Cuplike nuclei (prominent nuclear invaginations) in acute myeloid leukemia are highly associated with FLT3 internal tandem duplication and NPM1 mutation

BACKGROUND:

A small subset of patients with acute myeloid leukemia (AML) have cuplike nuclei. Other investigators have demonstrated that these neoplasms have distinctive clinicopathologic and molecular features.

METHODS:

The authors searched for patients who had AML with cuplike nuclei at their institution over a 10‐year interval. A strict definition for cuplike nuclei was used: ≥10% blasts with nuclear invaginations in ≥25% of the nuclear area. The relevant data were reviewed, and the results were compared with a control group of patients who had AML without cuplike nuclei.

RESULTS:

In total, 22 patients who had AML with cuplike nuclei were identified and were classified as AML without maturation (French‐American‐British classification M1) (AML M1). Compared with the control group (AML M1), patients who had AML with cuplike nuclei were associated significantly with fms‐like tyrosine kinase 3 (FLT3)‐internal tandem duplication (ITD) (86% vs 38%, respectively; P = .002); nucleophosmin 1 (NPM1) mutations (86% vs 19%; P < .0001); both mutations (77% vs 14%; P < .0001); normal karyotype (86% vs 40%; P = .003); bone marrow blast count (90% vs 84%; P = .016); myeloperoxidase positivity (95% vs 30% blasts; P = .001); higher D‐dimer levels (>5000 ng/mL vs 569 ng/mL; P = .001); and the absence of CD7 (91% vs 52%; P = .007), CD34 (82% vs 5%; P < .0001), and human leukocyte antigen, D‐related (59% vs 10%; P = .001). There were no differences in age, sex, or peripheral blood counts. The positive predictive value of recognizing AML with cuplike nuclei for FLT3‐ITD, NPM1, and both mutations was 81%, 86%, and 77%, respectively.

CONCLUSIONS:

Cuplike nuclei in AML were highly associated with the presence of NPM1 and FLT3‐ITD mutations and with several clinicopathologic and immunophenotypic features. Recognition of the distinctive morphologic features of AML with cuplike nuclei may be helpful in streamlining the workup of these neoplasms. Cancer 2009. © 2009 American Cancer Society.     

FLT3 inhibitors in the treatment of acute myeloid leukemia

Despite recent modest improvements in the chemotherapy regimens used to treat acute myeloid leukemia (AML), many patients diagnosed with AML ultimately die of the disease. Commonly occurring genetic alterations have been identified that strongly affect the prognosis for patients with AML. These alterations represent possible targets for investigational therapies that could act to specifically halt the aberrant growth of AML cells while limiting damage to normal cells. One such gene is the Fms-like tyrosine kinase 3 (FLT3) gene, which is mutated in approximately 30% of adult patients with AML and has a significant impact on prognosis. In particular, internal tandem duplications in FLT3 confer a poor prognosis to this large subgroup of patients with AML. Agents that target FLT3 are in development for the treatment of patients who have AML and offer a potential paradigm change in the current standard treatment of AML. For this report, the authors reviewed the prognostic significance of genetic alterations observed in AML with a focus on the therapeutic implications of targeting FLT3. The introduction of such agents may be the next major step toward the era of personalized therapy in AML.     

Next-generation sequencing of FLT3 internal tandem duplications for minimal residual disease monitoring in acute myeloid leukemia

Minimal Residual Disease (MRD) detection can be used for early intervention in relapse, risk stratification, and treatment guidance. FLT3 ITD is the most common mutation found in AML patients with normal karyotype. We evaluated the feasibility of NGS with high coverage (up to 2.4.10⁶ PE fragments) for MRD monitoring on FLT3 ITD. We sequenced 37 adult patients at diagnosis and various times of their disease (64 samples) and compared the results with FLT3 ITD ratios measured by fragment analysis. We found that NGS could detect variable insertion sites and lengths in a single test for several patients. We also showed mutational shifts between diagnosis and relapse, with the outgrowth of a clone at relapse different from that dominant at diagnosis. Since NGS is scalable, we were able to adapt sensitivity by increasing the number of reads obtained for follow-up samples, compared to diagnosis samples. This technique could be applied to detect biological relapse before its clinical consequences and to better tailor treatments through the use of FLT3 inhibitors. Larger cohorts should be assessed in order to validate this approach.     

Prognostic utility of six mutated genes for older patients with acute myeloid leukemia

Approximately 50% of older patients with acute myeloid leukemia (AML) do not obtain chromosomal abnormalities as an effective risk‐stratification, and present cytogenetically normal AML (CN‐AML). To develop a reliable prediction model for stratifying the risk of these elderly patients, we conducted a study with a discovery and validation design. As a result, we found the top 6 mutated genes in the discovery cohort of 26 case by the whole exome sequencing, and verified as recurrent mutations in the large cohort of 329 patients by Sanger sequencing. The top 6 genes were NPM1, FLT3‐ITD, DNMT3A, CEBPA double allele, IDH1 and IDH2 mutations, and the frequency of each gene in the combining cohort was 36.8%, 19.8%, 20.1%, 5.8%, 14.9% and 22.5%, respectively. In addition, clinical variables such as age, white blood cell counts, genes of IDH1 and DNMT3A mutations, European LeukemiaNet genotype (NPM1 mutations and lacking FLT3‐ITD or CEBPA double allele mutations) and treatment protocols were independent factors for predicting the probabilities of overall and event‐free survival. The prediction nomograms based on these significant factors showed accurate discrimination. In conclusion, we developed a reliable prediction model for stratifying the risk of elderly patients with CN‐AML.     

伴Fms样酪氨酸激酶3内部串联重复的急性髓系白血病临床特点及预后分析

目的 探讨Fms样酪氨酸激酶3内部串联重复(FLT3-ITD)的急性髓系白血病(AML)患者的临床特点及预后.方法 回顾性分析2011年6月至2014年3月收治的39例FLT3-ITD的AML患者临床资料.结果 FLT3-ITD突变的发生率为11.6％(39/337),39例FLT3-ITD AML患者中,M5所占比例最高(43.6％,17/39),其次为M2(28.2％,11/39);外周血白细胞计数平均为88.63×109/L,其中12例(30.8％)大于100×109/L;骨髓原始细胞比例平均为82.53％,其中33例(84.6％)大于50.00％.13例发生髓外浸润;17例核型正常,9例核型异常,3例未见核分裂象;13例患者伴随NPM1突变,2例伴有KIT突变,3例伴有DNMT3突变.37例接受治疗的患者中,第1个疗程获完全缓解(CR)16例(43.2％),第2个疗程获CR 4例(10.8％),2个疗程累积CR率为54.0％,诱导治疗相关病死率为21.6％ (8/37),死亡原因主要为感染及出血.中位随访时间12个月,20例CR患者的复发率为50.0％(10/20),无复发生存(RFS)率为45.0％(9/20);移植组17例患者的总生存及RFS均优于单纯化疗组的20例患者(P=0.004、0.020).结论 FLT3-ITD AML具有初发时外周血白细胞计数及骨髓原始细胞比例高、与M5亚型高度伴随的临床特点,异基因造血干细胞移植能明显提高患者总生存期及无复发生存期.     

Influence of cigarette smoking on the presentation and course of acute myeloid leukemia.

BACKGROUND: It is known that cigarette smoking is associated with an approximately 50% increase in leukemia risk. In order to detect a possible influence of cigarette smoking on initial characteristics at the time of presentation and on the course of the disease, we conducted a retrospective study in 643 patients with newly diagnosed acute myeloid leukemia. PATIENTS AND METHODS: The study comprised 339 males and 304 females (median age 59 years, range 18-84 years). Two hundred and ninety-six patients (46%), smoking at least one cigarette per day for 6 months, were considered as smokers, while 347 patients (54%) were non-smokers. RESULTS: Cigarette smoking was significantly related to male gender (P <0.0001), professional occupancy (P = 0.002), presence of organomegaly (P = 0.01), and lower peripheral blood and bone marrow leukemic cell involvement (P = 0.007 and P = 0.0001, respectively). Leukemia of French-American-British (FAB) M1 subtype was more frequent in non-smokers (P = 0.005). Although not statistically significant, smokers tended to have lower leukocyte counts than non-smokers. No difference was noted in terms of complete remission rates between smokers and non-smokers (67% compared to 64%). However, a higher rate of severe pulmonary infection was observed in smokers during induction chemotherapy (P = 0.02). Cigarette smoking (>or=20 pack-years or smoking duration >or=30 years) was significantly associated with shorter disease-free survival (P = 0.03) and overall survival (OS; P = 0.02 and P = 0.004, respectively). Other characteristics associated with poor prognosis included mainly older age, unfavorable karyotype, secondary acute myeloid leukemia (AML) and elevated World Health Organization (WHO) performance status. Cigarette smoking was associated with shorter OS in younger adults, but did not significantly influence survival in patients >60 years old. Cigarette smoking worsened the poor OS in patients with unfavorable karyotype, but did not significantly influence the prognosis of other karyotypic risk groups. In a multivariate analysis, only karyotypic grouping and age remained of prognostic value for the occurrence of disease-free and overall survival. CONCLUSIONS: Cigarette smoking has a deleterious effect on survival in AML by shortening complete remission duration and subsequent survival. It was associated with severe infections during aplasia. Leukemogenic compounds favoring complex karyotypic abnormalities could also be involved.     

老年急性髓细胞白血病患者FLT3-ITD基因突变的临床意义

 目的　分析老年急性髓细胞白血病（AML）Fms样酪氨酸激酶3内部串联重复序列（FLT3-ITD）基因突变及其临床意义。方法　采用聚合酶链反应-变性高效液相色谱技术（PCR-DHPLC）分析30例初发老年AML患者骨髓单个核细胞FLT3-ITD突变。结果　30例老年AML患者FLT3-ITD突变阳性率26.67 %（8／30）,对照组均未检测到该突变;FAB各亚型FLT3-ITD突变率不同,有M3型突变率较高的趋势;所检测到FLT3-ITD突变均为杂合突变,突变均在阅读框内;不同预后核型组FLT3-ITD突变阳性率不同,预后中等核型组突变率较高,达40.0 %（6／15）;显示FLT3-ITD突变阳性者具有高白细胞、白血病细胞、完全缓解（CR）率低等临床特点。结论　FLT3-ITD突变阳性老年AML患者预后差,且多发生于预后中等核型组;FLT3-ITD突变检测在一定程度上可以弥补细胞遗传学的不足,有可能成为老年AML患者常规检测项目,以指导治疗判断预后。     

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.     

A novel prognostic scoring model for newly diagnosed FLT3-ITD-positive acute myeloid leukemia

FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most common somatic mutations in acute myeloid leukemia (AML). However, the molecular structure characteristics and widely accepted prognostic factors for FLT3-ITD are still not well described. This study aimed to retrospectively examine 81 patients with FLT3-ITD-positive AML diagnosed and treated at the First Affiliated Hospital of Zhejiang University from December 2013 to March 2018 using the next-generation sequencing 185-gene platform. High variant allele frequency (VAF) [> 0.48, P = 0.0089 for overall survival (OS), P = 0.13 for relapse-free survival (RFS)], multiple ITDs (> 1 ITDs, P = 0.011 for OS, P = 0.033 for RFS) and longer insertion length (> 69 bp, P = 0.14 for OS, P = 0.0078 for RFS) predicted poor survival. The study further proposed an easily applicable scoring model for OS using the Least Absolute Shrinkage and Selector Operation (LASSO) Cox regression model. Also, an independent cohort of 30 patients was used for external model validation. The mode was expressed as follows: 0.659 × FLT3-ITD VAF + 0.375 × FLT3-ITD number + 0.807 × Age + 0.688 × DNMT3A + 1.939 × U2AF1 (FLT3-ITD VAF > 0.48 scored 1; FLT3-ITD number scored 1 if carried 1 ITD, 2 if carried ≥ 2 ITDs; age > 44 years scored 1, the presence of DNMT3A or U2AF1 scored 1; 0 for other conditions). It categorized patients into low-risk (L-R, score < 1, n = 20) and high-risk (H-R, score ≥ 1, n = 61) groups based on the risk score with a significant difference in survival (3-year OS, P < 0.0001; 3-year RFS, P = 0.0005). A prognostic nomogram that integrated these five factors was developed with a concordance index calculation [OS: 0.68, 95% CI (0.64-0.72)].     

急性髓细胞白血病NPM1和FLT3-ITD突变检测临床意义分析

目的:研究核仁磷酸蛋白1(NPM1)FMS样酪氨酸激酶3(FLT3)基因内部串联重复(ITD)突变在急性髓细胞白血病(AML)中发生的情况,并了解其临床特征及预后意义.方法:分别应用高分辨熔解曲线(HRM)和变性高效液相色谱技术(DHPLC)检测103例初诊AML患者NPM1和FLT3-ITD突变情况,并结合临床资料进行分析.结果:103例初诊AML患者中,31例发现NPM1基因突变,20例发现FLT3-ITD突变,阳性率分别为30.1％和19.4％,而在核型正常组中所占的比例分别为47.6％(20/42)和26.2％(11/42).FLT3-ITD突变型外周血白细胞计数高,t=2.21,P=0.037;骨髓原始细胞比例高,t=2.44,P=0.023;NPM1突变型亦表现为高外周血白细胞计数,t=2.24,P=0.034.在非M3患者中,NPM1突变型的CR与野生型差异无统计学意义,但第1次化疗的CR(76.9％)明显高于野生型患者(35.0％),x2=12.78,P=0.000 35;FLT3-ITD突变型患者的CR为58.8％,野生型患者为82.6％,两者比较,x2=4.48,P=0.034;FLT3-ITD突变型患者第1次化疗的CR为17.6％,而野生型患者为55.1％,两者比较,x2=6.23,P=0.012.31例NPM1基因突变中有6例合并FLT3-ITD突变,NPM1+/FLT3-ITD-组的CR最高(85.0％),1年内RR率最低(17.6％);NPM1-/FLT3-ITD+组的CR最低(54.5％),1年内RR率最高(50.0％).结论:NPM1和FLT3-ITD突变是AML患者常见的分子遗传学异常,与预后密切相关,可成为目前细胞遗传学预后分组的重要补充,对于指导AML患者的个体化治疗具有重要的临床价值.     

FLT3、NPM1、DNMT3A及IDH基因突变对非M3型急性髓系白血病预后影响的研究进展

非M3型急性髓系白血病(AML)是一组异质性恶性血液系统疾病,无论在形态学、免疫学、细胞遗传学、分子生物学及临床特点上都存在很大差异.细胞遗传学检测结果已经成为AML精确诊断、治疗选择和预后判断的主要依据之一,但由于在分子水平上存在高度的异质性,常规细胞遗传学技术检出率不高.有40%~50%的AML患者在初诊时用标准的染色体显带分析方法检测不到克隆性染色体畸变,被称为正常核型AML.非M3型AML较常见的分子遗传学改变为FLT3、NPM1、DNMT3A、IDH基因突变.文章主要就四种基因的特点、发病机制及对非M3型AML的预后影响作一综述.     

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.     

Sex disparity in acute myeloid leukaemia with FLT3 internal tandem duplication mutations: implications for prognosis

Incidence, molecular presentation and outcome of acute myeloid leukaemia (AML) are influenced by sex, but little attention has been directed at untangling sex‐related molecular and phenotypic differences between female and male patients. While increased incidence and poor risk are generally associated with a male phenotype, the poor prognostic FLT3 internal tandem duplication (FLT3‐ITD) mutation and co‐mutations with NPM1 and DNMT3A are overrepresented in female AML. Here, we have investigated the relationship between sex and FLT3‐ITD mutation status by comparing clinical data, mutational profiles, gene expression and ex vivo drug sensitivity in four cohorts: Beat AML, LAML‐TCGA and two independent HOVON/SAKK cohorts, comprising 1755 AML patients in total. We found prevalent sex‐associated molecular differences. Co‐occurrence of FLT3‐ITD, NPM1 and DNMT3A mutations was overrepresented in females, while males with FLT3‐ITDs were characterized by additional mutations in RNA splicing and epigenetic modifier genes. We observed diverging expression of multiple leukaemia‐associated genes as well as discrepant ex vivo drug responses, suggestive of discrete functional properties. Importantly, significant prognostication was observed only in female FLT3‐ITD‐mutated AML. Thus, we suggest optimization of FLT3‐ITD mutation status as a clinical tool in a sex‐adjusted manner and hypothesize that prognostication, prediction and development of therapeutic strategies in AML could be improved by including sex‐specific considerations.     

Inhibition of poly(ADP-ribose) polymerase 1 protects against acute myeloid leukemia by suppressing the myeloproliferative leukemia virus oncogene

An abnormal expression of poly(ADP-ribose) polymerase 1 (PARP-1) has been described in many tumors. PARP-1 promotes tumorigenesis and cancer progression by acting on different molecular pathways. PARP-1 inhibitors can be used with radiotherapy or chemotherapy to enhance the susceptibility of tumor cells to the treatment. However, the specific mechanism of PARP-1 in acute myeloid leukemia (AML) remains unknown. Our study showed that expression of PARP-1 was upregulated in AML patients. PARP-1 inhibition slowed AML cell proliferation, arrested the cell cycle, induced apoptosis in vitro and improved AML prognosis in vivo. Mechanistically, microarray assay of AML cells with loss of PARP-1 function revealed that the myeloproliferative leukemia virus oncogene (MPL) was significantly downregulated. In human AML samples, MPL expression was increased, and gain-of-function and loss-of-function analysis demonstrated that MPL promoted cell growth. Moreover, PARP-1 and MPL expression were positively correlated in AML samples, and their overexpression was associated with an unfavorable prognosis. Furthermore, PARP-1 and MPL consistently acted on Akt and ERK1/2 pathways, and the anti-proliferative and pro-apoptotic function observed with PARP-1 inhibition were reversed in part via MPL activation upon thrombopoietin stimulation or gene overexpression. These data highlight the important function of PARP-1 in the progression of AML, which suggest PARP-1 as a potential target for AML treatment.     

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.     

FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development

FMS‐like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase that plays an important role in hematopoietic cell survival, proliferation and differentiation. The most clinically important point is that mutation of the FLT3 gene is the most frequent genetic alteration and a poor prognostic factor in acute myeloid leukemia (AML) patients. There are two major types of FLT3 mutations: internal tandem duplication mutations in the juxtamembrane domain (FLT3‐ITD) and point mutations or deletion in the tyrosine kinase domain (FLT3‐TKD). Both mutant FLT3 molecules are activated through ligand‐independent dimerization and trans‐phosphorylation. Mutant FLT3 induces the activation of multiple intracellular signaling pathways, mainly STAT5, MAPK and AKT signals, leading to cell proliferation and anti–apoptosis. Because high‐dose chemotherapy and allogeneic hematopoietic stem cell transplantation cannot sufficiently improve the prognosis, clinical development of FLT3 kinase inhibitors expected. Although several FLT3 inhibitors have been developed, it takes more than 20 years from the first identification of FLT3 mutations until FLT3 inhibitors become clinically available for AML patients with FLT3 mutations. To date, three FLT3 inhibitors have been clinically approved as monotherapy or combination therapy with conventional chemotherapeutic agents in Japan and/or Europe and United states. However, several mechanisms of resistance to FLT3 inhibitors have already become apparent during their clinical trials. The resistance mechanisms are complex and emerging resistant clones are heterogenous. Further basic and clinical studies are required to establish the best therapeutic strategy for AML patients with FLT3 mutations.     

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.