Reduced Intensity Conditioned Volunteer Unrelated Donor Transplants Using Alemtuzumab Are Safe and Effective in Older Patients with Myelodysplastic Syndromes.
Authors: Lim ZiYi , Ho Aloysius , Kenyon Michelle , Devereux Stephen , Duarte Rafael , Pagliuca Antonio , Mufti Ghulam 
Published: October 2019

Abstract
Use of myeloablative conditioning HSCT regimens have been limited to a select group of patients with MDS. This is due in part to the high transplant related mortality, which is closely associated with increasing recipient age as well as the degree of HLA parity. We have conducted a prospectively designed, single-center study to assess the efficacy of an RIC regimen consisting of fludarabine, busulphan, and alemtuzumab (FBC) in 75 patients with MDS utilizing hematopoietic stem cells (HSC) from VUD. The RIC protocol consisted of 30 mg/m2 fludarabine iv from day −9 to −5; 4 mg/kg oral busulphan from day −3 to −2; and 20 mg alemtuzumab iv from day −8 to −4. Patients received cyclosporine A for GvHD prophylaxis. All patients possessed relative or absolute contraindications to conventional myeloablative HSCT. 30 patients received RIC on the basis of advanced age alone. 13 patients had been treated for IPA within 3 months of transplantation. Median age of patients was 52 years (range 24–68 years). The stem cell source was BM in 28 patients and PBSC in 47 patients; median CD34 cell doses were 2.25 x 106/kg (range:0.7–9.7) and 6.2 x 106/kg (range:0.7–17.8), respectively. 23 (31%) donor-recipients were mismatched on 1 or more HLA loci. 49 patients (65%) had an IPSS stage of ≥Int-2, and 55 (73%) had received induction chemotherapy prior to HSCT. 67 patients (89%) had stable disease or were in complete morphological remission at time of transplant. Mean time to engraftment was 13 days for neutrophil count >0.5 x 109/L, and 16 days for an unsupported platelet count >20 x 109/L. Three patients had primary graft failure. With a median follow-up of 315 days (range:36–2096), 38 patients (51%) were alive at the time the data were censored. The median follow-up for survivors was 752 days (range:74–2096). The Kaplan-Meier estimates of OS at years 1 and 2 were 55% and 47%, respectively. Similarly, at years 1 and 2, NRM was 10% and 30%, respectively, and DFS was 48% and 40%, respectively. Significantly, the OS and DFS curves plateau at day+902 and day+799, respectively, suggesting that longer term disease eradication can be achieved. The prognostic significance of IPSS, cytogenetic risk and disease status at transplantation was maintained in our cohort. 20 patients received DLI post transplantation. DLI was given for falling donor chimerism in 10 recipients, with re-establishment of full-donor chimerism in 9 patients. While DLI was effective against cytogenetic relapses (response rate 50%), it was less effective against established morphologic relapse (response rate 33%). Limited and extensive de novo chronic GVHD occurred in 14 patients (18%) and 12 patients (17%) respectively. Following DLI, the overall cumulative incidence of acute grade III-IV GvHD at 2 years was 25%. When chronic extensive GvHD was present in the study, it significantly correlated with a lower relapse rate (p<0.05). CMV reactivation occurred in 21 (28%) patients at a median time of 59 days (range:29–215 days) following transplantation, with 2 patients developing CMV disease. Two patients had IPA post-transplant; however, none of the 13 patients with recent IPA pre-transplant experienced progression of the infection. In our cohort of older patients with a high degree of HLA disparity and significant co-morbidities, RIC HSCT regimen utilizing FBC, can serve as a platform for durable engraftment, with a low incidence of GVHD, favorable TRM, and long-term DFS.