Available data suggest enhanced activity of monoclonal antibodies in combinations. In a previous study of iv bolus alemtuzumab plus rituximab in relapsed CLL, we have shown that the combination is safe and produces a response rate of 54% following a 4-week treatment period (

Blood 101: 3413, 2003
). As questions remain about the optimal dose, schedule and route of administration of alemtuzumab, we have been exploring alemtuzumab by civ followed by sc injections in combination with rituximab in pts with relapsed/refractory CLL who express both CD20 and CD52. Forty-five pts have been enrolled of whom 32 pts are evaluable (30 CLL, 1 CLL/SLL, 1 MZL). Six pts are too early and 7 are inevaluable [withdrawal of consent prior to treatment start (2), ineligible (2), removal from study and continuation of therapy with home physician (3)]. All pts received alemtuzumab 15mg by civ over 24 hours daily x 6 days on days 2–7 of the first course followed by 30mg sc twice weekly on days 3 and 5 of weeks 2 to 4 (one course). Rituximab was given at 375mg/m2 iv on day 1 followed by 500mg/m2 on days 8, 15, and 22. Maximum duration of therapy was 3 courses. Pts received standard premedication with acetaminophen and an antihistamine, and antiinfective prophylaxis with TMP/SMX and valacyclovir. CMV antigenemia was tested before and after completion of each course. The median age was 59 yrs (range 39–78), the median number of prior therapies was 3 (1–8), and the median b2M 3.8 mg/dL (1.7–13.6). Seventeen pts (53%) had Rai stage ≥ 3 disease. Eighteen pts (56%) were refractory to fludarabine and alkylators. All pts had prior rituximab; only 4 (13%) had received alemtuzumab. Sixteen pts (50%) responded [8 CR (25%), 1 PRn (3%), 7 PR (23%)] following one course. Response by site: peripheral blood 24/26 (92%), marrow 22/32 (69%), lymph nodes 13/26 (50%) and liver/spleen 8/9 pts (89). The combination was well tolerated with no unexpected toxicities. Most non-hematologic AEs were infusion-related and ≤ grade 2 by NCI toxicity criteria. Fevers and chills occurred in up to 56% of pts, fatigue in 34%, skin rashes in 19%, nausea in 16%, myalgias in 9%, and diarrhea in 6%. Although toxicites were more frequent with civ alemtuzumab than during the s.c. injections (with the exception of skin rashes), civ alemtuzumab was well tolerated. CMV reactivation occurred in 7 pts (22%) and was the most common infectious complication. In conclusion, the combination of civ/sc alemtuzumab plus rituximab has activity in patients with relapsed and refractory CLL. Most responses occurred after 4 weeks of therapy only. The combination is well tolerated. Side effects are predictable and manageable.

Topics:
alemtuzumab, brachial plexus neuritis, chronic lymphocytic leukaemia recurrent, intravenous infusion, continuous, rituximab, subcutaneous injections, chronic lymphocytic leukemia refractory, exanthema, toxic effect, acetaminophen

Disclosures: Rtuximab in CLL.; Berlex, Genentech.; Speaker’s bureau with Berlex and Genentech; advisory committee with Berlex.

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2006, The American Society of Hematology
2006
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