Arsenic trioxide replacing or reducing chemotherapy in consolidation therapy for acute promyelocytic leukemia (APL2012 trial).

As all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are widely accepted in treating acute promyelocytic leukemia (APL), deescalating toxicity becomes a research hotspot. Here, we evaluated whether chemotherapy could be replaced or reduced by ATO in APL patients at different risks. After achieving complete remission with ATRA-ATO-based induction therapy, patients were randomized (1:1) into ATO and non-ATO groups for consolidation: ATRA-ATO versus ATRA-anthracycline for low-/intermediate-risk patients, or ATRA-ATO-anthracycline versus ATRA-anthracycline-cytarabine for high-risk patients. The primary end point was to assess disease-free survival (DFS) at 3 y by a noninferiority margin of -5%; 855 patients were enrolled with a median follow-up of 54.9 mo, and 658 of 755 patients could be evaluated at 3 y. In the ATO group, 96.1% (319/332) achieved 3-y DFS, compared to 92.6% (302/326) in the non-ATO group. The difference was 3.45% (95% CI -0.07 to 6.97), confirming noninferiority (P < 0.001). Using the Kaplan-Meier method, the estimated 7-y DFS was 95.7% (95% CI 93.6 to 97.9) in ATO and 92.6% (95% CI 89.8 to 95.4) in non-ATO groups (P = 0.066). Concerning secondary end points, the 7-y cumulative incidence of relapse (CIR) was significantly lower in ATO (2.2% [95% CI 1.1 to 4.2]) than in non-ATO group (6.1% [95% CI 3.9 to 9.5], P = 0.011). In addition, grade 3 to 4 hematological toxicities were significantly reduced in the ATO group during consolidation. Hence, ATRA-ATO in both chemotherapy-replacing and -reducing settings in consolidation is not inferior to ATRA-chemotherapy (https://www.clinicaltrials.gov/, NCT01987297).

Chemotherapy or Allogeneic Stem Cell Transplantation as Salvage Therapy for Patients with Refractory Acute Myeloid Leukemia: A Multicenter Analysis.

INTRODUCTION: The overall outcome of patients with refractory AML (rAML) remains poor. Though allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered as the only curative therapy, it is routinely recommended only for patients after remission with salvage chemotherapy. OBJECTIVE: In this study, we evaluated the impact of salvage chemotherapy or allo-HSCT on the overall outcome in rAML. METHODS: We collected the clinical data of 220 patients from 4 medical centers and performed retrospective analysis of prognosis factors, including salvage chemotherapy, intensity of chemotherapy, and allo-HSCT. RESULTS: A total of 29 patients received allo-HSCT directly without salvage chemotherapy, 26 patients achieved complete remission (CR) or complete remission with incomplete hematological recovery (CRi) after transplantation and 4-year leukemia-free survival (LFS) and overall survival (OS) were 45.0 ± 10.7 and 51.0 ± 10.6%, respectively. Another 191 patients received salvage chemotherapy and 81 (42.2%) achieved CR or CRi. Thirty-four patients among them underwent subsequent allo-HSCT with 4-year LFS and OS of 46.0 ± 8.8 and 46.2 ± 9.0%. The 4-year LFS and OS in 26 patients who failed to obtain CR or CRi but received allo-HSCT with active disease were 32.9 ± 10.0 and 36.9 ± 10.8%, respectively. For patients who received salvage chemotherapy but not allo-HSCT, few of them became long-term survivors. In multivariate analysis, salvage chemotherapy and the intensity of chemotherapy failed to have significant impact on both OS and LFS. Allo-HSCT was the only prognostic factor for improved OS and LFS in multivariate analysis. CONCLUSIONS: These results indicate the benefit of allo-HSCT in patients with rAML and direct allo-HSCT without salvage chemotherapy could be treatment option.

MiR155 sensitized B-lymphoma cells to anti-PD-L1 antibody via PD-1/PD-L1-mediated lymphoma cell interaction with CD8+T cells.

BACKGROUND: MicroRNAs (miRs) are involved in lymphoma progression by regulating tumor cell interaction with microenvironment. MiR155 is overexpressed in diffuse large B-cell lymphoma (DLBCL) and its biological effect on tumor microenvironment needs to be futher investigated. METHODS: MiR155 was detected by quantitative real-time PCR in patients with newly diagnosed DLBCL. The mechanism of action of miR155 on lymphoma progression and tumor microenvironment was examined in vitro in B-lymphoma cell lines and in vivo in a murine xenograft model. RESULTS: Serum miR155 was significantly elevated, correlated with tumor miR155 expression, and indicated poor disease outcome in DLBCL. MiR155 overexpression was associated with decreased peripheral blood CD8+T cells and inhibition of T-cell receptor signaling. Of note, EBV-positive patients showed higher serum miR155 than EBV-negative patients. In co-culture systems of B-lymphoma cells with immune cells, miR155 induced Fas-mediated apoptosis of CD8+T cells, which could be targeted by anti-PD-1 and anti-PD-L1 antibodies. Moreover, miR155 enhanced lymphoma cell PD-L1 expression, recruited CD8+T cells by PD-1/PD-L1 interaction and inhibited CD8+T cell function via dephosphorylating AKT and ERK. MiR155-induced AKT/ERK inactivation was more obvious in CD8+T cells co-cultured with EBV-infected B-lymphoma cells. In vivo in a murine xenograft model established with subcutaneous injection of A20 cells, PD-L1 blockade particularly retarded miR155-overexpressing tumor growth, consistent with maintenance of CD8+T cells and their function. CONCLUSIONS: As a oncogenic biomarker of B-cell lymphoma, serum miR155 was related to lymphoma progression through modulating PD-1/PD-L1-mediated interaction with CD8+T cells of tumor microenvironment, indicating the sensitivity of B-cell lymphoma to PD-L1 blockade. Also CD8+T cells could be a therapeutic mediator of immune checkpoint inhibitors in treating EBV-associated lymphoid malignancies.

Importance of monitoring arsenic methylation metabolism in acute promyelocytic leukemia patients receiving the treatment of arsenic trioxide.

BACKGROUND: Arsenic trioxide [ATO, inorganic arsenite (iAsIII) in solution] plays an important role in the treatment of acute promyelocytic leukemia (APL). However, the long-term adverse effects (AEs) and the retention of arsenic among APL patients are rarely reported. In this study, we focused on arsenic methylation metabolism and its relationship with chronic hepatic toxicity, as we previously reported, among APL patients who had finished the treatment of ATO. METHODS: A total of 112 de novo APL patients who had completed the ATO-containing treatment were enrolled in the study. Arsenic species [iAsIII, inorganic arsenate (iAsV), and their organic metabolites, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA)] in patients' plasma, urine, hair and nails were detected by high-performance liquid chromatography combined with inductively coupled plasma mass spectrometry (HPLC-ICP-MS). Eighteen single nucleotide polymorphisms (SNPs) of the arsenic (+ 3 oxidative state) methylation transferase (AS3MT) gene, which was known as the main catalyzer for arsenic methylation, were tested with the polymerase chain reaction method. RESULTS: The study showed the metabolic pattern of arsenic in APL patients undergoing and after the treatment of ATO, in terms of total arsenic (TAs) and four species of arsenic. TAs decreased to normal after 6 months since cessation of ATO. But the arsenic speciation demonstrated significantly higher portion of iAsIII in patient's urine (40.08% vs. 1.94%, P < 0.001), hair (29.25% vs. 13.29%, P = 0.002) and nails (30.21% vs. 13.64%, P = 0.003) than the healthy controls', indicating a decreased capacity of arsenic methylation metabolism after the treatment of ATO. Urine primary methylation index (PMI) was significantly lower in patients with both chronic liver dysfunction (0.14 vs. 0.28, P = 0.047) and hepatic steatosis (0.19 vs. 0.3, P = 0.027), suggesting that insufficient methylation of arsenic might be related to chronic liver disorders. Two SNPs (A9749G and A27215G) of the AS3MT gene were associated with impaired urine secondary methylation index (SMI). CONCLUSIONS: The long-term follow-up of arsenic speciation indicated a decreased arsenic methylation metabolism and a probable relationship with chronic hepatic disorders among APL patients after the cessation of ATO. Urine PMI could be a monitoring index for chronic AEs of ATO, and the SNPs of AS3MT gene should be considered when determining the dosage of ATO.

Transarterial chemoembolization extends long-term survival in patients with unresectable hepatocellular carcinoma.

The long-term survival benefit of treating unresectable hepatocellular carcinoma (HCC) patients with transarterial chemoembolization (TACE) rather than conservative treatment remains controversial. This retrospective case-control study evaluated the survival of patients with unresectable HCC treated with TACE, relative to that of patients who received best supportive care.From January 2002 to December 2010, 522 of 2386 consecutive patients with unresectable HCC were enrolled. Patients were treated with TACE (n = 347) or best supportive care (non-TACE; n = 175). A survival analysis compared the survival of the 2 groups, as well as only those at Barcelona Clinic Liver Cancer Classification (BCLC)-C and Child-Pugh-B (39 TACE, 61 non-TACE).The median follow-up was 5 months (0.15-106 months).The overall median survival of the TACE group (8.0 months) was significantly longer than that of the non-TACE (2.0 months; P ≤ .01). Of the patients at BCLC-C and Child-Pugh-B, the overall median survivals of the TACE and non-TACE patients were 6.0 and 2.0 months, respectively (P ≤ .01); and the 1, 2, 3, 5, and 8-year overall survival rates were significantly superior in the TACE group (P ≤ .01). For all the patients, the independent predictors of survival were treatment modalities, portal vein tumor thrombosis, alpha-fetoprotein, and BCLC stage. Regarding the TACE patients, contributors to prognosis were portal vein tumor thrombosis, alpha-fetoprotein level, and the number of TACE procedures.TACE for unresectable HCC was associated with longer survival compared with best supportive care, especially for patients at BCLC-C and Child-Pugh-B.

MiR21 sensitized B-lymphoma cells to ABT-199 via ICOS/ICOSL-mediated interaction of Treg cells with endothelial cells.

BACKGROUND: MicroRNAs (miRs) are involved in tumor progression by regulating tumor cells and tumor microenvironment. MiR21 is overexpressed in diffuse large B-cell lymphoma (DLBCL) and its biological impact on tumor microenvironment remains unclear. METHODS: MiR21 was assessed by quantitative RT-PCR in patients with newly diagnosed DLBCL. The mechanism of action of miR21 on lymphoma progression and tumor angiogenesis was examined in vitro in B-lymphoma cell lines and in vivo in a murine xenograft model. RESULTS: Serum miR21 was significantly elevated in patients and associated with advanced disease stage, International Prognostic Index indicating intermediate-high and high-risk, and increased tumor angiogenesis. When co-cultured with immune cells and endothelial cells, miR21-overexpressing B-lymphoma cells were resistant to chemotherapeutic agents, but sensitive to Bcl-2 inhibitor ABT-199, irrespective of Bcl-2 expression on lymphoma cells. In both co-culture systems of Bcl-2positive and Bcl-2negative B-lymphoma cells, miR21 induced inducible co-stimulator (ICOS) expression on regulatory T (Treg) cells. Through crosstalking with Treg cells by ICOS ligand (ICOSL), endothelial cells were activated, resulting in stimulation of Bcl-2 expression and vessel formation. ABT-199 directly targeted Bcl-2 on endothelial cells, induced endothelial cell apoptosis and inhibited tumor angiogenesis. In a murine xenograft model established with subcutaneous injection of B-lymphoma cells, ABT-199 particularly retarded the growth of miR21-overexpressing tumors, consistent with the induction of endothelial cell apoptosis and inhibition of tumor angiogenesis. CONCLUSIONS: As a serum oncogenic biomarker of B-cell lymphoma, miR21 indicated B-lymphoma cell sensitivity to ABT-199 via ICOS/ICOSL-mediated interaction of Treg cells with endothelial cells.

[Prognostic factors analysis for R-CHOP regimen therapy in diffuse large B cell lymphoma].

OBJECTIVE: To reassess the prognostic factors of diffuse large B cell lymphoma (DLBCL) treated with R-CHOP therapy. METHODS: One hundred and twenty five patients were enrolled in this study from Feb. 2000 to Sep. 2006. They received 6 courses of R-CHOP regimen consisting of rituximab 375 mg/ m2, intravenously, d 1; cyclophosphamide 750 mg/m2, bolus intravenously, d 2; doxorubicin 50 mg/m2, bolus intravenously, d 2; vincristine 1.4 mg/m2, bolus intravenously, d 2 and prednisone 60 mg, orally, d 2 - 6. All the patients were evaluated and followed up after the treatment. RESULTS: Eighty six patients (68.8%) achieved complete response (CR), 16 (12.8%) partial response (PR), 11 (12.8%) stable disease (SD) and 12 (9.6%) progressive disease (PD). In univariate analysis, performance status (PS), clinical stage, LDH level, extranodal disease, international prognostic index (IPI) and bulky disease were statistically significantly correlated with the induction of CR; however, only PS, clinical stage and bulky disease remained significant in multi-variate analysis (P = 0.0098, 0.000 and 0.004, respectively). Twenty four month for time to treatment failure (TTF) rate, overall survival (OS) rate, and disease free survival (DFS) rate was (59.7 +/- 5. 3)%, (67.1 +/- 5.6)% and (77.6 +/- 5.8)%, respectively. In univariate analysis, LDH, clinical stage and PS exerted significant effect on TTF and OS rate, but not on DFS rate; age and extranodal disease was not related with TTF, OS and DFS rate. In multi-variate analysis, achieved CR was the only prognostic factor for TTF (P =0.001) and bulky disease had influence on DFS rate. LDH level, PS, and achieved CR was correlated with the OS rate in multi-variate setting (P = 0.002, 0.009 and 0.001 respectively). CONCLUSION: IPI score has its limitation in predicting the prognosis in the R-CHOP era in DLBCL. Other two relevant prognostic factors are bulky disease and achieved CR after 6 courses of treatment.