Early bilirubinemia after allogeneic stem cell transplantation-an endothelial complication

Abstract

Hyperbilirubinemia occurs frequently after allogeneic stem cell transplantation. Causes include primary liver damage and endothelial complications as major contributors. Here, we have investigated the impact of early bilirubinemia (EB) on posttransplant outcomes. Maximum total bilirubin levels (days 0-28) were categorized using maximally selected log rank statistics to identify a cut off for the endpoint non-relapse mortality (NRM) in a training cohort of 873 patients. EB above this cut off was correlated with NRM and overall survival (OS) and with pre- and posttransplant Angiopoietin-2, interleukin (IL)18, CXCL8 and suppressor of tumorigenicity-2 (ST2) serum levels, and the endothelial activation and stress index (EASIX). Clinical correlations were validated in a sample of 388 patients transplanted in an independent institution. The EB cut off was determined at 3.6 mg/dL (61.6 µM). EB predicted OS (HR 1.60, 95% CI 1.21-2.12, p < 0.001), and NRM (CSHR 2.14; 1.28-3.56, p = 0.004), also independent of typical endothelial complications such as veno-occlusive disease, refractory acute graft-versus-host disease, or transplant-associated microangiopathy. However, EB correlated with high Angiopoietin-2, EASIX-pre and EASIX-day 0, as well as increased levels of posttransplant CXCL8, IL18, and ST2. In summary, EB indicates a poor prognosis. The association of EB with endothelial biomarkers suggests an endothelial pathomechanism also for this posttransplant complication.

Fig. 1. Outcome after landmark (d + 28) of the training cohort (all patients, including those with SOS/VOD).

EB early bilirubinemia ≥3.6 mg/dL between days 0 and 28; SOS/VOD sinusoidal obstruction syndrome/veno-occlusive disease, none, no SOS/VOD and bilirubin <3.6 mg/dl; OS overall survival, NRM non-relapse mortality, TTR time to relapse.

Fig. 2. EB and pretransplant endothelial biomarkers.

EB and EASIX scores before conditioning therapy (a) and on day 0 of alloSCT (b) in patients without diagnostic criteria for SOS/VOD. c EB and pretransplant Angiopoietin-2 (ANG2) levels in patients with or without SOS/VOD by use of statin/UDA prophylaxis.

Fig. 3. EASIX and pretransplant angiopoietin-2 predict EB.

a ROC curves for EASIX-pre, EASIX d0, and the CIBMTR-COD score with endpoint EB (training cohort). Left panels: SOS/VOD patients are included, right panels: SOS/VOD patients are excluded. Tables show area under the curves (AUC) and confidential intervals (95%). b ROC curves for Angiopoietin-2 (ANG2) with endpoint EB (training cohort, SOS/VOD included). Left panel: no statin-based endothelial protection (SEP) with pravastatin and UDA, right panel: patients with SEP.

Fig. 4. EB associates with endothelial cell markers after alloSCT.

a Preconditioning and day +28 median serum levels of Angiopoietin-2 (ANG2) and CXCL8 (IL8) in patients with EB (no statins, no UDA). ANG2 levels remain high (paired Wilcoxon test 0.492), whereas IL8 levels increase (p = 0.025). b Specific increase of IL8 serum levels between preconditioning and day +28 in patients with EB, but not in patients without EB (no statins, no UDA). P values: Kruskal–Wallis tests comparing EB vs. no EB serum levels. c, d Time course of ST2 (c) and IL18 (d) median serum levels before alloSCT (pre) and within the first 28 days thereafter. Left panels: no statins, no UDA. Right panels: +statins + UDA. Red lines: patients experiencing EB, blue lines: no EB. P values: Kruskal–Wallis tests EB vs. no EB at the given time span. N = number of sera of individual patients collected at the given time span.

Fig. 5. EB-associated high NRM is reduced but not normalized by SEP.

Non-relapse mortality after d + 28 depending on EB and statin-based endothelial protection (SEP) (training cohort). a All patients including SOS/VOD. Hazard ratio (HR) of EB without SEP: 2.88 (95% CI 1.90–4.36, p < 0.001 compared with no EB), and 1.92 with SEP (1.11–3.35, p = 0.021 compared with no EB). b Excluding patients with SOS/VOD. HR of EB without SEP: 2.84 (1.75–4.63 p < 0.001 compared with no EB) and 2.01 with SEP (1.11–3.65, p = 0.022 compared with no EB).