Efficacy and Toxicity of Donor Lymphocyte Infusions in the Management of Mixed Donor-Recipient Chimerism Following Allogeneic Stem Cell Transplantation for Lymphoid Malignancies:- a Study of the LWP-EBMT
Authors: Robinson Stephen , Boumendil Ariane , Khvedelidze Irma , Finel Hervé , Peggs Karl , Malladi Ram K , Potter Victoria , Tsoulkani Anna , Vandenberghe Elisabeth , Chalandon Yves , Finke Jürgen , Marijt Erik , Furst Sabine , Schaap Michel , Hunter Hannah , Snowden John A , Wadehra Karan , Wittnebel Sebastian , Beelen Dietrich W. , Fegueux Nathalie , Kroeger Nicolaus , Dreger Peter , Montoto Silvia 
Published: October 2019

Abstract
Introduction
The development of mixed donor recipient (MDR) chimerism is a frequent occurrence following allogeneic transplantation (alloSCT) for lymphoid malignancies. There is evidence that achievement of full donor (FD) lympho-haematopoietic chimerism (LHC) is associated with a lower chance of disease recurrence and consequently donor lymphocyte infusions (DLI) are commonly employed in this setting. There is however a paucity of data describing both the efficacy of DLI in achieving FD LHC and their toxicity in terms of inducing graft versus host disease (GVHD). We therefore undertook a large survey within the EBMT to determine the efficacy and toxicity of DLI when used for MDR LHC.
Methods and Patients
All centres within the EBMT database that had administered DLI for MDR LHC in patients undergoing an alloSCT for lymphoid malignancies were invited to submit additional data for this study. Data was provided for 135 patients from 36 centres. The median age at diagnosis was 44.6 years (15-64) and the median age at SCT was 47 years (range 19-68). Patients were diagnosed with DLBCL (n=17), follicular NHL (n=45), Hodgkin lymphoma (n=21), mantle cell lymphoma (n=32), T cell lymphoma (n=14) and other lymphoid malignancies (n=6). Prior autologous transplantation had been performed in 45 patients. 122 patients underwent reduced intensity conditioning prior to transplantation from a matched sibling donor (n=90), unrelated donor (n=42) or mismatched family donor (n=3). T cell depletion (TCD) of the graft was performed in 33 cases.
Results
MDR LHC was demonstrated by analysis of whole blood (WB) in 34 patients and in T cell and myeloid lineages in 101 patients. The median time from alloSCT to the demonstration of MDR LHC was 4.9 months (range 4.6-63) and the median time to the 1st DLI was 7.8 months (range 1-63). Patients received a median of 2 DLI (range 1-20) at a median starting dose of 1x106 CD3/kg recipient (range 0.1-380 x 106/kg). Of the 135 patients receiving DLI 121 were assessable for response with 94 (78%) achieving full donor LHC, 24 (20%) remaining MDR, 2 patients became fully recipient and one patient had a mixed response (FD in T cells but MDR in myeloid lineage). For the patients that received DLI for T cell MDR chimerism (N=71, with 64 assessable for response) 55 (86%) became FD, 8 (12.5%) remained MDR and 1 became fully recipient. For patients that received DLI for myeloid MDR chimerism (with or without MDR chimerism in the T lineage) (N=30, with 29 assessable for response) 17 (59%) converted to full donor in the myeloid lineage, 10 (34%) remained MDR, 1 had a mixed response and 1 became full recipient. If patients required 3 or more DLIs the chance of conversion to FD fell significantly to 55% compared to 89% for those that only received 1 DLI (p<0.001). There was a trend to a higher rate of conversion to FD in patients that had received a T replete graft (81%) compared to those that had received a T depleted graft (52%)(p=0.063). The dose of the first DLI and donor type had no impact on conversion to DLI.
Acute GVHD developed in 45 of 134 (34%) evaluable patients after the 1st DLI (grade I in 12, grade II in 12, grade III in 6, grade IV in 8 and grade unknown in 7). Chronic GVHD developed in 36 of 130 (28%) evaluable patients which was extensive in 13 (10%). Acute GVHD (grades II-IV) was seen more commonly after the 1st DLI than after 2 or more DLIs (68% post 1st DLI vs 14% after 2 or more DLIs at 100 days p=0.002) and in patients undergoing unrelated donor transplantation (62% vs 23% at 100 days, p=0.02). Chronic GVHD was more common after DLIs given to patients that had received a TCD graft (39% vs 17% p=0.007). The median follow-up after the 1st DLI was 70 months (range 11-149). Relapse following DLI occurred in 36 (27%) patients which was more common in patients receiving DLI for myeloid MDR chimerism compared to T cell MDR (40% vs 22.5%). Disease relapse occurred in 36 (27%) patients after receiving the first DLI, 11 of whom had achieved full donor FD LHC prior to relapse. In a time-dependent Cox model conversion to FD LHC was not protective against relapse.
Conclusions. In this large series of patients with lymphoid malignancies the administration of DLI is an effective strategy for achieving FD chimerism particularly when the MDR chimerism is restricted to the T cell lineage. Development of GVHD is a significant complicating factor particularly in the unrelated donor setting and when the original graft was T cell depleted.

Disclosures
Robinson: Roche: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Sandoz: Speakers Bureau. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs. Finke:Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding. Beelen:Medac: Consultancy, Other: Travel Support.