Efficacy of programmed cell death 1 inhibitor maintenance therapy after combined treatment with programmed cell death 1 inhibitors and anti-CD19-chimeric antigen receptor T cells in patients with relapsed/refractory diffuse large B-cell lymphoma and high tumor burden.

We studied the efficacy and safety of the combined treatment with programmed cell death 1 (PD-1) inhibitors and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy and subsequent PD-1 inhibitor maintenance treatment in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and high tumor burden. Forty-four R/R DLBCL patients with high tumor burden were enrolled in this study. The experimental group of 26 patients received combined therapy with PD-1 inhibitors and anti-CD19-CAR T cells, while the control group of 18 patients received anti-CD19-CAR T-cell therapy alone. The objective response rate (ORR) was 65.39% and 61.11% in the combination and control groups, respectively. The PD-1 inhibitor maintenance therapy was selected for patients who achieved complete response or partial response in the combination therapy group. Progression-free survival and overall survival rates in the combination group were higher than those in the control group 3 and 12 months after CAR T-cell infusion. There was no significant difference in the grade of cytokine release syndrome or immune effector cell associated neurotoxic syndrome between the two groups. In the maintenance therapy group, only eight patients experienced grade 1 Common Terminology Criteria for Adverse Events (CTCAE) and three grade 2 CTCAE. Overall, we found that the ORR was not affected by the combination therapy with PD-1 inhibitors and anti-CD19-CAR T cells. However, patients who had achieved the ORR might benefit from PD-1 inhibitor maintenance therapy after combination therapy without increased side effects.

Effects of iron overload on the bone marrow microenvironment in mice.

OBJECTIVE: Using a mouse model, Iron Overload (IO) induced bone marrow microenvironment injury was investigated, focusing on the involvement of reactive oxygen species (ROS). METHODS: Mice were intraperitoneally injected with iron dextran (12.5, 25, or 50 mg) every three days for two, four, and six week durations. Deferasirox(DFX)125 mg/ml and N-acetyl-L-cysteine (NAC) 40 mM were co-administered. Then, bone marrow derived mesenchymal stem cells (BM-MSCs) were isolated and assessed for proliferation and differentiation ability, as well as related gene changes. Immunohistochemical analysis assessed the expression of haematopoietic chemokines. Supporting functions of BM-MSCs were studied by co-culture system. RESULTS: In IO condition (25 mg/ml for 4 weeks), BM-MSCs exhibited proliferation deficiencies and unbalanced osteogenic/adipogenic differentiation. The IO BM-MSCs showed a longer double time (2.07±0.14 days) than control (1.03±0.07 days) (P<0.05). The immunohistochemical analysis demonstrated that chemokine stromal cell-derived factor-1, stem cell factor -1, and vascular endothelial growth factor-1 expression were decreased. The co-cultured system demonstrated that bone marrow mononuclear cells (BMMNCs) co-cultured with IO BM-MSCs had decreased colony forming unit (CFU) count (p<0.01), which indicates IO could lead to decreased hematopoietic supporting functions of BM-MSCs. This effect was associated with elevated phosphatidylinositol 3 kinase (PI3K) and reduced of Forkhead box protein O3 (FOXO3) mRNA expression, which could induce the generation of ROS. Results also demonstrated that NAC or DFX treatment could partially attenuate cell injury and inhibit signaling pathway striggered by IO. CONCLUSION: These results demonstrated that IO can impair the bone marrow microenvironment, including the quantity and quality of BM-MSCs.

[Effect of the tetra-arsenic tetra-sulfide (As4S4) on the corrected QT interval in the treatment of acute promyelocytic leukemia].

OBJECTIVE: To evaluate the effect of tetra-arsenic tetra-sulfide (As4S4) therapy on the corrected QT interval (QTc) in the acute promyelocytic leukemia (APL) patients. METHODS: Ninety cases of APL treated with As4S4 were divided into two groups--the remission induction group and maintenance therapy group. Blood arsenic concentration was measured and a 12-lead electrocardiogram (ECG) was simultaneously performed before treatment and after remission in the induction group, and before and 2, 4, 6, 8, 10 courses after the treatment in the maintenance therapy group. QT interval on each ECG was measured and corrected by the Bazett formula. RESULTS: Oral administration of As4S4 could lead to the prolongation of QTc both in remission induction and maintenance therapy groups. QTc prolongation was related to the doses of As4S4 and blood arsenic levels. QTc prolongation and its variation range were increased with accumulative doses of As4S4 and the blood arsenic levels. In ten courses maintenance therapy patients, the average abnormal rate of QTc was 37.7%. Blood arsenic concentration was increased slowly with courses, but the variation had no statistical difference (P > 0.05). All the patients whose QTc was abnormal (> or = 440 ms) had neither symptoms nor serious cardiac events, such as ventricular tachycardia and Torsade de pointes and could complete the As4S4 therapy. CONCLUSION: Although As4S4 therapy can lead to QTc prolongation in the treatment of APL patients, it does not preclude the completion of the therapy.