Subcutaneous Injections of Low Doses of Humanized Anti-CD20 Veltuzumab for Treatment of Indolent B-Cell Malignancies.

Low IV doses of veltuzumab, a 2^nd generation humanized anti-CD20 monoclonal antibody with structure-function differences from chimeric rituximab, have shown clinical activity in non-Hodgkin's lymphoma (Morschhauser et al., J Clin Oncol, 2009; 27:3346-53). By avoiding lengthy IV administration and the need for dedicated infusion suites, subcutaneous (SC) injections of low-dose veluzumab may offer benefits to both patients and the healthcare system for treatment of B-cell malignancies, and this may be particularly useful in the setting of indolent disease.

A multicenter, phase I/II study was undertaken to evaluate the safety, tolerability, and preliminary efficacy of SC veltuzumab in previously untreated or relapsed CD20+ indolent non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL). All patients (pts) received 4 SC injections of veltuzumab 2 weeks apart at dose levels of 80, 160, or 320 mg. Efficacy was assessed by CT-based IWG (NHL) or hematology-based NCI/IWCLL (CLL) criteria 4 and 12 weeks later, with responding pts continuing follow-up. Other evaluations included AEs, safety laboratories, B-cell blood levels (CD19), serum veltuzumab levels, and human anti-veltuzumab antibody (HAHA) titers.

Twenty-six pts (10M/16F, median age 64), including 15 NHL pts (12 follicular, 3 other indolent NHL; 5 treatment naïve) most with stage III or IV disease (12/15), and 11 CLL pts (4 treatment naïve) most with Rai stage II or III disease, have now received SC veltuzumab at 80 mg (3 NHL, 3 CLL), 160 mg (9 NHL, 3 CLL) or 320 mg (3 NHL, 5 CLL) dose levels. Pre-treatment with antihistamines or steroids was not required. SC veltuzumab was well tolerated with only mild, transient injection-site reactions and tenderness, and no other safety issues. To date, all HAHA response results have been negative. In NHL pts, SC veltuzumab demonstrated good bio-availability, with a slow release pattern over several days, and a mean Cmax of 18.7, 19.5 and 64.0 μg/mL at 80, 160, and 320 mg dose levels, respectively. Depletion of circulating B cells was observed starting after 1^st injection. In the 15 NHL pts, the objective response rate (CR+CRu+PR) was 53% (8/15) with a complete response (CR) rate of 20% (3/15) and with 7/8 ORs currently continuing in remission, up to 6 months after treatment. The 11 CLL pts presented with mean white blood cell levels of 55K/μL (maximum 122K/μL) and achieved much lower serum veltuzumab levels, with mean Cmax values of 4.0, 2.5 and 21.0 μg/mL at the 80, 160, and 320 mg dose levels, respectively. There were no ORs, but 5 of 7 (71%) CLL pts with response assessments currently available showed stable disease with >70% decreases in B-cell levels for up to 12 weeks.

SC administration of veltuzumab is well tolerated, achieves slow but efficient delivery into the blood, and is pharmacologically active when given every 2 weeks for a total of 4 doses. In CLL with high levels of circulating leukemic cells, more frequent and prolonged dosing is likely required. However, in NHL, these low SC doses achieved sustained serum levels with objective response rates comparable to those seen even with higher IV doses.

Negrea:Immunomedics: Research Funding. Off Label Use: veltuzumab for investigational treatment of NHL/CLL. Allen:Immunomedics: Research Funding. Rai:Immunomedics: Research Funding. Elstrom:Immunomedics: Research Funding. Abassi:Immunomedics: Research Funding. Farber:Immunomedics: Research Funding. Teoh:Immunomedics: Employment. Horne:Immunomedics: Employment. Wegener:Immunomedics: Employment. Goldenberg:Immunomedics: Employment, Equity Ownership.