Fractionated subcutaneous rituximab is well-tolerated and preserves CD20 expression on tumor cells in patients with chronic lymphocytic leukemia

Abstract

A pilot study previously demonstrated that thrice-weekly, fractionated-dose intravenous rituximab (RTX) limits CD20 loss from chronic lymphocytic leukemia (CLL) B cells, thereby enhancing immunotherapeutic targeting. Here, we investigated the feasibility of giving 20 mg rituximab subcutaneously thrice weekly for up to 12 weeks in 4 previously treated CLL patients. Subcutaneous rituximab was well-tolerated with minimal injection site reactions; a variable degree of efficacy was observed, likely influenced by the size of the patients' B cell/CD20 burden. Subcutaneous RTX largely preserved CD20 expression on leukemic cells but the most effective therapeutic dosing regimen needs to be established (ClinicalTrials.gov Identifier: NCT00366418). Haematologica. 2010;95:329-332. doi: 10.3324/haematol.2009 This is an open-access paper. IntroductionThe anti-CD20 monoclonal antibody rituximab (RTX) has shown remarkable efficacy in non-Hodgkin's lymphomas (NHL).1,2 However, compared to therapy for NHL, RTX therapy in chronic lymphocytic leukemia (CLL) is associated with lower response rates.3 Possible explanations include lower CD20 levels on CLL cells compared to NHL cells. Alternatively, due to high tumor burden or substantial leukemic disease, there can be exhaustion of effector mechanisms which kill RTX-targeted CLL B cells, such as antibodydependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).4,5 Another potential limitation for standard dose, single-agent intravenous RTX therapy in CLL, manifested after saturation/exhaustion of clearance mechanisms, is the shaving reaction in which RTX/CD20 immune complexes on B cells are removed by effector cells expressing FcγR. 5,6 This process can reduce or completely abrogate the efficacy of subsequent RTX dosing. Fractionated dosing schedules that limit exhaustion of effector mechanisms may be more effective than current intravenous bolus schedules of 375 mg/m 2 RTX. A pilot trial suggested that low-dose RTX at 20 mg/m 2 intravenously thrice weekly promotes clearance of leukemic cells without inducing substantial loss of targeted CD20.7 This trial was limited to a four-week treatment duration and required frequent clinic visits for patients. In principle, low RTX doses can be selfadministered subcutaneously. If subcutaneous administration is safe and effective, it could be more convenient for patients than intravenous treatment and would make fractionated dosing over prolonged periods possible. Based on ease of use and tolerability considerations, subcutaneous injections in this pilot study were limited to 2 mL/day, thrice weekly, allowing for RTX doses of 20 mg due to its fixed formulation at 10 mg/mL. Design and Methods PatientsThis pilot phase I study used 20 mg subcutaneous RTX doses thrice weekly for 6-12 weeks (ClinicalTrials.gov Identifier: NCT00366418). Criteria for inclusion were active CLL, previous fludarabine treatment, CD20 expression on leukemic

Subcutaneous injections of low-dose veltuzumab (humanized anti-CD20 antibody) are safe and active in patients with indolent non-Hodgkin's lymphoma

“…36,37 In other diseases like immune thrombocytopenia (ITP), with presumably less antigen burden, 100 mg rituximab doses have shown activity, 38 and even in the face of the high leukemic burden in chronic lymphocytic leukemia, frequently repeated 20 mg subcutaneous rituximab doses given to 4 patients were shown to be active in one. 39 Thus, it is not surprising that low doses of veltuzumab could also be effective in nonHodgkin's lymphoma, as shown previously with intravenous administrations 27 or here with subcutaneous injections. In addition, subcutaneous injections of veltuzumab at the same low doses used here were also effective in immune thrombocytopenia with doses given only twice, two weeks apart, 40 and were capable of transiently decreasing the high levels of circulating leukemic cells in chronic lymphocytic leukemia, when given only 4 times with the same dosing schedule used in the present study.…”

Lessons for the clinic from rituximab pharmacokinetics and pharmacodynamics

“…On the contrary, a more gradual increase in the levels of antibody would entail a lower exhaustion of effector mechanisms and decreased shaving. 104,105 …”

Mechanisms of Subcutaneous Absorption of Rituximab in Rats

“…There is a substantial interest in utilizing s.c. delivery for monoclonal antibodies (mAbs) to improve patient convenience and potentially reduce treatment costs (Aue et al, 2010;Bittner and Schmidt, 2012;Richter et al, 2012). Mechanisms of mAb absorption after s.c. administration are not fully understood but are influenced by several kinetic processes, including transport through the extracellular matrix, uptake by the blood and lymphatic capillaries, and presystemic elimination (Porter and Charman, 2000;Swartz, 2001;Kagan et al, 2007).…”