Immunomodulation by Lymphodepletion and Donor Lymphocyte Infusion to Treat Post Allogeneic Transplantation Relapse
Authors: Guillaume Thierry , Gaugler Béatrice , Chevallier Patrice , Ayari Sameh , Delaunay Jacques , Moreau Philippe , Mohty Mohamad 
Published: October 2019

Abstract
Abstract 2084
Relapse of hematologic malignancies following allogeneic hematopoietic stem cell transplantation (HSCT) remains a major cause of treatment failure. For diseases other than CML, DLI remains relatively disappointing and retreatment with chemotherapy is required before resorting cell therapy. Lymphodepletion (LD) may enhance anti-tumor effects of transferred T cells. To prevent serious toxicity due to severe GvHD, we sequentially escalated both the LD and T cell doses infused with the DLI. LD consisted of Fludarabine (Flu) 25 mg/m2/d for 3 days followed by infusion of 1×107 CD3+ cells/kg. If no GvHD developed and disease persisted or progressed, the same LD was followed by a second DLI of 5×107 CD3+ cells/kg. In a second cohort, LD combined both cyclophosphamide (Cy) 600 mg/m2 for one day and Flu 25 mg/m2/d for 3 days followed by DLI at 5×107 CD3+ cells/kg. Eighteen pts, median age at transplant: 45 y (18-67), were treated for relapses of various non-CML hematologic malignancies (6 AML/MDS, 4 ALL, 3 HD, 2 T-NHL, 2 MM) following allogeneic transplantation (5 myeloablative conditioning, 12 RIC. Donors: 10 siblings, 7 MUD). DLI was the first relapse treatment or given following chemotherapy. Forty four DLIs were performed including 28 LD-DLIs. Prior to LD-DLI, eight patients received DLI not preceded by LD. Ten, 6 and 1 patient(s) received respectively 1, 2 or 3 LD-DLIs. The first LD-DLI was given at a median of 234 days (range 62 d–14y11m) following allogeneic transplantation. The first cohort (n=5) consisted of patients receiving LD with Flu alone. No severe toxicity was observed. In the second cohort (n=4) following a first LD-DLI with Flu alone, Cy was introduced along with Flu prior to DLI. Two patients developed GvHD: one cutaneous Grade II and another cutaneous grade III, liver Grade III and digestive Grade IV. The third cohort included 5 patients who had received prior DLI without LD and who were then treated with LD combining both Flu and Cy followed by high dose DLI (5×107 CD3+ cells/kg). Only one patient developed cutaneous Grade III GvHD. In the fourth group, 4 patients who had not yet received DLI, received LD with Flu and Cy followed by high dose DLI. In this latter group, one case of acute GvHD Grade IV was observed. The cumulative incidence of Grade II-IV acute GvHD was 29.4% with a median onset of acute grade II-IV GvHD following the last LD-DLI was 31 days (range 15–59). In comparison, the cumulative incidence of Grade II-IV GvHD in a control group of 54 patients (35 RIC, 19 myeloablative; donors: 50 siblings, 3 MUD, 1 mismatched unrelated donor) receiving DLI without lymphodepletion was 28.6% with a median onset of 34 days, range 12–120) not statistically different. Twelve patients received cytoreduction chemotherapy prior to DLI. In 9 patients, this failed to result in a complete remission, leaving 3 CRs after chemotherapy (2 AML, 1 MM). Following LD-DLI, 4 additional patients achieved a CR (1 AML, 2 ALL, and 1 T-NHL). After a median follow-up of 8 months (2 – 28.3) from the first LD-DLI, 8 patients (3 HD, 3 ALL, 1 AML, 1 MM) are alive; only 2 remain in CR (1 AML, 1 ALL). Ten patients died, 9 due to progression and 1 from lung cancer. Overall survival from the first LD-DLI is 40% at 2 years. The absolute number of leucocytes and the absolute number of CD4+ cells was compared prior to LD-DLI and 14 days following DLI; in those receiving Flu/Cy and DLI these were found to be decreased but not significantly (202±37 vs 113±38/mm3). The Treg cell population CD4+CD25high also decreased while the number of circulating CD11c+ (myeloid) dendritic cells and BDCA2+ (plasmacytoid) dendritic cells increased, none significantly. IL-7, IL-15 plasma levels remained undetectable at Day 14 post DLI. We conclude that LD-DLI in an escalated manner is not complicated by excessively severe GvHD while transient remission can be achieved. In our cohorts of patients, this did not translated into significant modification of T cells subsets or expansion of homeostatic cytokines. Based on these findings, continued studies with escalating doses are planned.

Disclosures:
Mohty: Genzyme: Consultancy, Honoraria, None, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria; Janssen Cilag: Consultancy, Honoraria; Celgene: Honoraria.