Early predictors of transplant-related mortality (TRM) after allogeneic bone marrow transplants (BMT): blood urea nitrogen (BUN) and bilirubin

Abstract

Summary:Transplant-related mortality (TRM) following allogeneic bone marrow transplantation (BMT) remains a major concern and early identification of patients at risk may be clinically relevant. In this study we describe a predictive score based on bilirubin and blood urea nitrogen (BUN) levels on day +7 after BMT. The patient population consisted of 309 consecutive patients who underwent BMT from sibling (n = 263) or unrelated donors (n = 46) for hematologic disorders between December 1990 and December 1996. Of 27 laboratory tests taken on day +7 after BMT, serum bilirubin (P = 0.02) and BUN (P = 0.007) were found to be independent predictors of TRM in multivariate analysis. The median levels of bilirubin (0.9 mg/dl) and of BUN (21 mg/dl) were then used as a cut-off and a score of 1 was given for values equal/greater than the median. There were 216 patients with scores 0-1 (low risk) on day +7 (bilirubin Ͻ0.9 and/or BUN Ͻ21) and 93 patients with score 2 (high risk) (bilirubin у0.9 and BUN у21): the latter had more grade III-IV acute graft-versus-host disease (P = 0.03), slower neutrophil (P = 0.02) and slower platelet engraftment (P = 0.002). The actuarial 5 year TRM is 22% for low risk vs 44% for high risk patients (P = 0.0003). For HLA-identical siblings TRM is 20% vs 35% (P = 0.01), for unrelated donors it is 20% vs 65% (P = 0.01). Day +7 score was highly predictive of TRM on multivariate analysis (hazard ratio 1.9, P Ͻ 0.01), after adjustment for year of transplant (P Ͻ 0.00001), unrelated vs sibling donors (P = 0.001), patient age (P = 0.01) and diagnosis (P = 0.01). These results were validated on an independent group of 82 allogeneic BMT recipients in a pediatric Unit who showed an actuarial TRM of 16% for low risk vs 46% for high risk patients (P = 0.002). This study suggests that it may be possible to identify patients with different risks of TRM on day +7 after BMT: high risk patients could be Allogeneic bone marrow transplantation (BMT) is associated with considerable morbidity and mortality, and several studies have addressed the issue of risk factors for major single complications such as interstitial pneumonitis, 1 acute GVHD 2,3 and graft rejection: 4 patient variables (older age), donor variables (older age, parous female donors for male recipients, degree of HLA matching) and transplant variables (longer interval from diagnosis to transplant, intensive regimens), are among these. A study from the Seattle group has looked at risk factors for veno-occlusive disease of the liver, another important complication of allogeneic BMT 5 and found that early increments in serum bilirubin level and body weight were highly predictive. Other studies have also addressed the impact of risk factors on post-BMT complications. [6][7][8][9][10] During the past decades we have improved our ability to prevent and/or treat such complications, and transplantrelated mortality (TRM) has been considerably reduced 11 and delayed: in our HLA-identical sibling program TRM was 39% before 1990 (385 patients) and occurred at a...

An early increase in serum levels of C-reactive protein is an independent risk factor for the occurrence of major complications and 100-day transplant-related mortality after allogeneic bone marrow transplantation

“…In a recent study including more than 300 patients, it was found that relatively small increases in bilirubin and blood urea nitrogen on day 7 after transplant increased the 100-day TRM from 10% to 28%. 6 Patients with a high risk score died more often of AGVHD, infections and multi-organ failure. In our study, almost 50% of MTC were VOD.…”

“…5 Also, an early increase in serum bilirubin and/or blood urea nitrogen (BUN) after BMT has been associated with TRM. 6 Tissue damage can lead to a systemic inflammatory response. C-reactive protein (CRP) is an acute phase protein produced by hepatocytes and is a reliable marker of systemic inflammation.…”

Biomarkers for acute GVHD: can we predict the unpredictable?

“…Developing a strategy for pre-emptive intervention against acute GVHD is more difficult to achieve, given the inherent treatment of some patients who would not have developed disease. In 1999, Bacigalupo et al 48 used a clinical scoring system, measured at day þ 7 after HCT, to predict risk of both acute GVHD and TRM. A pilot study in 18 patients followed, which treated highrisk patients with pre-emptive anti-thymocyte globulin, 49 and this clinical scoring system was then refined to include day þ 7 serum levels of BUN, cholinesterase, total proteins, gamma glutamyl transferase, along with donor type and cell dose.…”

Pre-emptive treatment of acute GVHD: a randomized multicenter trial of rabbit anti-thymocyte globulin, given on day+7 after alternative donor transplants

“…However, one first needs to identify patients at risk of GVHD soon after transplant, and with this aim, we worked on a scoring system on day þ 7 after HSCT, first based on day þ 7 bilirubin and blood urea nitrogen. 12 These two laboratory tests identify patients with a significantly different risk of GVHD and transplantrelated mortality (TRM), as shown in our Unit of adult transplants and validated in a separate pediatric Unit using a different central lab. 12 The next step was to test whether an early intervention with immunosuppression was feasible and whether it would reduce severe acute GVHD: we ran a small pilot study with ATG 1.25 mg/kg 3 Â starting on day þ 7, in 18 high-risk patients, and compared the results with a historic group of 20 untreated high-risk patients (controls), and showed reduced acute GVHD in patients receiving the additional dose of ATG on day þ 7.…”

“…12 These two laboratory tests identify patients with a significantly different risk of GVHD and transplantrelated mortality (TRM), as shown in our Unit of adult transplants and validated in a separate pediatric Unit using a different central lab. 12 The next step was to test whether an early intervention with immunosuppression was feasible and whether it would reduce severe acute GVHD: we ran a small pilot study with ATG 1.25 mg/kg 3 Â starting on day þ 7, in 18 high-risk patients, and compared the results with a historic group of 20 untreated high-risk patients (controls), and showed reduced acute GVHD in patients receiving the additional dose of ATG on day þ 7. 13 We were in the meantime refining the scoring system on day þ 7, and found other significant laboratory tests such as serum cholinesterase, total serum proteins and gamma glutamyl transferase: 14 the revised day þ 7 score identifies patients with a low risk (15%), an intermediate risk (40%) and a high risk of TRM (60%).…”