Prognostic features for response and survival in elderly patients with de novo acute myeloid leukemia treated with mitoxantrone and intermediate dose cytarabine

Forty-three fit elderly patients with de novo acute myeloid leukemia (AML) received chemotherapy with mitoxantrone and intermediate dose cytarabine (MIDAC) in a phase II clinical trial conducted by the Australasian Leukaemia and Lymphoma Group. The main aim of the study was to evaluate the tolerability and efficacy of MIDAC in inducing durable remissions. While the chemotherapy was generally well tolerated, less than half the patients achieved complete remission (CR) after induction and many of those in CR could not receive planned consolidation cycles. The median overall survival for all patients was 6.5 months and the median disease-free survival for those achieving CR was 8.3 months. Only 2 patients survived beyond 4 years. Factors significantly associated with shorter survival were adverse cytogenetics, marrow dysplasia and increasing age. These results suggest that only selected elderly patients with AML are likely to benefit from aggressive chemotherapy and that novel therapies are required to improve the poor prognosis of this group.     

影响老年急性髓系白血病患者预后的危险因素分析

目的 探讨影响老年急性髓系白血病患者预后的危险因素.方法 回顾性分析121例老年急性髓系白血病患者的临床资料.对比不同临床资料患者的完全缓解率和中位生存期.通过多因素Cox模型分析统计影响老年急性髓系白血病患者预后的危险因素.结果 本研究患者的中位生存期为131 d(95%可信区间109~154 d),诱导化疗后的完全缓解率为29.75%.年龄≤70岁、PS评分﹤2分、原发急性髓系白血病、骨髓原始细胞比例≤50%、接受标准化疗以及白细胞CD34表达阴性患者的完全缓解率升高(P﹤0.05);年龄≤70岁、PS评分﹤2分、原发急性髓系白血病、初治时的白细胞计数≤50×109/L、骨髓原始细胞比例≤50%、接受标准化疗以及白细胞CD34表达阴性患者的中位生存期延长(P﹤0.05);多因素Cox模型分析结果显示,年龄、PS评分、初治时白细胞计数以及治疗方案是影响老年急性髓系白血病患者预后的危险因素(P﹤0.05).结论 年龄、PS评分、初治时白细胞计数以及治疗方案是影响老年急性髓系白血病患者预后的危险因素.临床应通过整体评估,制定个体化的化疗方案,以改善患者的预后.     

Efficacy and safety of decitabine in combination with G-CSF,low-dose cytarabine and aclarubicin in newly diagnosed elderly patients with acute myeloid leukemia

Purpose

This prospective phase II, open label, study was designed to assess the efficacy and safety of D-CAG induction treatment for elderly patients with newly diagnosed AML.

Experimental Design

All patients in this study were treated with decitabine of 15 mg/m² for 5 days and G-CSF for priming, in combination with cytarabine of 10-mg/m² q12h for 7 days and aclarubicin of 10 mg/day for 4 days (D-CAG).

Results

Among 85 evaluable patients, overall response rate (ORR) and complete remission (CR) were 82.4% and 64.7%, respectively, after 1 cycle of therapy. The ORR in patients aged <70 years was 83.0% and 81.6% in patients aged ≥70 years. There was a significantly longer median overall survival (OS) in patients with response (16 months) than in those without response (7 months, p< 0.0001). The OS for patients aged ≥70 years and 60-69 years was 10 months and 12 months, respectively (p=0.4994). The two-year OS probability was 19.2% and the twenty-month survival rate was 33.8%. Induction mortality of D-CAG treated elderly patients with AML is 4.4%.

Conclusion

D-CAG regimen was well tolerated and showed a promising clinic efficacy in elderly patients with AML (≥70 years).     

Increased SYK activity is associated with unfavorable outcome among patients with acute myeloid leukemia

Recent discoveries have led to the testing of novel targeted therapies for the treatment of acute myeloid leukemia (AML). To better inform the results of clinical trials, there is a need to identify and systematically assess biomarkers of response and pharmacodynamic markers of successful target engagement. Spleen tyrosine kinase (SYK) is a candidate therapeutic target in AML. Small-molecule inhibitors of SYK induce AML differentiation and impair leukemia progression in preclinical studies. However, tools to predict response to SYK inhibition and to routinely evaluate SYK activation in primary patient samples have been lacking. In this study we quantified phosphorylated SYK (P-SYK) in AML cell lines and establish that increasing levels of baseline P-SYK are correlated with an increasing sensitivity to small-molecule inhibitors targeting SYK. In addition, we found that pharmacological inhibition of SYK activity extinguishes P-SYK expression as detected by an immunohistochemical (IHC) test. Quantitative analysis of P-SYK expression by the IHC test in a series of 70 primary bone marrow biopsy specimens revealed a spectrum of P-SYK expression across AML cases and that high P-SYK expression is associated with unfavourable outcome independent of age, cytogenetics, and white blood cell count. This study thus establishes P-SYK as a critical biomarker in AML that identifies tumors sensitive to SYK inhibition, identifies an at-risk patient population, and allows for the monitoring of target inhibition during treatment.     

Recent improvements in outcome for elderly patients with de novo acute myeloblastic leukemia

A retrospective analysis was performed on 263 consecutive patients aged over 60 with de novo acute myeloid leukemia (AML) diagnosed in a single institution between 1979 and 1998. Eighty-nine patients (33%) received only palliative treatment, while 174 patients (67%) were treated with different intensive chemotherapy regimens. The 5- and 10-year overall survival (OS) for the whole series was 7.7+/-1.2 and 4.3+/-1.6%, respectively. For patients receiving chemotherapy, OS was 10.5+/-2.5 and 7+/-2.6%, while for those patients receiving supportive treatment it was 1.1+/-1.1 and 0%, respectively (P=0.002). Within the group of patients receiving chemotherapy, the complete remission (CR) rate was 46%; treatment failure rate was 54% (36% due to treatment-related mortality and 18% due to resistant disease). Variables influencing CR rate were FAB subtype, CD7 positivity, chemotherapy regimen, creatinine level, hepatomegaly, and period of diagnosis. Median disease-free survival (DFS) duration was 8.4 months with a probability of being disease-free at 10 years of 10+/-5%. There were no significant differences in DFS according to age. According to the period of diagnosis (1979-1986 vs. 1987-1998), improvements in the CR rate (27 vs. 56%, P=0.0002), and OS (10.9 vs. 15.7 months, P=0.0007) were observed. This large single-center study of unselected de novo AML elderly patients substantiates the progressive improvement achieved in the management of elderly patients with AML, probably due to an improvement in supportive care and the administration of conventional induction chemotherapy.     

An mRNA expression signature for prognostication in de novo acute myeloid leukemia patients with normal karyotype

Although clinical features, cytogenetics, and mutations are widely used to predict prognosis in patients with acute myeloid leukemia (AML), further refinement of risk stratification is necessary for optimal treatment, especially in cytogenetically normal (CN) patients. We sought to generate a simple gene expression signature as a predictor of clinical outcome through analyzing the mRNA arrays of 158 de novo CN AML patients. We compared the gene expression profiles of patients with poor response to induction chemotherapy with those who responded well. Forty-six genes expressed differentially between the two groups. Among them, expression of 11 genes was significantly associated with overall survival (OS) in univariate Cox regression analysis in 104 patients who received standard intensive chemotherapy. We integrated the z-transformed expression levels of these 11 genes to generate a risk scoring system. Higher risk scores were significantly associated with shorter OS (median 17.0 months vs. not reached, P < 0.001) in ours and another 3 validation cohorts. In addition, it was an independent unfavorable prognostic factor by multivariate analysis (HR 1.116, 95% CI 1.035~1.204, P = 0.004). In conclusion, we developed a simple mRNA expression signature for prognostication in CN-AML patients. This prognostic biomarker will help refine the treatment strategies for this group of patients.     

地西他滨联合减剂量MAG方案治疗老年急性髓系白血病的疗效及安全性北大核心

目的:评价地西他滨联合减剂量MAG方案[米托蒽醌(MTN)+阿糖胞苷(Ara-C)+粒细胞集落刺激因子(G-CSF)]治疗老年急性髓系白血病(acute myeloid leukemia,AML)患者的疗效及安全性。方法:本研究回顾性分析2016年06月至2020年12月收治的50例初诊老年急性髓系白血病患者,使用地西他滨联合MAG方案进行2个周期化疗,评估其疗效及安全性。结果:50例患者均完成2个周期化疗,骨髓造血恢复后进行评估。其中完全缓解(complete response,CR)29例(58.00%),部分缓解(partial response,PR)14例(28.00%),总缓解率(overall response rate,ORR)为86.00%(43/50)。所有患者均出现Ⅲ-Ⅳ级血液学毒性,其中24例(48.00%)患者粒细胞缺乏期出现感染,16例(32.00%)出现Ⅱ度出血。31例(62.00%)出现Ⅰ-Ⅱ级恶心、呕吐、脏器损害等非血液学毒性,但均可耐受,无治疗相关死亡病例。性别、年龄、KPS评分对完全缓解率无明确影响(P>0.05)。细胞遗传学良好者较细胞遗传学不良者缓解率高,差异具有统计学意义(P<0.05)。结论:地西他滨联合减剂量MAG方案治疗老年急性髓系白血病疗效确切,缓解率高,毒副反应可耐受,适用于临床广泛应用。     

老年急性髓细胞白血病的临床特点

根据老年急性髓细胞白血病的临床特点,寻求治疗老年急性髓细胞性白血病的有效措施。回顾性分析25例老年急性髓细胞白血病的临床资料,治疗按个体差异分为姑息治疗组、小剂量HA化疗组及标准剂量联合化疗组,并对其治疗效果进行比较。老年急性髓细胞白血病,具有独特的生物学及临床特征;姑息治疗组3例,CR率为0;小剂量HA化疗组7例,CR率28.6%;标准剂量联合化疗组15例,CR率33.3%。标准剂量联合化疗组的CR率及平均存活期均高于小剂量HA化疗组,而诱导期死亡率则低于小剂量HA化疗组,但其差异均无统计学意义。对老年急性髓细胞性白血病的化学治疗应个体化,并辅以积极的综合治疗,才能有望提高疗效。     

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.     

老年人急性髓系白血病的治疗和预后因素

 急性髓系白血病（AML）主要见于老年人,老年人AML发病率疗效差且无公认的治疗策略。老年人AML的治疗,诱导缓解应在诊断后尽早开始,尽可能达到完全缓解（CR）。诱导治疗方案可根据患者一般状况、器官功能、年龄而选择标准化疗、小剂量阿糖胞苷化疗及支持治疗。缓解后需要巩固治疗,巩固治疗以三个疗程为宜,巩固治疗的强度以中剂量阿糖胞苷为宜。维持治疗对预后不良者可能有效。年龄和染色体核型是老年人AML重要的预后因素,结合患者一般状况器官功能确定个体化治疗方案,有可能提高老年人AML的疗效。     

Genetic variations of DNA repair genes and their prognostic significance in patients with acute myeloid leukemia

Common genetic variations in genes involved in DNA repair or response to genotoxic stress may influence both cancer susceptibility and treatment response individually or interactively. However, in acute myeloid leukemia (AML), the relevance of these genetic variations remains to be fully established. In this study, we analyzed 42 genetic variations among 15 candidate genes in 307 AML patients and 560 age‐sex matched controls. Their associations with chemotherapy response were further evaluated in combination with other well‐established prognostic factors. An increased risk of AML was found in individuals heterozygous for XPD 2251A>C (rs13181) with an odds ratio (OR) of 1.637 (95% confidence interval [CI]: 1.118–2.395), and the increased risk could be attributed to C allele (OR = 1.505, 95% CI: 1.061–2.134). Postchemotherapy response analysis revealed that AML patients heterozygous for ATM 4138C>T (rs3092856) or GG homozygous for TP53 215C>G (rs1042522) were independently linked to inferior treatment outcomes. These results uncover novel prognostic factors for AML patients treated with chemotherapy and may also indicate an etiological role of XPD in this disease.     

初治急性髓系白血病患者Bcl11a基因表达水平及其与预后的关系

目的 探讨急性髓系白血病（AML）患者Bcl11a基因表达水平及其临床意义.方法 通过实时荧光定量PCR方法检测80例初治AML患者及16例对照组Bcl11a基因的表达水平,分析其表达水平与疾病特征及临床疗效之间的关系.结果 初治AML患者Bcl11a表达水平高于对照组[0.039（0～ 0.504）比0.014（0.002 ～ 0.086）,P=0.004].以80例初治AML患者Bcl11a基因表达量的中位数作为分界点,将患者分为Bcl11a高表达组和低表达组各40例.Bcl11a低表达组AML患者中位年龄低于高表达组患者（29.5岁比41.0岁）,而初治AML患者在不同分层的性别、FAB分型、外周血象、骨髓原始细胞比例、遗传学危险度分层、免疫分型CD34表达间Bcl11a基因表达水平差异均无统计学意义（均P＞0.05）.Bcl11a基因低表达组患者完全缓解率高于高表达组[90％（36/40）比53％（21/40）,P=0.000],中位生存时间延长（268.0d比101.5 d,P=0.042）.结论 Bcl11a基因表达水平和AML患者年龄、疗效和预后存在一定的关系,Bcl11a基因高表达的AML患者预后较差.     

Clinical impact of CD200 expression in patients with acute myeloid leukemia and correlation with other molecular prognostic factors

CD200, a protein belonging to the immunoglobulin superfamily, has been associated with a poor prognosis in lymphoproliferative disorders and in acute leukemia. We studied the expression of CD200 in a series of 244 patients with diagnosis of acute myeloid leukemia (AML), to evaluate its impact on outcome and its possible association with other known prognostic factors.CD200 was found in 136/244 (56%) patients, in 41 of whom (30%) with high intensity of expression (MFI ≥ 11). CD200 was more frequent in secondary compared to de novo leukemia (p = 0.0006), in CD34 positive cases (p = 0.00001), in Bcl2 overexpressing cases (p = 0.01), in those wild-type Flt3 (p = 0.004) and with favorable or unfavorable compared to intermediate karyotype (p = 0.0003). CD200+ patients have a two-fold lower probability to attain complete remission, both in univariate (p = 0.006) and multivariate (p = 0.04) analysis. The negative impact of CD200 was found also in overall survival (p = 0.02) and was correlated with the intensity of expression of the molecule (p = 0.024). CD200 has an additive negative impact on survival in patients with unfavorable cytogenetic (p = 0.046) and in secondary leukemia (p = 0.05), and is associate with a worsening of outcome in patients with favorable biological markers, such as mutated NPM (p = 0.02), wild-type Flt3 (p = 0.034), negativity of CD34 (p = 0.03) and of CD56 (p = 0.03).In conclusion, CD200 is emerging as both a prognostic factor and a potential target of novel therapeutic approaches for AML, aiming to reverse the “do not eat me” signal of CD200 or to manipulate the suppressive immune microenvironment induced by CD200 binding to its receptor.     

Hematological features and treatment outcome in acute myeloid leukemia with t(8;21)

We analyzed the hematological features and treatment outcome in 18 patients with t(8;21) acute myeloid leukemia (AML) diagnosed in Queen Mary Hospital, Hong Kong. They comprised 15 cases of M2, two cases of M4 and one case of M1 according to FAB criteria. Auer rods (17 cases) and dysgranulopoietic features (15 cases) were very frequently observed. Two cases showed marrow eosinophilia while blast cells in one patient demonstrated erythrophagocytic activity. Chromosome changes in addition to t(8;21) were seen in 14 patients, the most common of which was loss of a sex chromosome (10 cases). Of the 14 patients treated with intensive chemotherapy, 13 (93 per cent) entered complete remission with a median event-free survival (EFS) and overall survival (OS) of 11 and 24 months respectively. The probability of EFS and OS at 3 years were 33±14·3 per cent and 55·1±15·6 per cent respectively with a median duration of follow-up of 22 months. When compared with AML having no t(8;21) treated similarly in the same period, we could not demonstrate a better clinical outcome for t(8;21) AML. © 1997 John Wiley & Sons, Ltd.     

Increased fibrinogen levels at diagnosis are associated with adverse outcome in patients with acute myeloid leukemia

Increased plasma fibrinogen levels are associated with shortened overall survival (OS) in some solid tumor types. In contrast, the prognostic significance of varying fibrinogen levels in acute myeloid leukemia (AML) at diagnosis is unknown. In this study, we assessed the prognostic significance of fibrinogen levels in AML patients. In a comprehensive retrospective single‐center study, we determined the survival rates of 375 consecutive AML patients undergoing at least one cycle of intensive chemotherapy induction treatment. Patients were dichotomized between low (<4.1 g/L) and high fibrinogen levels (≥4.1 g/L) at diagnosis of AML before initiation of treatment. Subsequently, quartile ranges were applied to analyze the association of varying fibrinogen levels on survival. We observed that the rates of complete remission, early death, and admission to intensive care unit were equal in the low versus high fibrinogen group. However, OS was significantly better in the low fibrinogen group (27.3 vs 13.5 months; p = 0.0009) as well as progression‐free survival (12.3 vs 7.8 months; p = 0.0076). This survival difference remained significant in the multivariate analysis (p = 0.003). Assessing quartiles of fibrinogen values, we further confirmed this observation. Our data suggest that high fibrinogen levels at diagnosis of AML are associated with unfavorable OS and progression‐free survival but not with increased mortality during induction treatment. Copyright © 2016 John Wiley & Sons, Ltd.     

Genetic alteration patterns and clinical outcomes of elderly and secondary acute myeloid leukemia

To illustrate the clinical and genetic features of elderly and secondary acute myeloid leukemia (AML) patients, we compared 145 elderly AML (e‐AML) and 55 secondary AML (s‐AML) patients with 451 young de novo AML patients. Both e‐AML and s‐AML patients showed lower white blood cell (WBC) and bone marrow (BM) blasts at diagnosis. NPM1, DNMT3A, and IDH2 mutations were more common while biallelic CEBPA and IDH1 mutations were less seen in e‐AML patients. s‐AML patients carried a higher frequency of KMT2A‐AF9. In treatment response and survival, e/s‐AML conferred a lower complete remission (CR) rate and shorter duration of event‐free survival (EFS) and overall survival (OS) compared with young patients. In multivariate analysis, s‐AML was an independent risk factor for OS but not EFS in the whole cohort. Importantly, intensive therapy tended to improve the survival of e/s‐AML patients without increasing the risk of early death, and hematopoietic stem cell transplantation (HSCT) could rescue the prognosis of s‐AML, which should be recommended for the treatment of fit patients.     

SAMHD1基因在初诊急性髓细胞白血病患者中的表达及其临床意义

目的:探讨SAMHD1基因在初诊急性髓细胞白血病（AML)患者中的表达及其临床意义。方法:实时定量PCR方法检测13例成人初诊AML患者与7例非恶性血液病患者SAMHD1 mRNA的表达,分析其临床意义。利用SPSS统计学方法分析SAMHD1基因表达高低与初诊白血病患者临床和实验室特征之间的相关性,采用Kaplan-Meier法以及COX回归模型进行多因素生存分析。结果:SAMHD1基因在AML患者中的表达低于非恶性血液病患者（P＜0.05）,且SAMHD1基因表达高低与患者性别、年龄、初诊时WBC、HGB、PLT、骨髓原始细胞百分比分布差异均无统计学意义;SAMHD1表达高低在预后良好与预后不良组间差异比较有统计学意义（P＜0.05),其中低表达组的OS低于高表达组。结论:SAMHD1基因在AML与非恶性血液病患者中表达差异具有统计学意义,且其可作为影响初诊AML患者OS的独立预后因素。     

High-dose cytarabine induction is well tolerated and active in patients with de novo acute myeloid leukemia older than 60 years

BACKGROUND:

High‐dose cytarabine (HiDAC) is safe and very effective in younger patients with acute myeloid leukemia (AML), but it generally is not well tolerated in the elderly.

METHODS:

The authors explored the safety and tolerability of a modified HiDAC induction regimen consisting of 6 daily doses of cytarabine at 2 g/m² in combination with 3 daily doses of daunorubicin at 45 mg/m² in 59 consecutive patients aged >60 years who had de novo AML diagnosed between July 1996 and February 2005.

RESULTS:

The median patient age was 68 years (range, 60‐86 years). The regimen was well tolerated. Infections were common and occurred in 39% of patients, but cerebellar toxicities occurred in only 7% of patients and were reversible. The day‐30 induction‐related mortality rate was 10%. Overall, 69% of patients achieved complete remissions (CR), and 80% received up to 3 consolidations with HiDAC. The median follow‐up for surviving patients was 53 months (range, 17‐114 months). The median overall survival was 15.3 months (range, 1‐114 months), and the relapse‐free survival was 13.8 months (range, 1‐113 months). Survival for patients who achieved CR was 27 months (range, 2‐114 months).

CONCLUSIONS:

The modified HiDAC regimen was well tolerated in patients aged >60 years with AML and was associated with low induction mortality and high rates of CR. Nevertheless, these high remissions still were associated with poor overall outcomes. Cancer 2011;. © 2011 American Cancer Society.     

Long‐term outcome and prognostic factors of elderly patients with acute promyelocytic leukemia

Studies focused on elderly acute promyelocytic leukemia (APL) are relatively limited. To evaluate prognostic impact in elderly APL, we compared the long‐term outcome of elderly APL patients (60–70 years) with younger patients (15–59 years) treated with all‐trans retinoic acid combined with anthracycline and cytarabine in the Japan Adult Leukemia Study Group (JALSG) APL97 study. Of 283 evaluable patients, 46 (16.3%) were elderly who had more frequent lower platelet (P = 0.04), lower albumin (P = 0.006) and performance status 3 (P = 0.02), higher induction death rate due to differentiation syndrome (P = 0.03), and non‐relapse mortality (NRM) during consolidation therapy (P = 0.001). Overall survival was significantly inferior in elderly patients (P = 0.005), but disease‐free survival and cumulative incidence of relapse were not. Better therapeutic approaches should be considered to reduce NRM during induction and consolidation therapy in elderly APL. This study was registered at http://www.umin.ac.jp/ctrj/ under C000000206.