miR-34a and miR-29b as indicators for prognosis of treatment-free survival of chronic lymphocytic leukemia patients in Chinese Uygur and Han populations.

The abnormal expression of miRNAs may play critical roles in the occurrence, development and prognosis of chronic lymphocytic leukemia (CLL), with potential ethnic differences being involved. p53 and immunoglobulin heavy chain variable region gene (IGVH) mutations were monitored and miRNA profile screening of CD19 + cells from Uygur CLL patients was performed, analyzed by miRNA arrays and verified using real-time PCR. There were 68 differentially expressed miRNAs in CD19 + B lymphocytes obtained from 6 Uygur CLL patients, of which miR-1295, miR-29b, miR-34a, miR-21 and miR-29c were the 5 most upregulated, and miR-181a, miR-126, miR-181b, miR-125a-5p and miR199b the 5 most downregulated miRNAs. miR-15a/miR-16-1 which might be important drivers of the disease, were not eliminated by profile screening. From the 68 differentially expressed miRNAs, 5 previously-reported CLL-related miRNAs were selected for further confirmation analyses, from which expression levels of miR-29b, miR-34a and miR-155 were found to be increased while miR-181a and miR-181b decreased. However, there were no differences in the expression levels of miR-15a/miR-16-1 between CLL patients and healthy donors, but the expression levels of miR-15a/miR-16-1 in CLL patients with a 13q deletion was depressed. In addition, there was no difference in the expression level of the above 7 miRNAs between 44 Han and 40 Uygur CLL patients. The expression levels of miR-29b, miR-181a and miR-181b correlated with IGVH mutations, while the expression levels of miR-34a, miR-29b and miR-181b correlated with a p53 abnormality in 84 Uygur and Han CLL patients. Taking p53 abnormality as the cut-off value criteria, low expression levels of miR-34a (cut-off value 4.65, P = 0.02) and miR-29b (cut-off value 4.71, P = 0.009) hinted at a poor treatment-free survival (TFS) prognosis for all CLL patients. Thus miR-34a and miR-29b may represent useful indicators for the prognosis of both Uygur and Han CLL patients.

[The expression and prognostic significance of microRNA-34a in Uygur and Han patients with chronic lymphocytic leukemia in Xinjiang Uygur Autonomous Region in China].

To investigate the expression of microRNA-34a (miR-34a) in patients with chronic lymphocytic leukemia (CLL) in Xinjiang Uygur and Han nationalities and its prognostic significance. Our data showed that miR-34a expression in Uygur and Han CLL patients was significantly higher than that in their respective healthy controls, while miR-34a levels were similar between Uygur and Han patients. By comparing with known prognostic factors, receiver operating characteristic (ROC) curves showed that miR-34a was a good predictive factor for the prognosis of CLL (demarcation value was 3.567 6). Survival analysis was further performed according to miR-34a expression level, that low expression of miR-34a translated into poor prognosis.

Distinct molecular genetics of chronic lymphocytic leukemia in Taiwan: clinical and pathogenetic implications.

Differences in chronic lymphocytic leukemia between the Asian and the Western population are widely known. To further clarify these ethnic differences, we profiled the molecular genetics in a cohort of 83 newly diagnosed patients from Taiwan. In detail, we assessed: (i) the usage and the mutational status of the clonotypic immunoglobulin heavy-chain variable region (IgHV) genes, (ii) the presence of VH CDR3 stereotypes, and (iii) TP53, NOTCH1, SF3B1, BIRC3, and MYD88 mutations. The IgHV gene repertoire was biased and distinct from that observed in the West with the most common IgHV genes being IgHV3-23, IgHV3-7, and IgHV3-48 In terms of IgHV gene mutational status, 63.8% of patients carried mutated rearrangements, whereas 22.4% of patients were assigned to stereotyped subsets (6.9% to major subsets and 15.5% to minor ones). The frequencies of NOTCH1, SF3B1, BIRC3 and MYD88 mutations were 9.6%, 7.2%, 1.2%, and 2.4%, respectively; however, the frequency of TP53 mutations was significantly higher (20.5%). Patients with TP53 mutations or del(17p), SF3B1 mutations and unmutated IgHV had a worse outcome compared to the other patients. In conclusion, the differences observed in IgHV properties suggest different pathogenetic factors implicated in the development of chronic lymphocytic leukemia, while the high frequency of TP53 mutations could in part explain the dismal outcome of these patients in Taiwan.

Analysis of common cytogenetic abnormalities in New Zealand pediatric ALL shows ethnically diverse carriage of ETV6-RUNX1, without a corresponding difference in survival.

BACKGROUND: The frequency of common cytogenetic abnormalities in pediatric acute lymphoblastic leukemia (ALL) is known to vary by geographic location and ethnic origin. This study aimed to determine the frequency of hypodiploidy, ETV6-RUNX1, BCR-ABL1, and MLL rearrangement within New Zealand's pediatric ALL population and to assess whether the frequency of these ALL prognostic markers varies according to ethnicity. PROCEDURE: The New Zealand Children's Cancer Registry provided information for all registered pediatric ALL patients that were diagnosed between 2000 and 2009, with medical records available for 246 patients. Each patient's medical record was reviewed to determine the frequency of hypodiploidy, ETV6-RUNX1, BCR-ABL1, MLL rearrangement, and cell lineage. Chi-square tests for independence were undertaken to compare the frequencies of cytogenetic abnormalities according to prioritized ethnicity. RESULTS: The frequency of cytogenetic ALL abnormalities in the New Zealand pediatric population were consistent with international reference values. A low frequency of ETV6-RUNX1 was evident for Maori pediatric ALL patients (5.4%, P = 0.018), when compared to Pacific peoples (21.1%) and non-Maori/non-Pacific peoples (27.4%). This has not impacted on outcome, however, with equivalent 5-year overall survival being observed in Maori (89.4%) compared to Pacific peoples (92.0%) and non-Maori/non-Pacific peoples (90.2%). CONCLUSIONS: A lower frequency of the favorable prognostic marker ETV6-RUNX1 was observed in Maori pediatric ALL patients. This did not translate into poorer survival. Future research into biological and nonbiological prognostic factors in this patient population may assist in explaining this finding.

Fine-mapping of HLA associations with chronic lymphocytic leukemia in US populations.

Chronic lymphocytic leukemia (CLL) displays remarkable ethnic predisposition for whites, with relative sparing of African-American and Asian populations. In addition, CLL displays among the highest familial predispositions of all hematologic malignancies, yet the genetic basis for these differences is not clearly defined. The highly polymorphic HLA genes of the major histocompatibility complex play a central role in immune surveillance and confer risk for autoimmune and infectious diseases and several different cancers, the role for which in the development of CLL has not been extensively investigated. The National Marrow Donor Program/Be The Match has collected HLA typing from CLL patients in need of allogeneic hematopoietic stem cell transplant and has recruited millions of volunteers to potentially donate hematopoietic stem cells. HLA genotypes for 3491 US white, 397 African-American, and 90 Hispanic CLL patients were compared with 50 000 controls per population from the donor registry. We identified several HLA alleles associated with CLL susceptibility in each population, reconfirming predisposing roles of HLA-A*02:01 and HLA-DRB4*01:01 in whites. Associations for haplotype DRB4*01:01∼DRB1*07:01∼DQB1*03:03 were replicated across all 3 populations. These findings provide a comprehensive assessment of the role of HLA in the development of severe CLL.

Validation of Western common recurrent chromosomal aberrations in Korean chronic lymphocytic leukaemia patients with very low incidence.

In Asia, the incidence of chronic lymphocytic leukaemia (CLL) is lower than in Western countries. Only a few studies of CLL have been conducted in Korea, and no long-term clinical outcome data are available. We assessed the frequency of common chromosomal aberrations in Korean CLL patients using interphase fluorescence in situ hybridization (FISH) and investigated their relationship to clinical outcomes. Between 2000 and 2011, conventional cytogenetic studies were performed in 58 patients, and FISH results were available in 48 patients. We used six DNA probes for the detection of del(13q14), trisomy 12, del(11q22), del(17p13), IGH rearrangement and del(6q23). Chromosomal aberrations were identified in 15 of 58 patients (26%) with conventional cytogenetic studies and in 25 of 48 patients (52%) with interphase FISH, including six patients with complex karyotypes. In contrast with the results of Western studies, trisomy 12 was the most common aberration, followed by IGH rearrangement, del(13q14), del(11q22) and del(17p13). Deletion of 6q23 was not observed, and isolated del(13q14) was less frequent than in Western studies. Compared with the other types of chromosomal aberrations, patients with del(11q22) and del(17p13) were more likely to be Rai stage 3-4 and Binet stage C, resulting in poor responses to chemotherapy and worse outcomes. In contrast, patient with trisomy 12 and isolated del(13q14) showed better responses and superior survival outcomes. The incidence of CLL is lower in Korea than in Western countries, and the frequency of chromosomal aberrations differs, perhaps reflecting differences in the pathogenic mechanism between ethnicities. Large prospective studies are needed to further assess the prognostic value of these results in Korean CLL patients.

[Detection of p53 gene deletion in Xinjiang patients with chronic lymphocytic leukemia by fluorescence in situ hybridization and its clinical significance].

OBJECTIVE: To investigate the presence of p53 gene deletion in Xinjiang patients with chronic lymphocytic leukemia and its clinical significance. METHODS: Interphase fluorescence in situ hybridization (FISH) was used to detect the p53 gene deletion in 77 patients with CLL. Presence of the deletion and its association with clinical and laboratory features as well as prognostic factors were analyzed. Kaplan-Meier method was used to calculate survivals, and the results were compared using a Log-rank test. RESULTS: p53 gene deletion was found in 10 (12.9%) of the patients but none from the control group (P<0.05). The deletion was found in 12.5% (4/32) of ethnic Hans and 13.3% (6/45) of ethnic Uyghurs (P>0.05). No significant different distribution of p53 gene deletion was found in regard to sex, age, ethnicity, peripheral blood cell count (except for Hb) or the levels of lactate dehydrogenase, ß2-micro globulin and CD38 (P>0.05). The deletion rate was higher in the group with high expression of ZAP-70 and patients with advanced stage disease than that in the group of low expression and early-stage CLL (P<0.05). Among 20 patients who received fludarabine therapy, the overall remission rate for those with p53 gene deletion (20%) was lower than those without (75%) (P<0.05). With a median follow-up time of 39.0 (8.0-136.0) months, 11 cases had died (14.3%), among them, 7 cases died from CLL and related complications, and all of them were founded p53 gene deletion. In patients with p53 gene deletion, the progression-free survival (18 months) was shorter than those without the deletion (55 months) (P<0.05). CONCLUSION: The p53 gene deletion has been found in more than 10% of patients with CLL, and the deletion rate did not significantly differ between ethnic Han and Uyghur patients. The deletion is associated with advanced stage of the disease. High-level ZAP-70 expression and the presence of p53 deletion are associated with shorter survival and poor response to fludarabine containing therapy. Therefore, drugs affecting the p53 signaling pathway should be avoided.

The prognostic significance of TP53 mutations in Chinese patients with chronic lymphocytic leukemia is independent of del(17p13).

The poor prognosis of chronic lymphocytic leukemia (CLL) patients with del(17p13) is well established. Several studies have shown that cases with TP53 mutations and TP53 mutations without del(17p13) may be adverse prognostic factors. We studied 173 well-characterized CLL patients by direct sequencing to detect TP53 mutations (exons 2-11). TP53 mutations were detected in 14.5% (25 of 173) of samples. Most patients with del(17p13) had TP53 mutations (72.2%). Mutations in the absence of del(17p13) were found in 8.3% in our cohort, which were higher than other countries. Compared with cases without TP53 alterations, TP53 mutations and deletions were both associated with advanced stages and unmutated immunoglobulin heavy-chain variable region status. Survival analysis showed that the occurrence of TP53 mutations and del(17p13) were associated with shorter overall survival (OS), treatment-free survival (TFS), and resistance to chemotherapy. TP53 mutations were the variables strongly associated with OS and TFS by multivariate Cox regression analysis. Moreover, we also found that cases with TP53 mutations in the absence of del(17p13) had a similar clinical and biological course and similar poor short OS as cases carrying del(17p13) in Chinese patients with CLL.

CD38 gene polymorphisms contribute to genetic susceptibility to B-cell chronic lymphocytic leukemia: evidence from two case-control studies in Polish Caucasians.

Given the recent findings on the importance of CD38 signaling in the pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL), we hypothesized that single nucleotide polymorphisms (SNP) in the CD38 gene may be related to B-CLL risk. We evaluated two potentially functional CD38 SNPs, intronic rs6449182 (184C>G) and missense rs1800561 (418C>T, Arg140Trp) in two hospital-based case-control studies (study A and validation study B). Genotyping was done using PCR-based assays in a total of 460 Polish Caucasian patients with B-CLL and 503 age-matched and gender-matched controls. We found that frequencies of both variant alleles (rs6449182 G and rs1800561 T) were significantly higher in B-CLL. In study A, logistic regression analysis revealed an association between B-CLL and genotypes: rs6449182 CG [odds ratio (OR), 3.57; 95% confidence interval (95% CI), 2.4-5.3], rs6449182 GG (OR, 5.2; 95% CI, 2.36-11.5), and rs1800561 CT (OR, 6.72; 95% CI, 1.5-30.1), although no homozygous rs1800561 TT genotype was detected in either study. These results were confirmed in study B, which showed an association between B-CLL and genotypes rs6449182 CG (OR, 4.00; 95% CI, 2.7-6.0), rs6449182 GG (OR, 12.84; 95% CI, 4.3-38.7), and rs1800561 CT (OR, 10.12; 95% CI, 1.3-81.6), and in the combined analysis of both studies. We also observed that rs6449182 G carriers had more advanced clinical stage (P=0.002) and tended to be younger at diagnosis (P=0.056). Furthermore, we found higher CD38 transcript levels and higher proportions of CD38-positive cells in carriers of rs6449182 G and rs1800561 T alleles (P<0.05 for all comparisons). In conclusion, our data show that CD38 SNPs may affect CD38 expression and contribute to the increased risk of B-CLL carcinogenesis.

South Asian chronic lymphocytic leukaemia patients have more rapid disease progression in comparison to White patients.

Ethnicity has a major impact on the prevalence of chronic lymphocytic leukaemia (CLL) and may also influence disease phenotype. We compared the clinical features of Southern Asian and White CLL patients managed within one UK region. Asians required treatment almost twice as often as Whites (HR, 1.94) and had a shorter time to first treatment (P = 0.0063). This difference remained significant after adjusting for stage, lymphocyte doubling time and IGHV status (P = 0.026). CLL was diagnosed at younger ages in Asians and racial-specific variations in IGHV usage were demonstrated. Our findings indicate that Southern Asian race has a negative impact on CLL phenotype.

Distinctive IgVH gene segments usage and mutation status in Chinese patients with chronic lymphocytic leukemia.

BACKGROUND AND OBJECTIVES: The incidence of chronic lymphocytic leukemia (CLL) in Asian countries is lower than that in the Western ones, where CLL is the most common leukemia. It is a clinically heterogeneous disease, with survival ranging from a few months to decades. The mutation status of the immunoglobulin variable heavy chain (IgVH) gene has significantly improved prediction of the risk for disease progression. We investigated the frequency and mutation status of IgVH gene expression in Chinese patients with CLL. METHODS: IgVH gene segments usage and mutation status were investigated by multiplex RT-PCR, and the relationship between IgVH somatic mutation status and the expression of CD38 and ZAP-70 was analyzed in 65 CLL patients. RESULTS: Forty-five (69.2%) patients had mutated IgVH, and 20 (30.8%) had unmutated IgVH. The most frequently expressed VH gene family was found to be VH3 (47.7%) followed by VH4 (40%), VH1 (6.2%), VH2 (4.6%) and VH7 (1.5%), with no expression of VH5 or VH6 gene families. VH1-69 and VH3-21 which commonly overused in Western CLL were very low in our cohort. IgVH gene mutation status was significantly associated with the expression of CD38. CONCLUSIONS: The frequency of IgVH gene families indicates significant difference in Chinese CLL patients compared with Western patients, suggesting involvement of ethnic and/or environmental factors in CLL disease initiation. The expression of them may be simple and reliable surrogates for the identification of IgVH mutations.

[Fluorescent in situ hybridization with a panel of probes detects molecular cytogenetic abnormalities in patients with chronic lymphocytic leukemia].

OBJECTIVE: To explore the characteristics and prognostic significance of molecular cytogenetic aberrations in Chinese patients with chronic lymphocytic leukemia (CLL) and the significance thereof in diagnosis of CLL. METHODS: A panel of probes (LSI D13S319, LSI p53, LSI ATM, CEP 12, LSI MYB, and LSI IGHC/IGHV) and interphase fluorescence in situ hybridization (FISH) were used to prospectively detect the cytogenetic abnormalities in 106 CLL patients, 82 males and 24 females, aged 62 (34 - 86). RESULTS: Molecular cytogenetic aberrations were found in 79 of the 106 CLL patients (74.5%) and 35 patients (33.0%) showed more than two kinds of abnormalities. The most frequent abnormality detected was del (13q14) in 48 cases (45.3%), followed by trisomy of chromosome 12 in 27 patients (25.5%), IgH translocation in 25 patients (23.6%), del (17p13) in 17 patients (16.0%), del (11q22) in 11 patients (10.5%) and del (6q23) in 5 patients (4.7%). The Del (13q14) rate of the group younger than 60 was 56.5%, significantly higher than that of the group aged > or = 60 (36.7%, P = 0.033). There was no significant relationship between molecular cytogenetic aberrations and sex and Binet stages (both P > 0.05). Kaplan-Meier survival analysis showed that the survival time was shorter in the patients with p53 or ATM gene deletion. Patients with sole Del (13q14) had longer survival time than those with other abnormalities. CONCLUSION: The frequencies of the chromosomal abnormalities in Chinese CLL patients are similar to those in Western countries. Panel FISH has greatly increased the sensitivity of cytogenetic analyses. Del (13q14) is the most frequent abnormality in CLL. Molecular cytogenetic aberrations detected with FISH have important prognostic significance in CLL.

Safety and efficacy of obinutuzumab in Chinese patients with B-cell lymphomas: a secondary analysis of the GERSHWIN trial.

BACKGROUND: Patients with relapsed/refractory B-cell lymphomas have limited treatment options. GERSHWIN is an open-label, single-arm, phase Ib study of obinutuzumab monotherapy in Chinese patients with histologically documented CD20+ relapsed/refractory chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), or follicular lymphoma (FL). The primary outcome measure of pharmacokinetics has been previously reported. We now present data on the secondary endpoint measures (e.g., safety, and efficacy and pharmacodynamics). METHODS: Patients received 1000 mg obinutuzumab intravenously on days 1, 8, and 15 of cycle 1 (CLL patients; first dose split over 2 days), and on day 1 of cycles 2-8. Each cycle lasted for 21 days; the treatment period was 24 weeks. All subjects receiving at least one dose of obinutuzumab were included in the analysis of safety, efficacy, as well as pharmacodynamics. RESULTS: A total of 48 patients (> 18 years of age) were enrolled (CLL: 12; DLBCL: 23; FL: 13). The subjects received a median of two lines of anticancer treatment prior to the enrollment. Thirty-five patients (72.9%) had at least one adverse event (AE). The most frequent AE was infusion-related reactions (15 patients; 31.3%), followed by pyrexia (11 patients; 22.9%). Treatment-related AEs were reported in 28 patients (58.3%), and included one death (interstitial lung disease). End-of-treatment (EoT) response rate was 33.3%. Best overall response rate was 47.9%. Most CLL patients achieved a partial response at EoT (58.3%). CD19+ depletion occurred in 75.0% of the patients with CLL, and all patients with FL and DLBCL. CONCLUSIONS: The safety and efficacy of obinutuzumab monotherapy in Chinese patients with B-cell lymphomas were similar to that observed in previous studies in non-Chinese patients; no new safety signals were observed. Clinical trial registration ID NCT01680991.

Chronic lymphocytic leukaemia and small lymphocytic lymphoma: overview of the descriptive epidemiology.

The 2001 World Health Organization classification scheme considers B-cell chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL) in an aggregate category (CLL/SLL) because of shared clinicopathological features. We have estimated age-adjusted incidence rates (IRs) of CLL and SLL in the population-based Surveillance, Epidemiology and End Results Program in the United States to analyse patterns of CLL and SLL separately and jointly. Age-standardized to the 2000 US population, overall IRs were 3.83 per 100 000 person-years for CLL (n = 15 676) and 1.31 for SLL (n = 5382) during 1993-2004. Incidence of the combined entity, CLL/SLL, was 90% higher among males compared to females, and the male:female IR ratio was significantly higher for CLL (1.98) than for SLL (1.67). CLL/SLL IRs were 25% and 77% lower among Blacks and Asian/Pacific Islanders, respectively, compared to Whites. A significant reporting delay was evident for CLL but not for SLL, so that CLL/SLL temporal trends must be interpreted cautiously. CLL and SLL IRs increased exponentially with age among all gender/race groups, with CLL IRs increasing more steeply with advancing age than SLL. Avenues of future research include assessment of delayed- and under-reporting to cancer registries and exploration of race, gender, and age effects in epidemiological studies.

Chronic lymphocytic leukaemia genetics overview.

Although the familial aspect of chronic lymphocytic leukaemia (CLL) has been appreciated for decades, it is only with the recent confluence of improved molecular and gene technologies and world-wide collaborative networks that accelerated progress has become apparent. In this summary we highlight selected themes in the genetics of CLL emphasizing the opportunities and challenges of this malignancy.

Korean patients with chronic lymphocytic leukemia show the similar types of chromosomal aberrations as those in Europe and North America.

Chronic lymphocytic leukemia (CLL) is frequent in the West, but rare in Korea. In this study, the frequency of chromosome aberration in Korean CLL patients was examined by applying interphase fluorescence in situ hybridization (FISH). Conventional cytogenetic test and FISH were performed on bone marrow aspirates obtained from 16 CLL patients. By applying DNA probes (Vysis, Downers Grove, IL, USA), the deletion in 11q22-23, 13q14, 13q34, and 17p13, and trisomy 12 were examined. With FISH, molecular cytogenetic aberration was detected in 10 of 16 patients [63%, 95% confidence interval (CI) 39-86], whereas with conventional cytogenetic test, chromosomal aberration was detected only in 2 out of 13 cases (15%, 95% CI 0-35). In total, the cases with one or more chromosomal aberrations were 11 out of 16 cases (69%, 95% CI 46-92). The most frequently detected aberration was the 13q14 deletion (69%, 95% CI 44-94), followed by trisomy 12 (19%, 95% CI 0-38) and 11q22 deletion (14%, 95% CI 0-33). No deletion in 17p13 was observed. In conclusion, CLL in Korean is a heterogeneous genetic disorder, showing similar genetic changes in Europe and North America.

Spectrum of mucocutaneous manifestations in an Asian cohort of patients with leukemia.

BACKGROUND: Literature on cutaneous manifestations of leukemia is limited. OBJECTIVE: To determine the pattern of mucocutaneous manifestations in adult Asian patients with leukemia and to establish their relation with the leukemia type. SUBJECTS AND METHODS: After previous consent, 196 consecutively registered patients with leukemia aged ≥18 years were recruited. All patients were prospectively followed for 3 months to evaluate the patterns of mucocutaneous involvement. The mucocutaneous manifestations were categorized into specific lesions with leukemic infiltration and non-specific lesions. RESULTS: Seventy-nine (40.3%) of 196 (males 128 and females 68) recruited patients showed one or more mucocutaneous manifestations. The total number of complaints observed was 87 with mean number of dermatoses per patient being 0.44. Specific manifestations (leukemia cutis) were present in six (3.06%) and nonspecific mucocutaneous manifestations in 73 (37.2%, reactive dermatoses n = 21 and infections n = 52). Cutaneous viral infections were significantly associated with acute lymphoblastic leukemia (P < 0.005). Antiviral prophylaxis with acyclovir significantly reduced the incidence of varicella-zoster infection (P = 0.016). CONCLUSION: Cutaneous manifestations are common in Asian patients with leukemia, and a thorough cutaneous examination will aid in their management.