Continuous Infusion/Subcutaneous Alemtuzumab (Campath-1H) Plus Rituximab Is Active for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL).

Abstract Despite impressive single-agent activity of monoclonal antibodies (moabs) in lymphoproliferative disorders, activity can be enhanced by combination with other active agents. We have previously shown that alemtuzumab can be combined safely with rituximab and that the combination is active in pts with relapsed/refractory chronic lymphoproliferative disorders (Blood 101: 3413, 2003). As the optimal dose, schedule and route of administration have not been established, and in the light of data on soluble CD52 levels in the serum of patients with chronic lymphocytic leukemia (CLL) and their association with prognosis, we are now investigating a continuous i.v. infusion (c.i.v.) followed by subcutaneous (s.c.) injection of alemtuzumab plus rituximab in pts with relapsed/refractory CLL with co-expression of CD52 and CD20. Rituximab is given at 375 mg/m2 i.v. on day 1 followed by 500 mg/m2 on days 8, 15, and 22. Alemtuzumab is administered at 15mg by c.i.v. daily for 6 days (days 2–7) followed by 30 mg s.c. twice weekly on days 3 and 5 of weeks 2 to 4. Up to 12 weeks of therapy can be given. Should pts continue beyond 4 weeks, no further c.i.v. of alemtuzumab is administered. All pts were premedicated with acetaminophen and an antihistamine, and received antiinfective prophylaxis with TMP/SMX and valacyclovir (or equivalent). CMV antigenemia and/or PCR testing was done prior to and at the completion of each course of therapy. Twenty-eight pts have been enrolled (26 CLL, 1 CLL/SLL, 1 MZL). Twenty pts are evaluable for response. Median age: 57 yrs (range 39–78), median number of prior therapies: 3 (1–5), median b2M 3.5 mg/dL (2.1–13.6). Ten pts (50%) had Rai stage ≥ 3. Six pts. (30%) were refractory to both fludarabine and alkylators. All evaluable pts received prior rituximab, but only 2 (10%) have been exposed to alemtuzumab. No pts received the combination of alemtuzumab plus rituximab before. Based on NCI-Working Group criteria for response, 6 pts (30%) achieved CR, 1 (5%) PRn, and 4 (20%) PR for an overall response rate of 55%. All responders achieved their maximum response after 4 weeks of therapy (one course) only. Response by site: liver/spleen 6 of 6 pts (100%), peripheral blood 13/15 (86%), marrow 14/20 (70%), and lymph nodes 8/15 (53%). No unexpected adverse events (AEs) occurred. Most non-hematologic AEs were infusion-related and ≤ grade 2 by NCI toxicity criteria: fevers (93%), chills (75%), fatigue (55%), skin rashes or injection site reactions (35%), nausea (25%), myalgias (20%), and diarrhea (10%). Although AEs occurred more frequently during c.i.v. alemtuzumab than during the s.c. injections, c.i.v. of alemtuzumab has been well tolerated compared to bolus infusions. No dose escalation was given prior to the start of the c.i.v. Infections occurred in 10 pts (50%) including CMV reactivation in 6 (21%). In summary, out data indicate a promising response rate in a poor prognosis group of pts after only 4 weeks of therapy. The combination is well tolerated. Side effects are predictable and manageable.