Allogeneic Stem Cell Transplantation with Immunodepleted Grafts for Lymphoproliferative Malignancies

Introduction: The treatment of lymphoproliferative disorders that fail initial therapy remains unsatisfactory. Allogeneic stem cell transplantation can be curative but has been associated with high treatment related mortality, particularly from graft vs. host disease (GvHD). Immunodepletion of the peripheral blood stem cell (PBSC) graft with alemtuzumab effectively prevents GvHD.

Methods: Patients with lymphoma (excluding diffuse large B-cell) in second or subsequent response were offered allogeneic stem cell transplantation if they had a human leukocyte antigen (HLA) compatible donor. Haematopoietic stem cells were mobilized with filgrastim (5-10 ug/kg) and PBSC were collected by apheresis. Patients were conditioned with myeloablative doses of chemotherapy or radiotherapy. For GvHD prophylaxis mobilized donor blood stem cells were incubated ex vivo with alemtuzumab (in the bag) for 30 minutes and infused intravenously. Post transplantation patients received therapeutic blood levels of cyclosporine until day 90. The end points of the study were frequency of GvHD, transplant mortality, disease recurrence and overall survival (OS) rates.

Results: Sixty one consecutive patients with lymphoma (follicular 17, marginal zone 2, Waldestrom’s macroglobulinaemia 2, transformed 16, peripheral T-cell 16 [all ALK negative] and lymphoblastic 8) underwent allogeneic transplantation. None had received a previous transplant. PBPC were from siblings in 53 patients and 8 from unrelated donors. Twenty patients were female and the median age was 47 years. The median CD34+ cell number infused was 4.71 (1.31 – 17.88) x10^6/kg. The median dose of alemtuzumab added into the bag was 10 mg. All recovered the blood counts at median of 13 days. Seventeen (28%) patients died, 11 (18%) of transplant related causes. Chimerism studies performed in 42 patients showed full donor chimerism in each case. GvHD (> grade 1) was seen in 8 patients (13%). Cytomegalovirus reactivation occurred in 21% but all responded to gancyclovir. Seventeen patients died, 11 (18%) of treatment related complications. Eight patients had disease recurrence, two of three achieved further response after donor leukocyte infusion and six died of the malignancy. At median follow up of 2260 15-4412) days 71% are alive in response. There was no difference in survival among the 4 histological groups or between chemotherapy and radiotherapy based conditioning. In univariate analysis female donor gender (for male patients) and GvHD were significant adverse factors for survival. Cox analysis showed that occurrence of GvHD (p= 0.001) was an independent significantly adverse factor for survival.

Conclusions: We conclude that ex vivo immunodepletion of grafts with alemtuzumab leads to reduced rates of GvHD and results in lesser treatment related mortality despite myeloablative conditioning. Recurrence rates appear low suggesting that in the absence of GvHD prescribing dose intense conditioning and allogeneic stem cell transplantation earlier, before the malignancy is refractory, could be an effective strategy for patients with advanced lymphoma.