Adult Recipients of Matched Related Donor Blood Cell Transplants Given Pretransplant Antithymocyte Globulin Have Less Graft-Versus-Host Disease and Transplant-Related Mortality: Follow-Up of a Matched Pair Analysis.
Authors: Russell James A. , Larratt Loree M. , Turner A. Robert , Chaudhry M. Ahsan , Jeje Oluyeme , Morris Donald , Brown Christopher , Quinlan Diana M. , Stewart Douglas A. 
Published: October 2019

Abstract
Because pretransplant antithymocyte globulin (ATG) seems to reduce GVHD and TRM after unrelated donor BMT we have investigated this agent in matched related donor (MRD) blood cell transplant (BCT). Fifty-four adults receiving rabbit ATG (Thymoglobulin, Genzyme), cyclosporine A (CSA) and methotrexate with a first MRD BCT were matched for disease and stage (AML 16 CR1, 2 CR2, 12 advanced, ALL 6 CR1, 1 CR2, 2 advanced, CML 1 AP, 1 CP2, CLL 3 rel/ref, NHL 8 rel/ref, MM 2 rel/ref) with 54 patients not given ATG. Myeloablative conditioning for ATG pts comprised fludarabine (Flu) 50 mg/m 2 x 5 with busulfan (Bu) 4mg/kg PO x 4 (7), Bu 3.2mg. kg IV x 4 (36) or Bu 3.2mg. kg IV x 4 plus TBI 200cGy x 2 (10) and VP16 60mg/kg + TBI 1200cGy (1). Controls were given VP16 60mg/kg + TBI 1200cGy (26) or 500cGy (2), TBI 1200cGy + Cyclophosphamide (Cy) 120mg/kg (2) or Cy 180mg/kg (2), Bu 4mg/kg PO x 4 + Cy 120mg/kg and Bu 4mg/kg PO x 4 + Flu 50 mg/m 2 x 5. The ATG was given at a total dose of 4.5 mg/kg over 3 days finishing day 0. Surviving ATG recipients were followed for 49 to 89 months (median 72) and control pts for 90–137 months (median 110). Rates of acute GVHD (aGVHD) grade II–IV, aGVHD grade III–IV, chronic GVHD (cGVHD) and extensive cGVHD were 15±5% vs. 32±6% (p=0.036), 6±3% vs. 13±5% (p = ns), 67±7% vs. 97±3% (p = 0.035) and 50±7%vs. 95±5% (p = 0.005) in the ATG and control groups respectively. Patients given ATG had fewer sites of involvement by cGVHD than the control group (mean 1.87±0.22 vs 2.72±0.24, p = 0.013). Those ATG pts with cGVHD were treated for a median of 382 days compared with 473 for controls (p = ns). Of 46 ATG recipients with grade 0 - I aGVHD 41 lived beyond 105 days. Twenty-five discontinued CSA at 44 – 890 days (median 75) and 16 developed cGVHD while still on CSA. Of 37 control patients with grade 0 - I aGVHD 31 lived beyond 105 days, 8 stopped CSA at 62 – 145 days (median 110) and 21 developed cGVHD while still taking CSA. Of 35 ATG recipients alive beyond 4 years 11 had never received immunosuppressive treatment for cGVHD compared with one of 27 controls (p = 0.008). Non-relapse mortality with and without ATG respectively was 4±3% vs 17±5% at 100 days and 9±4% vs 34±7% at 4 years (p = 0.002). Three of 9 pts given oral Bu with Flu died of transplant-related causes. Deaths were GVHD related in 3 ATG treated patients vs 14 controls (p=0.007). Despite a trend to more relapse with ATG (43±7% vs. 22±7% at 4 years, p = 0.053) survival was 66±7% in the patients given ATG vs 50±7% in the controls (p=0.046). This study indicates that MRD BCT recipients given regimens including Flu, oral or IV Bu and ATG experience less cGVHD, lower mortality related to both acute and cGVHD and probably improved quality of life in survivors compared with previous protocols. It is unlikely that substituting Flu for Cy with Bu or differences in CSA taper contributed to the improved results but it is possible that IV Bu may have done so to some extent. Attempts to improve outcomes further will need to address the problem of relapse.