Hongming Zhu

Mutations of Epigenetic Modifier Genes as a Poor Prognostic Factor in Acute Promyelocytic Leukemia Under Treatment With All-Trans Retinoic Acid and Arsenic Trioxide

Background Acute promyelocytic leukemia (APL) is a model for synergistic target cancer therapy using all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which yields a very high 5-year overall survival (OS) rate of 85 to 90%. Nevertheless, about 15% of APL patients still get early death or relapse. We performed this study to address the possible impact of additional gene mutations on the outcome of APL. Methods We included a consecutive series of 266 cases as training group, and then validated the results in a testing group of 269 patients to investigate the potential prognostic gene mutations, including FLT3-ITD or -TKD, N-RAS, C-KIT, NPM1, CEPBA, WT1, ASXL1, DNMT3A, MLL (fusions and PTD), IDH1, IDH2 and TET2. Results More high-risk patients (50.4%) carried additional mutations, as compared with intermediate- and low-risk ones. The mutations of epigenetic modifier genes were associated with poor prognosis in terms of disease-free survival in both training (HR = 6.761, 95% CI 2.179–20.984; P = 0.001) and validation (HR = 4.026, 95% CI 1.089–14.878; P = 0.037) groups. Sanz risk stratification was associated with CR induction and OS. Conclusion In an era of ATRA/ATO treatment, both molecular markers and clinical parameter based stratification systems should be used as prognostic factors for APL.

The 12-year follow-up of survival, chronic adverse effects, and retention of arsenic in patients with acute promyelocytic leukemia

To the editor: Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) have demonstrated notable success in the treatment of acute promyelocytic leukemia (APL).[1][1][⇓][2]-[3][3] However, few studies have reported the adverse effects (AEs), long-term toxicity, and secondary carcinogenesis of

Progress in the treatment of acute promyelocytic leukemia: optimization and obstruction

The past three decades have witnessed a great progress in the treatment of acute promyelocytic leukemia (APL). The current application of all-trans retinoic acid, arsenic trioxide (ATO), and anthracycline-based chemotherapies has been proved to be highly effective. Based on the risk factors of APL, optimization of the treatment emphasizes the role of ATO in induction, consolidation and maintenance therapy as a substitute to chemotherapy in low- and intermediate-risk patients, and in potential reduction of chemotherapy in high-risk group without impact on the outcome. However, early death and relapse remain obstacles to further improvement of the rates of remission and long-term survival, and the acute and chronic adverse effects of ATO should be considered for more appropriate management. Efforts should be made to more rationally obtain improved outcomes through the use of less toxic regimens.

All-trans retinoic acid and arsenic combination therapy benefits low-to-intermediate-risk patients with newly diagnosed acute promyelocytic leukaemia: a long-term follow-up based on multivariate analysis

All-trans retinoic acid (ATRA) and chemotherapy have enabled great improvements in the treatment of acute promyelocytic leukaemia (APL). High initial white blood cell (WBC) and low platelet counts are generally considered as independent risk factors for APL (Sanz et al, 2000). However, the relapse rate has been reported to be as high as 5–30% (Tallman, 2007). In 2001, a pilot clinical trial was held at Shanghai Institute of Haematology to treat APL with ATRA and arsenic combination therapy (Shen et al, 2004), and the 5-year follow-up (Hu et al, 2009) showed high efficacy. Since then, this approach has been shown not to be inferior to or even better than ATRA and chemotherapy. In the present study, we updated the follow-up to clarify the long-term survival and the risk factors in APL patients when using the ATRA and arsenic combination therapy. Between February 2001 and July 2010, 217 newly diagnosed APL patients were included in this study. Informed consent was obtained in all patients. The criteria for diagnosis, cytogenetic analysis and molecular tests for PML-RARA transcripts were performed as previously described (Shen et al, 2004), together with the treatment protocol (Table SI). Briefly, for induction therapy, all patients received ATRA and arsenic until documented complete remission (CR). Idarubicin (IDA) was given in case of high-risk patients. Three courses of consolidation therapy followed induction. The maintenance therapy consisted of 5 cycles of sequential use of ATRA, arsenic and low-dose chemotherapy (6-mercaptop-

Influence of body mass index on incidence and prognosis of acute myeloid leukemia and acute promyelocytic leukemia: A meta-analysis

Previous studies have demonstrated an association between high body mass index (BMI) and acute myeloid leukemias (AML), particularly acute promyelocytic leukemia (APL). However, the effect of obesity and overweight on the incidence of AML is not supported by all studies, and the relationship between obesity and prognosis of AML and APL has not been established. Thus, we conducted a meta-analysis to determine the role of BMI on the risk and clinical outcome of AML, including APL. Twenty-six eligible studies enrolling 12,971 AML (including 866 APL) patients were retrieved and analyzed. Overweight and obesity was associated with an increased incidence of AML (relative risk [RR], 1.23; 95% confidence interval [CI], 1.12–1.35; P < 0.001). High BMI did not significantly affect overall survival (OS) (hazard ratio [HR], 0.97; 95% CI, 0.92–1.03; P = 0.323) or disease-free survival (HR, 0.98; 95% CI, 0.88–1.10; P = 0.755) in patients with non-APL AML. By contrast, APL patients with high BMI had shorter OS (HR, 1.77; 95% CI, 1.26–2.48; P = 0.001) and a higher risk of differentiation syndrome (HR, 1.53; 95% CI, 1.03–2.27, P = 0.04). Overall, our findings suggest that patients with overweight or obesity have a higher incidence of AML, and high BMI is a predictor of adverse clinical outcomes in APL.

Arsenic trioxide at conventional dosage does not aggravate hemorrhage in the first-line treatment of adult acute promyelocytic leukemia

The arsenic trioxide (ATO) plus all‐trans retinoic acid (ATRA) therapy has demonstrated a tremendous success in the first‐line treatment of acute promyelocytic leukemia (APL). Actually, early death (ED) is currently thought as a major challenge in APL. ATO has been reported to inhibit platelet function in vitro, and whether it increases the ED rate by exacerbating the hemorrhagic symptoms remains to be investigated.

The severe cytokine release syndrome in phase I trials of CD19-CAR-T cell therapy: a systematic review

CD19 chimeric antigen receptor (CAR) T cell therapy has shown impressive results in treating acute lymphoblastic leukemia (B-ALL), chronic lymphoblastic leukemia (B-CLL), and B-cell non-Hodgkin lymphoma (B-NHL) over the past few years. Meanwhile, the cytokine release syndrome (CRS), which could be moderate or even life-threatening, has emerged as the most significant adverse effect in the clinical course of this novel targeting immunotherapy. In this systematic review, we analyzed the incidence of severe CRS in 19 clinical trials selected from studies published between 2010 and 2017. The pooled severe CRS proportion was 29.3% (95% confidence interval [CI] 12.3–49.1%) in B-ALL, 38.8% (95%CI 12.9–67.6%) in B-CLL, and 19.8% (95%CI 4.2–40.8%) in B-NHL. In the univariate meta regression analysis, the proliferation of CD19-CAR-T cell in vivo was correlated with the severe CRS. Specifically, total infusion cell dose contributed to the severe CRS occurring in B-ALL patients but not in B-CLL or B-NHL patients. Tumor burden was strongly associated with the severity of CRS in B-ALL. Besides, post-HSCT CD19 CAR-T cell infusion represented lower severe CRS incidence. Further investigations into the risk factors of CRS in B-CLL and B-NHL are needed.

Risk of Onset of Hematological Malignancies in Patients Infected with the Hepatitis B Virus: Results from a Large-Scale Retrospective Cohort Study in China

The hepatitis B virus (HBV) is a major global issue, because an increased risk of hepatocellular carcinoma among patients infected with HBV is well established. Recently, it has been suggested that HBV is associated with other human cancers. However, the association between HBV and the risk of onset of hematological malignancies remains controversial. The aim of this large-scale retrospective cohort study was to evaluate the association between HBV infection and hematological malignancies. A retrospective analysis of 86,115 newly admitted patients at Shanghai Ruijin Hospital was performed. A cohort of patients previously exposed to HBV (n = 1,874) and a cohort of individuals without a positive test for anti-hepatitis B core antigen (anti-HBc; n = 45,118) were compared to assess the risk of hematological malignancies. Anti-HBc was positive in 61.2% cases and 54.3% controls (p = 0.0001). The risk of B cell non-Hodgkins lymphoma, acute lymphoblastic leukemia, and multiple myeloma was higher in the HBV-infected cohort than in the non-HBV-infected cohort. In conclusion, patients infected with HBV have a substantially increased risk of hematological malignancies.

The Time to Clearance of Peripheral Blood Blasts Predicts Complete Remission and Survival in Chinese Adults with Acute Myeloid Leukemia

The value of clearance of peripheral blood blasts (PBB) as a predictor of outcomes in acute myeloid leukemia (AML) is controversial. To investigate the prognostic significance of the time to clearance of PBB after induction in Chinese patients with AML, a retrospective analysis of 146 patients with newly diagnosed AML at Shanghai Ruijin Hospital was performed. Patients were categorized into early blast clearance (EBC; ≤5 days) and delayed blast clearance (DBC; >5 days) groups based on a receiver operating characteristic analysis. Complete remission (CR) after induction chemotherapy was related to the time to clearance of PBB (p < 0.001). Relapse-free survival (RFS; p = 0.003) and overall survival (p < 0.001) were longer in the EBC group. Multivariate analysis demonstrated that the time to clearance of PBB and cytogenetic risk independently predicted CR and RFS. Early clearance of PBB after induction chemotherapy can be a significant predictor of survival outcomes in AML patients.