Title - Reduced Intensity Conditioning in Transplants for Patients with Sickle Cell Disease: Effect of “Late” Alemtuzumab

Alemtuzumab (humanized CD52-monoclonal antibody), a potent T cell inhibitor, is often included in reduced-intensity conditioning (RIC) regimens. Modeled on the successes of such regimens, newer alemtuzumab-containing RIC regimens are being increasingly used for patients with hemoglobinopathies. We retrospectively reviewed the possible impact of “late” alemtuzumab (i.e., administered on days -10 through -8) with respect to engraftment and acute/chronic GvHD in nine pediatric patients (median age 10 y, range 5.1-18.6yrs)with sickle cell disease who underwent stem cell transplantation from HLA-matched sibling donors.  All patients received alemtuzumab 10 mg IV daily on days –10 through –8, fludarabine 35 mg/m²/day IV on days –7 to –4, and melphalan 70 mg/m² IV on day -3 and day -2.  Alemtuzumab was given relatively close to the day of transplant with intent to diminish the incidence of graft versus host disease. Eight out of 9 patients received marrow and 1 patient received marrow and cord blood. Median nucleated cell dose was 2.3 x 10⁸/kg (Range: 1.46-4.3), with median CD34 cell dose of  1.6 x 10⁶/kg (range: 0.9-5.5). Median time to neutrophil and platelet engraftment was 15.5 and 36 days, respectively, in our study. All of the patients received the GvHD prophylactic regimen comprising of Cyclosporine and Mycophenolate, both beginning on day -1 of transplant.  All patients have been followed a minimum of 3.5yrs post-transplant.  One patient developed mild acute GvHD of the skin and another developed limited chronic skin GvHD (taken off immunosuppressants at 2 yrs post transplant). Two patients experienced graft failure within three months and a third one within 14 months post transplant (two of whom underwent successful second transplants 12 mos and 18 mos later while the third elected to not undergo retransplantation and is now transfusion dependent). 6 patients became durably engrafted and remain disease-free.Since 3 of the 9 patients rejected their grafts, the conditioning regimen was modified to include the same three agents but with alemtuzumab given between days -21 and -19. Results in five subsequent pts have yielded no instances of graft rejection.  Due to its relatively long half-life (15-21 days), alemtuzumab, when given close to the day of stem cell infusion, may reduce the likelihood of acute GvHD but may also lead to in-vivo T-cell depletion of the donor graft, thereby increasing the probability of graft loss.  In this small study, this latter effect outweighed the possible benefit of reducing the likelihood of acute GvHD.  This may be particularly true in this patient population which comes to transplantation with an intact, and often sensitized, immune system.