Impact of underlying disease and total body irradiation on the incidence of graft-versus-host disease after allogeneic hematopoietic cell transplantation.

Background: Multiple factors have been described to influence the risk of acute or chronic graft-versus-host disease (aGVHD or cGVHD) after allogeneic hematopoietic cell transplantation (HCT), including underlying chronic myeloid leukemia (CML) and high-dose total body irradiation (TBI). However, the impact of the underlying disease or low-dose TBI on the risk of GVHD in the modern era has not been determined.

Objective: To determine risk factors for GVHD in the modern era in the setting of antithymocyte globulin (ATG)-based GVHD prophylaxis.

Study Design: This retrospective study included 1,219 patients with hematologic malignancy who underwent first peripheral blood allogeneic HCT using myeloablative fludarabine and busulfan conditioning ± low-dose total body irradiation, along with ATG, cyclosporine, and methotrexate as GVHD prophylaxis. The adjusted cumulative incidence of GVHD was compared between patient subgroups using multivariable competing risks regression.

Results: When disregarding the underlying disease, risk factors for grade 2-4 aGVHD were donor type other than matched sibling donor (non-MSD) and lack of low-dose TBI (non-TBI). Risk factors for grade 3-4 aGVHD were non-MSD, non-TBI, and CMV donor negative/recipient positive serostatus (D-R+). Risk factors for moderate-severe cGVHD were ≤9/10 HLA match, non-male/male, and non-TBI. In models including the underlying disease, additional significant risk factors were chronic lymphocytic leukemia (CLL) for grade 2-4 aGVHD (sub-hazard ratio over acute myeloid leukemia [SHR] 3.16, 95% CI 1.97-5.08, p<0.001); CLL and acute lymphoblastic leukemia (ALL) for grade 3-4 aGVHD (SHR for CLL 3.54, 95% CI 1.54-8.17, p=0.003 and SHR for ALL 2.26, 95% CI 1.26-4.04, p=0.006); and myelofibrosis (MF) for moderate-severe cGVHD (SHR 2.14, 95 CI 1.34-3.41, p=0.001).

Conclusions: In the modern era when using ATG for GVHD prophylaxis, newly identified risk factors include CLL and non-TBI for grade 2-4 aGVHD; CLL, ALL, and non-TBI for grade 3-4 aGVHD; and MF and non-TBI for moderate-severe cGVHD. These findings, if confirmed in a separate cohort, should be taken into consideration when tailoring the prophylaxis of and monitoring for GVHD.