Reduced Intensity Allogeneic Transplantation Using BEAM-Alemtuzumab in Patients with Lymphoid Malignancy: Long Term Results and Impact of Intervention with DLI.
Authors: Das-Gupta Emma P. , Byrne Jennifer L. , Craddock Charles , Robinson Stephen , Devereux Stephen , Pagliuca Antonio , McQuaker Grant , Haynes Andrew P. , Mufti Ghulam , Russell Nigel H. 
Published: April 2020

Since 1997, 91 patients with lymphoid malignancy have undergone reduced intensity allogeneic transplantation using BEAM-Alemtuzumab conditioning (BCNU, etoposide, Ara-C, melphalan and Alemtuzumab on days −5 to −1). The median age of the patients was 44.7 years (range 7.6 – 65.0). 70 patients had an HLA identical (n=65) or 1 antigen mismatched (n=5) sibling, 21 a fully matched (n=17), 1 antigen mismatched (n=2) or 2 antigen mismatched (n=2) unrelated donor (VUD). Fludarabine (30mg/m2 days −9 to −7) was added in patients receiving VUD transplants. The median follow up post transplant is 3.4 years (0.2 to 8.5). DLI was used for persisting disease, relapse or mixed chimerism. Pre-transplant histology was low-grade NHL (n=29), mantle cell lymphoma (MCL) (n=10), Diffuse large B cell lymphoma (DLCL) (n=19), CLL/PLL (n=15), PTCL (n=7), Hodgkin’s lymphoma (n=11). The stem cell source was PBSC (n=78), BM (n=12), PBSC/BM (n=1) and cord blood (n=1). 13 patients received prior autologous transplantation. Cyclosporin and methotrexate (10mg/m2 days +1, +3, +6) were used for GVHD prophylaxis.

Engraftment occurred in 79/86 evaluable patients (92%). 73% achieved CR post-transplant. 64 patients remain alive and 57/64 (89%) are in CR. Acute GVHD occurred in 17/81 (21%) evaluable patients but only 2 developed grade III/IV acute GVHD pre-DLI. Chronic GVHD developed in 11/78 (14%) evaluable cases pre-DLI. The estimated 1 year TRM was 10% for patients undergoing first transplantation and 38% for those who had received a previous autograft (p=0.003). The estimated relapse risks at 2 and 5 years were 20% and 27% respectively. The estimated 3 year EFS and OS were 49% and 65% respectively, the discrepancy highlighting the impact of DLI-based therapy. There was no significant difference in OS between patients receiving sibling and VUD transplants. In patients with sibling donors the estimated 3 year OS was 79% for those below the median age compared to 47% for those above (p=0.006). This was due to the higher TRM in older patients (6% below median vs 31% above at 2 years, p = 0.012). The effect of age on OS and TRM could not be analysed for patients receiving MUD transplants due to the small number of events. 17 patients received DLI as treatment for persistent or relapsed disease post-transplant. 7 patients developed acute GVHD post-DLI (1 grade I, 4 grade II, 2 grade III) and 5 patients developed chronic GVHD (2 limited, 3 extensive). One patient died of extensive chronic GVHD. 8/17 patients who received DLI are now in CR, including patients with CLL/PLL (3/3), MCL (2/2) and FL (3/3) but none with DLCL. Thus the current PFS at 3 years taking into account the effect of DLI is 59% overall and 64% for low-grade NHL, 58% for CLL/PLL, 57% for PTCL, 68% for Hodgkin’s lymphoma, 57% for MCL and 48% for DLCL.

These results demonstrate that BEAM-Alemtuzumab conditioning for allogeneic HSCT supported by DLI for residual/relapsed disease results in excellent long term disease control with a low TRM and risk of GVHD. Patient age at transplantation and previous autologous transplantation have a significant impact on OS and TRM.