Pilot Randomized Trial Comparing the Effects of Alemtuzumab and Cyclosporine Versus Tacrolimus, Methotrexate and Sirolimus on Graft Versus Host Disease Prevention, Engraftment and Immune Reconstitution After Reduced Intensity Unrelated Donor Transplantation.

Abstract 1245

A clearly superior graft-versus-host disease (GVHD) prophylaxis regimen has not been established for patients undergoing reduced intensity allogeneic hematopoetic stem cell transplantation (HSCT) from matched unrelated donors (URD). Encouraging results have been reported with both the combination of alemtuzumab plus cyclosporine (AC) (Chakraverty R et al Blood 2002) and the regimen of tacrolimus, methotrexate, and sirolimus (TMS) (Antin JH et al, Blood 2003) in the URD setting. These two regimens work by biologically distinct mechanisms and may have markedly different effects upon engraftment and immune reconstitution. As part of a randomized pilot study, we prospectively assessed the effects of the AC and TMS regimens on GVHD, engraftment, and immune reconstitution in the setting of targeted lymphocyte-depleting chemotherapy and reduced-intensity allogeneic HSCT from HLA-matched URD. Twenty patients (median age 53 yrs; range 24–70) with high risk hematologic malignancies (median prior regimens = 4; chemo-resistant disease = 35%) received disease-specific induction chemotherapy (DA-EPOCH-FR or FLAG) prior to transplantation for disease control and lymphocyte depletion. All patients then received conditioning with fludarabine 30 mg/m²/day × 4 days and cyclophosphamide 1200 mg/m²/day IV × 4 days followed by a T-cell replete mobilized peripheral blood allograft from a 10/10 HLA-matched URD. Patients were randomized at the time of enrollment to receive either: AC (n=10): alemtuzumab 20 mg/day IV over 8 hours Days -8 to -4 and cyclosporine starting at Day -1 with a 10% per week taper starting at Day +100 or TMS (n=10): tacrolimus and sirolimus starting at Day -3 with a 33% taper at Day +63 and Day +119 and methotrexate 5 mg/m² IV, days +1, +3, +6, and +11. Treatment related mortality at Day +100 and 1 year for all 20 patients was 5% and 17% respectively. Actuarial event free and overall survival at 1 year after transplantation were 70% and 85% respectively; cumulative incidence of relapse at 1 year was 15%. There were no graft rejections on either arm. Median CD3⁺ chimerism in the AC vs TMS group was 86% vs 99% at Day+14 (p=0.025), 100% vs 98% at Day+28 (p=0.63) and 100% in both groups at Day+100 (p=0.83). Median CD14⁺/15⁺ chimerism in the AC vs TMS group was 93% vs 100% at Day+14 (p=0.020), 99% vs 100% at Day +28 (p=0.12) and 100% in both groups at Day +100 (p=0.89). The overall incidence of acute GVHD in the AC arm was 30% (Grade II-IV = 20%; Grade III-IV = 10%) and 40% in the TMS arm (Grade II-IV = 20%, Grade III-IV = 10%). With a median follow-up of 18 months, chronic GVHD was seen in 70% of patients in the AC arm (mild =10%, moderate = 40%, severe = 20%) and 60% in the TMS arm (moderate = 40%, severe = 20%). Patients on the AC arm had significantly less T-lymphocyte recovery by Day +14 compared with the TMS arm (median CD3⁺ = 1 cells/μl vs 356 cells/μl; CD4⁺ = 0 cells/μl vs 243 cells/μl; CD8⁺ = 0 cells/μl vs 59 cells/μl; each p<0.0001); this was less disparate at Day +28 (median CD3⁺ = 45 cells/μl vs 398 cells/μl; CD4⁺ = 36 cells/μl vs 218 cells/μl; CD8⁺ = 5 cells/μl vs 152 cells/μl; each p≤0.002). By Day +100, lymphocyte recovery was not appreciably different between the two groups (median CD3⁺ = 242 cells/μl vs 445 cells/μl CD4⁺ = 106 cells/μl vs 212 cells/μl, CD8⁺ = 72 cells/μl vs 135 cells/μl; each p>0.03). NK-cell recovery was slightly less in the AC arm compared with the TMS arm at Day +14 (median NK = 14 cells/μl vs 70 cells/μl; p=0.01) and at Day +28 (median NK = 29 cells/μl vs 150 cells/μl; p=0.02). There was no difference by Day +100 (median NK = 124 cells/μl vs 88 cells/μl; p=0.31). B-cell reconstitution was negligible in both groups up through Day +100. At median 18 month follow-up, patients treated on the AC arm had experienced a total of 28 episodes of Grade III-IV infections compared with 23 episodes on the TMS arm. These initial data suggest that AC and TMS provide approximately equivalent GVHD prevention and comparable time to full donor chimerism. However, the AC regimen was associated with later lymphocyte and NK cell recovery and a higher number of infectious episodes, raising a potential concern for increased infection risk with the AC regimen. It is also notable that despite delayed lymphocyte recovery in the AC arm, there were still comparable rates of acute GVHD with the TMS arm. Based on these initial data, we have expanded patient accrual and extended enrollment to recipients of HLA-mismatched URD.