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A dose-escalation study of recombinant human interleukin-18 in combination with rituximab in patients with non-Hodgkin lymphoma.

ABSTRACT: Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. Rituximab is a CD20 monoclonal antibody with activity against human B-cell lymphomas. A phase I study of recombinant human (rh) IL-18 given with rituximab was performed in patients with CD20+ lymphoma. Cohorts of 3-4 patients were given infusions of rituximab (375 mg/m2) weekly for 4 weeks with escalating doses of rhIL-18 as a 2-hour intravenous infusion weekly for 12 consecutive weeks. Toxicities were graded using standard criteria. Blood samples were obtained for safety, pharmacokinetic, and pharmacodynamic studies. Nineteen patients with CD20+ B-cell non-Hodgkin lymphoma were given rituximab in combination with rhIL-18 at doses of 1, 3, 10, 20, 30, and 100 ?g/kg. Common side effects included chills, fever, headache, and nausea. Common laboratory abnormalities included transient, asymptomatic lymphopenia, hyperglycemia, anemia, hypoalbuminemia, and bilirubin and liver enzyme elevations. No dose-limiting toxicities were observed. Biologic effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-?, GM-CSF, and chemokines were observed after dosing. Objective tumor responses were seen in 5 patients, including 2 complete and 3 partial responses. rhIL-18 can be given in biologically active doses by weekly infusions in combination with rituximab to patients with lymphoma. A maximum tolerated dose of rhIL-18 plus rituximab was not determined. Further studies of rhIL-18 and CD20 monoclonal antibodies in B-cell malignancies are warranted.

SUBMITTER: Robertson MJ

PROVIDER: S-EPMC3770482 | biostudies-literature | 2013 Jul-Aug

REPOSITORIES: biostudies-literature

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A dose-escalation study of recombinant human interleukin-18 in combination with rituximab in patients with non-Hodgkin lymphoma.

Robertson Michael J MJ Kline Justin J Struemper Herbert H Koch Kevin M KM Bauman John W JW Gardner Olivia S OS Murray Sharon C SC Germaschewski Fiona F Weisenbach Jill J Jonak Zdenka Z Toso John F JF

Journal of immunotherapy (Hagerstown, Md. : 1997) 20130701 6

Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. Rituximab is a CD20 monoclonal antibody with activity against human B-cell lymphomas. A phase I study of recombinant human (rh) IL-18 given with rituximab was performed in patients with CD20+ lymphoma. Cohorts of 3-4 patients were given infusions of rituximab (375 mg/m2) weekly for 4 weeks with escalating doses of rhIL-18 as a 2-hour intravenous infusion weekly for 12 consecutive weeks. Toxicit ...[more]

PMID: 23799412

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Project description:BackgroundIn the clinical use of third-line treatment of non-Hodgkin lymphoma (NHL), the combination treatment is increasingly used due to problems such as drug resistance, and while their efficacy has been proven, whether they are economical has become a new issue. A recent trial showed copanlisib plus rituximab combination therapy (CRCT) had better efficacy in the treatment of relapsed indolent NHL (iNHL) compared to rituximab monotherapy (RM). However, the long-term cost and effectiveness of this regimen is not known. We are the first to evaluate the cost effectiveness of CRCT in third-line treatment of relapsed iNHL from the perspective of US payers.MethodsWe used a Markov model to evaluate cost and quality-adjusted life years (QALYs) which included a population from CHRONOS-3 with mean age of 62.5 years and total cycle length of 16.3 years. The cycle length was 1 month, adverse reaction rates were from CHRONOS-3, mean body surface area was referenced from published literature, cost values are referenced from published literature and Drugbank, utility values were referenced from the published literature, and the primary endpoint was the incremental cost-effectiveness ratio (ICER). The willingness to pay (WTP) threshold was set at $150,000 per QALYs, and one-way sensitivity analysis and probabilistic sensitivity analysis were used to verify the robustness of the model. All costs are expressed in 2021 dollars and costs and utilities have been calculated at a discount rate of 3% per year.ResultsCRCT and RM obtained 6.53 QALYs and 5.15 QALYs, respectively, and the ICER of CRCT vs. RM was $358,895.2/QALYs. Parameters having the greatest impact on the robustness of the model were the drug cost of copanlisib and the utility value of the progression-free survival (PFS) state. When the WTP threshold was $150,000, the probability of CRCT and RM being the most cost effective was 0.4% and 99.6% respectively.ConclusionsFrom a US payer perspective, CRCT is not cost-effective in treating relapsed iNHL at current prices compared to RM. But given its positive clinical efficacy, appropriate price discounts or assistance programs should be considered to make CRCT more affordable to patients with relapsed iNHL.

Dataset Information

A dose-escalation study of recombinant human interleukin-18 in combination with rituximab in patients with non-Hodgkin lymphoma.

Publications

A dose-escalation study of recombinant human interleukin-18 in combination with rituximab in patients with non-Hodgkin lymphoma.

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