Risk Factors for Acute Graft-Versus-Host Disease (GvHD) after Related Donor HLA-Matched Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Adult Leukemia: Identification of Modifiable and Non-Modifiable Factors. A CIBMTR Study.

Allogeneic HSCT is a curative therapy for leukemia and other hematologic malignancies and disorders. Acute Graft-versus-Host Disease (aGvHD) is a significant cause of morbidity and mortality that limits the success of HSCT. No large analysis of this complication has been recently performed. Risk factors for aGvHD after HLA-matched sibling myeloablative unmanipulated HSCT were analyzed in 1960 adult (≥18 yrs) patients treated for AML (n=761), ALL (n=303), or CML (n=896) and reported to the CIBMTR registry from 1995–2002 by 226 centers worldwide. All patients received cyclosporine+methotrexate (CSA+MTX) alone (85%) or CSA+MTX+other agents (15%) for aGvHD prophylaxis. 635 (32%) patients developed grade II-IV aGvHD before day +100 post–HSCT. Outcome was measured as time from HSCT to onset of aGvHD Grade II-IV with death as a competing risk. Statistically significant risk factors for aGvHD in the univariate analysis were: Age ≥ 40 vs < 40 at HSCT, RR (95% CI, P) =1.35 (1.16–1.58, P=0.0001); Race, White/Black vs. Asian/Hispanic, RR=1.65 (1.31–2.08, P<0.0001); Recipient Gender, Female vs Male RR=0.83 (0.71–0.98, P=0.025); Stem Cell Source, Peripheral Blood (PB) vs. Bone Marrow (BM), RR=0.76 (0.65–0.89, P=0.0008); Disease, CML vs. AML, RR=1.26 (1.06–1.5, P=0.008), and ALL vs AML, RR=1.12 (0.88–1.42, P=0.37); Disease Status at HSCT, Not in Remission vs. Remission, RR=1.29 (1.03–1.62, P=0.029); Conditioning Regimen, CyTBI vs. BuCy, RR=1.39 (1.18–1.62, P<0.0001); KPS at HSCT, ≤ 80 vs > 80, RR=1.34 (1.12–1.60, P=0.0016); and Donor ever Pregnant, Yes vs No/Male, RR=1.21 (1.10–1.43, P=0.034). Other factors not significant in the univariate analysis were year of HSCT (1995–1998 vs. 1999–2002), recipient/donor sex-matching, time from diagnosis to HSCT, recipient/donor CMV status, donor gender, ABO compatibility, and planned G-CSF use post-HSCT. Multivariate analysis of time to onset of aGvHD Grade II-IV was performed by using a Cox proportional hazards model with backwards step-wise selection and P > 0.05 to remove each clinical factor from the model. Significant independent predictors of aGvHD Grade II-IV risk were: Conditioning Regimen, CyTBI vs BuCy, RR (95% CI, P) RR=1.4, (1.2–1.7, P<0.0001); PB vs BM in Patients 18–39 yrs at HSCT, RR=1.4 (1.1–1.8, P=0.0023); Disease, CML vs. AML/ALL, RR=1.3 (1.1–1.6, P=0.0003); Race, White/Black vs. Asian/Hispanic, RR=1.5 (1.2–1.9, P=0.0003); KPS, ≤ 80 vs > 80, RR=1.3 (1.05–1.5, P=0.014) and recipient/donor CMV status, at least one + vs −/ −, RR=0.8 (0.7–0.99, P=0.04). For pts ≥ 40 yrs at BMT, PB was not an independent risk factor for aGvHD Grade II-IV. There are modifiable risk factors for aGvHD Grade II-IV which include conditioning regimen, stem cell source (in younger patients) and CMV negative donors for CMV negative recipients. There are non-modifiable risk factors such as recipient age, race and gender and underlying diagnosis. Identifying patients at high risk for aGvHD Grade II-IV may allow for individualized risk modification and result in altering treatment strategies.