Decreased serum albumin as a biomarker for severe acute graft-versus-host disease after reduced-intensity allogeneic hematopoietic cell transplantation

Abstract

Biomarkers capable of predicting the onset and severity of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (HCT) would enable preemptive and risk-stratified therapy. Severe aGVHD leads to gastrointestinal protein loss, resulting in hypoalbuminemia. We hypothesized that decreases in serum albumin at onset of aGVHD would predict the risk of progression to severe aGVHD. We identified 401 patients who developed aGVHD grades II-IV after reduced-intensity allogeneic HCT and reviewed all available serum albumin values from 30 days before HCT to 45 days after initiation of treatment for aGVHD. A ≥0.5 g/dL decrease in serum albumin concentration from pretransplantation baseline to the onset of treatment for aGVHD predicted the subsequent development of grade III/IV aGVHD (versus grade II aGVHD) with a sensitivity of 69% and a specificity of 73%. Overall mortality at 6 months after initiation of aGVHD treatment was 36% versus 17% for patients with and without ≥0.5 g/dL decreases in serum albumin, respectively (P = .0009). We conclude that change in serum albumin concentration from baseline to initiation of aGVHD treatment is an inexpensive, readily available, and predictive biomarker of GVHD severity and mortality after reduced-intensity allogeneic HCT.

Figure 1. Change in absolute (A) and relative (B) serum albumin concentration in patients with peak grade 2 acute GVHD (solid line) versus peak grade 3/4 acute GVHD (dashed line)

Albumin concentration (ordinate) is in grams per deciliter.

Figure 2. Receiver-operator characteristic (ROC) curves for serum albumin as a predictor of peak grade 3/4 acute GVHD

Dashed line represents ROC of absolute serum albumin concentration at initiation of systemic therapy for acute GVHD. Solid line represents ROC of change in serum albumin concentration from baseline at initiation of systemic therapy for acute GVHD.

Figure 3. Overall survival from initiation of therapy for acute GVHD

Solid line represents survival in patients with an insignificant albumin decrease (<0.5 g/dL), while dashed line represents survival in patients with an albumin decrease of ≥0.5 g/dL.

Figure 4. Cumulative incidences of relapse (A) and non-relapse mortality (B), stratified by change in serum albumin at initiation of acute GVHD treatment

Figure 5. Non-relapse mortality from time of initiation of acute GVHD treatment

“False-positive” line represents patients with an albumin decrease of ≥0.5 g/dL, but who did not progress to grade 3/4 acute GVHD. Non-relapse mortality is increased only in patients with an albumin decrease and severe acute GVHD, suggesting that the prognostic value of albumin decrease is linked entirely to its ability to predict severe acute GVHD.

Figure 6. Receiver-operator characteristic curve for serum albumin decrease ≥0.5 g/dL alone (solid line) and in combination with other clinical factors (dashed line) in predicting progression to grade 3/4 acute GVHD

The initial ROC curve (solid line) has an area under the curve of 0.76. The incorporation of other clinical variables (donor type, degree of HLA disparity, time to acute GVHD onset, patient age, and bilirubin, creatinine, and platelet count at acute GVHD treatment initiation) resulted in an ROC curve with an area under the curve of 0.79 (dashed line).