High Levels of Donor Chimerism Early after Non-Myeloablative Transplantation Predictive of Overall and Progression Free Survival but Not Risk of Acute Graft Versus Host Disease for Patients with AML or MDS.
Authors: Alyea Edwin P. , Li Shuli , Kim Haesook , Ho Vincent T. , Cutler Corey , Lee Stephanie J. , Gribben John , Stone Richard M. , DeAngelo Daniel J. , Ritz Jerome , Antin Joseph H. , Soiffer Robert J. 
Published: October 2019

Abstract
Non-myeloablative (NST) transplantation is increasingly used in the treatment of patients with AML and MDS who are not candidates for myeloblative transplant. Relapse of disease remains a major cause of treatment failure after NST. Predictive factors to identify patients at high risk of relapse are needed to identify patients who would benefit from additional interventions. Attainment of a high degree of donor engraftment achieved early after transplantation may indicate the presence of a more significant allo-immune effect. We have performed a retrospective analysis of 64 patients with AML and MDS receiving NST, assessing the impact of donor chimerism when measured early after transplantation on outcome. Overall survival (OS), progression free survival (PFS) and risk of graft versus host disease (GVHD) were compared for patients achieving ≥90 % or <90% donor derived hematopoiesis when measured 1 month after transplant. All patients received fludarabine 30 mg/m2/day x 4 days and intravenous busulfan (Busulfex)0.8 mg/kg/day x 4 days for conditioning. All patients received calcineurin-inhibitor based GVHD prophylaxis. All patients received PBSC with G-CSF at 5 mcg/kg beginning day 1 after transplantation. Chimerism was measured using FISH for sex mismatched patient donor pairs or by STR analysis. 37 patients had ≥90% donor derived hematopoiesis, 27 patients had <90% donor derived hematopoiesis after transplantation. The two groups had similar characteristics with a median age of 57 yrs (range 21–70) for patients ≥90% and 58 yrs (range 32–69) for patients <90%. Of patients achieving ≥90%, 23 patients had AML and 14 MDS. Of patients <90%, 13 had AML and 14 with MDS. 7 of 16 (44%) patients with early stage disease(AML in CR1 or early stage MDS) achieved ≥90% donor hematopoiesis, while 30 of 48 (63%) patients with advanced disease achieved ≥90%. 17 of 29 (59%) patients with unrelated donors achieved ≥90% donor derived hematopoiesis, while 20 of 33 (61%) patients with matched related donors achieved ≥90% donor derived hematopoiesis. 21 of 32 (66%) patients with donor-recipeint sex mismatch achieved ≥90% while 16 of 32 (50%) patients with same sex donors were ≥90%. The median follow-up for surviving patients achieving ≥90% donor chimerism was 12 months and 15 months for those <90%. Patients achieving ≥90% donor chimerism had a significantly improved 1-year (71% versus 41%) and 2-year (39% versus 19%) OS (p=0.05). Similarly, for patients achieving ≥90% donor chimerism, there was a trend toward an improved PFS at 1-year (49% versus 30%) and 2-years (32% versus 19%) (p=0.08). There was no difference in the risk of developing stage 2–4 acute GVHD, 19% for both patients above and below 90%. Achieving high levels of donor chimerism when measured early after NST predicts for an improved overall survival and there is a trend toward an improved progression free survival. This may represent the presence of an enhanced graft versus leukemia effect in these patients. The degree of donor chimerism does not predict the development of acute GVHD. These results suggest that patients with <90% donor derived hematopoiesis may be candidates for strategies to enhance donor chimerism.