The multicenter CLL2H trial of the GCLLSG evaluated subcutaneous alemtuzumab 3 × 30 mg weekly in fludarabine refractory CLL. From September 2002 to February 2006, 103 patients were enrolled and received at least one dose of alemtuzumab. Median age was 63 (35.1–81.8) years, 72% were male, 74% were Binet C, and a median of 3 (1–10) prior lines had been given. Unfavorable genetics were frequent (17p deletion: 29%, 11q deletion: 19%, unmutated IgVH: 68%, TP53 mutation 34%).
Subcutaneous treatment was performed on an outpatient basis in 96% and had to be temporarily interrupted in 65 patients due to neutropenia (27%), anemia (3%), thrombocytopenia (8%), infections (36%), and was stopped early in 65 cases due to insufficient response (43%), hematotoxicity (14%) and infections (29%). The median alemtuzumab dose given was 722 (3–2203) mg.
Toxicity during treatment period was mostly grade I/II apart from hematotoxicity. Grade 3/4 neutropenia, thrombocytopenia, anemia occurred in 56%, 57%, and 50% of patients, respectively. Grade 3/4 non-cytomegalovirus infection occurred in 29%. CMV reactivation was observed in 15 % total, Grade 3/4 occurred in 8% of patients. All CMV episodes were successfully treated with anti-CMV therapy, and there was no CMV-related death. Injection site reaction occurred in 34% and was grade 1 or 2 except in 1 patient who had grade 3 reaction.
Pegfilgrastim prophylaxis was scheduled for the second half of the trial. Grade 3/4 neutropenia occurred in 70% vs 46% and non-CMV infections occurred in 32% vs 24% in the first and second half, respectively.
Development of anti-alemtuzumab antibody was assessed in samples from 21 patients. Plasma anti-alemtuzumab antibody was detectable in only 1 patient, who had a concentration marginally above the detection threshold and was found to be negative in a re-test 5 months later. Stable disease was achieved in this patient.
After a median follow-up time of 37.9 months, there were 75 (73%) deaths, 56% due to disease progression, 31% due to infection, and 13% not related to CLL. Overall response rate was 34% (CR 4%, PR 30%), median progression free survival time was 7.7 months, and median overall survival time was 19.1 months.
Clinical and biologic parameters (age, sex, B-symptoms, stage, ECOG, number of prior lines, node size, hepato-spenomegaly, WBC, LDH, β2-MG, TK, VH status, genomic aberrations and TP53 mutation) were evaluated for their prognostic role. In univariate analyses, OS was significantly inferior for age > 65 y (12.2 vs 29.0 mo, p<.001), ECOG > 1 (10.8 vs 21.5 mo, p=.011), TK > median (26U/L) (14.9 vs 29.0 mo, p=.001), and β2- MG > 5 (13.6 vs 27.2 mo, p=.004). Median PFS and OS were not different for 17p-, 11q-, other cytogenetic and TP53 mutation subgroups. Multivariate analysis by Cox regression revealed only age (HR 1.6, p<.001) as significant prognostic factor, while TK (p=.11), β2- MG (p=.089), and 17p- (p=.528) showed no significant impact.
The choice of next therapy significantly affected survival. Seventy-four patients received subsequent salvage treatment or allogeneic stem cell transplantation (SCT). The median OS since next therapy in these patients was 11.5 months. The 2-year OS rate for allogeneic SCT as compared to other subsequent treatments (chemo-, immuno-, or chemoimmunotherapies) was 86% and 27% (p=0.009).
Disclosures: Stilgenbauer:Bayer: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding.