Switching fractioned R-CHOP cycles to standard r-chop cycles guided by endoscopic ultrasonography in treating patients with primary gastric diffuse large B-cell lymphoma

© 2020 Liu et al. Background: Primary gastric diffuse large B-cell lymphoma (PG-DLBCL) is a common subtype of extranodal non-Hodgkin lymphoma (NHL), with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) as the commonly used treatment regimen. However, full cycles of standard R-CHOP present the risk of severe bleeding or perforation, even leading to emergency surgery, especially for those with deep lesions in their first 1–2 cycles of treatment. This study aims to explore the safety and efficacy of fractioned R-CHOP (rituximab d0, 50% dose of CHOP d1 and d5) followed by standard R-CHOP cycles in PG-DLBCL patients guided by endoscopic ultrasonography (EUS). Patients and Methods: Thirty-one PG-DLBCL patients were analyzed in this retrospective study. All patients had lesions infiltrated to at least the 3rd layer of the stomach under EUS at baseline. Patients switched to standard R-CHOP if they showed the reduced infiltrated layers and restricted lesions after fractioned R-CHOP cycles. Results: The overall response rate, 5-year progression-free survival (PFS) and overall survival (OS) of patients in our study were 93.5%, 75% and 84%, respectively. No treatment delay or dosage reduction from gastric adverse event was observed. None of the patients in our study suffered from severe bleeding or perforation during the treatment. Kaplan–Meier analyses showed that PG-DLBCL patients characterized by multiple localization, lesions ≥3cm, having B symptoms, lower serum albumin level, and elevated LDH level were associated with worse PFS and OS. Conclusion: Our data indicate that it might be an effective approach in treating deeply infiltrated PG-DLBCL patients by switching fractioned R-CHOP to standard R-CHOP cycles guided by EUS

Phase I study of the Syk inhibitor sovleplenib in relapsed or refractory mature B-cell tumors

Sovleplenib (HMPL-523) is a selective spleen tyrosine kinase (Syk) inhibitor with antitumor activity in preclinical models of B-cell malignancy. We conducted a dose-escalation and dose-expansion phase I study of sovleplenib in patients with relapsed/refractory mature Bcell tumors. Dose escalation followed a 3+3 design; patients received oral sovleplenib (200-800 mg once daily [q.d.] or 200 mg twice daily [b.i.d.], 28-day cycles). During dose expansion, patients were enrolled into four cohorts per lymphoma classification and treated at the recommended phase 2 dose (RP2D). Overall, 134 Chinese patients were enrolled (dose escalation, n=27; dose expansion, n=107). Five patients experienced dose-limiting toxicities: one each of amylase increased (200 mg q.d.), febrile neutropenia (800 mg q.d), renal failure (800 mg q.d.), hyperuricemia and blood creatine phosphokinase increased (200 mg b.i.d.) and blood bilirubin increased and pneumonia (200 mg b.i.d.). RP2D was determined as 600 mg (>65 kg) or 400 mg (≤65 kg) q.d. The primary efficacy end point of independent review committee–assessed objective response rate in indolent B-cell lymphoma was 50.8% (95% CI, 37.5–64.1) in 59 evaluable patients at RP2D (follicular lymphoma: 60.5%, marginal zone lymphoma: 28.6%, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, 0%). The most common (≥10% patients) grade ≥3 treatment-related adverse events in the doseexpansion phase were decreased neutrophil count (29.9%), pneumonia (12.1%) and decreased white blood cell count (11.2%). Pharmacokinetic exposures increased doseproportionally with ascending dose levels from 200–800 mg, without observed saturation. Sovleplenib showed antitumor activity in relapsed/refractory B-cell lymphoma with acceptable safety. Further studies are warranted

Predicting central nervous system relapse in primary breast diffuse large B-cell lymphoma using the stage-modified IPI score: A retrospective cohort study

Objective: The existing Central Nervous System-International Prognostic Index (CNS-IPI) provides insufficient guidance for predicting central nervous system (CNS) relapse in individuals with primary breast diffuse large B-cell lymphoma (DLBCL). This retrospective cohort study sought to examine the potential of the stage-modified IPI in predicting CNS relapse within this specific patient population. Patients and methods: We examined the baseline characteristics of 76 consecutive patients diagnosed with primary breast DLBCL, calculating the stage-modified IPI score for each individual. Utilizing a competing risk regression (CRR) model, we conducted both univariate and multivariate analyses to explore the relationship between potential prognostic factors and the occurrence of CNS relapse. Results: In our cohort, the rates of CNS disease at 2 and 5 years since the diagnosis of primary breast DLBCL are 3.9% and 7.8%, respectively. Among patients experiencing CNS relapse, 80% presented with a parenchymal brain mass. Individuals with a high stage-modified IPI score (1–3 points) had a significantly higher incidence of CNS relapse (p = 0.031), a shorter time from the initial diagnosis of primary breast DLBCL to the first CNS relapse (p = 0.010), as well as relapse at any site (p = 0.012), compared to those with a low score (0 points). Univariate analysis identified stage (Hazard Ratio (HR): 4.098, p = 0.024), stage-modified IPI score (HR: 11.582, p = 0.012), and radiation therapy (HR: 5.784, p = 0.026) as significant risk factors. In multivariate analysis, in addition to radiation therapy (HR: 7.258, p = 0.012), the stage-modified IPI score (1–3 points versus 0 points) emerged as an independent and reliable predictor for CNS relapse (HR: 12.945, p = 0.016). Conclusion: Our study underscores the significance of stage-modified IPI scores in predicting CNS relapse for patients with primary breast DLBCL. Validation of these findings through further research is essential, along with exploring potential prevention and intervention approaches

Structure-Directed Discovery of Potent Soluble Epoxide Hydrolase Inhibitors for the Treatment of Inflammatory Diseases

Soluble epoxide hydrolase (sEH) has been identified as an attractive target for anti-inflammatory drug design in recent years. Picomolar level compound G1 against sEH was obtained by introducing the hydrophilic group homopiperazine and hydrophobic fragment propionyl onto the structure of lead compound A. G1 showed good microsomal stability, a moderate plasma protein binding rate, and good oral bioavailability and was well tolerated in rats. G1 has significant analgesic effects on CFA-induced AIA mice, ameliorated the pancreatic injury in acute pancreatitis induced by l-arginine, reversed pancreatic injury, edema, and neutrophil infiltration, and increased the survival time of C57BL/6 mice in a lipopolysaccharide (LPS)-induced sepsis model. Moreover the expression levels of sEH, COX-2, NOS-2, vascular cell adhesion molecule (VCAM), IL-6, MCP-5, and tumor necrosis factor α (TNF-α) were measured by Western blot or enzyme-linked immunosorbent assay (ELISA), with varying degrees of decrease. These results suggested that G1 is a drug candidate worthy of further evaluation for the treatment of inflammation-induced diseases such as arthritis, acute pancreatitis, and sepsis