Campath-1H May Have Activity in the Treatment of Multiple Myeloma.
Previously we have demonstrated that multiple myeloma cell lines and primary cells express CD52, the antigenic target of Campath-1H, and that they undergo apoptosis following treatment with alemtuzumab in-vitro (Gasparetto et al. ASH #3210,2002). Based on these observations, we initiated a clinical trial where patients with advanced, multiply relapsed MM were treated with subcutaneous (sc) alemtuzumab as a single agent. Nine patients (6 men/4 women, age range 45–69 yrs) were initially treated with the standard dose of 30mg sc three times per week for up to 12 weeks. All patients had at least 4 lines of prior therapy and 8/9 patients had undergone high dose chemotherapy followed by autologous peripheral blood stem cell transplant. Treatment related toxicities included pancytopenia in all patients with grade IV neutropenia in the first four patients, necessitating withdrawal from study. Subsequently, all patients were treated with G-CSF and aggressive transfusion support and no further patients were removed from study due to cytopenias. All patients were prophylaxed with Famvir, Fluconazole and Septra and no opportunistic infections were noted during treatment. Two patients developed acute renal insufficiency that reversed when alemtuzumab was discontinued. One patient completed the entire 12 weeks of treatment. One patient had a PR with a 40% reduction in M-protein after two months of treatment, which reversed once Campath-1H was discontinued. Pharmacokinetic studies of one patient demonstrated that it required 8–10 weeks of treatment using the sc protocol to achieve serum levels of alemtuzumab of 1ug/ml, the level considered to be tumoricidal in-vivo. Based on this observation, the treatment protocol was modified so that the initial week of escalating doses was given IV to achieve more rapid therapeutic levels. Following this, sc alemtuzumab was given as above. One patient with non-secretory multiple myeloma with relapsed disease following 5 prior lines of therapy has been treated with this modified protocol. Treatment with alemtuzumab and growth factor support in this patient has been well tolerated except for the development of RSV pneumonia. At 4 weeks, a PET scan demonstrated a significant overall decrease in metabolic activity in multiple bony areas consistent with a response to treatment. These initial results suggests that alemtuzumab is associated with significant toxicities in patients with advanced multiple myeloma including pancytopenia, infections and possibly renal insufficiency but all of these were reversible and have been minimized with aggressive prophylactic therapy. Alemtuzumab does appear to have modest activity against MM in this heavily pre-treated group suggesting that it should be explored in combination with other agents and at earlier stages of disease.
Gasparetto, C; Horwitz, ME; Gockerman, JP; de Castro, CM; Moore, JO; Smith, CA; Davis, P; Lassiter, M; Houser, L; Chao, NJ; Rizzieri, D
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