High Response Rate to DLI Based Strategies for the Treatment of Refractory Disease/Relapse Following Allogeneic HSCT for Lymphoproliferative Disease.
Authors: Russell Nigel H. , Byrne Jenny L. , Das-Gupta Emma P. , Gilyead Michelle , Haynes Andy P. 
Published: October 2019

Abstract
Allogeneic HSCT is increasingly being performed for lymphoproliferative disease, particularly with reduced intensity conditioning (RIC). DLI are an important part of this strategy however there is a paucity of information in this setting although responses have been reported in Hodgkin’s disease and follicular lymphoma. We have treated 17 patients (median age 51 year; 30–62yr) with refractory disease (n=7) or disease relapse (n=10) following allogeneic HSCT for lymphoma with a DLI based strategy. The diagnosis was CLL, including 1 Richter’s (n=5); mantle cell lymphoma (n=4); high grade NHL (n=4) and follicular NHL (n=4). 15 patients received RIC transplants with either Beam/Alemtuzumab (n=11), or fludarabine/melphelan/alemtuzumab (n=4). Two patients received myeloablative conditioning with TBI and cyclophosphamide. The median time to DLI was 0.96 years (0.23 to 4.58yr) and in 15/17 the donor was a matched sibling (n=13) or 1 antigen mismatched sibling (n=2) and in 2 cases was an unrelated donor. At DLI, 6 patients had mixed chimaerism (20–95%) and 8 had full donor chimaerism with the chimaerism status being unknown in 5 cases. Patients with low grade disease received DLI either alone (n=7) or following initial radiotherapy (n=1). Patients with high-grade NHL, MCL or Richter’s transformation of CLL (n=11) all received chemtherapy pre-DLI. For the 15 sibling donors the median first dose of CD3+ cells infused was 2.0 x 10 7/kg ( range 0.5–6 x 10 7/kg) following which 6 achieved CR. 6 patients received a 2nd infusion (median dose 5 x 10 7/kg) with 2 achieving CR and 1 patient receiving a 3rd DLI and achieving CR. Both MUD DLI recipients achieved a CR after 2 and 3 infusions. Overall 10 out of 17 patients achieved a CR including 3/4 patients with CLL, 4/4 with MCL; 3/4 with follicular NHL but none of the 5 patients with high-grade NHL/Richter’s transformation responded. The median CD3 cell dose required to achieve CR for sibling donors was 2x 107/kg whereas non-responders received a median of 5.0 x 107/kg. An additional patient with CLL who developed aplasia following the first DLI had a second transplant from the same donor and is in CR at 14m giving a final overall CR rate of 70%. Response to DLI was independent of chimaerism status at relapse. Acute GvHD developed in 11 patients and was grade II in 8/10 and grade 111/IV in 3 cases. 1 patient died in CR of acute GvHD. Chronic GvHD developed in 9 of 11 surviving patients. Only 1 patient with mantle cell lymphoma has relapsed at 18m post-DLI. The median follow-up for the surviving patients is 34m (range 6m–60m). The overall survival at a median of 30 months post DLI is 58%. We conclude that lymphoma patients, particularly those with low grade NHL including mantle cell lymphoma relapsing following an allogeneic transplant have a high response rate to DLI based strategies,superior to that seen in myeloma and comparable to that seen in CML. Furthermore these responses appear durable with a low risk of relapse. Patients with high-grade disease appear to have a poor response rate despite using pre-DLI chemotherapy