Donor Lymphocyte Infusion Management and Impact on Transplant Outcome after Reduced Intensity Conditioning Allogeneic Transplantation.
Authors: Michallet Mauricette , Le Quoc-Hung , Michallet Anne-Sophie , Thiebaut Anne , Tavernier Emannuelle , Rafii Hanadi , Revesz Daniela , Troncy Jacques , Praire Aline , Gadolet Elodie , Dubois Valerie , Gebuhrer Lucette , Hequet Olivier , Bourgeot Jean-Paul , Nicolini Franck E. 
Published: October 2019

Abstract
Management of donor lymphocyte infusions (DLI) after reduced intensity conditioning regimen allogeneic hematopoietic stem cell transplantation (RICT) remains not clear and needs prospective studies. We performed a retrospective analysis on 47 patients (29 males and 18 females) who received 94 DLI among 96 patients who underwent RICT in our institution. Twenty-four patients received 1 DLI (D) [mean dose: 0.3x108 CD3 /Kg (0.01–1)] and 70 escalating doses (ED) [2 DLI (n=10), 3 DLI (n=9), 4 DLI (n=1), 5 DLI (n=1), 6 DLI (n=1) and 8 DLI (n=1)] from 0.1 to 5.6x108 CD3/Kg. The diagnosis pretransplant was acute leukemias (n=10) and myelodysplasia (n=3), chronic myeloid leukemia (n=2), Hodgkin (n=7) and non Hodgkin lymphomas (n=6), multiple myeloma (n=14) and solid tumours (n=5). Twenty patients have already been transplanted before RICT and 9 patients were in complete remission (CR), 19 in partial response (PR), 18 in evolutive disease (EDis). As hematopoietic stem cells, 22 patients received peripheral blood and 25 bone marrow and as conditioning 26 patients received busulfan, fludarabine and anti-thymocytes globulines (ATG), 13 patients TBI 2 grays associated to fludarabine (n=8) and 6 grays associated with cyclophosphamide (n=5), 5 patients received cyclophosphamide and ATG and 3 patients aracytine, idarubicine and fludarabine. After transplant and before any DLI, 21 developped acute GVHD (11 grade I, 8 grade II and 2 grade III). The indications and results after DLI are given in the Table 1.
Only 4 patients received DLI for two different indications within time: 2 for relapse firstly and partial chimerism secondly and 2 according to protocol requirement firstly and for relapse secondly. After DLI, we noted 18 acute GVHD (7 grade I, 4 grade II, 6 grade III and 1 grade IV), 9 were resolutive after specific therapy and 18 patients developed chronic GVHD (13 limited and 5 extensive). Probability of overall survival at 2 years of patients who underwent RICT including DLI (n=47) was significantly better than for patients undergoing RICT without DLI (n=57) [43% (95%CI 30.5–60.4) vs 31.5 (95%CI 18.8–52.8) (p=0.01)] but there was no difference when we consider EFS [20.7% (95%CI 11.6–36.8) vs 21.6% (11–42.5) (p=0.49)]. We performed for patients receiving DLI a multivariate analysis stratified on diagnosis studying sex, age, status at transplant and mean dose of infused lymphocytes and we demonstrated that lymphocyte dose had a significant negative impact on EFS (HR= 1.06 95% CI 1.01–1.10) (p=0.01). To better understand the real place of DLI within allogeneic immunotherapy against malignancies, we need more details about the results of DLI in retrospective analysis but principally prospective studies in the future.
TABLE 1
Indication of DLI Nb of patients Nb of DLI DLI (D) DLI (ED) Dose x 10 exp8 CD3/Kg Response to DLI Evolutive Disease N = 34 23 2.26 10 13 1.46 EDis 5 1.6 2 3 0.66 CR 6 1.5 2 4 0.45 PR Mixed Chimerism N = 7 6 1.5 5 1 0.7 Total Donor 1 1 1 0 0.7 Mixed Chimerism Protocol N = 6 1 1 1 0 0.1 CR 3 1.6 2 1 0.34 PR 2 2 1 2 0.52 EDis