The Clinicopathological Impact of Granulocyte-Macrophage Colony-Stimulating Factor Gene Expression and Different Molecular Prognostic Biomarkers in Egyptian Acute Myeloid Leukemia Patients

Background: Acute myeloid leukemia (AML) is characterized by clonal expansion of myeloid precursors with diminished capacity for differentiation. It develops as the consequence of a series of genetic changes in a hematopoietic precursor cell. Purpose This study aimed to investigate the correlation between GM-CSF gene expression and different molecular prognostic markers such as FLT3-ITD, NPM1 mutation A and CEBPA gene expression in 100 Egyptian AML patients. As well as, correlation with the response to induction therapy, DFS andOS in these patients. Methodology: Quantitative assessment of GM-CSF gene expression was performed by qRT-PCR. Additional prognostic molecular markers were determined as FLT3-ITD and NPM1 mutation A together with quantitative assessment of CEBPA gene expression by qRT-PCR. Results: Patients with high GM-CSF expression levels had better OS and DFS with p value 0.004 and 0.02, respectively. However, no statistically significant difference between low andhigh GM-CSF gene expression was found regarding the response to therapy (p value= 0.08). Most patients with low CEBPA expression had resistant disease together with poor OS and DFS (P value =     

Meta-analysis for the potential application of FLT3-TKD mutations as prognostic indicator in non-promyelocytic AML

A meta-analysis was performed to demonstrate the prognostic significance of FLT3-TKD mutations in acute myeloid leukemia (AML). The overall hazard ratio (HR) of FLT3-TKD/FLT3-wild type (WT) for disease-free survival (DFS) was 1.20. The overall HRs for overall survival (OS) of FLT3-TKD to FLT3-ITD and FLT3-WT were 0.87 and 1.18. For non-promyelocytic AML with intermediate cytogenetics, the overall HR for DFS of FLT3-TKD/FLT3-ITD was 0.71. The HR for OS of FLT3-TKD/FLT3-ITD was 0.75. Adult AML patients with FLT3-TKD mutations exhibit better outcomes than those with FLT3-ITD. The patients with FLT3-TKD mutations with intermediate cytogenetics had similar OS as those with FLT-WT mutations.     

CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations.

PURPOSE: To assess the prognostic relevance of mutations in the CEBPA gene encoding CCAAT/enhancer binding protein alpha (C/EBP alpha) in a large prospective series of younger adults with acute myeloid leukemia (AML) and normal cytogenetics. PATIENTS AND METHODS: The entire CEBPA coding region was sequenced in diagnostic samples from 236 AML patients 16 to 60 years of age with normal cytogenetics who were uniformly treated on two consecutive protocols of the AML Study Group Ulm, and CEBPA mutation status was correlated with clinical outcome. RESULTS: CEBPA mutations were detected in 36 (15%) of 236 patients. Twenty-one (9%) of 236 patients had mutations predicted to result in loss of C/EBP alpha function. Remission duration and overall survival (OS) were significantly longer for the 36 patients with CEBPA mutations (P =.01 and P =.05, respectively). On multivariate analysis, wild-type CEBPA was an independent prognostic marker affecting remission duration (hazard ratio, 2.85; P =.01) and OS (hazard ratio, 1.87; P =.04). Analysis of cooperating mutations (both types of activating FLT3 mutations and MLL partial tandem duplications) showed that FLT3 mutations had no significant prognostic influence in patients with CEBPA mutations. Furthermore, there was no significant overlap between the subgroup of patients with CEBPA mutation with predicted loss of C/EBP alpha function and patients with FLT3 or MLL mutations, suggesting that CEBPA loss-of-function mutations define a distinct biologic subclass of AML with normal cytogenetics. CONCLUSION: Mutant CEBPA predicts favorable prognosis and may improve risk stratification in AML patients with normal cytogenetics.     

急性髓系白血病患者骨髓涂片FMS样酪氨酸激酶3、NPM1和c-kit基因检测及临床研究

目的：探讨提取贮存骨髓涂片DNA的方法,通过对急性髓系白血病（AML）患者FMS样酪氨酸激酶3（FLT3）、NPM1及c-kit基因突变进行检测,分析三种基因突变与AML临床特征之间的关系。方法收集55例AML患者骨髓涂片,采用聚合酶链反应（PCR）、DNA测序和分子克隆方法对FLT3-内部串联重复（ITD）、NPM1和c-kit基因突变进行检测及分析,记录患者疾病缓解、进展及生存时间。结果实验证实对于低温冻存、未经瑞特染色、未用化学方法固定的骨髓涂片标本及室温贮存、经瑞特染色脱色后的标本均能用苯酚∶氯仿∶异戊醇法成功提取DNA。从骨髓涂片中提取的DNA可用于PCR、直接测序和分子克隆测序分析。在55例AML患者中,FLT3-ITD阳性10例（18.2%）,其中9例为杂合型突变,1例为纯合型突变。FLT3-ITD阳性组较阴性组完全缓解（CR）率低,无事件生存（EFS）和总生存（OS）时间短（P＜0.05）。NPM1基因杂合型突变9例（16.4%）,全部为A型突变。10个月以内NPM1突变组患者EFS率比野生组高（P＜0.05）,19个月以内NPM1突变组OS率比野生组高（P＜0.05）。9例NPM1突变患者中FLT3-ITD阳性3例,CR率由高到低依次为NPM1+ FLT3-ITD-、NPM1- FLT3-ITD-、NPM1- FLT3-ITD+、NPM1+ FLT3-ITD+（P＜0.05）,且NPM1- FLT3-ITD+是影响OS的危险因素（RR＝1.250,P＝0.005）。55例患者中,c-kit基因突变2例（3.6%）,分别为D816H突变型和D816V突变型;c-kit基因突变患者与FLT3-ITD阳性及NPM1突变患者无重叠。结论 FLT3-ITD突变为AML患者预后不良的分子标志,NPM1基因突变可能提示预后较好,NPM1- FLT3-ITD+是影响OS的危险因素。AML中c-kit基因突变率低,未见其与FLT3、NPM1基因突变重叠。     

TET2合并DNMT3A突变及其他共存基因突变对急性髓系白血病患者预后的影响

  目的  探究TET2合并DNMT3A突变及其他共存基因突变对成人非M3型急性髓系白血病（acute myeloid leukemia,AML）患者预后的影响。  方法  回顾性分析2018年1月至2021年9月于南昌大学第一附属医院确诊的初治且行血液肿瘤相关突变基因外显子二代测序检测的512例成人 AML（非 M3 型）患者的临床资料,分析患者的临床特征、疗效及生存情况。  结果  本研究共纳入110例AML患者,TET2突变组64例,DNMT3A单突变组46例。男性50例（45.5%）,中位年龄54（15～79）岁。TET2基因突变频率为12.5%（64/512）,98.4%（63/64）患者突变基因数≥2个,每例患者平均合并5.2个突变基因。NPM1（43.8%）、DNMT3A（42.2%）、FLT3-ITD/TKD（40.6%）、CEBPA（26.6%）、TTN（20.3%）为TET2突变常见的共存突变基因。TET2合并DNMT3A突变患者初次诱导完全缓解（complete response,CR）率为46.2%,略低于TET2单突变患者的76.9%（P=0.077）,与DNMT3A单突变患者无显著性差异（P=0.952）。TET2合并DNMT3A突变患者的中位总生存（median overall survival,mOS）时间为9.5个月,明显低于TET2单突变患者（P=0.002）,而与DNMT3A单突变患者无显著性差异（P=0.414）。三者的中位无复发生存（median relapse- free survival,mRFS）时间无显著性差异（P>0.05）。在TET2突变背景下,合并K/NRAS突变患者的CR率为28.6%,明显低于无K/NRAS突变患者的75.0%（P=0.030）,合并FLT3-ITD突变患者的mOS明显短于无FLT3-ITD突变患者（P=0.030）。多因素分析显示年龄≥60岁、合并FLT3-ITD突变、初次诱导未达CR是影响TET2突变AML患者总生存时间（overall survival,OS）的独立危险因素,DNMT3A突变不影响TET2突变患者OS。  结论  TET2突变是AML患者常见突变,且常合并共存基因突变。共存基因突变与TET2突变共同影响AML患者预后。基于二代测序的基因突变检测对指导AML精确分层及精准治疗具有重要意义。      

Associations Between Age,Cytogenetics, FLT3-ITD,and Marrow Leukemia Cells Identified by Flow Cytometry

Objectives: To explore the relationships between age, cytogenetic subgroups, molecular markers, and cellswith leukemic aberrant immunophenotype in patients with acute myeloid leukemia (AML). Methods: In thisstudy, we evaluated the correlations between age, cytogenetic subgroups (normal, balanced and unbalancekaryotype), molecular mutations (NPM1, FLT3-ITD, and CEBPA mutations) and marrow leukemia cells (LC)identified by flow cytometry in 256 patients with de novo AML. Results: From age group 10-19 years to agegroup ≥ 60 years, the percentage of LC decreased from 67.0 ± 18.4% to 49.0 ± 25.1% (F = 2.353, P = 0.041).LC percentage was higher in patients with balanced karyotypes (65.7 ± 22.4%), than those with unbalancedkaryotypes (46.0 ± 26.6%) (u = 3.444, P = 0.001) or a normal karyotype (49.9 ± 22.1%) (u = 5.093, P < 0.001).Patients with FLT3-ITD (64.3 ± 19.5%) had higher LC percentages compared with those without (54.2 ± 24.3%)(u = 2.794, P = 0.007). Conclusions: Associations between age, cytogenetics, molecular markers, and marrowleukemia cells may offer beneficial information to understand the biology and pathogenesis of AML.     

Landscape of TET2 mutations in acute myeloid leukemia

We investigated ten-eleven translocation 2 (TET2) mutations in acute myeloid leukemia (AML), their correlation with other gene mutations and prognostic value. By deep-sequencing, 131 somatic TET2 mutations were identified in 87/318 (27.4%) patients. Of 87 mutated cases, 44 (50.6%) carried two mutations. TET2 mutations were concomitantly observed with mutations in NPM1, FLT3-ITD, FLT3-TKD, JAK2, RUNX1, CEBPA, CBL and KRAS. However, TET2 mutations rarely concomitantly occurred with IDH1mut or IDH2mut (2/251 or 0/184; P=0.046 and P=0.003, respectively). TET2 mutations were associated with normal karyotype AML (CN-AML) (62/206 (30.1%) CN-AML vs 20/107 (18.7%) aberrant karyotype; P=0.031), higher white blood cell count (mean 65.3 vs 40.3 × 10(9)/l, P=0.023), lower platelet count (mean 68.6 vs 92.4 × 10(9)/l, P=0.03) and higher age (67.5 vs 65.2 years, P<0.001). Survival analyses were restricted to de novo CN-AML patients (n=165) and showed inferior event-free survival (EFS) of TET2 mutations compared with TET2wt (median: 6.7 vs 18.7 months, P=0.009). This negative effect of TET2 mutation on EFS was particularly observed in patients 65 years (median: 8.9 months vs not reached (n.r.), P=0.027) as well as in patients of the European LeukemiaNet favorable-risk subgroup, that is, patients harboring mutated CEBPA and/or mutated NPM1 without FLT3-ITD (median: 10.3 vs 41.3 months, P=0.048). These data support a role for TET2 as an important prognostic biomarker in AML.     

Specific pattern of protein expression in acute myeloid leukemia harboring FLT3-ITD mutations

FLT3 activating mutations can be detected in about 35% of acute myeloid leukemia (AML). FLT3 internal tandem duplications (FLT3-ITD) represent the majority of FLT3 mutations (25 - 30%) while FLT3-TKD (tyrosine kinase domain) mutations can be found in about 7% of AML patients. In this study, we addressed the question whether especially primary AML cells carrying FLT3-ITD mutations show differences in terms of their protein expression pattern compared to FLT3 wild-type blasts. We investigated bone marrow samples that were isolated at diagnosis from 36 AML patients expressing either FLT3 wild-type (n = 16) or an activating FLT3 mutation (FLT3-ITD, n = 15; FLT3-TKD, n = 5). Proteomic analysis was performed by means of surface enhanced laser desorption/ionization-time of flight (SELDI-TOF) mass spectrometry which has shown its high efficiency in finding biomarkers in solid tumors. Here, we demonstrate that a large series of proteins is differently expressed in primary AML blasts harboring FLT3-ITD mutations. Furthermore, there are also significant differences of the protein expression profile between FLT3-ITD and FLT3-TKD mutations. Interestingly, further analysis of FLT3-ITD positive AML according to its response to the induction chemotherapy demonstrates putative prognostic markers for this subgroup of AML. We suggest that SELDI-TOF mass spectrometry represents a promising tool of proteomic analysis of AML that might help to establish new prognostic markers in AML.     

Do AML patients with DNMT3A exon 23 mutations benefit from idarubicin as compared to daunorubicin? A single center experience

Mutations in DNMT3A encoding DNA methyltransferase 3A were recently described in patients with acute myeloid leukemia. To assess their prognostic significance, we determined the mutational status of DNMT3A exon 23 in 288 patients with AML excluding acute promyelocytic leukemia, aged from 18 to 65 years and treated in Toulouse University Hospital. A mutation was detected in 39 patients (13.5%). All DNMT3A exon 23+ patients had intermediate-risk cytogenetics. Mutations significantly correlated with a higher WBC count (p less than 0.001), NPM1 and FLT3-ITD mutations (p=0.027). DNMT3A mutations were conserved through xenotransplantation in immunodeficient mice. No difference in outcome between DNMT3A exon 23+ and DNMT3A exon 23- patients was found even if the results were stratified by NPM1 or FLT3-ITD status. However, DNMT3A exon 23+ patients had better median DFS (not reached vs 11.6 months, p=0.009) and OS (not reached vs 14.3 months, p=0.005) as compared to DNMT3A exon 23- patients when treated with idarubicin, whereas patients treated with daunorubicin had similar outcome regardless the DNMT3A status. This study shows that DNMT3A mutations have no impact on outcome but could be a predictive factor for response to idarubicin and thus, could have a direct influence in the way AML patients should be managed.     

FLT3基因突变在急性早幼粒细胞白血病中的表达及临床意义

目的:检测急性早幼粒细胞白血病（acute promyelocytic leukemia,APL）患者FMS样酪氨酸激酶3（FLT3）基因内部串联重复（ITD）突变和酪氨酸激酶结构域（TKD）突变的表达,并探讨临床意义。方法:提取APL患者骨髓单个核细胞DNA,采用聚合酶链反应及测序技术检测FLT3-ITD和FLT3-TKD,分析临床资料及预后。结果:在77例APL患者中,23例（29.9%）检出 FLT3-ITD,7例（9.1%）检出FLT3-TKD点突变,具体包括5例D835Y、1例N841I、1例D835Y和D835H复合杂合子。FLT3-ITD与高白细胞计数相关（P=0.033）,而FLT3-TKD并无此相关性。与无FLT3基因突变患者相比,尽管FLT3-ITD和TKD突变患者的完全缓解率（CR）、总生存期（OS）、无事件生存期（EFS）均相对更差,除FLT3-TKD与缩短EFS显著相关（P=0.043）外,差异均无统计学意义。值得注意的是,无论是FLT3-ITD（P=0.011）还是FLT3-TKD（P= 0.034）均提示高复发风险。多因素分析表明FLT3-ITD（HR=6.381,P=0.037）、FLT3-TKD（HR=5.198,P=0.009）、骨髓早幼粒细胞比例（HR=1.174,P=0.020）、高白细胞计数（WBC>10×109/L）（HR=9.067,P=0.011)可作为独立预后因素提示高复发风险。结论:FLT3-ITD和TKD在APL中均有表达,FLT3-ITD患者的白细胞计数高。虽然FLT3基因突变对APL患者的CR率和OS无显著影响,但可作为一个有价值的指标用于评估复发风险。     

Frequency of FLT3 Internal Tandem Duplications in Adult Syrian Patients with Acute Myeloid Leukemia and Normal Karyotype

Objective: Activating mutations of the fms-like tyrosine kinase 3 gene (FLT3) by internal tandem duplications (ITDs) in the juxtamembrane domain (JMD) have been reported in ~30% of adult acute myeloid leukemia (AML) patients with cytogenetically normal karyotype (CN). However, FLT3/ITD mutations are frequently accompanied with leukocytosis, high percentage of blasts in bone marrow (BM), and increased the risk of treatment failure in AML patients. FLT3-ITD mutated AML patients mainly with normal karyotype have higher relapse probability and shorter duration of complete remission (CR) after chemotherapy, so FLT3-ITD mutation is considered as an independent poor prognostic factor in AML. Methods: FLT3-ITD and FLT3-KTD were studied by polymerase chain reaction (PCR) and restriction fragment length polymorphism- PCR (RFLP-PCR) in 44 adults AML patients with cytogenetically normal karyotype (AML-CN) at diagnosis to characterize FLT3 status. The results were correlated with the prognostic factors. Results: In this study, FLT3-ITD mutations were identified in 7 (15.9%) of the 44 AML-CN patients. Among the 7 patients with FLT3/ITD mutations, 6 patients revealed a typical ITDs mutation (fragment size was 329 bp) and one patient showed untypical ITD mutation (fragment size was ~400 bp). Whereas 37 patients (61.7%) were FLT3-ITD. None of all AML-CN patients examined showed FLT3-KTD mutations. Conclusions: Our results support that FLT3-ITD are independent adverse prognostic factors for elderly AML-CN patients and are associated with low overall survival (OS), low rate of CR, high relapse rate (RR), and high percentage of BM blast at diagnosis. We concluded, FLT3 mutation analysis should be performed as a routine test in AML-CN patients.     

Fms-Like Tyrosine Kinase 3 Mutations in Childhood Acute Leukemias and their Association with Prognosis

Introduction: In recent years, Fms-like tyrosin kinase (FLT) 3 has been the subject of several studies as a prognostic marker. Objective: In this study, the presence of FLT3 mutations in childhood acute leukemias patients and their association with prognosis were investigated. Materials and Methods: A total of 120 patients, 80 with acute lymphoblastic leukemia (ALL) and 40 with acute myeloblastic leukemia (AML), were included. Real time polymerase chain reaction methods on a high resolution melting analysis device were used to determine FLT3 mutations. Results: FLT3/ITD (internal tandem duplication) mutations were found in 6 (7.5%) of the patients with ALL and in 9 (22.5%) of those with AML, whereas no FLT3/TKD (trans kinase domain) mutation was evident in any case. There was no difference between the ALL patients positive and negative for FLT3/ITD with regard to overall survival (OS), event free survival (EFS) and disease free survival (DFS) (p=0.37, p=0.23, p=0.023, respectively). However, in FLT3/ITD positive and negative AML patients, there was a statistically significant difference in OS (p=0.0041), but not EFS and DFS (p=0.09, p=0.095, respectively). A significant difference was found between age and FLT3/ITD positivity (p=0.036). Conclusion: We found that FLT3/ITD positivity increased with age and that it was associated with decrease in OS in AML patients, providing further evidence that it is an independent factor negatively influencing prognosis.     

Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group.

Internal tandem duplications (ITDs) of the FLT3 gene have been observed in about 35% of APL cases. If FLT3-ITD is associated with a worse outcome in patients with acute myeloid leukemia (AML) in general, its prognostic value in acute promyelocytic leukemia (APL) is still a matter of debate. We investigated incidence, associated clinical features, and prognostic implication of FLT3-ITD, but also FLT3-D835 point mutation and N-Ras or K-Ras mutations in 119 APL patients, all prospectively enrolled in the two consecutive APL-93 and APL-2000 trials. Mutation incidences were 38, 20, and 4%, for FLT3-ITD, FLT3-D835, and Ras, respectively. The presence of FLT3-ITD was associated with high white blood cell count, high Sanz index, M3-variant subtype, and V/S PML-RAR alpha isoforms. Complete remission (CR), induction death, and death in CR rates were not affected by FLT3 or Ras mutations, as well as cumulative incidence of relapse. However, a trend for a shorter overall survival (P=0.09) was observed in FLT3-ITD patients, because of a very poor postrelapse survival (P=0.02). This feature, which has been also reported in patients with AML in general, is suggestive of an underlying genetic instability in FLT3-ITD patients, leading to the acquisition of additional unknown bad-prognosis gene mutations at relapse.     

化学法提取贮存骨髓涂片DNA检测Fms样酪氨酸激酶3基因突变预测急性髓系白血病患者预后

目的 探讨用化学法(苯酚:氯仿:异戊醇法)从贮存的骨髓涂片中提取微量DNA检测Fms样酪氨酸激酶3内部串联重复(FLT3-ITD)突变情况,分析其对急性髓系白血病(AML)预后的预测价值.方法 采用化学法从58例-20℃贮存1~5年的骨髓涂片(AML 48例和非恶性血液病10例)中提取微量DNA,采用聚合酶链反应(PCR)技术检测患者FLT3-ITD突变情况.结果 48例初治AML患者中6例(12.5%)检测到FLT3-ITD,10例非恶性血液病患者中均未检测到FLT3-ITD.FLT3-ITD阳性AML患者初次诱导完全缓解(CR)率较FLT3-ITD阴性者低[0(0/6)比77.78%(21/27),P=0.001],总生存时间短(x2=7.274,P=0.007).肝、脾大和FLT3突变是影响AML患者初次化疗CR的危险因素(OR=7.2,P=0.12;OR=36.3,P=0.10).FLT3-ITD是初治AML患者不良预后的危险因素(RR=9.088,P=0.029).结论 使用化学法提取贮存的AML患者骨髓涂片微量DNA可在临床中应用,是进行回顾性分子生物学研究的重要实验方法.从骨髓涂片中提取微量DNA检测FLT3-ITD可用于预测AML预后.     

T-LAK cell-originated protein kinase presents a novel therapeutic target in FLT3-ITD mutated acute myeloid leukemia

Gain-of-function mutations of FLT3 (FLT3-ITD), comprises up to 30% of normal karyotype acute myeloid leukemia (AML) and is associated with an adverse prognosis. Current FLT3 kinase inhibitors have been tested extensively, but have not yet resulted in a survival benefit and novel therapies are awaited. Here we show that T-LAK cell-originated protein kinase (TOPK), a mitotic kinase highly expressed in and correlated with more aggressive phenotype in several types of cancer, is expressed in AML but not in normal CD34+ cells and that TOPK knockdown decreased cell viability and induced apoptosis. Treatment of AML cells with TOPK inhibitor (OTS514) resulted in a dose-dependent decrease in cell viability with lower IC₅₀ in FLT3-mutated cells, including blasts obtained from patients relapsed after FLT3-inhibitor treatment. Using a MV4-11-engrafted mouse model, we found that mice treated with 7.5 mg/kg IV daily for 3 weeks survived significantly longer than vehicle treated mice (median survival 46 vs 29 days, P < 0.001). Importantly, we identified TOPK as a FLT3-ITD and CEBPA regulated kinase, and that modulating TOPK expression or activity resulted in significant decrease of FLT3 expression and CEBPA phosphorylation. Thus, targeting TOPK in FLT3-ITD AML represents a novel therapeutic approach for this adverse risk subset of AML.     

DNMT3A、FLT3-ITD合并NPM1基因突变正常核型急性髓系白血病患者的临床特征及预后分析

目的 分析DNMT3A、FLT3-ITD合并NPM1基因突变的正常核型急性髓系白血病(AML)患者的临床特征,探讨该类患者的预后.方法 回顾性分析2005年12月至2014年6月就诊的109例正常核型AML患者的临床特征及预后.其中DNMT3A/FLT3-ITD/NPM1+AML患者共25例,单独FLT3-ITD+ AML患者共32例,单独NPM1+AML患者24例,单独DNMT3A+ AML患者28例.结果 25例DNMT3A/FLT3-ITD/NPM1+ AML患者平均年龄46岁,伴有高白细胞(81.7×109/L)及较高的骨髓原始细胞(66.3％).其中,17例选择大剂量化疗,8例行异基因造血干细胞移植,与DNMT3A+、FLT3-ITD+、NPM1+AML组比较,差异均无统计学意义.25例DNMT3A/FLT3-ITD/NPM1+患者的3年总生存率为17.65％,3年无病生存率为13.88％,与DNMT3A+、FLT3-ITD+、NPM1+AML组差异均有统计学意义(P值分别为0.049 9、0.036 1、0.013 4),3年无病生存率差异无统计学意义(均P＞ 0.05).结论 DNMT3A、FLT3-ITD合并NPM1基因突变的正常AML患者往往合并高的外周血白细胞及骨髓原始细胞,预后较差.     

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.