Defining The Optimal Dose Of Alemtuzumab In Unrelated Donor Reduced Intensity Allografts: A UK Retrospective Study

Acute and chronic graft versus host disease (GVHD) represent major causes of morbidity and mortality following reduced intensity unrelated donor allografts, particularly in older patients. Alemtuzumab (AL, humanised anti-CD52 antibody) is highly effective at reducing the incidence of both forms of GVHD. There are a number of reported schedules used in this setting, with doses of between 50-100mg AL administered over 2-5 days. The timing of AL administration relative to stem cell return is also likely to have a significant impact on the depletion of donor T cells, but comparative data for unrelated donor transplants are lacking and the optimal dose and schedule remain unknown. In this three-centre retrospective study, we compared the post-transplant outcomes of patients receiving the same chemotherapeutic backbone of fludarabine 150mg/m² and melphalan 140mg/m² (flu-mel) along with the originally described AL regimen (100mg administered as 20mg/day, day -7 to -3, n=79), with those of patients receiving flu-mel and one of two alternative AL schedules: 60mg administered as 30mg/day, day -4 and -2, n=72; or 50mg administered as 10mg/day, day -7 to -3, n=107. In keeping with prior pharmacokinetic studies of de-escalating schedules in sibling donor cohorts, the day 1 serum AL levels in the 60mg cohort (median 4.7 mcg/ml, range 1.75-8.02 mcg/ml, n=14), did not differ significantly from historical data for the 100mg schedule. Donor lymphocyte infusions were given for mixed chimerism in all centres according to similar schedules starting at 6 months post transplantation. Median age at transplantation differed significantly between cohorts at 52, 45 and 56 years for the 100mg, 60mg and 50mg cohorts respectively (p = 0.005). Other statistically significant differences between cohorts were CMV status (p = 0.006) and disease indication (p = 0.0005); with AML patients constituting a majority in the 50mg cohort and lymphoproliferative disorder patients a majority in the 100mg cohort. No significant differences were detected between cohorts for HLA matching status (mismatched in 21/79 [27%], 12/72 [17%] and 33/107 [31%] respectively, p = 0.11), graft type (p = 0.06), or disease status at transplantation (p = 0.09). The incidences of acute grade II-IV GVHD were 35%, 32%, and 38% (p = 0.6) for the 100mg, 60mg and 50mg cohorts respectively, whilst those for grade III-IV GVHD were 4%, 6%, and 15% (p = 0.02). The corresponding incidences of chronic GVHD at 2 years were 29%, 28% and 39% respectively (p = 0.38). A trend towards a higher incidence of chronic GVHD in the 50mg cohort was confirmed by comparison with the combined data for the other 2 cohorts (29% vs 39%, p = 0.17). In the high-risk CMV cohort (seropositive recipient), reactivation requiring anti-viral therapy occurred in 97%, 77% and 76% respectively (p = 0.02). The incidences of full donor T-cell chimerism (>97% donor according to assay sensitivity) at day 100 were 56%, 29% and 44% respectively (p = 0.02). There were no significant differences with respect to non-relapse-related mortality at two years post-transplant (28%, 27% and 29% respectively, p = 0.57). Although univariate analyses of relapse rates and overall survival were confounded by the differences in patient characteristics between cohorts, no significant differences were observed (relapse rate at 3 years 20%, 20%, and 26%, p = 0.39; overall survival at 3 years 59%, 64% and 37%, p = 0.05). In conclusion, this study represents the first attempt to define an optimal dosing schedule for AL in unrelated donor allograft recipients, and suggests that significant reduction in AL dose is achievable for patients receiving flu-mel conditioning with unrelated donor grafts. There was evidence of more acute grade III-IV GVHD with the 10mg/day x5 schedule, and a trend towards a higher incidence of chronic GVHD, whilst the 30mg/day x2 schedule delivered similar results to the 20mg/day x5 schedule, perhaps in keeping with the comparable day 1 serum AL levels. Lower alemtuzumab doses were associated with a modest reduction in the risk of CMV reactivation in high-risk patients. Whilst the usual caveats associated with retrospective cross-institutional comparative studies apply, the data suggest that reduction to 30mg/day x2 is not associated with any significant detrimental impact and may be preferable on economic grounds.