and cumulative incidence of refractory leukemia or recurrence (CIR) for this group being similar to those of patients aged birth to 9 years: EFS: 58.3% ± 5.4% versus 66.6% ± 4.9% (P = .20); OS: 68.9% ± 5.1% versus 75.1% ± 4.5% (P = .36); and CIR: 21.9% ± 4.4% versus 25.3% ± 4.2% (P = .59). The EFS and OS estimates for patients aged 10 to 15 years overlapped those for patients aged 16 to 21 years. However, the cumulative incidence of toxic death was significantly higher for patients aged 10 to 21 years compared with younger patients (13.2% ± 3.6% vs 4.5% ± 2.0%; P = .028).

CONCLUSIONS.

The survival rate for older children with AML has improved on the results of a recent trial and is now similar to that of younger patients. However, deaths from toxicity remain a significant problem for patients in the older age group. Future trials should focus on improving supportive care while striving to develop more effective antileukemic therapy. Cancer 2012. © 2012 American Cancer Society.     

Impact of remission induction chemotherapy on survival in older adults with acute myeloid leukemia

BACKGROUND: Significant controversy surrounds the use of remission induction chemotherapy (IC) in older adults with acute myeloid leukemia (AML). Earlier clinical trials have yielded conflicting results and possibly a minor survival benefit, often offset by a longer hospitalization time. METHODS: To evaluate the role of IC in patients with AML, a case control study of patients 60 years or older treated at the Cleveland Clinic Taussig Cancer Center between 1997 and 2005 was conducted. Forty-four patients who did not receive IC were matched by a propensity analysis to 138 patients who received an anthracycline-based regimen. RESULTS: The unadjusted median survival of patients who did not receive IC was 53 days, compared with 197 days (P < .001) for those who did. After further adjusting for age, gender, race, leukocyte count at presentation, AML cytogenetics, history of prior hematologic disorder, and assessing for comorbidities, not receiving IC was still associated with worse survival (hazards ratio of 1.88; 95% confidence interval, 1.15-3.05 [P = .01]). Additional predictors of poor outcomes in older adults with AML included higher leukocyte count at presentation, poor-risk cytogenetics, and African-American race (compared with Caucasians). CONCLUSIONS: The study suggests improved outcomes in older adults with AML who undergo remission induction therapy.     

大剂量阿糖胞苷巩固治疗急性髓系白血病患者的疗效及预后分析

目的:探讨大剂量阿糖胞苷（HDAC）用于急性髓系白血病(AML)患者完全缓解后巩固治疗的安全性及预后分析。方法:回顾性分析2016年03月至2020年03月就诊空军军医大学第二附属医院血液科的49例接受HDAC方案作为巩固治疗的AML患者,观察巩固治疗中三系细胞减少持续时间、输血量及治疗中的不良事件,记录OS及RFS时间,并进行基因突变与预后分析。结果:49例患者共进行121个疗程,中位2.7（1~4）个疗程。巩固化疗期间共发生感染34例次（28.1%）。2年RFS率及OS率分别为64.3%、76.8%。多因素分析结果提示巩固化疗次数和伴有FLT3-ITD基因突变是影响患者复发的独立预后不良因素（P值分别为0.019和0.024）。而复发是影响OS的独立预后不良因素（P=0.008）。结论:HDAC用于AML患者巩固治疗的安全性好。巩固治疗≤2次是导致疾病复发的不良因素,伴有FLT3-ITD基因突变不能从HDAC中获益。     

Smoking adversely affects survival in acute myeloid leukemia patients

Smoking adversely affects hematopoietic stem cell transplantation outcome. We asked whether smoking affected outcome of newly diagnosed acute myeloid leukemia (AML) patients treated with chemotherapy. Data were collected on 280 AML patients treated with high-dose cytarabine and idarubicin-containing regimens at Roswell Park Cancer Institute who had smoking status data at diagnosis. Patients' gender, age, AML presentation (de novo vs. secondary), white blood cell (WBC) count at diagnosis, karyotype and smoking status (never vs. ever) were analyzed. Among the 161 males and 119 females with a median follow-up of 12.9 months, 101 (36.1%) had never smoked and 179 (63.9%) were ever smokers. The proportion of patients between never and ever smokers was similar to respect to age, AML presentation, WBC count at diagnosis or karyotype based on univariate analysis of these categorical variables. Never smokers had a significantly longer overall survival (OS) (60.32 months) compared to ever smokers (30.89; p = 0.005). In multivariate analysis incorporating gender, age, AML presentation, WBC count, karyotype and smoking status as covariates, age, karyotype and smoking status retained prognostic value for OS. In summary, cigarette smoking has a deleterious effect on OS in AML.     

Outcomes of patients who undergo aggressive induction therapy for secondary acute myeloid leukemia

BACKGROUND:

Response and survival in 96 patients with secondary acute myeloid leukemia (sAML) who received aggressive induction chemotherapy was reviewed.

METHODS:

The median follow‐up of survivors was 2.3 years. A total of 70 (73%) patients achieved a morphologic complete remission (CR) confirmed by absence of leukemic blasts by flow cytometry.

RESULTS:

For all 96 patients, the median event‐free survival (EFS) was 8 months, and overall survival (OS) was 13.6 months (range, 1‐119 months). Eight patients died shortly after induction therapy because of disease or side effects, and 13 are currently in continuous first remission. The median disease‐free survival (DFS) for all 70 patients who achieved a morphologic CR was 9 months (range, 1‐51 months), with a 64% chance of surviving 1 year. Patients with AML after previous chemotherapy or radiation therapy had a higher morphologic remission rate compared with those arising from myelodysplastic syndrome or myeloproliferative disease (82% vs 62%; P = .027). However, among the patients from the 2 groups who attained a morphologic remission, there was no difference in terms of CR rate (P = .94), DFS, EFS, or OS (P = .55, .83, and .71, respectively). This is a similar DFS to the group of 7 patients who went directly to ablative allogeneic transplant rather than having induction therapy first. In this population of patients who received aggressive chemotherapy, Charlson comorbidity index or a higher number of factors recognized as high risk in leukemia patients did not affect the chance of OS, DFS, and EFS, although having more recognized leukemia risk factors was related to a lower chance of surviving 1 year. However, it is important to note that those with higher comorbidity indexes were underrepresented in this aggressively treated cohort.

CONCLUSIONS:

The data from the current study demonstrate that many patients with sAML can tolerate aggressive induction therapy and attain remission, but duration of response and the chance of long‐term survival remain poor. Cancer 2009. © 2009 American Cancer Society.     

Prognostic value of FLT3 mutations among different cytogenetic subgroups in acute myeloid leukemia

BACKGROUND:

The impact of FMS‐like tyrosine kinase 3 (FLT3) mutations and mutation burden among cytogenetic subgroups of patients with acute myeloid leukemia (AML) other than normal karyotype (NK) AML is unclear.

METHODS:

Patients with newly diagnosed AML were divided among 3 cytogenetic subgroups: core binding factor (CBF) AML, NK‐AML, and poor‐risk AML.

RESULTS:

In total, 481 patients were included: 13% had, CBF‐AML, 57% had NK‐AML, and 30% had poor risk AML, and the frequency of any FLT3 mutations was 20%, 32%, and 7.6% in the respective cytogenetic subgroups. FLT3 mutation did not have an impact on event‐free survival (EFS) in patients with CBF‐AML (P = .84) and poor‐risk AML (P = .37). In patients with NK‐AML, EFS was worse in the FLT3‐internal tandem duplication (ITD) group (20 weeks vs 41 weeks; P < .00,001) but not in the FLT3‐tyrosine kinase domain (TKD) point mutation group (61 weeks vs 41 weeks; P = .15). Worse EFS and overall survival (OS) were observed among patients with NK‐AML and higher FLT3‐ITD burden but not among patients with FLT3‐TKD mutation. In multivariate analysis, FLT3‐ITD mutation was prognostic of EFS in patients with NK‐AML (hazard ratio, 3.1; P = .03).

CONCLUSIONS:

FLT3 mutations did not have a prognostic impact in patients with AML who had good‐risk and poor‐risk karyotypes. In patients with NK‐AML, FLT3‐ITD mutations led to worse survival, which was even worse among patients who had high mutation burden. Cancer 2011. © 2010 American Cancer Society.     

Prognostic Significance of Fms-Like Tyrosine Kinase 3 Internal Tandem Duplication Mutation in Non-Transplant Adult Patients with Acute Myeloblastic Leukemia: A Systematic Review and Meta-Analysis

Background: Fms-like tyrosine kinase-3, internal tandem duplication (FLT3-ITD) mutation, is a known predictor for worse outcome in patients with acute myeloblastic leukemia (AML). However, the prognostic significance of FLT3-ITD mutation in adult, non-transplant patients is still unclear therefore we conducted a systematic review and meta-analysis to explain this issue. The main outcome was overall survival (OS), while additional outcomes included event-free survival (EFS). Methods: Seven Databases (ScienceDirect, Scopus, PubMed, Cochrane, SpringerLink, ProQuest, and EBSCOhost) were searched up to August 2020.  Studies investigating the prognostic value of AML in adults with FLT3-ITD mutational status were selected. Studies which patients had received transplantation, diagnosed with acute promyelocytic leukemia (APL) or secondary AML were excluded. The selected studies were divided into subgroups based on their cytogenetic profile. Summary hazard ratios (HR) and 95% confidence intervals (CI) were calculated using fixed-effects models. Heterogeneity tests were conducted and presented in I2 value. Forest plot was presented to facilitate understanding of the results. Publication bias was analyzed by Funnel Plot test. Results: A total of ten studies describing research conducted from 1999 to 2020, met the inclusion criteria for this study. Nine studies reported OS and four studies reported EFS in HR. The highest HR for OS is 6.33 (95% CI, 2.61-15.33; p < 0.001), for EFS is 3.58 (95% CI, 1.59 – 8.05); p = 0.002)., while the lowest for OS is 1.33 (95% CI, 0.88-2.01; P = 0.174) and for EFS is 1.29 (95% CI, 0.75-2.23; p = 0.34). Nine studies were included in meta-analysis with HR for OS 1.91 (95% CI, 1.59–2.30, p < 0.00001), whereas 4 studies were included in meta-analysis for EFS with HR 1.64 (95% CI, 1.25–2.14; p = 0.0003). Conclusion: FLT3-ITD mutation is associated with worse prognosis in adult, non-transplant patients with AML, both for OS and EFS.     

Overexpression of CXCR4 predicts adverse overall and event-free survival in patients with unmutated FLT3 acute myeloid leukemia with normal karyotype

BACKGROUND: CXC chemokine receptor 4 (CXCR4) expression in acute myeloid leukemia (AML) is reported to correlate with FLT3 gene mutation and poorer prognosis. The prognostic significance of CXCR4 expression in patients with AML that have a normal karyotype and no evidence of FLT3 gene mutations was examined. METHODS: The prognostic significance of CXCR4 expression in 122 AML patients with normal karyotype and no evidence of FLT3 gene mutation treated at our institution between 1997 and 2003 was analyzed. All patients received intensive chemotherapy according to institutional protocols; 84% received cytarabine-containing regimens. Bone marrow biopsy or clot specimens obtained before treatment were immunostained for CXCR4. RESULTS: There were 70 men and 52 women with a median age of 62 years (range, 22-82 years). Median follow-up was 18 months (range, <1-97 months). Seventy-six patients achieved complete remission (CR); 39 had recurrence. Sixty-six patients died, including 9 with no evidence of disease. CXCR4 was positive in 70 and negative in 52 patients, with CR rates of 58% and 71%, respectively (P = .09). Multivariate analysis demonstrated that CXCR4 expression, presence of multilineage dysplasia, and high creatinine level predicted poorer overall (OS) and event-free (EFS) survival. CONCLUSIONS.: The results suggest that CXCR4 expression is associated with poor prognosis in AML patients with an unmutated FLT3 gene.     

Phase III study of all-trans retinoic acid in previously untreated patients 61 years or older with acute myeloid leukemia.

The purpose of our study was (i) to evaluate the impact of all-trans retinoic acid (ATRA) given as adjunct to chemotherapy and (ii) to compare second consolidation vs maintenance therapy in elderly patients with acute myeloid leukemia (AML). A total of 242 patients aged >or=61 years (median, 66.6 years) with AML were randomly assigned to ATRA beginning on day +3 after the initiation of chemotherapy (ATRA-arm, n=122) or no ATRA (standard-arm, n=120) in combination with induction and first consolidation therapy. A total of 61 patients in complete remission (CR) were randomly assigned to second intense consolidation (n=31) or 1-year oral maintenance therapy (n=30). After induction therapy the intention-to-treat analysis revealed a significant difference in CR rates between the ATRA- and the standard-arm (52 vs 39%; P=0.05). Event-free (EFS) and overall survival (OS) were significantly better in the ATRA-compared to the standard-arm (P=0.03 and 0.01, respectively). OS after second randomization was significantly better for patients assigned to intensive consolidation therapy (P<0.001). The multivariate model for survival revealed lactate dehydrogenase, cytogenetic risk group, age, and first and second randomization as prognostic variables. In conclusion, the addition of ATRA to induction and consolidation therapy may improve CR rate, EFS and OS in elderly patients with AML.     

含高三尖杉酯碱方案治疗初治急性髓系白血病46例效果和生存分析

目的探讨以高三尖杉酯碱（HHT）为主的化疗方案治疗急性髓系白血病（AML）的缓解率,评价AML不同染色体核型、基因突变对总生存（OS）率、无事件生存（EFS）率的影响。方法将80例初治AML患者用随机信封法分为HAA、HDA、DA、IA方案治疗组,比较各组诱导完全缓解（CR）率,并将AML患者分为染色体核型“好、中、差”三组,分别比较OS、EFS。结合患者是否表达预后较差的基因突变,利用染色体与基因型两者总体评价OS、EFS。结果用含有HHT方案治疗初治AML46例,总CR率78．3％（36／46）,高于DA方案组总CR率66．7％（10／15）及IA方案组的63．2％（12／19）,三种方案组CR率差异无统计学意义（P〉0．05）。不同染色体核型对于生存具有较大影响,染色体核型“差”者OS、EFS较染色体核型“好”或“中”者下降程度显著。结合染色体和基因型分组对于显示预后总体OS、EFS的下降趋势更明显。结论含HHT的治疗方案CR率与传统DA、IA方案相似,提示高三尖杉酯碱治疗的有效性。不同染色体及基因突变对于AML预后具有较大影响。     

Current event‐free survival after sequential tyrosine kinase inhibitor therapy for chronic myeloid leukemia

BACKGROUND:

Imatinib is an effective tyrosine kinase inhibitor (TKI) for patients with chronic myeloid leukemia (CML) in chronic phase (CP). Although some patients may fail on therapy with imatinib, effective salvage therapy is available with second‐generation TKIs. Current measurement of efficacy for each therapy is judged by its individual impact on overall survival and event‐free survival (EFS).

METHODS:

In total, 586 patients with CML in CP who received imatinib were included in this analysis in 2 cohorts: imatinib as front‐line therapy (n = 281) or after failure on interferon‐α (IFN‐α) (n = 305). By accounting for successful salvage treatment (ie, regain of complete cytogenetic response), the current EFS (CEFS) rate was calculated to obtain a more accurate impression of the outcome of patients with CML who received treatment with sequential TKIs.

RESULTS:

For patients who received imatinib after failing on IFN‐α, the 7‐year EFS rate was 61%, whereas the CEFS rate was 69%. The 7‐year EFS rate for patients who received imatinib as initial therapy was 81% compared with a 7‐year CEFS rate of 88%.

CONCLUSIONS:

CEFS provided a more accurate representation of the outcome of patients with CML in CP. These patients may frequently be treated successfully with subsequent TKIs after experiencing failure on the first TKI. Cancer 2011. © 2010 American Cancer Society     

Disease biology rather than age is the most important determinant of survival of patients > or = 60 years with acute myeloid leukemia treated with uniform intensive therapy

BACKGROUND: The objectives of the current study were to evaluate the outcome of patients > or = 60 years with acute myeloid leukemia (AML) treated uniformly with high-dose daunorubicin containing induction and modified high-dose cytosine arabinoside containing postremission therapy, and to identify factors predictive of complete disease remission (CR) and survival. METHODS: Between 1998 and 2002, the authors treated 117 newly diagnosed patients (acute promyelocytic leukemia excluded) with AML > or = 60 years (median, 67 years; range, 60-82 years). Karyotype (Medical Research Council classification) at diagnosis was categorized as good risk (n = 3), intermediate risk (n = 69), adverse risk (n = 26), and suboptimal/not done (n = 19). A normal karyotype was seen in 41 patients and 40 (34%) had secondary AML. RESULTS: The outcome of induction included the following: CR, 62 (53%); early death, 5 (4%); death during hypoplasia, 14 (12%); and resistant disease, 36 (31%). The 3-year event-free (EFS) and overall survival (OS) rates were 9% (95% confidence interval [95% CI], 3-16%) and 17% (95% CI, 9-29%), respectively. In a univariate analysis, cytogenetics, lactate dehydrogenase level, leukocyte count, and performance status were the significant factors for EFS and OS. Age was not a significant prognostic factor for either CR or survival. In a multivariate model, adverse-risk cytogenetics, previous history of myelodysplastic syndrome or antecedent hematologic disorder, and high leukocyte count (> 30 x 10(9)/L) were independent adverse prognostic factors for survival. The impact of adverse karyotype on EFS and OS was time dependent and was observed after 50 and 150 days, respectively. CONCLUSIONS: The authors concluded that candidacy for intensive therapy in older patients should be based on biologic features of disease and fitness, rather than on age.     

伴NRAS基因突变的急性髓系白血病患者的临床特征及生存分析北大核心

目的:探讨伴有NRAS基因突变的急性髓系白血病(acute myeloid leukemia,AML)患者的临床特征及生存分析。方法:回顾性分析2016年05月至2019年12月就诊于空军军医大学唐都医院血液内科的225例初诊AML患者的临床资料,采用二代测序技术进行基因突变检测,分析NRAS基因突变患者的临床特征并进行预后分析。结果:共有36例(16%)患者检测到NRAS基因突变,全部为错义突变,33例突变位点位于2号外显子12、13号密码子,2例位于3号外显子61号密码子,1例位于4号外显子109密码子。中位突变比例为21.99%(1%~49.85%)。伴有NRAS基因突变的患者中位年龄为44(9~85)岁。年龄分布、前期血液病史、初诊时外周血细胞计数、骨髓原始细胞比例等与无NRAS患者差异相比均无统计学意义。伴有NRAS突变组的患者一疗程诱导化疗完全缓解率高于NRAS野生型组(P=0.033),但复发率也较高(P=0.055)。伴NRAS基因突变组患者的中位OS时间为22个月,无NRAS基因突变组患者的中位OS时间为28个月,两组OS时间无统计学差异(P=0.485);两组患者的RFS时间存在统计学差异(P=0.036)。采用“3+7”方案诱导治疗的患者中位OS时间40个月,8例采用DEC+CAG方案诱导化疗的患者中位OS时间为15个月(P=0.027)。36例患者中31例伴有其他基因突变,生存分析显示NRAS同时伴DNMT3A突变组患者的预后更差(P=0.019)。结论:AML患者NRAS突变率16%,均为错义突变,大部分位于2号外显子12、13号密码子。伴有NRAS突变的患者CR率高,复发率也高,RFS时间短于无NRAS突变组。“3+7”方案诱导治疗缓解率更高。NRAS伴DNMT3A突变提示预后差。     

Outcomes after induction chemotherapy in patients with acute myeloid leukemia arising from myelodysplastic syndrome

BACKGROUND:

Secondary acute myeloid leukemia (AML) from an antecedent myelodysplastic syndrome (MDS)/myeloproliferative neoplasm is associated with a poor prognosis. The authors evaluated predictive factors in patients with secondary AML treated with anthracycline‐based induction therapy.

METHODS:

This was a retrospective review of secondary AML patients treated with induction therapy. Age, International Prognostic Scoring System, Eastern Cooperative Oncology Group performance status, cytogenetics, duration of MDS/myeloproliferative neoplasm, and prior MDS/myeloproliferative neoplasm treatment were evaluated for their impact on complete response (CR), CR with low platelets, and overall survival (OS).

RESULTS:

The authors evaluated 61 secondary AML patients who received induction chemotherapy; 59% (36 patients) achieved CR/CR with low platelets (95% confidence interval [CI], 46%‐71%), and median OS was 6.5 (95% CI, 3.9‐8.1) months. Three factors were associated with lower CR/CR with low platelets and OS: poor risk cytogenetics, prior treatment with hypomethylating agents or lenalidomide, and longer time to transformation to AML. Of those treated with hypomethylating agents or lenalidomide, 32% achieved CR/CR with low platelets versus 78% in the group not treated with a hypomethylating agent or lenalidomide (odds ratio [OR], 0.13; 95% CI, 0.04‐0.42). Median OS for those treated with a hypomethylating agent or lenalidomide was 3.7 versus 10.5 months for those not treated with a hypomethylating agent or lenalidomide (P < .0001). The CR/CR with low platelets rate for those with intermediate risk cytogenetics was 70% versus 35% for those with poor risk (OR, 4.33; 95% CI, 1.38‐13.6). Those with poor risk cytogenetics had a median OS of 2.8 versus 7.5 months for those with intermediate risk (P = .01).

CONCLUSIONS:

Prior treatment with hypomethylating agents or lenalidomide, poor risk cytogenetics, and longer time to transformation to AML are independent negative predictive factors for response and OS in patients with secondary AML after induction therapy. Cancer 2011. © 2010 American Cancer Society.     

中剂量阿糖胞苷用于老年急性髓系白血病患者巩固强化治疗的临床观察

目的 分析初治老年急性髓系白血病(AML)患者诱导缓解后应用中剂量阿糖胞苷(MDAC)巩固治疗的临床效果及不良反应.方法 61例2个疗程内达完全缓解(CR)的老年AML(M3除外)患者,分别应用MDAC和常规剂量阿糖胞苷(SDAC)进行巩固强化治疗,对其临床资料进行回顾性分析.结果 MDAC组26例,SDAC组35例,MDAC组与SDAC组的无复发生存(RFS)时间分别为42.7和16.0个月(P=0.002),总生存(OS)时间分别为44.6和18.2个月(P=0.004),累积复发率分别为26.9%(7/26)和54.3%(19/35)(x2=4.567,P=0.033),3年生存率分别为23.1%(6/26)和8.6%(3/35)(x2=2.496,P=0.114).两组不良反应发生率差异均无统计学意义(均P>0.05).结论 老年AML患者应用MDAC巩固强化治疗,可延长早期达CR患者的RFS及OS时间,不良反应发生率与SDAC相似.     

Favorable survival maintained in children who have myeloid leukemia associated with Down syndrome using reduced-dose chemotherapy on Children's Oncology Group trial A2971: A report from the Children's Oncology Group

BACKGROUND:

Children who are treated for myeloid leukemia associated with Down syndrome (DS) experience superior survival compared with children who have myeloid leukemia without DS. To maintain excellent outcomes while avoiding toxicity, the Children's Oncology Group (COG) conducted the phase 3 trial COG A2971, the first trial solely designed to provide uniform treatment of myeloid leukemia in North American children with DS. A2971 eliminated 2 induction drugs and 3 months of maintenance therapy from the standard‐timing regimen of dexamethasone, cytarabine, 6‐thioguanine, etoposide, and rubidomycin/daunomycin (DCTER) used in the previous study (Children's Cancer Group [CCG] 2891).

METHODS:

COG A2971 was a multi‐institutional, nonrandomized, clinical trial that enrolled 132 patients who had DS with either acute myeloid leukemia (n = 91) or myelodysplastic syndrome (n = 41).

RESULTS:

The median follow‐up was 4.8 years (range, 0.8‐8.6 years), the median age at diagnosis was 1.7 years (range, 0.3‐13.6 years), and the median white blood cell count was 6200/μL (range, 900‐164,900/μL). The remission rate (92.7% ± 6%) was similar to that reported in the CCG 2891 study (91.3% ± 5%; P = .679). The 5‐year event free survival (EFS) rate was 79% ± 7% (vs 77% ± 7% in CCG 2891; P = .589), the disease‐free survival (DFS) rate was 89% ± 6% (vs 85% ± 6% in CCG 2891; P = .337), and the overall survival rate was 84% ± 6% (vs 79% ± 7% in CCG 2891; P = .302). Induction day‐14 bone marrow response trended toward a more favorable outcome (EFS: P = .12). Age >4 years was an adverse risk factor (5‐year EFS rate: 33% ± 38% for children aged >4 years [median, 8.5 years; n = 6] vs 81% ± 7% for children ages 0‐4 years [median, 1.7 years; n = 126]; P = .001).

CONCLUSIONS:

The COG A2971 trial reduced the chemotherapy dose and maintained survival to that achieved by the CCG 2891 trial in children who had myeloid leukemia associated with DS. Cancer 2012. © 2012 American Cancer Society.     

An antecedent diagnosis of refractory anemia with excess blasts has no prognostic relevance in acute myeloid leukemia of older adult patients.

BACKGROUND: Conflicting results have been reported about the prognostic relevance of antecedent myelodysplastic syndrome (MDS) in acute myeloid leukemia (AML) of older adults. PATIENTS AND METHODS: Data from 87 intensively treated AML patients (median age 69 years) were analyzed, with the aim of comparing therapeutic results and toxicity between de novo and AML secondary to a previous MDS (s-AML). Rate of CD34+ cells mobilization and feasibility of autologous stem cell transplantation (ASCT) were also compared. RESULTS: Complete remission rate, death in induction and primary resistance were not statistically different between the two groups. Median time for neutrophil recovery was similar, while s-AML patients required a longer time for platelet recovery (P = 0.04). There was no difference as to eligibility for consolidation as well as for mobilization and feasibility of ASCT. S-AML had negligible impact on overall survival (OS) and disease-free survival (DFS). In the multivariate analysis the only parameter significantly related to either OS or DFS duration was adverse karyotype (P = 0.02 and 0.04, respectively). CONCLUSIONS: A diagnosis of s-AML does not represent a clinically relevant prognostic factor in elderly AML patients treated with aggressive therapy. Furthermore, s-AML patients can be mobilized and autografted with comparable results as opposed to de novo cases.     

Role of CD135/CD117 on Prognosis and Overall Survival of Acute Myeloid Leukemia

Background: The key proliferative RTKs for AML include c-KIT receptor (CD117) and FLT-3 receptor (CD135).The aim of this study was to evaluate the CD135 and CD117 expression, co-expression of CD135 and CD117(CD135+CD117), and the association of that co-expression with Event Free Survival (DFS) and Overall Survival (OS)rates. Material and Methods: We analyzed CD117 and CD135 expression on AML blasts by flow cytometry and itsassociation with Event Free Survival (DFS) and Overall Survival (OS) in 66 AML treated on Hematology-OncologyResearch Center, Iran, Tabriz. Results: The overall OS and EFS were 50% and 80.3% respectively during our study.Cox-regression analysis revealed that a poor EFS was significantly associated a low CD135 (HR 0.34, 95% CI0.13–0.88, P = 0.02). Conclusion: This is the first study from Iran to show that the expressions of CD135, CD117 iseasily measurable by routine diagnostic flow-cytometry, and CD135+117 were not significantly associated with CR,EFS, or OS .     

Estrogen receptor methylation is associated with improved survival in adult acute myeloid leukemia.

Estrogen receptor methylation (ERM) is a frequent molecular alteration in adult acute myeloid leukemia (AML). In this study, we sought to determine the clinical characteristics and prognostic significance of ERM in AML. ERM was determined for 268 patients who had leukemic blasts available for molecular analysis. ERM was measured by Southern blot analysis, and results were obtained for 261 patients (ages 17-69). ERM ranged from 0-99.1%, with a median of 25%. One hundred sixty patients (61%) had ERM values over 15% and were considered ERM+. In a subset of patients analyzed, ERM+ samples had markedly lower ER gene expression compared with ERM- samples. In multiple regression analyses of patient and disease characteristics at diagnosis, two factors had significant independent association with ERM: ERM decreased with increasing age (P = 0.0001) and was significantly lower in patients with French-American-British classification M4 or M5 (P = 0.0019). In regression analyses of outcome measures, ERM had no significant impact on complete remission rate after initial induction therapy. However, ERM+ patients had significantly better overall survival [OS; 18% at 6 years; 95% confidence interval (CI), 12-24% versus 9%; CI, 3-14% for ERM- patients; P = 0.022]. In multiple regression analyses, OS increased with increasing ERM (P = 0.0044). Similar results were seen for relapse-free survival (23% at 6 years; CI, 15-32% for ERM+ versus 10%; CI, 2-19% for ERM-), although the effect of ERM was not statistically significant (P = 0.15 in multiple regression analysis). Our results indicate that ERM at diagnosis may be a favorable prognostic factor for OS in adult AML.