Subcutaneous Injections of Low-Dose Anti-CD20 Veltuzumab for Treatment of Relapsed Immune Thrombocytopenia (ITP).

Veltuzumab, a 2^nd-generation humanized anti-CD20 monoclonal antibody with structure-function differences from rituximab, has demonstrated clinical activity at low doses in non-Hodgkin's lymphoma (Morschhauser et al., J Clin Oncol, 2009; 27:3346-53). Since chimeric anti-CD20 rituximab is therapeutically active in ITP, we conducted a clinical trial of low-dose veltuzumab in ITP, initially administered by intravenous (IV) infusion, but following development of a high-concentration formulation, now administered by subcutaneous (SC) injection.

A multicenter, phase I/II study was undertaken to evaluate the safety and tolerability of low-dose veltuzumab in adults who had ITP for at least 6 months, had failed ≥1 standard therapy, and presented with platelets ≤30K/≤L, but without major bleeding. All patients received 2 doses of veltuzumab 2 weeks apart (without steroids) and were followed for up to 12 weeks, with responding patients continuing in long-term follow-up. Efficacy was assessed by an increase in platelet count with confirmation at least 1 week apart. Responses were classified as complete (CR, >150K/μL), partial (PR, 50-150K/μL), or minor (MR, 30-50K/μL). Adverse events and safety laboratories were evaluated using NCI CTC v3 toxicity grades. Other evaluations included circulating B-cell levels (CD19), veltuzumab serum levels, and human anti-veltuzumab antibody (HAHA) titers.

The study has enrolled 25 patients (7M/18F, 21-92 years old, 5 post-splenectomy) with 7 receiving 2 IV veltuzumab doses at 80 (N=3), 120 (N=3), or 200 mg (N=1), and 10 receiving 2 SC doses at 80 (N=3), 160 (N=4), or 320 mg (N=3) during the completed Phase I portion of the study. The Phase II portion is now underway with 8 additional patients having received 2 SC veltuzumab doses at 320 mg. The 25 patients had a median duration of ITP of 1.8 years (range 0.2 - 20) with previous treatments including steroids (N=24), IVIG/anti-D (N=15), azathioprine/danazol (N=7), rituximab (N=5), TPO-R agonists (N=3) and vincristine/Doxil (N=2). One patient had a Grade 3 infusion reaction after receiving ∼100 mg veltuzumab at first IV dose. Otherwise veltuzumab was well tolerated with a limited number of Grade 1 infusion/injection reactions and no other safety issues. B cells were depleted rapidly with both IV and SC dosing with recovery times yet to be determined. At 80 and 120 mg x 2, IV veltuzumab achieved expected serum levels (mean Cmax 20.3 and 46.0 μg/mL, respectively) with a mean serum half-life of ∼1 week after last dose. SC veltuzumab had slower release over several days with lower serum levels, but comparable availability/exposure. Two patients developed low-level HAHA titers of uncertain clinical significance. Of 21 patients now with post-treatment response assessments, 13 (62%) achieved an objective response (CR+PR+MR), including 6 (29%) CRs. Responses, including CRs, occurred with both SC and IV administrations, and across all dose levels, with the highest OR (CR) rate of 100% (60%) seen in patients with more recently diagnosed ITP (≤1 year), albeit in small numbers of patients (N=5). Of 6 CRs, 5 are still continuing with a current median duration of response of 9 months (2.5 - 15 mo.)

Low-dose veltuzumab (2 doses, 2 weeks apart) demonstrates promising activity in relapsed ITP, including durable complete responses. Compared to IV infusions, subcutaneous injections offer practical benefits to both patients and the healthcare system, and the study is continuing to provide additional/confirmatory data for further clinical development of SC veltuzumab in ITP.

Saleh:Immunomedics: Research Funding. Off Label Use: veltuzumab, an investigational anti-CD20 antibody in clinical studies. Liebman:Immunomedics: Research Funding. Bernstein:Immunomedics: Research Funding. Negrea:Immunomedics: Research Funding. Bussel:Immunomedics: Research Funding. Onyegbula:Immunomedics: Research Funding. Farber:Immunomedics: Research Funding. Abassi:Immunomedics: Research Funding. Cosgriff:Immunomedics: Research Funding. Pennington:Immunomedics: Research Funding. Horne:Immunomedics: Employment. Teoh:Immunomedics: Employment. Gomaa:Immunomedics: Employment. Wegener:Immunomedics: Employment. Goldenberg:Immunomedics: Employment, Equity Ownership.