J. He

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.

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.

Clinical analysis and prognostic significance of hepatitis B virus infections for diffuse large B-cell lymphoma with or without rituximab therapy

The aim of this study was to analyze the clinical features of hepatitis B surface antigen (HBsAg)-positive and negative diffuse large B-cell lymphomas (DLBCLs) and to compare the outcomes and serum hepatitis B virus (HBV)-DNA loads of patients treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) regimens with rituximab (RCHOP) or without. A total of 451 DLBCL patients, of which 90 were HBsAg-positive and 361 were HBsAg-negative, were retrospectively reviewed. We compared onset age, gender, Ann Arbor stage, international prognostic index (IPI), lactate dehydrogenase (LDH) and β2-microglobulin (β2-M) levels, as well as overall survival (OS) rates and HBV-DNA loads under CHOP or RCHOP regimens. The OS rate of the HBsAg-positive DLBCL patients was significantly lower than that of HBsAg-negative DLBCL patients and the HBsAg-positive DLBCL patients had an earlier median onset age. HBsAg-positive DLBCL patients had poorer OS rates compared with HBsAg-negative patients (62.2% HBsAg-positive vs. 76.2% HBsAg-negative, P=0.018). HBsAg-positive DLBCL patients with HBV-DNA loads >103 cps/ml during chemotherapy had significantly lower OS rates than those with lower HBV-DNA loads (48.4% HBV-DNA elevated vs. 71.2% HBV-DNA normal, P=0.037). HBsAg-positive DLBCL patients treated with RCHOP had a significantly higher OS rate (79.6%) compared with the 41 CHOP-treated patients (43.9%; P<0.001). HBsAg-positive DLBCL patients with an earlier median onset age and elevated HBV-DNA during chemotherapy had poorer prognoses. HBsAg and HBV-DNA during chemotherapy may be used as prognostic indicators for patients with DLBCL. Rituximab improves the outcome of HBsAg-positive DLBCL patients when administered in combination with anti-viral lamivudine.

Vernodalol enhances TRAIL-induced apoptosis in diffuse large B-cell lymphoma cells

Tumor necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL) is a potent anti‐tumor agent that triggers apoptosis in cells from multiple types of carcinoma but not in normal cells. However, diverse mechanisms are associated with insensitivity to TRAIL in various cancers. TRAIL efficacy may be enhanced by combining TRAIL with a sensitizer. In this study, vernodalol, a sesquiterpene lactone, sensitized diffuse large B‐cell lymphoma (DLBCL) cells to TRAIL‐induced apoptosis. Vernodalol increased the expression of death receptor (DR) 5, and silencing of DR5 with a small interfering RNA (siRNA) reduced the effect of vernodalol on TRAIL‐mediated apoptosis. Additionally, vernodalol up‐regulated the expression of CCAAT/enhancer‐binding protein (C/EBP) homologous protein (CHOP), a transcription factor. Inhibition of CHOP with a siRNA diminished DR5 expression and vernodalol‐induced sensitization to the TRAIL treatment. In addition, a c‐Jun N‐terminal kinase (JNK) inhibitor blocked the vernodalol‐induced up‐regulation of DR5, indicating that the effect depended on JNK activation. Furthermore, the down‐regulation of induced myeloid leukaemia cell differentiation protein (Mcl‐1) played an important role in vernodalol/TRAIL‐induced apoptosis, as Mcl‐1 overexpression prevented this apoptotic effect. Moreover, the vernodalol/TRAIL combination inhibited tumor growth in a xenograft model. Based on our results, vernodalol enhanced TRAIL‐induced apoptosis by down‐regulating Mcl‐1 and up‐regulating DR5, and the effects of DR5 depended on JNK activation and CHOP induction. Therefore, combining TRAIL with vernodalol, a naturally occurring agent, may represent a promising therapeutic approach for DLBCL.