Anti-CD25 Monoclonal Antibody for Graft-Versus-Host Disease Prophylaxis Following Unrelated Donor Peripheral Blood Stem Cell Transplantation,

Enhanced risk of graft-versus-host disease (GVHD) makes one of major critical barriers to successful unrelated donor hematopoietic stem cell transplantation (URD-HSCT). Antithymocyte globulin (ATG) has been combined to standard GVHD prophylaxis regimens and significantly reduced GVHD in URD-HSCT. But ATG is associated with increases of infections and post-transplant lympholiferative disease (PTLD). Thus it is valuable to find alternative immunosuppressive agent for GVHD prophylaxis in URD-HSCT. Basiliximab and daclizumab, two anti-CD25 monoclonal antibodies, prevent graft failure in renal transplantation, which also effectively treat steroid-refractory graft-versus-host disease (GVHD). However, only few researches report that anti-CD25 monoclonal antibodies prevent GVHD. Here we firstly retrospectively explored the prophylactic effects of basiliximab or daclizumab against GVHD in 93 patients with hematological malignancies following unrelated donor peripheral blood stem cell transplantation (URD-PBSCT).

Between April 2004 and May 2011, 93 patients with hematological malignancies received basiliximab or daclizumab additional to standard GVHD prophylaxis regimens and underwent URD-PBSCT in our department. Their clinical data were retrospectively collected and analyzed. All patients received GVHD prophylaxis regimen consisting of cyclosporine A, short-course methotrexate, mycophenolate mofetil and an anti-CD25 monoclonal antibody. Basiliximab was administrated to 71 patients at a dose of 20 mg, while daclizumab was given to 22 patients at a dose of 1 mg/kg on day 0 (2 hours before transplantation) and day +4. Eighteen patients were 8/8 identical, 41 were 7/8 identical and 34 were 6/8 identical at HLA-A,-B,-Cw and -DRB1. The median number of infused nucleated cells and CD34⁺ cells were 7.5×10⁸/kg and 5.8×10⁶/kg, respectively.

i) All the recipients achieved engraftment. The median time to neutrophil recovery and platelet recovery were 12 days and 15 days, respectively. The rates of grade II-IV and III-IV acute GVHD (aGVHD) were 35.5% and 18.3%, respectively. Chronic GVHD (cGVHD) developed in 43.4% of evaluable patients. The limited cGVHD rate was 27.6% and the extensive cGVHD rate was 15.8%. The transplantation-related mortality (TRM) was 19.4% while relapse rate (RR) was 10.8%. The 2-year overall survival (2-yr OS) reached 74.2% and disease free survival (2-yr DFS) accumulated to 69.6% during a median follow-up of 24 months.

ii)The side effects of basiliximab and daclizumab were moderate and tolerable. The infectious rate was 66.7% including 44.1% bacterial infection, 10.8% probable or proven invasive fungal infection, and 11.8% mixed infection. The infection-related mortality was 7.5%. The CMV reactivation rate was 46.2% and only one patient suffered CMV pneumonia. Moreover there was no clinical evidence of PTLD.

iii) There were no significant differences in aGVHD onset and survival between daclizumab and basiliximab group. However, basiliximab presented superior prophylactic effects on cGVHD than daclizumab (cGVHD rate, 31.1% versus 66.7 %, P=0.007).

iiii) The aGVHD rate, cGVHD rate, RR, TRM, 2-yr OS and 2-yr DFS were compared among different HLA matching groups. There were significant differences in the occurrence of grade II-IV aGVHD (11.1% versus 36.6%, P=0.047) and cGVHD(18.8% versus 51.6%, P=0.03) between HLA 8/8 identical group and HLA 7/8 identical group. Comparing HLA 8/8 identical group versus HLA 6/8 identical group, there were not only significant decreases in the rate of grade II-IV aGVHD (11.1% versus 47.1%, P=0.01) and grade III-IV aGVHD (5.6% versus 32.4%, P=0.039), but also a significant increase in the RR (22.2% versus 2.9%, P=0.043). There were no significant differences between HLA 7/8 identical group and HLA 6/8 identical group. Interestingly, the survival was not significantly different among three HLA matching groups.

Basiliximab or daclizumab prevents GVHD efficiently and feasibly following URD-PBSCT, especially in HLA identical or only one allele mismatched recipients. Furthermore, anti-CD25 monoclonal antibodies benefit the outcome, even for those recipients with two or more HLA disparities. Basiliximab has similar effects on aGVHD prophylaxis but superior effects on cGVHD prophylaxis than daclizumab. Further prospective and randomized control studies are needed.

Off Label Use: Drug: basiliximab (Simulect, Novartis Pharmaceuticals); daclizumab (Zenapax, Roche Pharmaceuticals). Purpose: for graft-versus-host disease prophylaxis following unrelated donor peripheral blood stem cell transplantation.