Near-triploid acute lymphoblastic leukemia with TEL/AML1 translocation

An 11-year-old girl was diagnosed as B-precursor acute lymphoblastic leukemia (ALL) with co-expression of myeloid antigens. Cytogenetic analysis revealed a near-triploid (75-82 chromosomes/cell) abnormal chromosomal complement.Fluroscent in situ hybridization studies indicated presence of TEL/AMLI fusion genes. We discuss the prognostic relevance of TEL/AML1 in this rare near-triploid subtype of ALL.     

Biology and clinical significance of the TEL/AML1 rearrangement

The accurate identification of chromosomal abnormalities in patients with leukemia is essential for diagnosis and treatment assignment. Recent technical improvements in the detection of such aberrations have demonstrated that the previously unrecognized chromosomal translocation t(12;21) is the most prevalent structural aberration in childhood acute lymphoblastic leukemia. Both genes involved, translocation ets like gene (or ETV6) on chromosome 12 and acute myeloid leukemia 1 gene (or CBF alpha) on chromosome 21 had been identified for several years previously, which facilitated the rapid development of molecular diagnostic assays and their implementation in therapy trials. Although first described less than four years ago, the TEL/AML1 story is an excellent example of how close collaboration between physicians and molecular biologists is mandatory for achieving general insights into the molecular pathogenesis of leukemia and for further improvements in diagnosis and in monitoring response to chemotherapy.     

EQUAL FREQUENCY OF TEL/AML1 ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN WITH AND WITHOUT DOWN SYNDROME

Constitutional trisomy 21 is the most prominent predisposing factor to childhood leukemia, whereas the t(12;21)(p13;q22) with its molecular genetic counterpart, the TEL/AML1 fusion gene, is the most common acquired chromosomal rearrangement in childhood B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). Thus, it was somewhat surprising that according to the currently available literature the incidence of TEL/AML1+ BCP ALL is extremely low in patients with Down syndrome (DS). To further investigate this issue in a population-based fashion, the authors retrospectively assessed the number of DS patients with a TEL/AML1+ ALL in two consecutive Austrian ALL multicenter trials. Accordingly, they were able to analyze 8 of 10 individuals with DS and a BCP ALL, including 2 who suffered from a TEL/AML1+ leukemia. Based on this observation we concluded that individuals with a constitutional trisomy 21 may have the similar likelihood to develop a TEL/AML1+ leukemia as BCP ALL patients without this specific predisposing factor.     

Equal frequency of TEL/AML1+ acute lymphoblastic leukemia in children with and without Down syndrome

Constitutional trisomy 21 is the most prominent predisposing factor to childhood leukemia, whereas the t(12;21)(p13;q22) with its molecular genetic counterpart, the TEL/AML1 fusion gene, is the most common acquired chromosomal rearrangement in childhood B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). Thus, it was somewhat surprising that according to the currently available literature the incidence of TEL/AML1+ BCP ALL is extremely low in patients with Down syndrome (DS). To further investigate this issue in a population-based fashion, the authors retrospectively assessed the number of DS patients with a TEL/AML1+ ALL in two consecutive Austrian ALL multicenter trials. Accordingly, they were able to analyze 8 of 10 individuals with DS and a BCP ALL, including 2 who suffered from a TEL/AML1+ leukemia. Based on this observation we concluded that individuals with a constitutional trisomy 21 may have the similar likelihood to develop a TEL/AML1+ leukemia as BCP ALL patients without this specific predisposingfactor.     

Equal frequency of TEL/AML1 rearrangements in children with acute lymphoblastic leukemia with and without Down syndrome

Constitutional trisomy 21 is the most prominent predisposing factor to childhood leukemia, whereas the t(12;21)(p13;q22) with its molecular genetic counterpart, the TEL/AML1 fusion gene, is the most common acquired chromosomal rearrangement in childhood B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). Thus, it was somewhat surprising that according to the currently available literature the incidence of TEL/AML1⁺ BCP ALL is extremely low in patients with Down syndrome (DS). To further investigate this issue in a population-based fashion, the authors retrospectively assessed the number of DS patients with a TEL/AML1⁺ ALL in two consecutive Austrian ALL multicenter trials. Accordingly, they were able to analyze 8 of 10 individuals with DS and a BCP ALL, two of whom who suffered from a TEL/AML1⁺ leukemia. Based on this observation they concluded that individuals with BCP leukemia and a constitutional trisomy 21 may have similar likelihood to have a TEL/AML1 rearrangement as BCP ALL patients without this specific predisposing factor.     

TEL/AML1 基因阳性急性淋巴细胞白血病患儿CCLG-ALL-2008方案疗效分析

目的探讨CCLG-ALL-2008方案治疗TEL/AML1融合基因阳性儿童急性淋巴细胞白血病(ALL)效果以及影响因素。方法回顾分析2008年6月至2014年12月初诊并治疗的99例TEL/AML1融合基因阳性患儿及329例无特异性融合基因的B系ALL患儿的临床和生物学特征,随访至2015年10月,观察两组患儿的生存状态和影响因素。结果两组患儿初诊时的年龄和外周血白细胞数相近;在诱导缓解治疗第8天的泼尼松敏感实验、第15天骨髓呈M3状态、第33天和第12周微小残留病灶(MRD)1.0×10-3的比例两组患儿的差异均无统计学意义(P0.05)。随访期间,TEL/AML1融合基因阳性患儿的复发率为14.14%(14/99),无特异性融合基因组为20.97%(69/329),差异无统计学意义(χ2=2.27,P=0.132);无特异性融合基因组病死率(16.72%)高于TEL/AML1融合基因阳性组(8.08%),差异有统计学意义(χ2=4.52,P=0.033)。TEL/AML1融合基因阳性组与无特异性融合基因组的5年总生存率(OS)分别为(86.1±4.9)%和(79.0±2.8)%,5年无复发生存率(RFS)分别为(80.7±5.1)%和(72.0±3.1)%,5年无事件生存率(EFS)分别为(78.9±5.1)%和(69.6±3.1)%,差异均无统计学意义(P0.05)。COX模型分析显示第12周MRD水平是影响OS、RFS、EFS的独立预后因素(P均0.001)。结论接受CCLG-ALL-2008方案治疗的ALL患儿,TEL/AML1融合基因阳性是预后良好的指标,第12周MRD≥1.0×10-3应推荐更强烈的治疗方案。     

p16 inactivation associated with aggressive clinical course and fatal outcome in TEL/AML1-positive acute lymphoblastic leukemia

The authors describe a 7-year-old boy with TEL/AML1-positive pre-B acute lymphoblastic leukemia, with hemizygous 9p21 deletion at presentation and no p16(INK4A) protein expression. Despite an initial response to a standard chemotherapy regimen, the patient suffered two hematologic relapses and died 34 months after diagnosis. The authors discuss the possibility that complete p16(INK4A) gene inactivation may adversely modify the prognostic significance of TEL/AML1 fusion in childhood acute lymphoblastic leukemia, and present evidence from clinical and in vitro observations in favor of this assumption.     

AML1-ETO阳性的儿童急性髓系白血病疗效分析

目的探讨儿童急性髓系白血病m2型伴AML1-ETO阳性患儿的疗效及预后相关因素。方法2003年1月至2008年12月收住AML1-ETO阳性儿童m233例,并对患儿进行总结分析、随访。了解患儿临床特征,免疫分型,染色体核型治疗及疗效,生存情况及影响治疗的因素。结果33例AML1-ETO阳性儿童第一疗程诱导缓解率为63.5%,中位随访时间32个月,目前仍处于CR状态25例占75.5%,5例患儿骨髓复发,复发率为15.1%,高白细胞数,多脏器受累,免疫表型CD5＋6以及第一疗程诱导治疗未达缓解者预后不良,并伴有较低的生存率。结论儿童急性髓系白血病M2伴有AML1-ETO阳性患儿预后是好的。强烈化疗高剂量阿糖胞苷能帮助提高疗效。提高生存率。高白细胞计数,累及多脏器以及CD56标记阳性和初次诱导治疗的缓解不佳,影响总的生存率。     

儿童急性髓性白血病M2型AML1／ETO融合mRNA检测及其临床意义

目的：研究AML1／ETO融合mRNA在儿童急性髓白血病M2型中的表达及其对残留白血病监测及预后的指导意义。方法：通过逆转录酶／聚合酶链反应（RT－PCR）方法扩增M2型患者的AML1／ETO融合mRNA,并结合临床资料综合分析。结果：36例AML M2中27例AML1／ETO融合基因阳性,占75％;RT－PCR方法阳性率明显高于染色体分析;AML1／ETO融合基因阳性病人缓解率（74％）高于阴性病人（56％）;通过AML1／ETO融合mRNA的检测可监测体内残留白血病情况,AML1／ETO阳性病人经治疗后转阴并持续阴性者预后好;而持续阳性者预后差;由阴性转阳性者可预示复发。结论：RT－PCR检测AML1／ETO融合mRNA为更敏感的细胞遗传学诊断方法,定期检查可以监测体内微小残留白血病,为治疗、预后判断提供了有效手段。     

Patients with Fanconi anemia and AML have different cytogenetic clones than de novo cases of AML

Specific cytogenetic clones might distinguish patients with unrecognized Fanconi anemia (FA) who present with acute myeloid leukemia (AML) from those with sporadic AML. Cytogenetic reports in literature cases of FA and AML were compared with de novo cases enrolled on CCG-2961. Gain of 1q, gain of 3q, monosomy 7, deleted 7q, gain of 13q, and deleted 20q were more frequent in FA AML; t(8;21), trisomy 8, t(9;11), t(6;9), and inversion 16 were exclusive to de novo AML cases. Observation of the FA AML cytogenetic clonal patterns should raise suspicion of an underlying leukemia predisposition syndrome and influence management. Pediatr Blood Cancer 2012; 59: 922-924. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.     

伴t(8;21)/AML1-ETO阳性的儿童急性髓系白血病的临床特点及预后研究

目的分析伴t(8;21)/AML1-ETO阳性的儿童急性髓系白血病（AML）的临床特点、生物学特征及预后。方法对伴t(8;21)/AML1-ETO阳性的55例AML患儿的临床资料进行回顾性分析,采用Kaplan-Meier 曲线评估患儿的无事件生存（EFS）率、无病生存(DFS)率和总生存(OS)率,COX回归模型评估预后因素。结果①55例伴t(8;21)/AML1-ETO阳性患儿中,4例放弃治疗,4例化疗1疗程后失访,47例患儿进行了双诱导方案化疗,1疗程、2疗程完全缓解率分别为71%和94%,复发10例（21%）,47例患儿的5年EFS率、DFS率、OS率分别为（56.1±7.9）%、（59.8±8.1）%、（72.0±8.1）%。②多因素分析显示年龄是影响患儿预后的独立危险因素,年龄越大出现事故或死亡的风险性越大（P<0.05）。③缓解后继续巩固强化规范化疗的患儿（n=27）5年OS率明显高于不规范化疗的患儿（n=13）［（47.5±17.1）% vs （38.9±17.3）%,P<0.01］。结论伴t (8;21)/AML1-ETO阳性儿童AML是一类具有高度异质性的疾病,其治疗完全缓解率高,远期疗效好,年龄是决定远期疗效的重要因素之一,完全缓解后进行巩固强化规范化疗疗效较好。     

Low efficacy of methotrexate in childhood acute myeloid leukemia (AML): single-agent therapeutic window study in relapsed AML

BACKGROUND: The efficacy in pediatric acute myeloid leukemia (AML) of single-agent methotrexate (MTX) at a higher dose than previously applied, 1,000 mg/m2, given as a theoretically beneficial 36-hr continuous infusion, is unknown, but may be beneficial based on preclinical data. PROCEDURE: We performed a therapeutic window study in children with first relapsed AML treated in four different countries. RESULTS: Based on a comparison between the percentage of leukemic blasts in the bone marrow shortly before and 7-10 days after the MTX infusion, none of the first cohort of nine patients showed a good response, defined as a reduction of blasts of at least 50%. Therefore, the study was closed, concluding that the probability of a good response in this patient-group was most likely to be less than 30%. By that time, another four patients had been enrolled, of which one patient with a late relapsed AML FAB type M7 showed a good response. Toxicity of MTX was limited and tolerable. CONCLUSIONS: This study shows that single-agent MTX in the applied regimen in pediatric relapsed AML has limited efficacy. However, it also demonstrates the feasibility of an international and therapeutic window phase II study in pediatric relapsed AML.     

Viral surveillance using PCR during treatment of AML and ALL

1 Background

While viral surveillance of cytomegalovirus (CMV), Epstein–Barr virus (EBV), and adenovirus using PCR is routine in patients undergoing hematopoetic stem cell transplant and solid organ transplant, the utility in the nontransplant pediatric leukemia population is unknown. Our institution screens patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) for viral DNAemia by PCR as part of clinical care.

2 Procedure

This retrospective chart review included patients treated for newly diagnosed or relapsed AML or ALL between April 2010 and September 2014. We retrieved data for viral PCR screening, detection and quantification, duration of positivity, and prophylaxis or treatment.

3 Results

One hundred eleven patients were included in analyses. Forty (36.0%) had at least one blood PCR positive for EBV, CMV, or adenovirus. Patients with ALL had significantly higher rates of persistent viral detection and treatment than those with AML (P < 0.02, P < 0.01, respectively). International patients had significantly higher rates of viral detection (P < 0.01), persistence (P < 0.01), any treatment (P < 0.03), and antiviral treatment (P < 0.01); 16.9% of patients who received intravenous immunoglobulin (IVIG) prophylactically had viral detection compared to 63% of patients who did not receive prophylactic IVIG (P = 0.0008).

4 Conclusions

Patients with ALL were more susceptible than those with AML to viral reactivation that was persistent or resulted in treatment. Patients with relapsed ALL, refractory ALL, or infantile ALL are most likely to benefit from asymptomatic screening for CMV and adenovirus. International patients are at higher risk for reactivation and may merit screening. EBV reactivation was not significant and does not warrant screening.     

Improved outcome in pediatric AML due to augmented supportive care

We conducted a retrospective review of patients treated following the MRC acute myeloid leukemia (AML) 10 protocol to determine if supportive care measures sequentially introduced by our institution led to a significant improvement in treatment‐related mortality (TRM) in newly diagnosed pediatric patients with AML. Patients were partitioned based on supportive care measures into era1, from 1996 to 2002 (n = 20), and era2, from 2003 to 2011 (n = 40). The introduced supportive care measures reduced the TRM from 23.4% in era1 to 2.5% in era2 (P = 0.034). The results demonstrate that supportive care is a significant factor in determining the outcome of childhood AML. Pediatr Blood Cancer 2012; 59: 919–921. © 2012 Wiley Periodicals, Inc.     

超大剂量阿糖胞苷在小儿急性髓细胞白血病的治疗探讨

目的应用超大剂量阿糖胞苷(SHDAra-C)对急性髓细胞白血病(AML)患儿进行缓解后治疗,探讨其疗效及安全性。方法在患者取得骨髓缓解后应用SHDAra-C共五个疗程,第一疗程Ara-C总剂量达36 g/m2,其后每疗程Ara-C总剂量18 g/m2,累计Ara-C总剂量达108 g/m2。结果8例AML患儿有7例完成了5个疗程HDAra-C化疗(1例只完成4疗程),除1例骨髓复发放弃治疗外,余7例均获CCR至今,CCR时间6~76月,无一例化疗相关性死亡。结论SHDAra-C是小儿AML化疗获得长期无病生存的重要治疗方法,有效且相对安全,其治疗效果值得更大规模的临床病例观察,治疗机理有待更深入的实验研究。     

Curing childhood acute myeloid leukemia (AML) at the half-way point: promises to keep and miles to go before we sleep

Childhood and adolescent acute myeloid leukemia (AML) is traditionally one of the hardest childhood cancers to successfully treat and had an overall survival well under 10% in the 1960s. Initial progress was made by three major events: (1) active chemotherapeutic agents were identified which led to remissions for the first time in this disease; (2) cooperative groups were instituted leading to important clinical trials; and (3) several single institutions began experimenting with the role of allogeneic matched sibling donor (MSD) BMT as effective intensification. Over the last 25 years, the cure rate has improved from <20% to 50% or higher. Most of the clinical research during this time of great advancement focused on two major themes: (1) the role of aggressive induction therapy in not only improving CR rates but in post-remission outcomes; and (2) the role of aggressive post-remission therapy in further improving survival, with an emphasis on high-dose Ara C-based chemotherapy, BMT, and supportive care. But we have "miles to go before we sleep." Some of the challenges that will lead to ongoing reduction of population-based mortality for AML through young adulthood include: (1) improving access of adolescents to pediatric AML therapy; (2) stratification by prognostic factors; (3) individualized therapy based on individual genetics and leukemia cell biology; (4) and the use of novel therapies including targeted immuno-conjugates and "small molecules" which disrupt abnormal signal transduction pathways. This brief review looks at both the advances over the last three decades as well as discusses the challenges moving forward for ultimately curing all children with this disease.