A single-center cytogenetic study of 629 Chinese patients with de novo acute myeloid leukemia--evidence of major ethnic differences and a high prevalence of acute promyelocytic leukemia in Chinese patients

Cytogenetic information is important in the diagnosis, classification, and prognostication of acute myeloid leukemia (AML). Data obtained from multicenter treatment trials are well published. In this study, we contribute cytogenetic data from a large series of 629 Chinese patients with de novo AML that were karyotyped in a single laboratory. A higher prevalence of acute promyelocytic leukemia was observed when compared with non-Chinese series. The difference was most prominent in the younger age group. Abnormalities at chromosomal region 11q23 and inv(16) seemed uncommon. These ethnic differences may indicate underlying genetic susceptibility to AML development and/or environmental differences. More comprehensive data on AML in the elder population are needed to assess the role of cytogenetics in predicting prognosis and guiding treatment in this large subgroup of patients.     

Prognostic importance of cytogenetic subgroups in de novo pediatric acute nonlymphocytic leukemia

Reports of close associations between recurring chromosomal abnormalities and the clinical behavior of acute nonlymphocytic leukemia (ANLL) have stimulated efforts to define this disease in cytogenetic terms. Here we report on the leukemic cell karyotypes of 155 children with ANLL who were treated from 1980 to 1987 in consecutive programs of chemotherapy at this institution. Of 121 cases with adequate banding, 20% were normal, 30% had miscellaneous clonal abnormalities, and 50% were classified into known cytogenetic subgroups: inv(16)/del(16q) (n = 15), t(8; 21) (n = 14), t(15;17) (n = 9), t(9;11) (n = 9), t(11;V)/del(11q) (n = 7) and -7/del(7q) (n = 6). The inv(16)/del(16q) cases showed a nearly equal distribution of myelocytic and monocytic French-American-British (FAB) subtypes; only four of these patients presented with M4Eo morphology. Despite a 100% remission induction rate, patients with inv(16)/del(16q)-positive ANLL fared no better overall than the entire group; only 40% of this subgroup were event-free survivors at 2 years from diagnosis (P = .23). Patients with inv(16)/del(16q) frequently had CNS involvement at diagnosis (eight of 15) or initially relapsed in this site (three of eight). Event-free survival (EFS) was clearly superior for young patients with FAB M5 leukemia and the t(9;11) (P = .041). These patients were clinically indistinguishable from others with the FAB disease subtype, yet their responses to etoposide-containing therapies were noteworthy. By contrast, children with structural abnormalities involving 11q23, other than t(9;11), were infants (median age, 6 months) with FAB M4 or M5 leukemia, hyperleukocytosis, and frequent coagulation abnormalities. Patients with such changes [t(11;V) or del(11q)] relapsed early during postremission therapy: none remained disease-free more than 16 months from diagnosis. Because of resistant leukemia, patients with monosomy 7/del(7q) had a poor remission induction rate (17%; P = .0015); patients with the t(15;17) were also poor responders to induction therapy (44%; P = 0.02) because of hemorrhagic deaths. These results identify several cytogenetic subtypes of pediatric ANLL that may represent unique disease processes for which more effective early cytoreduction [-7/del(7q), t(11;V)], better supportive care measures [t(15;17)], or more effective CNS prophylaxis [inv(16)/del(16q)] would be warranted.     

成人急性淋巴细胞白血病患者骨髓ERG基因表达水平及其与预后的相关性

目的:探讨成人急性淋巴细胞白血病(ALL)患者ETS相关基因(ERG)的表达水平及其临床意义.方法:实时荧光定量PCR法检测91例初治成人ALL患者ERG的表达水平,并分析其与临床预后的关系.结果:91例ALL骨髓标本中ERG表达水平显著高于对照组,P<0.001.ALL患者ERG表达水平与就诊时外周血白细胞计数(WBC)、血红蛋白(HGB)、血小板计数(PLT)和血清乳酸脱氢酶(LDH)水平均无明显相关性,P均>0.05.B-ALL患者ERG表达水平与T-ALL组比较差异无统计学意义,P=0.547.BCR/ABL基因阳性ALL患者ERG表达水平与BCR/ABL阴性者比较差异无统计学意义,P=0.889.伴有髓系抗原表达组ALL患者与未伴有髓系抗原表达组之间ERG表达水平也差异无统计学意义,P=0.150.尽管ERG高表达ALL患者的CR率(72.7%)与低表达组(75.4%)比较差异无统计学意义,P=0.804,但ERG高表达ALL患者的复发率(62.5%)显著高于ERG低表达组(34.6%),P=0.047.ERG高表达ALL患者的总生存率显著低于ERG低表达组,P=0.016.结论:ERG高表达可能是ALL一个重要的预后不良因素,检测ALL患者ERG表达水平有助于判定预后,指导治疗.     

Genetic and cytogenetic changes in acute lymphoblastic leukemia

In recent years, a number of non-random chromosomal alterations have been identified in specific populations of acute lymphoblastic leukemic cells of either B-cell or T-cell lineage. The most frequently involved chromosomal sites are 1q, 4q, 6q, 7q, 8q, 9p, 9q, 10q, 11p, 12p, 14q, 19p and 22q. Genes located near frequent breakpoints include c-myc, c-abl and the genes for the T-cell alpha and beta receptors. In addition, approximately 20 other genes potentially involved in the leukemic process are located near less frequently encountered, but consistent, chromosomal breakpoints.     

Mutations of perforin gene in Chinese patients with acute lymphoblastic leukemia

To address whether mutations and single nucleotide polymorphisms (SNPs) in perforin gene (PRF1) are correlated with acute lymphoblastic leukemia (ALL) in Chinese, we screened mutations in codon region of PRF1 in 111 ALL patients, and correlated the results with patients’ immunophenotype, karyotype and fusion genes. Four novel monoallelic missense and two novel monoallelic synonymous mutations (G198R, R225Q, D486G, R509K, S388S and Q540Q) were identified in 9 B-ALL, of whom 7 cases carried BCR-ABL gene, one carried MLL-AF4 fusion gene, and one lost two chromosomes. Our results suggest that mutations in PRF1 may play a role in the pathogenesis of B-ALL.     

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.     

Osteonecrosis in pediatric patients with acute lymphoblastic leukemia

The authors report five pediatric patients with acute lymphoblastic leukemia (ALL) in whom symptomatic aseptic osteonecrosis developed on therapy. All patients had been on treatment with a modified BFM protocol and developed osteonecrosis in the maintenance phase of the protocol. The avascular necrosis was multifocal in all. The authors' data suggest that dexamethasone used in the reinduction phase of the protocol may be the responsible agent although no definite proof exists. Since only symptomatic patients are reported, the true frequency of this complication may be significantly higher.     

Toward a clinically relevant cytogenetic classification of acute myelogenous leukemia

Cytogenetic studies with Giemsa banding were performed on the bone marrow cells of 384 patients with acute myelogenous leukemia treated between 1975 and 1983. An abnormal karyotype was detected in 54% of patients, being present in 100% of metaphases (AA) in 31% and only a proportion of cells (AN) in 22%. Specific translocations or other abnormalities were noted in 22% of patients, the most common of which were t(8;21) (q22;q22) in 7%, t(15;17) (q22;q21) and inv (16) (p13q22) in 5.5%, t(9;22) (q34;q11) in 3% and abnormalities of 11q23 in 1.3%. Loss of the Y chromosome was noted in 21 patients, associated with t(8;21) in 11 patients and the sole abnormality in eight patients (45, X, -Y). Most (66%) of the other abnormalities involved addition of chromosome 8 or loss or deletion of 5 or 7 (+8, -5 or -7, 5q- or 7q- group). The remaining patients had miscellaneous abnormalities (MA). A marked assymetry was noted in the distribution of important clinical prognostic variables such as age, sex, history of an antecedent hematologic disorder and presence of Auer rods within the various cytogenetic categories. The specific translocation/abnormalities were more common in younger patients (p less than 0.01). Analysis of response, remission duration and survival demonstrated that inv 16 and t(8;21) were favorable prognostic categories; diploid, t(15;17) and 45,X,-Y had intermediate prognosis, and all other categories were unfavorable prognostic groups. The response rate and survival for diploid patients (NN) was superior to patients with abnormalities. No difference in response rate, CR duration or survival was noted between the AA and AN groups. A prognostic classification according to cytogenetic category based on clinical associations is proposed which will be tested prospectively in subsequent studies.     

Clinical challenges in de novo pediatric acute myeloid leukemia

Introduction: Although the prognosis of pediatric acute myeloid leukemia (pAML) has improved, with current survival rates up to 75%, relapse rates remain high.

Areas covered: The low number of patients, the heterogeneous genomic landscape of AML, novel diagnostic techniques, divergent available treatment protocols, and dose-limiting toxicity of conventional agents all contribute to the complexity of AML treatment. This review gives an overview of the current clinical challenges with respect to diagnostics, treatment, and supportive care in pAML.

Expert commentary: Due to intensified treatment regimens and improved supportive care measures, the outcome for pAML patients has improved substantially over the past years. However, most treatment protocols still rely on conventional chemotherapeutic agents with significant toxicity. Although targeted therapies promise to reduce the need for high doses of conventional agents with a subsequent decrease in toxicity, the effectiveness of these strategies remains unsatisfactory today. International collaborations are needed in order to address the ongoing therapeutic challenges of reducing toxicity while increasing effectivity. Consensus on risk-group classification, a common chemotherapy backbone and evidence-based supportive care guidelines are necessary in this context, at the same time enabling intergroup studies on new agents in subgroups.     

Prognostic significance of surface marker expression on blasts of patients with de novo acute myeloblastic leukemia

The prognostic significance of the expression of surface membrane antigens on the blasts of 123 consecutive patients with de novo acute myeloblastic leukemia (AML) was evaluated. For this purpose, reactivity of monoclonal antibodies (mAbs) CLB-ERY3 (antiblood-group H antigen), VIM-D5 (CD15), WT1 (CD7), MY7 (CD13), MY9 (CD33), VID-1 (antihuman leukocyte antigen locus DR [anti-HLA DR]), VIM-2 (CDw65L), VIM-13 (CD14), 63D3 (CD14) and anti-TdT with leukemic blast cell populations was prospectively analyzed with respect to the rates of complete remission (CR), continuous complete remission (CCR), and survival. The overall rate of CR was 65%, the 6-year rates of overall CCR and survival were 23% and 13%, respectively (median period of patient observation, 30 months). Of all Abs tested, four (CLB-ERY3, MY7, anti-TdT, and VIM-D5) were found to be of prognostic value. Reactivity of CLB-ERY3, MY7, and anti-TdT was predictive for CR (CLB-ERY3+, 43% v CLB-ERY3-, 73%, P less than .02; MY7+, 59% v MY7-, 91%, P less than .003; TdT+, 28% v TdT-, 71%, P less than .001, respectively) and probability of survival (significantly lower survival rates: CLB-ERY3+, P less than .02; MY7+, P less than .03; and TdT+ cases, P less than .001, respectively). Reactivity of VIM-D5 was significantly associated with a higher probability of CCR (P less than .01). Our results confirm earlier reports on the prognostic significance of expression of CD13 and TdT in AML and indicate CLB-ERY3 (antiblood-group H antibody) and VIM-D5 (CD15) as further markers predictive for the clinical outcome in patients with de novo AML.     

Urolithiasis in pediatric patients with acute lymphoblastic leukemia.

We evaluated the incidence, timing, and consequences of urolithiasis in children with acute lymphoblastic leukemia (ALL). A total of 20 patients with urolithiasis were identified from 2095 patients with ALL treated at St Jude Children's Research Hospital on consecutive protocols between 1968 and 1998. For remission induction therapy, all patients received daily prednisone; continuation chemotherapy regimens differed by protocol with some including pulses of prednisone or dexamethasone and others no glucocorticoid. Patients with urolithiasis were older at diagnosis of ALL than those without urolithiasis (median age, 7.5 vs 5.0 years; P=0.03) and less likely to be black (P=0.03) than white or Hispanic, but sex and treatment era did not differ. Presenting symptoms included abdominal or flank pain, hematuria, and dysuria. All stones analyzed biochemically were calcium stones. The incidence of urolithiasis after completion of therapy was 1.8 per 10 000 person-years. Compared to this baseline rate, the relative risk of urolithiasis was 45 (P<0.01) during induction therapy, 22 (P<0.01) during continuation therapy with glucocorticoids, and 5.1 (P>0.05) during continuation therapy without glucocorticoids. Urolithiasis occurred 4.5 times more often during continuation treatment with glucocorticoids than without (P<0.05). Seven patients (35%) had recurrent urolithiasis. Patients with ALL are at risk of developing calcium renal stones during chemotherapy, especially when a glucocorticoid is included.     

Alcohol intake and incidence of de novo adult acute leukemia

In a case-control study of adult acute leukemia we defined alcohol intake as either non-regular (<1 drink per week), light (1–5 drinks per week), moderate (6–8 drinks per week) or heavy (>8 drinks per week). An inverse association was found for light and moderate beer intake (RR = 0.58; 95% CI: 0.44, 0.76). In contrast, a positive association was found for moderate and heavy wine intake (RR = 2.1; 95% CI: 1.2, 3.8). Divergent results might reflect the effect of different nutrients in beer and wine, unmeasured confounding, or differing impacts of selection bias on these associations.     

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。     

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.     

Pretreatment prognostic factors and treatment outcome in elderly patients with de novo acute myeloid leukemia.

BACKGROUND: Elderly patients with acute myeloid leukemia (AML) generally have an unfavorable clinical course and are under-represented in clinical trials. The aim of this study was to analyze the prognosis and treatment outcome of elderly AML patients. PATIENTS AND METHODS: We studied 205 AML patients aged 65 years or older at our hospital. Prior to study initiation, we designated 13 variables to be analyzed for their impact on complete remission (CR) rate and overall survival (OS). RESULTS: Induction regimen (standard chemotherapy) and good performance status (PS) (Eastern Cooperative Oncology Group PS 0-1) independently influenced the achievement of CR. Multivariate analysis also determined five poor prognostic factors for OS: poor PS (score 2-4), presence of comorbidities, elevated serum lactate dehydrogenase level (> or =2x upper normal limit), extreme leukocytosis (> or =100 x 10(9)/l) and marked thrombocytopenia (< or =20 x 10(9)/l). Age was not an independent contributing factor in terms of either CR attainment or OS duration. Low-risk patients, who possessed one or less non-leukocytosis poor prognostic factor, had significantly longer disease-free survival and OS than their high-risk counterparts. CONCLUSIONS: Elderly AML patients should be risk-stratified at diagnosis. Anthracycline-based induction chemotherapy would be the best therapeutic option for such patients.     

miR-128在急性淋巴细胞白血病中的表达

目的 探讨miR-128在急性淋巴细胞白血病(ALL)中的表达及其意义.方法 采用实时荧光定量聚合酶链反应法对62例ALL患者和20例骨髓正常患者骨髓单个核细胞miR-128的相对表达量进行检测,并与患者的临床资料进行相关性分析.结果 miR-128在ALL患者中的相对表达量高于健康对照组(P＜0.05),但其在急性B淋巴细胞白血病(B-ALL)及急性T淋巴细胞白血病(T-ALL)中的表达水平差异无统计学意义(P＞0.05),miR-128的表达与是否存在bcr-abl融合基因及其mRNA的表达水平均无相关性(均P＞ 0.05).结论 miR-128在ALL患者中表达上调,可作为临床诊断ALL的潜在分子标志物,bcr-abl融合基因的表达对miR-128在ALL中的表达无明显影响.     

Treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

In the pre-imatinib era, treatment outcomes of adult patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) were dismal. Despite the use of intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), complete remission and overall survival rates were less than 70% and 20%, respectively. However, imatinib, in combination with conventional chemotherapy, has dramatically changed outcomes, producing approximately 95% complete remission and 50% overall survival with or without allogeneic HSCT. Current research is now focusing on how to prevent relapse. Improvement of postremission therapy is indispensable. Although allogeneic HSCT during first complete remission is still the first choice for feasible patients, post-HSCT imatinib therapy and imatinib plus chemotherapy combinations should also be studied. New BCR-ABL tyrosine kinase inhibitors are expected to improve outcomes in imatinib-resistant leukemia. Our hope is that, in the near future, Ph-positive ALL will become a leukemia in which allogeneic HSCT is offered only for relapsed or refractory cases.