Jieping Chen

Effect of adding gemtuzumab ozogamicin to induction chemotherapy for newly diagnosed acute myeloid leukemia: a meta-analysis of prospective randomized phase III trials

BACKGROUND Gemtuzumab ozogamicin (GO) is a targeted antineoplastic agent comprised of a recombinant anti-CD33 humanized antibody linked to calicheamicin. Previous trials have showed conflicting results concerning the efficacy and toxicity of adding GO to induction chemotherapy for newly diagnosed acute myeloid leukemia (AML). A systematic review and meta-analysis was conducted to resolve this controversial issue. PATIENTS AND METHODS Summary data from five randomized phase III trials compared adding GO to induction chemotherapy with induction chemotherapy alone for newly diagnosed AML were meta-analyzed. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and relapse-free survival (RFS), and pooled odds ratios (ORs) and 95% CIs for complete remission (CR) rate, incidences of resistance disease, relapse and toxicity were calculated. RESULTS Data of 3596 patients (1798 GO and 1798 controls) from five randomized phase III trials were analyzed. Compared with induction chemotherapy alone, adding GO significantly prolonged OS (HR 0.93, 95% CI 0.86-1.00, P=0.05) and RFS (HR 0.87, 95% CI 0.79-0.95, P=0.003), decreased the incidences of resistant disease (OR 0.71, 95% CI 0.55-0.93, P=0.01) and relapse (OR 0.75, 95% CI 0.63-0.90, P=0.002), but had no effect on CR rate (OR 1.15, 95% CI 0.91-1.46, P=0.24). Sensitivity analysis yielded similar results. Subgroup analysis identified that cytogenetics might be an influencing factor for the effect of adding GO. In addition, the risks of grade 3-4 nausea/vomiting, diarrhea and liver aspartate transaminase (AST) elevation were increased in GO arm. CONCLUSIONS Adding GO to induction chemotherapy for newly diagnosed AML can significantly prolong OS and RFS, decrease incidences of resistant disease and relapse, but may increase risks of grade 3-4 nausea/vomiting, diarrhea and liver AST elevation.

Blastic Plasmacytoid Dendritic Cell Neoplasm

A 20-year-old man was admitted to our facility (Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, People’s Republic of China) in December 2008 for an evaluation of skin nodules. Four months before presentation, the patient had noted a nodule on his right thigh that was increasing in bulk; also, additional nodules were beginning to appear. On examination, the skin lesions were observed to be predominantly nodules, in association with several plaques, and were distributed over the trunk and limbs. The majority of the nodules ranged from 1 to 3 cm in diameter, and the temperature of the skin lesions was normal. Skin pigmentation varied between pale and deep red coloration (Figs 1A and 1B). No palpable swelling in the superficial lymph nodes or signs of tenderness in the sternum were detected. The liver and spleen were not palpable. The CBC was normal. The bone marrow was normal on examination. A computed tomography scan of the chest and abdomen revealed no enlarged lymph nodes in the mediastinum or retroperitoneum. Full-layer skin biopsies of the chest and back were undertaken. Images with hematoxylin and eosin staining showed confertim lymphoid tumor cells distributed along the dermal collagen fibers (Fig 2A), some with light staining in the cytoplasm, and others with large, deeply stained nuclei (Fig 2B). Immunohistochemistry was performed using the immunoperoxidase method. The results showed positive CD4 (staining in cytoplasm, Fig 3A), CD34, CD43, CD56 (staining on membrane; Fig 3B), and CD99, a percentage of Ki67-positive cells larger than 50%, negative CD3, CD20, CD57, terminal deoxynucleotidyl transferase (Fig 3C), ALK, epithelial membrane antigen, myeloperoxidase (Fig 3D) and CD79a, and analyses suggested positive results for the presence of lysosome. Considering these findings, the patient fulfilled the requirements for the diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN). After chemotherapy with etoposide, cyclophosphamide, vincristine, prednisone,andmethotrexatewasadministered,thenodulesdecreasedin sizetemporarily,butresurgedto3cmindiameter2weeks later.Changing thechemotherapeuticregimentomitoxantrone,cyclophosphamide,vincristine, and dexamethasone did not result in an obvious decrease in the number and size of the skin nodules, some of which even increased to approximately4cmindiameter.Thepatient laterreceivedchemotherapy (programunknown) in another hospital without an obvious effect and died soon after, in May 2009.

Variation in Dicer Gene Is Associated with Increased Survival in T-Cell Lymphoma

Dicer, an endonuclease in RNase III family, is essential for the RNA interference (RNAi) pathway. Aberrant expression of Dicer has been shown in various cancers including some subtypes of T cell lymphoma (TCL), which influences patient prognosis. A single-nucleotide polymorphism (SNP) rs3742330A>G has been identified in the Dicer gene, located in the 3′ untranslated region (3′ UTR) that is important for mRNA transcript stability. We investigated whether rs3742330 is associated with the survival in 163 TCL patients. Significant association between Dicer rs3742330 and TCL survival were found. Patients carrying the GG genotype (n = 12) had a significantly increased overall survival (OS) compared with those carrying the GA and AA genotypes (n = 70 and n = 81, respectively; p = 0.031). Moreover, the significant association was maintained for patients with mature T type (n = 134; p = 0.026). In multivariate Cox-regression analysis, rs3742330 proved to be an independent predictor for OS, together with the commonly used International Prognostic Index (IPI) and BAFF rs9514828, another SNP we have previously reported to be associated with TCL survival, with hazard ratios (HRs) for patient death rate of 8.956 (95% CI, 1.210 to 66.318; p = 0.032) for the GA genotype and 10.145 (95% CI, 1.371 to 75.084; p = 0.023) for the AA genotype. Furthermore, we observed cumulative effects of Dicer rs3742330 and BAFF rs9514828 on TCL survival. Compared with patients carrying zero unfavorable genotype, those carrying one and two unfavorable genotypes had an increased risk of death with a HR of 7.104 (95% CI, 0.969–53.086; p = 0.054) and 14.932 (95% CI, 1.950–114.354; p = 0.009), respectively, with a significant dose-response trend (ptrend  = 0.004). In conclusion, Dicer rs3742330 is associated with TCL survival, suggesting that genetic variation might play a role in predicting prognosis of TCL patients.

Polymorphisms in MicroRNA-Related Genes Are Associated With Survival of Patients With T-Cell Lymphoma

OBJECTIVE Elaborate evaluation of prognosis of T-cell lymphoma (TCL) is vital for current therapy and future stratified and individualized therapy. MicroRNAs (miRNAs) play important roles in cancer development and prognosis. We aimed to assess the effects of single nucleotide polymorphisms (SNPs) in miRNA-related genes on the survival of patients with TCL. PATIENTS AND METHODS We genotyped 13 SNPs selected from 12 miRNA-related genes in 220 TCL patients and explored the association of SNPs with survival. RESULTS Among the 13 SNPs, four (DROSHA rs6877842, DICER rs3742330, mir149 rs2292832, and mir499 rs3746444) were significantly associated with TCL survival after adjusting for subtype and International Prognostic Index score. In stratified analyses, all four SNPs remained significantly associated with survival in patients with mature T type. Of the four SNPs, only mir149 rs2292832 was not significantly associated with survival in patients with an International Prognostic Index score of 0-1. Furthermore, a dose-dependent cumulative effect of the four SNPs on TCL survival was observed by counting the number of unfavorable genotypes. Survival tree analysis also showed higher order interactions between these SNPs. CONCLUSION The results suggested that miRNA-related polymorphisms are associated with survival of TCL patients; thus, they may be used individually and jointly to predict survival of patients with TCL.

Cytokine BAFF Gene Variation Is Associated with Survival of Patients with T-cell Lymphomas

Purpose: Cytokine BAFF is a potent molecule for the activation and survival of B cells, and it also plays an important role in T-cell function. Genetic polymorphism (rs9514828C>T) in BAFF has been associated with elevated BAFF transcription. We sought to determine whether rs9514828 is associated with T-cell lymphoma (TCL) survival. Experimental Design: BAFF rs9514828 genotypes and survival of TCL were analyzed in the discovery group including 150 patients, and the results were replicated in an independent validation group of 120 patients. Kaplan–Meier analysis was conducted to compare survival among different genotypes. Cox proportional hazard models were used to identify independent significant variables. Luciferase reporter gene assays were conducted to examine the function of rs9514828 variant. Results: We found that BAFF rs9514828 polymorphism was significantly associated with TCL survival. In pooled analysis of two independent groups, the favorable rs9514828 TC and TT genotypes had significantly better five-year survival rates compared with the CC genotype (47% and 53% vs. 22%, P = 2.27 × 10−5 for log-rank test). Multivariate Cox regression analysis showed that rs9514828 was an independent prognostic factor, with HRs for patient death being 0.48 [95% confidence interval (CI), 0.32–0.71] for the CT and 0.47 (95% CI, 0.23–0.93) for the TT genotypes. Reporter gene assays indicated that the rs9514828T allele had significantly higher promoter activity than the rs9514828C counterpart. Conclusion: These findings suggest that functional polymorphism in BAFF might be a genetic determinant for the survival of patients with TCL. Clin Cancer Res; 18(8); 2250–6. ©2012 AACR.

High Doses of Daunorubicin during Induction Therapy of Newly Diagnosed Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis of Prospective Clinical Trials.

The right dose of daunorubicin (DNR) for the treatment of newly diagnosed acute myeloid leukemia (AML) is uncertain. Previous trials have shown conflicting results concerning the efficacy of high or low doses of daunorubicin to induction chemotherapy for newly diagnosed AML. A systematic review and meta-analysis was conducted to resolve this controversial issue. We compared the efficacy and safety of high doses of daunorubicin (HD-DNR) and traditional low doses of daunorubicin (LD-DNR) or idarubicin (IDA) during induction therapy of newly diagnosed AML. Data of 3,824 patients from 1,796 articles in the literature were retrieved and six randomized controlled trials were analyzed. The primary outcomes were overall survival (OS), disease-free survival (DFS), and event-free survival (EFS). The secondary outcomes included complete remission (CR), relapse, and toxicity. The meta-analysis results suggest that comparing HD-DNR with LD-DNR, there were significant differences in CR (RR = 1.19, 95%CI[1.12,1.18], p<0.00001), OS(HR = 0.88, 95%CI[0.79,0.99], p = 0.002), and EFS (HR = 0.86, 95%CI [0.74, 1.00], p = 0.008), but not in DFS, relapse, and toxicity. There were no statistically significant differences in any other outcomes between HD-DNR and IDA. The analysis indicates that compared with LD-DNR, HD-DNR can significantly improve CR, OS and EFS but not DFS, and did not increase occurrence of relapse and toxicity.

Risk of genome-wide association study-identified genetic variants for non-Hodgkin lymphoma in a Chinese population

Recent genome-wide association studies have identified 15 single nucleotide polymorphisms (SNPs) associated with non-Hodgkin lymphoma (NHL) and its subtypes. Because the incidence and subtype portion of NHL between the Chinese population and Caucasian populations are substantially different, we assessed the associations of these SNPs with NHL risk in a case-control study consisting of 792 cases and 1542 controls derived from the Chinese population. Odds ratios (OR) and 95% confidence intervals (CI) were computed by logistic regression. False-positive report probability was also assessed for significant findings. We found that the allele frequencies of the 15 SNPs in our study population significantly differed from those in Caucasian populations, with rs13397985, rs735665 and rs11083846 being extremely rare in Chinese. Only two variants (rs872071 in IRF4 and rs2647012 in HLA class II) were significantly associated with NHL risk in Chinese, with the ORs of 1.20 (95% CI, 1.05-1.38; P = 0.009) and 1.20 (95% CI, 1.03-1.39; P = 0.018) for per allele of rs872071 and rs2647012, respectively, calculated using an additive model. These results indicate a substantial different genetic background for susceptibility to NHL among the different ethnic populations.

Aberrant DNA methylation of acute myeloid leukemia and colorectal cancer in a Chinese pedigree with a MLL3 germline mutation.

Unlike genetic aberrations, epigenetic alterations do not modify the deoxyribonucleic acid (DNA) coding sequence and can be reversed pharmacologically. Identifying a particular epigenetic alteration such as abnormal DNA methylation may provide better understanding of cancers and improve current therapy. In a Chinese pedigree with colorectal carcinoma and acute myeloid leukemia, we examined the genome-wide DNA methylation level of cases and explored the role of methylation in pathogenesis and progression. DNA methylation status in the four cases, which all harbor a MLL3 germline mutation, differed from that of the normal control, and hypermethylation was more prevalent. Also, more CpG sites were hypermethylated in the acute-phase AML patient than in the AML patient in remission. Fifty-nine hyper- or hypomethylated genes were identified as common to all four cases. Genome-wide DNA methylation analysis demonstrated that differentially methylated sites among acute myeloid leukemia and colorectal carcinoma cases and the control were in both promoters (CpG island) and gene body regions (shelf/shore areas). Hypermethylation was more prevalent in cancer cases. The study supports the suggestion that the level of DNA methylation changes in AML progression.

Genetic polymorphisms of NAT2 and risk of acute myeloid leukemia: A case-control study

Abstract Our purpose was to investigate the possible associations between N-acetyltransferase-2 (NAT2) gene polymorphisms and the risk of acute myeloid leukemia (AML) in Chinese Han population. A case-control study was conducted including 98 AML cases and 112 healthy controls. NAT2 gene 2 polymorphisms rs1799930 and rs1799931 were genotyped using direct sequencing. Chi-square test was performed to compare the genotype and allele distribution differences between groups. Odds ratio (OR) with 95% confidence interval (CI) was calculated to estimate the association between NAT2 gene polymorphisms and AML onset. A remarkable decrease trend of rs1799931 GA genotype was detected in AML patients compared with controls, whereas the ancestral GG genotype frequency increased in cases (P < .05). And the mutant A allele of rs1799931 significantly reduced the risk of AML by 0.585-fold versus the ancestral G allele carriers (OR = 0.585, 95% CI = 0.361–0.950). But the distributions of rs1799930 genotype and allele were similar between groups (P > .05). Our findings suggested that NAT2 gene polymorphism rs1799931 was associated with decreased risk of AML and was likely to be a protective factor against AML development.

Prognostic Factors of Lymphoma Patients after Autologous Stem Cell Transplantation

UNLABELLED BacKGROUND: Hematopoietic stem cell transplantation (HSCT) is considered to be a cure for lymphoma. However, factors related to its prognosis remain unclear. MATERIAL AND METHODS Eighty patients diagnosed with lymphoma and treated with autologous HSCT (Auto HSCT) were recruited. The primary endpoints included overall survival (OS) and progression-free survival (PFS). RESULTS After a median follow-up of 37.9 months, the 3-year OS was 75%. Univariate analysis showed age (P=0.020), elevated lactate dehydrogenase (LDH) (P=0.031), international prognostic index (IPI) (P=0.015), Eastern Cooperative Oncology Group (ECOG) (P=0.048), bone marrow involvement (P=0.038), and time to neutrophil recovery (P=0.043) were prognostic factors of lymphoma. Multivariate analysis revealed IPI (hazard ratio [HR] 1.60, 95% confidence interval [CI] 1.09-2.34, P=0.016) and time to neutrophil recovery (HR 2.69, 95% CI 1.02-7.07, P=0.045) were independent factors correlated with OS. CONCLUSIONS IPI and neutrophil recovery are recommendatory predictors for lymphoma patients after Auto HSCT.