Efficacy of Donor Lymphocyte Infusions in Myelodysplastic Syndromes Relapsing after Allogeneic Stem Cell Transplantation: Importance of Karyotype.
Authors: Selleslag Dominik L.D. , Nollet Friedel , Billiet Johan , Van Droogenbroeck Jan , Van Hoof Achiel , Van Eygen Koen , Hidajat Melanny , Criel Arnold 
Published: October 2019

Abstract
Few studies have reported on the efficacy of donor lymphocyte infusions (DLI) for myelodysplastic syndromes (MDS) relapsing after T-cell depleted allogeneic stem cell transplantation. Since 1996 we have treated 11 patients with DLI as a single therapeutic modality (without chemotherapy) for a relapse of MDS after allogeneic stem cell transplantation. Median age of the patients was 56 years (range 23 to 73 years). Initial diagnosis was RAEB (4 patients), RAEBt (3 patients), secondary AML(3 patients) and MDS with fibrosis (1 patient). Conditioning was myeloablative in 10 patients ( TBI -Cyclophosphamide, Busulfan-Cyclophosphamide or Busulfan-Melphalan) and non-myeloablative in 1 patient (Busulfan-Fludarabine-ATG). Source of stem cells was peripheral blood in all patients. Donors were HLA-identical siblings in 10 patients and HLA-matched unrelated in 1 patient. Allografts were T-cell depleted with Campath 1H in the bag in 8 of 11 patients. GVHD prophylaxis was cyclosporin in all patients combined with methotrexate in the 3 patients receiving unmodified stem cells. Relapse of MDS occurred at a median of 123 days (54 to 373 days) after allograft. At the time of DLI the percentage of blast cells in the bone marrow ranged from 3 % to 50 % (median 6 %); donor chimerism ranged from 14 % to 91 % (median 72%). The total dose of CD3 lymphocytes ranged from 0.1 to 30 x 10 7 /kg (median 0.6 x 10 7/kg) and was administered in 1 to 4 infusions (median 1). Time interval between first and second DLI varied between 7 and 180 days.Three of the 11 patients achieved a durable complete remission with 100 % donor chimerism after DLI. These 3 patients are currently disease free at 20, 30 and 40 months from the first DLI. All durable responses were associated with limited chronic GVHD requiring temporary immunosuppressive therapy. Time interval between the first DLI and the achievement of complete donor chimerism varied between 6 weeks and 9 months. One of the 11 patients achieved a short state of complete chimerism for 4 weeks and died from relapse 146 days after DLI. Five of the 11 patients progressed after DLI and 4 of them died from disease progression at 29 to 112 days after first DLI. Two patients died at 26 and 97 days after the first DLI from acute GVHD grade IV after having received only 1 x 10 6 CD3 lymphocytes /kg from HLA-identical sibling donors. None of the 6 patients with a complex karyotype responded to DLI while 3 of 3 patients with a single chromosomal abnormality ( t(1,14), t(1,17), t(1,3)) had a durable response (p-value = 0.01). We conclude that DLI is a powerful therapy for about 30 % of MDS patients relapsing after T-cell depleted allogeneic stem cell transplantation. DLI may result in durable remissions particularly in patients with non-complex cytogenetic abnormalities. However, even low doses of donor T lymphocytes may cause mortality from severe GVHD.