X. Ye

Reduced-intensity allogeneic transplantation combined with imatinib mesylate for chronic myeloid leukemia in first chronic phase

Reduced-intensity allogeneic transplantation combined with imatinib mesylate for chronic myeloid leukemia in first chronic phase

Donor TLR9 gene tagSNPs influence susceptibility to aGVHD and CMV reactivation in the allo-HSCT setting without polymorphisms in the TLR4 and NOD2 genes.

Owing to ethnicity of the population, those best confirmed polymorphisms in the TLR (toll-like receptor)4 and NOD2 genes with significantly prognostic impact on allogeneic hematopoietic SCT (allo-HSCT) seem to be more applicable to Europeans and are nonpolymorphic in the Asian population. The influence of innate immunity gene polymorphisms on the outcomes of allo-HSCT in those populations has been questioned. We evaluated the influence of 10 candidate single nucleotide polymorphisms (SNPs) in the TLR1, TLR2, TLR3, TLR8 and TLR9 genes on the outcomes of allo-HSCT in a Chinese population including 138 pairs of patients and unrelated donors and a second cohort of 102 pairs of patients and HLA-identical sibling donors. We found that two tagSNPs in the TLR9 gene in the donor side, +1174 A/G (rs352139) and +1635 C/T (rs352140), influenced the risk of acute GVHD (aGVHD) and CMV reactivation. Furthermore, the presence of the susceptible haplotype (A–C) in donor may be an informative predicator of worse OS at 5 years compared with those with the G–C and G–T haplotypes (58% vs 82.9%, P=0.024). Our data suggested an unrecognized association between donor TLR9 tagSNPs and the risk of HSCT-related complications in a population without polymorphisms in the TLR4 and NOD2 genes.

Superiority of preemptive donor lymphocyte infusion based on minimal residual disease in acute leukemia patients after allogeneic hematopoietic stem cell transplantation.

Donor lymphocyte infusion (DLI) was used as salvage therapy in leukemia relapse after allogeneic hematopoietic stem cell transplantation (allo‐HSCT), but existing results on DLI administration to acute leukemia patients were disappointing. Although increasing minimal residual disease (MRD) after HSCT had been proven to be highly indicative of posttransplant relapse, preemptive DLI (pDLI) based on MRD has not been well evaluated.

Relationship between TNFA, TNFB and TNFRII gene polymorphisms and outcome after unrelated hematopoietic cell transplantation in a Chinese population

This study aimed to analyze the association between cytokine gene polymorphisms and outcome following allogeneic hematopoietic SCT (allo-HSCT). A total of 138 unrelated donor/recipient pairs who underwent allo-HSCT from 2001 to 2009 were tested for TNFA-1031 (T>C), -863 (C>A), -857 (C>T), -238 (G>A), TNFB+252 (A>G) and TNFRII codon 196 (T>G) single nucleotide polymorphisms by multiplex SnaPshot analysis. Transplantation involving recipients and/or donors with TNFA-857 C/C genotype or TNFB+252 G allele-positivity resulted in a higher incidence of acute GVHD (aGVHD), which was independent of HLA mismatching. In multivariate analysis, TNFA-857 C/C genotype donors (relative risk (RR)=2.29, P=0.006) and TNFB+252 G allele-positive recipients (RR=1.789, P=0.036) were found to be significantly associated with an increased incidence of aGVHD. TNFA-857 C/C genotype donors (RR=3.748, P=0.002) and TNFB+252 G allele-positive recipients (RR=1.823, P=0.063) were also associated with the development of grades II–IV aGVHD. TNFRII polymorphism in recipients was also related to relapse rate, but no significant associations were found between TNFA, TNFB or TNFRII 196 genotype and cGVHD, relapse or overall survival after transplantation. These results provide the first report of an association between TNFA, TNFB and TNFRII polymorphic features and outcome of allo-HSCT in a Chinese population, and suggest an interaction between TNFA-857 and TNFB+252 genotypes and risk of aGVHD.

The beneficial impact of missing KIR ligands and absence of donor KIR2DS3 gene on outcome following unrelated hematopoietic SCT for myeloid leukemia in the Chinese population

The effect of natural killer (NK) cell alloreactivity on the outcome of unrelated hematopoietic SCT (HSCT) remains a topic of debate. NK cell alloreactivity after allogeneic HSCT is regulated by killer-cell Ig-like receptors (KIRs). To investigate the influence of KIRs on outcome after unrelated HSCT, we retrospectively analyzed the HLA and KIR genotypes of 116 donor–recipient pairs. We found that missing KIR ligands in recipients were significantly associated with a decreased leukemic relapse risk (P=0.019, HR=0.329), mainly in myeloid disease (P=0.003, HR=0.193). This beneficial effect was seen in AML/myelodysplastic syndrome and also in chronic myeloid leukemia. In myeloid disease, missing KIR ligands also improved 5-year OS (P=0.034, HR=0.430) and disease-free survival (DFS) (P=0.024, HR=0.445). Meanwhile, the presence of donor-activating KIR2DS3 gene was associated with increased relapse risk (P=0.003, HR=5.046), decreased OS (P=0.004, HR=3.181) and DFS (P=0.003, HR=2.919) in myeloid disease. No effect was seen in patients with lymphoid disease. Our study indicated that, in unrelated HSCT for myeloid leukemia, missing KIR ligands in recipients offered a lower relapse risk and a long-term survival advantage. The presence of KIR2DS3 in the donor was an important risk factor for myeloid leukemia.

A Retrospective Analysis of Cytogenetic and Clinical Characteristics in Patients With Multiple Myeloma

Background:Cytogenetic alterations in patients with multiple myeloma (MM) represent important risk factors in terms of prognosis. In this study, the impact of the cytogenetic aberrations of MM on patient clinical features and outcome was investigated. Methods:Conventional cytogenetic analysis with R-banding technique and molecular cytogenetic characterization by interphase fluorescence in situ hybridization (FISH) were used to detect aberrant chromosomal arrangements, including 17p13 and 13q14 deletions, 14q32 rearrangement and 1q21 amplification, in bone marrow nucleated cells from 65 patients. Results:About 16.9% of patients showed aberrations by conventional cytogenetic analysis, whereas 49.2% of patients showed aberrations by interphase FISH analysis. Abnormalities of 13q14, 1q21, 14q32 and 17p13 were detected in 27.7%, 13.8%, 16.9% and 29.2%, respectively. Patients with a 13q14 deletion or combined with 17p13 deletion frequently had a late stage of the disease, and tended to have elevated serum levels of &bgr;2 microglobulin and lower levels of albumin. The progression-free survival and overall survival of FISH-positive patients were lower than for those without detectable abnormalities, especially in the conventional chemotherapy arm. Conclusions:These findings demonstrate that myeloma cells are prone to exhibiting a complex aberration and that FISH is superior to conventional cytogenetic analysis with a higher detection rate of chromosomal abnormalities. Patients with a 17p13 or 13q14 deletion, 14q32 rearrangement and 1q21 amplification were more likely to have a poor prognosis for MM.

An effective diagnostic index for lymphoma-associated hemophagocytic syndrome

Background Lymphoma-associated hemophagocytic syndrome (LAHS) is a highly fatal immune disorder. Poor prognosis is partly attributed to under diagnosis or delayed diagnosis. Aim Early identification of LAHS patients based on the laboratory findings could improve the outcomes. Design Retrospective observational cross-sectional study. Methods From January 2011 to June 2016, 282 adult patients with hemophagocytosis in bone marrow were enrolled, and 114 hemophagocytic lymphohistiocytosis (HLH) patients with definite underlying cause were finally included for analysis. The HLH patients were further divided into LAHS (76 out of 114) and non-malignancy-associated HLH (38 out of 114) groups. Results Compared to non-malignancy-associated HLH, LAHS patients had significantly elevated lactate dehydrogenase (LDH) levels, increased thickness of spleen, higher proportion of patients with lymphadenopathy and significantly decreased peripheral blood cell count. In multivariate logistic regression model analysis, thickness of spleen ≥5cm (OR = 17.9, 95%CI 1.35-236.6; P = 0.028), IL-6 level ≥55.1pg/mL (OR = 12.01, 95%CI 1.03-138.9; P = 0.047) and IL-10 level ≥425.9pg/mL (OR = 51.18, 95%CI 2.53-1035.1; P = 0.010) were independent predictors of LAHS diagnosis. Based on the regression parameters, we established a diagnostic index with weighted risk scores of 1 assigned to thickness of spleen and IL-6 level respectively, and a score of 3 assigned to IL-10 level. A diagnostic index ≥ 2 points had the best AUC value (0.889) with 84.2% of sensitivity and 93.7% of specificity for predicting LAHS. Conclusions LAHS can be considered when HLH patients have a diagnostic index ≥2 points, so actively looking for evidence of lymphoma and effective chemotherapy may be necessary.

Clinical features and outcomes in secondary adult hemophagocytic lymphohistiocytosis

Background Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by an infrequent but immune-mediated life-threatening disease, with confusing clinical manifestations, rapidly deteriorating health, high morbidity and mortality and challenging diagnosis. Aim The purpose of this study was to improve the recognition and understanding of HLH. Design Retrospective observational cross-sectional study. Methods Data were collected for all cases of adult patients diagnosed with HLH in a large cohort managed at a single medical center from January 2011 to December 2015. Results The median age was 52 years (range 18-90 years) and 123 (60.0%) were male. Over 95% patients manifested fever, hyperferritinemia and elevated lactate dehydrogenase. Underlying triggers of HLH were as follows: 119 (58.0%) malignancies, 83 (40.5%) infections, 14 (6.8%) unknown triggers and 14 (6.8%) autoimmune disorders. The median overall survival was 55 days. And elderly patients (age ≥60 years) had a markedly worse survival compared with young patients (age <60 years) (median overall survival 24 days vs. 159 days, respectively; P <0.001). In a multivariable analysis, platelet <40 × 109/l (HR = 2.534; 95% CI 1.152-5.573; P = 0.021), PT prolonged >3 s (HR = 1.909; 95% CI 1.127-3.234; P = 0.016) and malignancy (HR = 1.614; 95% CI 1.008-2.582; P = 0.046) were correlated with poor survival. Conclusion HLH adult patients had very complex clinical manifestations as well as underlying diseases. Patients with PLT <40 ×109/l, PT prolonged >3 s and malignancy had inferior survival. It is of great importance to improve our understanding of this syndrome.