Phase I/II Study of Subcutaneous Injections of Low-Dose Anti-CD20 Veltuzumab in Relapsed Immune Thrombocytopenia,

Subcutaneous (SC) injections of veltuzumab, a 2nd-generation humanized anti-CD20 monoclonal antibody with structure-function differences from rituximab, may offer potential benefits to both patients and the healthcare system. In non-Hodgkin's lymphoma, SC veltuzumab was well tolerated and demonstrated activity (Negrea et al., Haematologica, 96:567–73, 2011) comparable to that demonstrated earlier with low veltuzumab doses delivered intravenously (Morschhauser et al., J Clin Oncol, 2009;27:3346–53). Since this route of administration may also be effective and particularly convenient for treating autoimmune disease, a clinical study of SC veltuzumab was undertaken in immune thrombocytopenia (ITP).

A multicenter, phase I/II study was conducted to evaluate veltuzumab in adults with primary ITP who failed ≥1 standard therapy and presented with platelets ≤30K/μL, but without major bleeding. All patients received 2 doses of veltuzumab 2 weeks apart (without steroids or other premedications required). Veltuzumab was initially administered IV, but then by SC injection after a higher concentration formulation became available. By recent international working group categories, efficacy was evaluated separately for patients with newly-diagnosed or persistent disease (≤1 year duration) compared to patients with chronic disease (>1 year), with best responses (on at least 2 occasions, one week apart) classified as complete (CR, >150K/μL), partial (PR, 50–150K/μL), or minor (MR, 30–50K/μL). Adverse events (AEs) and safety laboratories were evaluated by NCI CTC v3 toxicity grades. Other evaluations included circulating B-cell levels (CD19), veltuzumab serum levels, and human anti-veltuzumab antibody (HAHA) titers.

A total of 41 patients were entered in this study, with 7 patients receiving 2 IV veltuzumab doses of 80 (N=3), 120 (N=3), or 200 mg (N=1), and 34 receiving 2 SC doses of 80 (N=9), 160 (N=10), or 320 mg (N=15). 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 AEs (All NCI CTC v3.0 Grade 1–2 transient infusion/injection reactions) and no other safety issues. ORs and CRs occurred with both SC and IV administrations, and across all dose levels. Of 9 patients (6 female/3 male; median 54-years old) with ITP ≤1 year and treated with steroids and/or immunoglobulins, 7 (78%) achieved an objective response (OR: CR+PR+MR), including 3 (33%) CRs. Of 32 patients (19 female/13 male; median 51-years old) with ITP > 1 year, (47% 5 – 31 years) and additional therapies [splenectomy (N=8), azathioprine (N=9), rituximab (N=6), tpo-receptor agonists (N=5), chemotherapy (N=5)], 19 (59%) still achieved ORs, including CRs in 4 (13%) patients with ITP for 1.4, 2.0, 2.4 and 25 years. Of 7 CRs, the median relapse-free survival was 1.2 years, and 3 still continue 1.8 – 3.5 years after treatment. Most PRs and MRs relapsed by 6 months. However, of 6 such patients who were then retreated, 4 patients achieved responses comparable to their initial response, while another patient (with a 31-year history of ITP) achieved a CR after receiving veltuzumab in combination with prednisone. With both IV and SC dosing, and at all doses, B cells were depleted rapidly after the first administration of veltuzumab, with recovery starting 12 to 16 weeks after treatment. Compared to IV dosing, SC veltuzumab had slower release over several days with lower serum levels, but approximately comparable availability/exposure. Four patients developed low-level HAHA titers of uncertain clinical significance.

Low-dose SC veltuzumab was convenient, well tolerated and with promising activity in relapsed ITP. With only 2 SC doses, patients with limited disease duration of ≤1 year achieved high rates of objective responses [78%], including 33% durable CR's. In patients with long-standing disease (47% with ITP for 5 – 31 years) and who were often heavily pretreated, CRs occurred less frequently, but there was still activity [59% ORs]. Higher doses and extended dosing SC regimens may be more effective in this more refractory population.

Liebman:Immunomedics: Research Funding. Saleh:Immunomedics: Research Funding. Bussel:Immunomedics: Research Funding. Bernstein:Immunomedics: Research Funding. Negrea:Immunomedics: Research Funding. Onyegbula:Immunomedics: Research Funding. Farber:Immunomedics: Research Funding. Horne:Immunomedics: Employment. Wegener:Immunomedics: Employment. Goldenberg:Immunomedics, Inc.: Consultancy, Employment, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.