[Prognostic value of KIT and other clonal genetic mutations in core-binding factor acute myeloid leukemia].

Objective: To evaluate the prognostic significance of clonal gene mutations using next-generation sequencing in patients with core-binding factor acute myeloid leukemia (CBF-AML) who achieved first complete remission after induction chemotherapy. Methods: The study, which was conducted from July 2011 to August 2017 in First Affiliated Hospital of Soochow University, comprised 195 newly diagnosed patients with CBF-AML, including 190 patients who achieved first complete remission after induction chemotherapy. The cohort included 134 patients with RUNX1-RUNXIT1(+) AML and 56 patients with CBFß-MYH11(+) AML. The cohort age ranged from 15 to 64 years, with a median follow-up of 43.6 months. Overall survival (OS) and disease-free survival (DFS) were assessed by the log-rank test, and the Cox proportional hazards regression model was used to determine the effects of clinical factors and genetic mutations on prognosis. Results: The most common genetic mutations were in KIT (47.6% ) , followed by NRAS (20.0% ) , FLT3 (18.4% ) , ASXL2 (14.3% ) , KRAS (10.7% ) , and ASXL1 (9.7% ) . The most common mutations involved genes affecting tyrosine kinase signaling (76.4% ) , followed by chromatin modifiers (29.7% ) . Among the patients receiving intensive consolidation therapy, the OS tended to be better in patients with CBFß-MYH11(+) AML than in those with RUNX1-RUNXIT1 (+) AML (P=0.062) . Gene mutations related to chromatin modification, which were detected only in patients with RUNX1-RUNXIT1(+) AML, did not affect DFS (P=0.557) . The patients with mutations in genes regulating chromatin conformation who received allo-hematopoietic stem cell transplantation (allo-HSCT) achieved the best prognosis. Multivariate analysis identified KIT exon 17 mutations as an independent predictor of inferior DFS in patients with RUNX1-RUNXIT1(+) AML (P<0.001) , and allo-HSCT significantly prolonged DFS in these patients (P=0.010) . Conclusions: KIT exon 17 mutations might indicate poor prognosis in patients with RUNX1-RUNXIT1(+) AML. Allo-HSCT may improve prognosis in these patients, whereas allo-HSCT might also improve prognosis in patients with mutations in genes related to chromatin modifications.

[The prognostic value of cloned genetic mutations detected by second-generation sequencing in RUNX1-RUNX1T1 positive acute myeloid leukemia patients receiving intensive consolidation therapy].

Objective: To investigate the prognostic value of clonal gene mutations detected by second-generation sequencing in patients with positive RUNX1-RUNX1T1 acute myeloid leukemia (AML) who received high-dose chemotherapy or autologous transplantation (intensive consolidation therapy) in the first complete remission (CR(1)) state. Methods: 79 AML patients with positive RUNX1-RUNX1T1 who received intensive consolidation therapy in CR(1) state from July 2011 to August 2017 were analyzed retrospectively. Kaplan-Meier curve and Cox regression model were used to figure out the effect of leukocyte counts at onset and gene mutations for prognosis. Results: C-KIT, FLT3, CEBPA and DNMT3A gene mutations were found in 25 (31.6%) , 6 (7.6%) , 7 (8.9%) and 1 (1.3%) patient among the population. Mutations in C-KIT exon17 and C-KIT exon8 were detected in 19 (24.1%) and 5 (6.3%) cases, respectively, and mutations of FLT3-ITD were confirmed in 5 (6.3%) cases. The higher leukocyte counts presented at onset of leukemia, the shorter overall survival (OS) was seen in these patients (P=0.03) . Patients with C-KIT exon17 mutation had significantly shorter OS (P=0.01) and disease free survival (DFS) (P=0.006) compared with those without gene mutations, and patients with FLT3-ITD gene mutation got the inferior OS (P=0.048) and DFS (P=0.071) . Conclusion: In AML patients with positive RUNX1-RUNX1T1 receiving intensive consolidation therapy, the white blood cell counts at onset of leukemia, C-KIT mutations in exon 17, and FLT3-ITD gene mutations suggest poor prognosis, which would contribute to elaborate risk stratification, personalized treatment and predict prognosis for these patients.

[Effects of IL10-592 locus of AA genotype on the incidence of aGVHD and survival after HLA-matched unrelated allogeneic hematopoietic stem cell transplantation].

OBJECTIVE: To explore the impact of IL10-592 (rs1800872) single nucleic acid polymorphism (SNP) on the prognosis of HLA matched unrelated hematopoietic stem cell transplantation (HSCT). METHODS: The polymorphism of IL10-592 in 104 recipient-donor pairs and 100 healthy volunteers was analyzed with sequence based typing (SBT). RESULTS: When the genotype of IL10-592 in donors and recipients matched, AA/AA genotype had higher incidence of Ⅲ-Ⅳ aGVHD than AC/AC or CC/CC genotype (47.1%, 3.7%, 0, P=0.002). When the genotype of IL10-592 in donors and recipients mismatched, recipients with AC genotype or donors with AA genotype, there was significant different incidence of Ⅲ-ⅣaGVHD among donors or recipients with different genotype (P=0.046, P=0.041). The recipients with AA genotype had higher incidence of Ⅲ-Ⅳ aGVHD than AC or CC genotype (27.8% vs 10.2%, 11.1%; P=0.072), and higher incidence of intestinal aGVHD (22.2% vs 5.1%,11.1%; P=0.040) , lower incidence of 2-year overall survival (OS: 48.2% vs 75.1%, 85.7%; P=0.002), lower incidence of 2 year disease free survival (DFS: 48.5% vs 66.3%, 76.2%; P=0.045). Patients had higher incidence of Ⅲ-Ⅳ aGVHD with donors of AA genotype than with donors of AC or CC genotype (26.5% vs 8.9%, 0; P= 0.024), and higher incidence of intestinal aGVHD (20.4% vs 4.4%, 0; P=0.026). In multivariate analysis, the genotype of IL10-592AA in recipients and donors had increased risk of Ⅲ-Ⅳ aGVHD (OR=3.3, P= 0.049; OR=3.9, P=0.043). There were no statistical differences on the incidence of cGVHD and relapse. CONCLUSION: In HLA-10/10 matched unrelated HSCT, the presence of IL10-592 AA genotype in recipients and/or donors is an adverse factor for Ⅲ-ⅣaGVHD, worse OS and 2-year DFS.

The impact of KIR2DS4 alleles and the expression of KIR in the development of acute GVHD after unrelated allogeneic hematopoietic SCT.

The role of killer Ig-like receptors (KIR) in SCT was analyzed. A total of 75 Chinese patients were transplanted with T-depleted hematopoietic stem cells from unrelated donors. Among the 75 donor-recipient pairs, 60 were HLA 10/10 matched and 15 had some mismatches at HLA-C. Transplants from KIR haplotype B/x group donors showed significantly higher overall survival rates compared with those from KIR haplotype A/A donors (relative risk (RR) 3.1 (95% confidence interval (CI) 1.1-8.6), P=0.007). In the haplotype A/A group, a higher risk of acute GVHD (aGVHD) (RR 9.0 (95% CI 1.2-66.9), P=0.01), especially grade III-IV aGVHD (P=0.006), was observed when the donor was homozygous for the full-length expressed KIR2DS4*00101 allele. Real-time PCR showed that a high expression of inhibitory KIR (2DL1 and 3DL1) in the early stages (<90 days) after transplantation correlated with the development of aGVHD (z=2.558, P=0.011). Our findings indicated a significant association of full-length KIR2DS4 or KIR2DL1/3DL1 expression with the occurrence of aGVHD. In aggregate these results suggested that combining KIR and HLA genotyping could help in the selection of transplant donors and improve the outcome of transplantation. Dynamic detection of KIR2DL1/3DL1 expression would be beneficial for prediction of aGVHD after transplantation.

Epidemiological and aetiological evidence for transmission of Lyme disease by adult Ixodes persulcatus in an endemic area in China.

Involvement of adult Ixodes persulcatus ticks in the transmission of Lyme disease in Hailin County, Heilongjiang Province, China, is reported. In 1986 from April through August adult I. persulcatus was the dominant tick in this endemic area with an infection rate of 43% for the Lyme disease spirochaete, Borrelia burgdorferi. The incidence of Lyme disease cases presenting the symptom of erythema chronicum migrans (ECM) within this area was correlated with the seasonal abundance of adult I. persulcatus and the number of people bitten by ticks. The frequency of ECM formation in all age groups varied and was associated with the frequency of tick bites. In addition, a strain of B. burgdorferi was isolated from a pool of six female I. persulcatus collected from this area. We demonstrate that the seasonal abundance of adult I. persulcatus and its frequent attachment to humans result in the spring and summer transmission of Lyme disease in this endemic area. The role of immature I. persulcatus in Lyme disease transmission is apparently minimal.

Clinical manifestations and epidemiological characteristics of Lyme disease in Hailin county, Heilongjiang Province, China.

Clinical manifestations and epidemiological characteristics of Lyme disease in Hailin county, Heilongjiang Province, China have been reported. The clinical picture of erythema chronicum migrans (ECM) is variable. ECM in the form of annular erythematous patch is uncommon. It is an extensive and indurated lesion. In some instances, a vesicle or necrosis appears in the center of the lesion. Secondary erythema may present in some patients. The neurologic abnormalities consist of meningitis, facial palsy, and polyneuritis. Cardiac abnormalities are rare. In addition, there were cases with lymphadenosis benigna cutis (LABC), which had heretofore only been reported in Europe. The attack rate of ECM is 8.4%. There was a significant sex difference, and most cases occurred in May and June. All patients had a history of tick bite. The prevalence rates of neurologic abnormalities and arthritis were 4.6% and 6.6%, respectively. Three strains of spirochete that are closely related to Borrelia burgdorferi were isolated from Ixodes persulcatus ticks and facial palsy patients. From the above results it is concluded that a focus of Lyme disease exists in this region.