Planned Granulocyte Colony-Stimulating Factor Adversely Impacts Survival after Allogeneic Hematopoietic Cell Transplantation Performed with Thymoglobulin for Myeloid Malignancy

Abstract

The in vivo depletion of recipient and donor T lymphocytes using antithymocyte globulin (ATG; Thymoglobulin) is widely adopted in allogeneic hematopoietic stem cell transplantation (HCT) to reduce the incidence of both graft failure and graft-versus-host disease (GVHD). However, excess toxicity to donor lymphocytes may hamper immune reconstitution, compromising antitumor effects and increasing infection. Granulocyte-colony stimulating factor (G-CSF) administered early after HCT may increase ATG-mediated lymphotoxicity. This study aimed to investigate the effect of an interaction between ATG and post-transplantation granulocyte colony-stimulating factor (G-CSF) on allogeneic HCT outcomes, using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. We studied patients age ≥18 years with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) who received Thymoglobulin-containing preparative regimens for HLA-matched sibling/unrelated or mismatched unrelated donor HCT between 2010 and 2018. The effect of planned G-CSF that was started between pretransplantation day 3 and post-transplantation day 12 was studied in comparison with transplantations that did not include G-CSF. Cox regression models were built to identify risk factors associated with outcomes at 1 year after transplantation. A total of 874 patients met the study eligibility criteria, of whom 459 (53%) received planned G-CSF. HCT with planned G-CSF was associated with a significantly increased risk for nonrelapse mortality (NRM) (hazard ratio [HR] 2.03; P <.0001; 21% versus 12%) compared to HCT without G-CSF. The 6-month incidence of viral infection was higher with G-CSF (56% versus 47%; P = .007), with a particular increase in Epstein-Barr virus infections (19% versus 11%; P = .002). The observed higher NRM with planned G-CSF led to lower overall survival (HR, 1.52; P = .0005; 61% versus 72%). There was no difference in GVHD risk between the treatment groups. We performed 2 subgroup analyses showing that our findings held true in patients age ≥50 years and in centers where G-CSF was used in some, but not all, patients. In allogeneic peripheral blood HCT performed with Thymoglobulin for AML and MDS, G-CSF administered early post-transplantation resulted in a 2-fold increase in NRM and a 10% absolute decrement in survival. The use of planned G-CSF in the early post-transplantation period should be carefully considered on an individual patient basis, weighing any perceived benefits against these risks.

Keywords: Antithymocyte globulin; Filgrastim; Granulocyte colony-stimulating factor; Hematopoietic stem cell transplantation; Thymoglobulin.

Figure 1:. Relapse and Non-relapse mortality

A: Relapse: The 1-year adjusted incidence of relapse was 31% (95% CI 27-35%) after planned G-CSF and 30% (95% CI 26-35%) without G-CSF, p=0·17 B: Non-relapse mortality: The 1-year adjusted incidence of non-relapse mortality was 21% (95% CI 18-25%) after planned G-CSF and 12% (95% CI 9-15%) without G-CSF, p<0·0001

Figure 2:. Disease-free Survival and Overall Survival

A: Disease-free survival: The 1-year adjusted incidence of disease-free survival was 47% (95% CI 43-52%) after planned G-CSF and 58% (95% CI 53-63%) without G-CSF, p=0·0006 B: Overall survival: The 1-year adjusted incidence of overall survival was 61% (95% CI 56-65%) after planned G-CSF and 72% (95% CI 68-76%) without G-CSF, p=0·0001