Wenjuan Yu

Prognostic factors of patients with newly diagnosed acute promyelocytic leukemia treated with arsenic trioxide-based frontline therapy

Prognostic factors for patients with acute promyelocytic leukemia (APL) treated in the context of arsenic trioxide (ATO)-based frontline regimes have not been established clearly. We retrospectively analyzed the clinical features, immunophenotypes, Fms-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD), and outcomes of 184 consecutive newly diagnosed APL patients treated by intravenous ATO-based therapy. The median age was 40 years (14-77 years). The early death rate was 4.9% (9/184 patients). With a median follow-up time of 36 months (9-74 months), the 3-year relapse-free survival (RFS) and overall survival (OS) were 93.3% and 92.2%, respectively. Interestingly, there was no meaningful association between 3-year RFS and initial white blood cell count, FLT3-ITD status, or type of PML-RARA isoforms. In multivariable analysis, the CD56 expression was the only independent risk factor in terms of RFS (hazard ratio, 4.70; P=0.005). These results suggested that ATO-based therapy may ameliorate the unfavorable influence of previously known high-risk features; moreover, CD56 expression remains to be a potentially unfavorable prognostic factor in APL patients.

Therapeutic experience of adult acute myeloid leukemia in a single institution of China and its relationship with chromosome karyotype

One hundred and ninety-six untreated de novo acute myeloid leukemia (AML) patients were treated with homoharringtonine + cytosine arabinoside (HA) based induction therapy composed of three chemotherapeutic drugs (HAD/M, D-daunorubicin-DNR, M-mitozantrone-MTZ) used in our hospital for the past 12 years. The patient population was relatively young (median age 37, oldest patient 67), and patients were excluded if they had prior MDS or prior chemotherapy or radiotherapy. Complete remission (CR) rate, disease free survival (DFS) and overall survival (OS) of the patients were calculated. One hundred and fifty-three patients who had karyotype results were divided into four groups according to Southwestern Oncology Group (SWOG) criteria. Differences of CR rate, DFS and OS of different groups were evaluated. The CR rate of all 196 cases was 153/196 (78.1%), and 95.3% of these were within 1 – 2 courses. Median DFS of the 153 CR patients was 23.8 (range from 1.0 to 153) months. DFS rates at 3 years and 5 years were 41.1% and 35.9%, respectively. The median OS of 196 patients was 19.3 (0.5 – 154) months. The probabilities of 3-year and 5-year OS were 31.5% and 29.2%, respectively. CR rate, DFS and OS of the different cytogenetic risk groups were also be analyzed. According to SWOG criteria, patients were classified into favorable, intermediate, adverse and unknown (a group where the meaning of chromosomes are unclear) groups. CR rate, median DFS and OS were 91.9%, 90.8 months and 94.4 months for the favorable group; 86.4%, 22.0 months and 22.8 months for the intermediate group; 59.4%, 9 months and 10.5 months for the adverse group; 76.0%, 22.0 months, 16.1 months for the unknown group, respectively. The differences among the four groups were statistically significant (P = 0.001, 0.0033, 0.0001). We conclude that triple-drugs induction regimens based on HA (HAD/M) are highly effective in adult AML in China. Cytogenetics is the important prognostic factor. SWOG karyotype subtyping criteria was appropriate for our patients, the prognosis of the unknown group was similar to that of the intermediate group.

The risk of hepatitis B virus reactivation and the role of antiviral prophylaxis in hepatitis B surface antigen negative/hepatitis B core antibody positive patients with diffuse large B-cell lymphoma receiving rituximab-based chemotherapy.

Abstract The risk factors and the role of prophylactic antiviral therapy of hepatitis B virus (HBV) reactivation in patients with hepatitis B surface antigen (HBsAg) negative/hepatitis B core antibody (HBcAb) positive disease remain controversial. We reviewed 629 patients with diffuse large B-cell lymphoma (DLBCL). Among 629 patients, 150 of 246 patients with resolved HBV (HBsAg negative and HBcAb positive) were treated with rituximab-combined therapy. Among these 150 patients, none of 104 patients (0.0%) who were hepatitis B surface antibody (HBsAb) positive experienced HBV reactivation versus four of 46 patients (8.7%) who were HBsAb negative (p = 0.008). One of 113 patients (0.9%) with International Prognostic Index (IPI) 0–2 suffered HBV reactivation versus three of the remaining 37 patients (8.1%) with IPI 3–5 (p = 0.047). HBsAb and IPI are potential risk factors for HBV reactivation. The use of prophylactic agents may not be recommended for these patients until the occurrence of HBV reactivation.

Epigenetic priming with decitabine followed by low-dose idarubicin/cytarabine has an increased anti-leukemic effect compared to traditional chemotherapy in high-risk myeloid neoplasms

Abstract Decitabine (DAC) is commonly used for the treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Previous studies have indicated DAC sequentially combined with idarubicin was an effective treatment for myeloid neoplasms. Therefore, a clinical study was conducted of the sequential combination of DAC followed by low-dose idarubicin/cytarabine in high-risk myeloid neoplasms. A total of 30 patients with a diagnosis of high-risk MDS, AML evolving from MDS or relapsed/refractory AML were enrolled in the study. DAC was administered 20 mg/m2 daily for 3 consecutive days. Idarubicin (3 mg/m2/day) was administered 24 h after the last administration of DAC for 5–7 consecutive days, combined with cytarabine (30 mg/m2/day) for 7–14 days. The overall complete remission rate was 66.67%. The results demonstrate that epigenetic priming with decitabine followed by low-dose idarubicin/ytarabine has an increased anti-leukemia effect compared to traditional chemotherapy in high-risk myeloid neoplasms.

Low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor priming regimen versus idarubicin plus cytarabine regimen as induction therapy for older patients with acute myeloid leukemia

Abstract With limited data available on the low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor (CAG) regimen in newly diagnosed older patients with acute myeloid leukemia (AML), this study aimed at comparing the efficacy and toxicity of CAG with idarubicin plus cytarabine (IA) remission induction therapy in these patients. A total of 154 consecutive patients (52 with CAG and 102 with IA) were retrospectively analyzed. The patients in the CAG group had a higher median age (68 vs. 65 years, p = 0.002) and a higher proportion of previous myelodysplastic syndrome (25.0% vs. 2.9%, p < 0.0001) compared to those in the IA group. The complete remission rates with the CAG and IA regimens were 55.8% and 52.9% (p = 0.864). The median overall survival (12.1 vs. 11.7 months, p = 0.650) and 3-year disease-free survival rates (29.6% vs. 48.6%, p = 0.657) were not statistically different in the two groups. The CAG regimen might be an alternative to conventional chemotherapy in older patients with AML.

Hypofibrinogenemia as a clue in the presumptive diagnosis of acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a medical emergency. In order to evaluate the usefulness of initial coagulation parameters in the predictive value of APL diagnosis, 1304 consecutive newly diagnosed acute leukemia patients, including APL (n=211), non-APL acute myeloid leukemia (n=781) and acute lymphoblastic leukemia (n=312) were retrospectively evaluated between January 2011 and May 2015. The area under curve (AUC) of fibrinogen was the largest among the coagulation markers based on receiver operating characteristic (ROC) analysis. The optimum cutoff value of fibrinogen was 1.87g/L (AUC=0.912, sensitivity 80.1% and specificity 88.8%). The optimum cutoff value of D-dimer was 2191μg/L (AUC=0.786, sensitivity 81.1% and specificity 67.8%). The AUC difference between the fibrinogen and D-dimer was significant (P<0.001). Other coagulation markers showed less predictive power. Importantly, in the analysis of high white blood cell count (over 10×109/L) subgroup, a low fibrinogen level could efficiently discriminate APL patients from controls (AUC=0.983, sensitivity 96.4% and specificity 94.4%) with a criterion value ≤1.71g/L. Thus, our results suggest that a low fibrinogen level could be a key marker in early prediction of APL diagnosis.

Impact of Chemotherapy Delay on Overall Survival for AML with IDH1/2 Mutations: A Study in Adult Chinese Patients.

The effect of time from diagnosis to treatment (TDT) on overall survival of patients with acute myeloid leukemia (AML) remains obscure. Furthermore, whether chemotherapy delay impacts overall survival (OS) of patients with a special molecular subtype has not been investigated. Here, we enrolled 364 cases of AML to assess the effect of TDT on OS by fractional polynomial regression in the context of clinical parameters and genes of FLT3ITD, NPM1, CEBPA, DNMT3a, and IDH1/2 mutations. Results of the current study show IDH1/2 mutations are associated with older age, M0 morphology, an intermediate cytogenetic risk group, and NPM1 mutations. TDT associates with OS for AML patients in a nonlinear pattern with a J shape. Moreover, adverse effect of delayed treatment on OS was observed in patients with IDH1/2 mutations, but not in those with IDH1/2 wildtype. Therefore, initiating chemotherapy as soon as possible after diagnosis might be a potential strategy to improve OS in AML patients with IDH1/2 mutations.

High Expression of TET1 Predicts Poor Survival in Cytogenetically Normal Acute Myeloid Leukemia From Two Cohorts

Ten-Eleven-Translocation 1 (TET1) plays a role in the DNA methylation process and gene activation. Recent reports suggest TET1 acts as an oncogene in leukemia development. However, the clinical relevance and biological insight of TET1 expression in cytogenetically normal acute myeloid leukemia (CN-AML) is unknown. In this study, quantification of TET1 transcript by real-time quantitative PCR in bone marrow blasts was performed in 360 CN-AML patients. As a result, high TET1 expression was more common in M0/M1 morphology and genes of NPM1 mutations, and underrepresented in CEBPA double allele mutations in our AML patients. In addition, we found overexpression of TET1 was associated with an inferior overall survival and event free survival in the two independent cohorts. Notably, mRNA and miRNA integrative analyses showed aberrant expression of several hub oncogenes appear to be regulated by some miRNAs like miR-127-5p, miR-494, miR-21 and miR-616 in high TET1 expressers. In conclusion, the TET1 gene expression might serve as a reliable predictor for patients survival in AML.

Clinical and biological characteristics of acute myeloid leukemia with 20–29% blasts: a retrospective single-center study

Abstract It is controversial whether acute myeloid leukemia (AML) patients with 20–29% bone marrow (BM) blasts should be considered AML or myelodysplastic syndromes (MDS). We retrospectively studied 382 patients, including 108 AML with 20–29% BM blasts (AML20–29), 210 AML with ≥30% BM blasts (AML ≥ 30), and 64 MDS with 10–19% BM blasts (MDS-EB2). We found that AML20–29 were more similar to MDS-EB2 in terms of advanced age, less blood count, the increased presence of poor-risk cytogenetics. The frequency of mutated genes in AML20–29 had both the characters of AML and MDS. Median overall survival of AML20–29 and MDS-EB2 were similar and shorter than those of AML ≥ 30 (p = .045). Multivariate analysis showed inferior survival with increased age, low platelet count and FLT3 mutations. Our findings suggest that AML20–29 have clinical features more similar to MDS than AML.

Prognostic utility of six mutated genes for older patients with acute myeloid leukemia

Approximately 50% of older patients with acute myeloid leukemia (AML) do not obtain chromosomal abnormalities as an effective risk‐stratification, and present cytogenetically normal AML (CN‐AML). To develop a reliable prediction model for stratifying the risk of these elderly patients, we conducted a study with a discovery and validation design. As a result, we found the top 6 mutated genes in the discovery cohort of 26 case by the whole exome sequencing, and verified as recurrent mutations in the large cohort of 329 patients by Sanger sequencing. The top 6 genes were NPM1, FLT3‐ITD, DNMT3A, CEBPA double allele, IDH1 and IDH2 mutations, and the frequency of each gene in the combining cohort was 36.8%, 19.8%, 20.1%, 5.8%, 14.9% and 22.5%, respectively. In addition, clinical variables such as age, white blood cell counts, genes of IDH1 and DNMT3A mutations, European LeukemiaNet genotype (NPM1 mutations and lacking FLT3‐ITD or CEBPA double allele mutations) and treatment protocols were independent factors for predicting the probabilities of overall and event‐free survival. The prediction nomograms based on these significant factors showed accurate discrimination. In conclusion, we developed a reliable prediction model for stratifying the risk of elderly patients with CN‐AML.