Background: Relapsed/refractory (R/R) Hodgkin lymphoma (HL) remains a significant clinical challenge. We hypothesized that using an immune checkpoint inhibitor to activate the immune cells in the tumor microenvironment, and concurrently targeting tumor cells with the CD30 antibody-drug conjugate brentuximab vedotin (BV) could overcome resistance. E4412 is a Phase 1 ECOG-ACRIN sponsored study of the combinations of BV and ipilimumab (Ipi) and nivolumab (Nivo) in patients with R/R HL. Here we present the updated safety and response data on the full cohort of patients treated with BV + Nivo (Arms D-F). Methods: Patients with confirmed R/R HL were treated with Nivo 3 mg/kg and BV 1.2 mg/kg (Arm D) or 1.8 mg/kg (Arm E) with a 3 + 3 design, and an expansion cohort (Arm F) of 9 patients. BV and Nivo are given every 21 days for 16 cycles; Nivo may be continued for an additional year. Dose limiting toxicity (DLT) was defined within the first cycle of therapy. Results: As of 3/10/17 19 patients (1 ineligible) have been treated. Median age was 40, range (21-70); 9 patients were male. Patients were treated with a median of 3 prior therapies. Eight patients had prior SCT; 4 patients had prior BV. Safety: Nineteen of 19 patients are evaluable for safety. There were 2 significant treatment related adverse events (AEs): 1 patient in Arm E experienced a DLT (pneumonitis grade 3 with grade 3 dyspnea and hypoxia, and typhilits), and made a full recovery; 1 elderly patient in Arm F had grade 5 pneumonitis occurring in cycle 2. There were no other Grade 4 or 5 AEs; grade 3 AEs were one each: rash, puritis, and neutropenia. The most common grade 1-2 AEs were: transaminitis (9), peripheral sensory neuropathy (8), and rash (6); other grade 1-2 AEs included: diarrhea (4), blurry vision (3), and myalgias (2). One grade 1-2 infusion reaction was noted, this patient was able to receive subsequent therapy with pre-medication. Response: Response is shown below in Figure 1. Seventeen of 18 eligible patients are evaluable for response, one patient died after cycle 2 and response could not be assessed. The overall response rate (ORR) for the combination was 89%, with a CR rate of 50% (9/18) (95% CI: 26%-74%). There were 2 CRs and 1 PR in patients treated with prior BV. The 6 month PFS is 91% (95% CI: 75-100%), and median OS with a median follow-up of 6 months is not reached. Conclusion: In this study of the combination of Nivo and BV for R/R HL, therapy was generally well tolerated, however two patients experienced pneumonitis. In a heavily pretreated patient population, the ORR of 89% and CR rate of 50% suggests a deepening of response compared to either therapy alone. Optimization of this strategy is planned with ongoing accrual to cohorts receiving BV + Ipi + Nivo. Data will be updated to include longer term PFS and OS by the time of the meeting.
Background and Aims Aberrantly glycosylated IgA1 molecules are important in the pathogenesis of IgA nephropathy. A proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) are cytokines involved in immunoglobulin class switching and production of galactose deficient IgA1(Gd IgA1). We aimed to study the association of serum levels of APRIL and BAFF with the clinical severity and pathological grading of IgA nephropathy (IgAN) and to assess the strength of the association by studying the clinicopathological correlation. Method The research study was conducted as a single-center longitudinal observational study. The study subjects were recruited based on the pathological diagnosis of primary IgA nephropathy. The plasma levels of APRIL, BAFF and Gd IgA1 were estimated using enzyme-linked immunosorbent assay (ELISA). All the study subjects were followed up for one year to study the renal outcome. Results In our study group of thirty-eight patients, the median estimated glomerular filtration rate(eGFR) was 33.9(15.9,79.4) ml/minute/1.73m2. The median levels of the cytokines APRIL and BAFF were 170.81(82.45, 550.61) ng/L and 6.66(3.39,16.33) ng/ml respectively. The baseline characteristics of the study group is given in table 1. APRIL levels had significant positive correlation with Gd IgA1 levels (correlation coefficient 0.556, p=0.003) in patients with IgAN. We also observed that patients with elevated APRIL levels had elevated BAFF levels also (correlation coefficient 0.657, p <0.001). Patients who had crescents, mesangial hypercellularity and endocapillary proliferation in biopsy had elevated APRIL and BAFF levels whereas patients with segmental sclerosis and tubular atrophy had low levels of APRIL(Table 2). However, the levels of APRIL and BAFF did not show any significant correlation with eGFR and proteinuria at time of presentation. At the end of one year, 12(31.5%) patients reached end stage renal disease (ESRD) and these patients had lower levels of APRIL, BAFF, and Gd IgA1. It was also seen that eighty-three percent of those who reached ESRD had chronic changes in biopsy like tubular atrophy and interstitial fibrosis(p=0.05). Hence the severity of tubulointerstitial fibrosis in histology correlated well with progression to end stage renal disease as seen in most glomerular diseases. But we did not find any association between APRIL, BAFF, and Gd IgA1 levels and the decline in eGFR over one year. Conclusion We conclude that levels of APRIL and BAFF are associated with elevated levels of Gd IgA1 in patients with IgAN and had a significant association with proliferative lesions in renal biopsy. But these cytokines levels did not have any association with the eGFR at time of presentation nor decline in eGFR over one year.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.