[Association of polymorphisms of KIR2DL4 gene with leukemia among ethnic Hans from southern China].

OBJECTIVE To assess the association of polymorphisms of KIR2DL4 gene with leukemia among ethnic Hans from southern China. METHODS A total of 590 leukemia patients were recruited, which included 283 cases of acute lymphoblastic leukemia (ALL), 277 cases of acute myeloid leukemia (AML), and 80 cases of chronic myeloid leukemia (CML). Meanwhile, 306 healthy controls were randomly selected from volunteer blood donors. Both groups were subjected to sequence-based typing of the entire coding sequence of the KIR2DL4 gene using an in-house assay. The genotype for each sample was determined with Assign 4.7 SBT software. The frequencies of each detected KIR2DL4 allele, the 9A type KIR2DL4 allele and 10A type KIR2DL4 allele of the ALL, AML and CML groups were compared with those of the control group. RESULTS Five KIR2DL4 alleles, namely KIR2DL4*001, *005, *006, *008 and *011, were detected in the ALL, AML and CML groups as well as the control group. A significant difference was detected in the frequencies of KIR2DL4*011 and 10A type KIR2DL4 allele between the ALL group and the control group (KIR2DL4*011: OR = 1.66, P = 0.01; 10A type KIR2DL4: OR = 0.42, P = 0.03), but was lost after P correction (Pc > = 0.05). No significant difference was detected in the frequencies of KIR2DL4 alleles, the 9A type KIR2DL4 and 10A type KIR2DL4 allele between the AML and CML patient groups compared with the control group (P > 0.05, Pc > 0.05). CONCLUSION The allelic diversity of the KIR2DL4 locus showed no significant association with leukemia among ethnic Hans from southern China.

The impact of FLT3 mutations on treatment response and survival in Chinese de novo AML patients.

OBJECTIVE: Two distinct forms of FMS-like tyrosine kinase 3 (FLT3) mutations, internal tandem duplication (ITD) in the juxtamembrane domain and point mutation within the activation loop of the tyrosine kinase domain (TKD), have been identified in considerable number of patients with AML. This study was aimed to analyze the impacts of these mutations on clinical outcomes, and assess the efficacy of different therapeutic regimens (allo-HSCT, sorafenib, or conventional chemotherapy) for AML patients with FLT3 mutations after the standard induction therapy. MATERIALS AND METHODS: We analyzed DNA samples from 158 consecutive de novo AML patients (18-60 years, excluding APL) with FLT3 mutations between July 2010 and October 2015. RESULTS: We found that AML patients with FLT3-TKD mutations have more favorable clinical outcomes than those with FLT3-ITD mutations. We also found that allo-HSCT therapy subgroup achieved longer OS and RFS than non-allo-HSCT therapy subgroup for FLT3-ITD positive patients (p < 0.001, p = 0.071). However, compared with the clinical outcomes in non-primary refractory patients, sorafenib did not show an obvious beneficial effect for the primary refractory patients. Further study on a large scale is still recommended. CONCLUSIONS: FLT3-TKD-mutated AML patients have more favorable clinical outcomes than those with FLT3-ITD mutations. Allo-HSCT therapy subgroup achieved longer OS and RFS than non-allo-HSCT therapy subgroup for FLT3-ITD positive patients. Compared with the clinical outcomes in non-primary refractory patients, sorafenib did not show an obvious beneficial effect for the primary refractory patients.

Cytogenetic profiles of 2806 patients with acute myeloid leukemia-a retrospective multicenter nationwide study.

The cytogenetic and molecular data is recognized as the most valuable prognostic factor in acute myeloid leukemia (AML). Our aim was to systemically analyze the cytogenetics of Korean AML patients and to compare the cytogenetic profiles of various races to identify possible geographic heterogeneity. We retrospectively reviewed medical records of 2806 AML patients diagnosed at 11 tertiary teaching hospitals in Korea between January 2007 and December 2011. The most common recurrent chromosomal abnormality was t(8;21) (8.8 %, 238/2717), but t(15;17) showed an almost same number (8.6 %,235/2717). Among de novo AML, the most frequent aberrations were t(15;17), observed in 229 (10.7 %). The most common French-American-British (FAB) classification type was M2 (32.2 %), and recurrent cytogenetic abnormalities correlated with the FAB subtypes. Among 283 secondary AML cases, myelodysplastic syndrome was the most common predisposing factor. About 67.1 % of the secondary AML cases were associated with chromosomal aberrations, and chromosome 7 abnormalities (n = 45, 15.9 %) were most common. The incidence of FLT3 internal tandem duplication mutation was relatively low at 15 %. Our study reports certain similarities and differences in comparison to previous reports. Such discrepancies call for extensive epidemiological studies to clarify the role of genetic as well as geographic heterogeneity in the pathogenesis of AML.

MTHFR gene polymorphism and risk of myeloid leukemia: a meta-analysis.

An increasing body of evidence has shown that the amino acid changes at position 1298 might eliminate methylenetetrahydrofolate reductase (MTHFR) enzyme activity, leading to insufficient folic acid and subsequent human chromosome breakage. Epidemiological studies have linked MTHFR single-nucleotide polymorphism (SNP) rs1801131 to myeloid leukemia risk, with considerable discrepancy in their results. We therefore were prompted to clarify this issue by use of a meta-analysis. The search terms were used to cover the possible reports in the MEDLINE, Web of Knowledge, and China National Knowledge Infrastructure (CNKI) databases. Odds ratios were estimated to assess the association of SNP rs1801131 with myeloid leukemia risk. Statistical heterogeneity was detected using the Q-statistic and I (2) metric. Subgroup analysis was performed by ethnicity, histological subtype, and Hardy-Weinberg equilibrium (HWE). This meta-analysis of eight publications with a total of 1,114 cases and 3,227 controls revealed no global association. Nor did the subgroup analysis according to histological subtype and HWE show any significant associations. However, Asian individuals who harbored the CC genotype were found to have 1.66-fold higher risk of myeloid leukemia (odds ratio, 1.66; 95 % confidence interval, 1.10 to 2.49; P h = 0.342; I (2) = 0.114). Our meta-analysis has presented evidence supporting a possible association between the CC genotype of MTHFR SNP rs1801131 and myeloid leukemia in Asian populations.

Analysis of WT1 mutations, expression levels and single nucleotide polymorphism rs16754 in de novo non-M3 acute myeloid leukemia.

The single nucleotide polymorphism (SNP) rs16754 of the WT1 gene has been described as a possible prognostic marker in patients with acute myeloid leukemia (AML). However, the results in this field are not reproducible in different cohorts. In this study, we investigated WT1 mutations, expression levels and SNP rs16754 in a cohort of 122 adult patients with AML. As the major allele (65.6%) in a Chinese population, WT1(GG) was associated with younger age (≤ 60) and lower percentage of blasts than WT1(GA/AA). Meanwhile, improved overall survival (OS, p = 0.035) and disease-free survival (DFS, p = 0.021) were observed in WT1(GG) compared with WT1(GA/AA). We then found that WT1 mutation, occurring in 8% of patients with AML, did not predict clinical outcome. Finally, WT1 levels were higher in patients with WT1(GG) than in those with WT1(GA/AA). However, high levels of WT1 (> median) predicted worse OS (p = 0.015) and DFS (p = 0.034) than low levels of WT1 (≤ median). However, further studies are required to elucidate the mechanism of why WT1(GG), which was associated with higher median expression of WT1 that predicts worse OS and DFS compared to low expression of WT1, predicted better OS and DFS compared with WT1(GA/AA). In summary, WT1 rs16754 and WT1 expression have a significant impact on clinical outcome in patients with AML.

T cell-depleted partial matched unrelated donor transplant for advanced myeloid malignancy: KIR ligand mismatch and outcome.

To evaluate the applicability of high-dose conditioning, CD34 selection, and enhanced natural killer (NK) cell alloreactivity reported as promising after haploidentical transplantation, we tested the same strategy for patients with advanced/high-risk myeloid leukemia lacking either related or well-matched unrelated donors (URD). In a prospective multicenter clinical trial using pretransplantation conditioning of thiotepa (5 mg/kg/day × 2), fludarabine (40 mg/mg/M(2)/day × 5), and total body radiation (800 cGy) plus thymoglobulin (2.5 mg/kg/day × 2), as well as a CD34 selected filgrastim stimulated peripheral blood graft from a partial matched URD, we treated 24 patients. The patients (median age 40 [range: 22-61]) were mismatched at 1-3 of 10 HLA loci with their donors; all were mismatched at HLA-C. Thirty-seven percent were ethnic or racial minorities. Twenty-one of 24 engrafted promptly with 1 primary graft failure and 2 early deaths. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) (34%, 95% confidence interval [CI], 14-54%), chronic GVHD (20%, 95% CI, 2%-38%), and relapse (26%, 95% CI, 8%-84%) were unaffected by KIR ligand donor:recipient mismatch (n = 5) versus KIR ligand match (n = 19). Only 3 (12%) had grade III-IV GVHD. Nonrelapse occurred in 17% (95% CI, 30%-31%) by 100 days and in 35% (95% CI, 15%-55%) by 1 year. Two-year survival and leukemia-free survival were each 40% (95% CI, 21%-59%) and was similar in KIR ligand matched or mismatched patients. Infections, mostly in the first 2 months, were frequent, and were the cause of death in 5 patients (35% of deaths). T cell recovery and NK cell proliferation and functional maturation were not altered by KIR ligand match or mismatch status. For these high-risk patients, this high intensity regimen and T depleted approach yielded satisfactory outcomes, but logistical difficulties in arranging URD grafts for patients with high-risk, unstable leukemia limited accrual. Improvements in peritransplantation disease control and additional measures to augment the allogeneic graft-versus-leukemia effect are still required.

Maternal and birth characteristics in relation to childhood leukaemia.

Our objective was to investigate the association of childhood leukaemia with selected maternal and birth characteristics by conducting a population-based case-control study using linked cancer registry and birth certificate records for Washington State. We compared maternal and infant characteristics of 595 Washington-born residents <20 years old with leukaemia diagnosed during 1981-2003, and 5,950 control children, using stratified analysis and logistic regression. Maternal age 35+ years (odds ratio [OR] 1.5; 95% confidence interval [CI] 1.1, 2.0), infant birthweight 4,000+ g (OR 1.4; 95% CI 1.1, 1.8), neonatal jaundice (OR 1.5; 95% CI 1.1, 2.1), and Down's syndrome (OR 31.3; 95% CI 6.4, 153.4) were associated with an increased risk of leukaemia. Among women with 2+ pregnancies, having at least two prior early (<20 weeks' gestation) fetal deaths was also associated with an increased risk (OR 1.5; 95% CI 0.97, 2.1). Maternal unmarried status (OR 0.7; 95% CI 0.6, 0.9) and African American race (OR 0.5; 95% CI 0.3, 0.9) were associated with a decreased risk. These results were more marked for acute lymphocytic leukaemia (ALL) than for acute myeloid leukaemia (AML), and for leukaemia diagnosed <5 years of age. These results may provide clues to the aetiology of childhood leukaemia. Genetic epidemiological studies are needed to expand our knowledge of inherent and possibly prenatal influences on the occurrence of this disease.

Mutations of AML1 in non-M0 acute myeloid leukemia: six novel mutations and a high incidence of cooperative events in a South-east Asian population.

Point mutations of AML1 are uncommon and predominantly reported in a rare minimally differentiated acute myeloid leukemia (M0 AML). Few data exist regarding the frequency of AML1 mutations in non-M0 cases. We screened 284 consecutive adult Thai patients with de novo AML and found that 3.9% had AML1 mutations. The highest incidence occurred in M6. Six novel mutations were uniquely identified in non-M0 cases. Sixty-four percent of the non-M0 patients with AML1 mutations had coexisting genetic abnormalities including FLT3 mutation in 36%. Our study provides evidence to support the model of multiple co-operating events, which could also be critical in the development of leukemia in non-M0 AML patients with mutated AML1. The prognostic significance of these novel mutations remains to be determined.

Ethnicity and survival in childhood acute myeloid leukemia: a report from the Children's Oncology Group.

We evaluated differences in outcome by ethnicity among children with acute myeloid leukemia (AML). We analyzed 791 children in the CCG 2891 trial and confirmed positive findings in 850 children in the CCG 2961 trial. Hispanic and black children treated with chemotherapy in CCG 2891 had significantly inferior overall survival (OS) from study entry compared with white children (37%+/- 9% vs 48%+/- 4% [P = .016] and 34% +/- 10% vs 48% +/- 4%, [P = .007], respectively). Significantly fewer black children had related donors. Analyses of CCG 2961 confirmed that black children had significantly decreased OS rates compared with white children (45% +/- 12% vs 60% +/- 4%; P = .007) The difference in OS rates between Hispanic and white children approached statistical significance (51% +/- 8% vs 60% +/- 4%; P = .065) Only 7.5% of black children on CCG 2961 had an available family donor. In conclusion, Hispanic and black children with AML have worse survival than white children. Access to chemotherapy, differences in supportive care or leukemia phenotype, and reduced compliance are unlikely explanations for this difference because therapy was given intravenously according to CCG protocols. Fewer black children than expected had an available family marrow donor.

Outcome of ethnic minorities with acute or chronic leukemia treated with hematopoietic stem-cell transplantation in the United States.

PURPOSE: We previously reported a higher risk of mortality among Hispanics after allogeneic hematopoietic stem-cell transplantation (HSCT). However, it is not known how specific post-transplantation events (acute or chronic graft-versus-host disease [GVHD], treatment-related mortality [TRM], and relapse) may explain mortality differences. The purpose of this study was to examine the relationship between ethnicity and post-transplantation events and determine their net effect on survival. PATIENTS AND METHODS: We identified 3,028 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or chronic myeloid leukemia reported to the International Bone Marrow Transplant Registry between 1990 and 2000 who received an HLA-identical sibling HSCT after a myeloablative conditioning regimen in the United States. There were 2,418 white patients (80%) and 610 ethnic minority patients (20%), of whom 251 were black (8%), 122 were Asian (4%), and 237 were Hispanic (8%). Cox proportional hazards regression was used to compare outcomes between whites and ethnic minorities while adjusting for other significant clinical factors. RESULTS: No statistically significant differences in the risk of acute or chronic GVHD, TRM, or relapse were found between whites and any ethnic minority group. However, Hispanics had higher risks of treatment failure (death or relapse; relative risk [RR] = 1.30; 95% CI, 1.08 to 1.54; P = .004) and overall mortality (RR = 1.23; 95% CI, 1.03 to 1.47; P = .02). CONCLUSION: The higher risks of treatment failure and mortality among Hispanics may be the net result of modest but not statistically significant increases in both relapse and TRM and cannot be accounted for by any single transplantation-related complication. Further studies should examine the role of social, economic, and cultural factors.

Ethnicity variables in the incidence rates of leukemias in New Zealand populations: implications for stem-cell transplantation.

New Zealand has a population of 4 million people comprising four main ethnic groups: Caucasian (72.9%), New Zealand Maori (14.7%), New Zealand Pacific Islands people (5.6%), and Asians (6.3%). We examined 10 years of data (1993-2002) from the New Zealand Cancer Registry to determine if there are ethnic differences in leukemia incidence in New Zealand, and we relate this to availability of stem-cell transplantation. We found that New Zealand Asians have a generally lower incidence of all leukemias investigated. New Zealand Maori have an increased risk of acute myeloid leukemia (RR 1.5 in the age group 25-49 and RR 1.31 in the age group 50-74), relative to New Zealand Caucasians. New Zealand Pacific Islanders have an increased risk of chronic myeloid leukemia (RR 2.13 in the age group 25-49 and RR 1.52 in the age group 50-74). Stem-cell transplantation is a standard curative treatment for ages 25-49, and current opinion is extending the acceptable age up to age 60, in certain cases. We conclude that, among New Zealand Maori and New Zealand Pacific Islanders, there is an increased risk of acute myeloid leukemia and chronic myeloid leukemia in age groups suitable for stem-cell transplantation. However, both of these ethnic groups have previously been shown to have a reduced chance of finding a 6/6-matched unrelated donor on international registries. This leads to disproportionate provision of transplantation health care among the ethnic groups in New Zealand.

Differences in prognostic factors and outcomes in African Americans and whites with acute myeloid leukemia.

Whites have a more favorable prognosis than African Americans for a number of cancers. The relationship between race and outcome is less clear in acute myeloid leukemia (AML). Using data from 7 Cancer and Leukemia Group B studies initiated from 1985 to 1997, we conducted a retrospective cross-sectional analysis of 2570 patients (270 African American and 2300 white) with de novo AML who received induction chemotherapy. African Americans were younger than whites (48 versus 54 years, P <.001). African Americans also had different cytogenetic risk group distributions than whites (P <.001): they were more commonly classified in the favorable (23% versus 14%) and unfavorable (31% versus 23%) groups, and less commonly classified in the intermediate group (47% versus 63%). African American men had a lower complete remission (CR) rate (54%, compared with 64% for white men, 65% for white women, and 70% for African American women, P =.001) and a worse overall survival compared with all other patients (P =.004), when known risk factors are taken into account. African Americans and whites with AML differ with respect to important prognostic factors. African American men have worse CR rates and overall survival than whites and African American women, and should be considered a poor-risk group.

Geographical and ecological analyses of childhood acute leukaemias and lymphomas in north-west England.

Childhood leukaemias and lymphomas have been associated with exposure to environmental factors, including infections, which show geographical variation. This study examined the geographical distribution of the incidence of acute leukaemia and lymphoma using Manchester Children's Tumour Registry (MCTR) data 1976-2000. A total of 910 children were included, all of whom had histologically and/or cytologically verified leukaemia or lymphoma. At the time of their diagnoses, all the children were aged 0-14 years and were resident in the counties of Greater Manchester or Lancashire. Standardized morbidity ratios were calculated. Poisson regression was used to examine the relationship between incidence rates and small-area (census ward) population density, ethnic composition and deprivation index. There was a monotonic relationship between acute lymphoblastic leukaemia (ALL) incidence and population density (P = 0.05). Higher rates were seen in more densely populated areas. There was evidence for a monotonic relationship between the incidence of the mixed cellularity subtype of Hodgkin's disease (HD) and the Townsend deprivation score (P = 0.001). Markedly higher incidence was associated with greater levels of unemployment and household overcrowding. The results for ALL and mixed cellularity HD support the involvement of environmental factors, such as infections, in disease aetiology.

Ethnicity and prognosis in acute myeloid leukemia.

Ethnicity has been described as a prognostic factor in breast cancer and in childhood acute lymphocytic leukemia but not in adult acute myeloid leukemia (AML). We reviewed the records of 225 consecutive AML patients who were diagnosed and treated between 1983 and 1995. Data were collected concerning demographic factors, presenting clinical features, and treatment protocols. We categorized ethnicity as follows: European Jews, non-European Jews, and Arabs. We assessed the role of ethnicity controlling for other known prognostic factors on treatment outcome and survival in this population. Older age, high leukocyte count at diagnosis, and high-risk chromosomal aberrations were significantly associated with overall survival in univariate analysis. In multivariate analysis high leukocyte count and high-risk chromosomal aberrations exerted an independent negative effect on survival. European origin was associated with longer event-free survival in univariate analysis (P = 0.024) and longer overall (P < 0.01) and event-free (P < 0.01) survival but not with a higher remission rate in multivariate analysis. For AML patients who achieved remission after induction chemotherapy and survived its complications, European origin is an independent favorable prognostic factor for long-term remission and survival in Israel. These findings may reflect better socioeconomic status, social support, increased compliance with treatment protocols, or better psychological coping mechanisms with malignancy.

Geographic heterogeneity of cellular characteristics of acute myeloid leukemia: a comparative study of Australian and Japanese adult cases.

We assessed a large number of adults (368 from Australia and 494 from Japan) with de novo acute myeloid leukemia (AML) to define the biological differences between the two populations. In this study, AML was classified using the French-American-British (FAB) criteria into seven groups (M1-M7). M2 was more common in Japan than in Australia, whereas M4 occurred more frequently in Australia than in Japan. Other FAB subtypes were evenly distributed. Cytogenetically, Japanese M2 displayed a higher frequency of t(8;21) than Australian (33.1% vs 15.3%, P < 0.05). The t(15;17), inv/del(16), 11q23 aberrations and 5/7/8 abnormalities were seen at similar frequencies. Immunophenotypically, Japanese M4/M5 more frequently displayed CD13 and CD14 than Australian, whereas the stem cell markers, CD34 and HLA-DR were observed at a relatively higher rate in Australian M3 than in Japanese M3. The B cell antigen, CD19 was more frequently seen in Japanese M2 than in Australian M2, but found more often in Australian M5 than in Japanese M5. In both populations, a close relationship was observed between the expression of CD19 and t(8;21). These findings suggest different biological characteristics of AML between the two populations, the main differences being generated by a higher frequency of t(8;21) chromosomal abnormality in Japanese AML. Leukemia(2000) 14, 163-168.

High frequency of acute promyelocytic leukemia among Latinos with acute myeloid leukemia.

A high frequency (24%) of acute promyelocytic leukemia (APL) was noted among acute myelocytic leukemia (AML) cases at the Los Angeles County-University of Southern California (LAC-USC) Medical Center, in comparison with the expected frequency of 5% to 15%. Because of the high proportion of Latinos in this center, we questioned if APL is more common in this ethnic group. The proportion of APL among the 80 AML patients of Latino origin was significantly higher (30; 37.5%) when compared with the 62 non-Latinos (4; 6.5%) (P = .00001). In an attempt to verify this finding on a larger group of patients, we analyzed 276 pathologically verified cases of AML in patients aged 30 to 69 years from the entire County of Los Angeles, registered on an ongoing population-based epidemiologic study of AML. APL was more frequent among the 47 Latinos (24.3%) than in the 229 non-Latinos (8.3%) (P = .0075). APL is seen in younger patients with AML, but Latino AML patients also had a higher frequency of APL after accounting for their younger age (age-adjusted odds ratio for APL among Latinos in LAC-USC Medical Center, 9.4 [95% confidence interval (CI) 2.9, 30] P = .0002; among Latinos in the population-based study, 3.0 [95% CI 1.3 to 6.9] P = .01). The different ethnic distribution of AML was found to be due to a higher proportion of APL cases per se, and not to a lower proportion of any other French-American-British subtype (P = .0004). These results, from two different populations of AML patients, indicate that Latinos with AML have a higher likelihood of the APL subtype of disease, which may suggest a genetic predisposition to APL and/or exposure to distinct environmental factor(s).

Acute myeloid leukemia subtypes and response to treatment among ethnic minorities in a large US urban hospital.

From January 1, 1987, to August 30, 1991, 86 consecutive new cases of AML diagnosed at the LAC-USC Medical Center were analyzed. A significant difference in the FAB subtypes of AML was observed among different racial groups, with AML-M3 more common in Latinos (40%) and AML-M2 in Orientals (52%). Sixty-seven patients received induction chemotherapy with TAD (thioguanine-cytosine arabinoside-daunorubicin) or like regimens. Median follow-up time of all patients was 16 months. Forty-three patients (64%) achieved complete remission. The median overall survival of those who received induction was 10.5 months. The complete remission rates and overall survival were similar among patients of different ethnic backgrounds.