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Published on: May 2, 2013
Surrogates of Endothelial Injury Predict Survival After Post-transplant Cyclophosphamide
Anmol Baranwal1, Kimberly J Langer2, Mohamed A Kharfan-Dabaja3
1Division of Hematology, Mayo Clinic, Rochester, Minnesota; Cancer Centers of Southwest Oklahoma, Lawton, Oklahoma.
Insights
The endothelial activation and stress index (EASIX) score predicts non-relapse mortality (NRM) in patients undergoing allogeneic hematopoietic stem cell transplant (alloHCT) with post-transplant cyclophosphamide (PT-Cy). A new EASIX-HTN model helps stratify transplant risk.
Area of Science:
- Hematology
- Transplant Immunology
- Oncology
Background:
- Post-transplant cyclophosphamide (PT-Cy) is a standard GVHD prophylaxis after allogeneic hematopoietic stem cell transplant (alloHCT).
- Cyclophosphamide can cause endothelial injury, suggesting a role for endothelial dysfunction markers in predicting outcomes.
- The Endothelial Activation and Stress Index (EASIX) score is a marker of endothelial dysfunction.
Purpose of the Study:
- To evaluate the prognostic ability of the EASIX score and HCT-CI in predicting non-relapse mortality (NRM) after alloHCT with PT-Cy.
- To identify factors influencing survival in patients receiving PT-Cy for GVHD prophylaxis.
- To develop a composite risk model for stratifying patients undergoing alloHCT with PT-Cy.
Main Methods:
- Retrospective review of 199 adult patients with hematologic malignancies undergoing alloHCT and receiving PT-Cy.
- Calculation of EASIX scores from laboratory values between day -28 and conditioning start.
- Analysis of HCT-CI, EASIX scores, and pre-transplant hypertension for predicting NRM and overall survival (OS) using competing risk and Cox-proportional hazard models.
Main Results:
- High log2-EASIX scores were significantly associated with higher 1-year NRM (34.5% vs. 12.3%, P = .003).
- High log2-EASIX score (HR 2.92) and pre-alloHCT hypertension (HR 2.15) independently predicted 1-year NRM.
- The novel EASIX-HTN composite risk model effectively stratified patients into low, intermediate, and high-risk groups with significantly different 1-year OS.
Conclusions:
- The EASIX score is a significant predictor of survival in patients undergoing alloHCT with PT-Cy.
- The EASIX-HTN composite risk model provides a valuable tool for pre-transplant risk stratification.
- Multiorgan failure is a common cause of NRM, especially in patients with pulmonary comorbidities.
Abstract:
Post-transplant cyclophosphamide (PT-Cy) is becoming the standard of care for preventing graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplant (alloHCT). Cyclophosphamide is associated with endothelial injury. We hypothesized that the endothelial activation and stress index (EASIX) score, being a marker of endothelial dysfunction, will predict non-relapse mortality (NRM) in alloHCT patients receiving PT-Cy for GVHD prophylaxis. We evaluate the prognostic ability of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and EASIX scores, and report other factors influencing survival, in patients with hematologic malignancies undergoing alloHCT and receiving PT-Cy-based GVHD prophylaxis. Adult patients with hematologic malignancies who underwent alloHCT and received PT-Cy for GVHD prophylaxis at the three Mayo Clinic locations were included in this study. We retrospectively reviewed the Mayo Clinic database and the available electronic medical records to determine the patient, disease, and transplant characteristics. An HCT-CI score of ≥3 was considered high. The EASIX score was calculated from labs available between day -28 (of alloHCT) to the day of starting conditioning and analyzed on log2 transformed values. A log2-EASIX score ≥2.32 was considered high. The cumulative incidence of NRM was determined using competing risk analysis, with relapse considered as competing risk. Overall survival (OS) from transplant was determined using Kaplan-Meier and log-rank methods. Cox-proportional hazard method was used to evaluate factors impacting survival. A total of 199 patients were evaluated. Patients with a high log2-EASIX score had a significantly higher cumulative incidence of NRM at 1 year after alloHCT (34.5% versus 12.3%, P = .003). Competing risk analysis showed that a high log2-EASIX score (HR 2.92, 95% CI 1.38 to 6.17, P = .005) and pre-alloHCT hypertension (HR 2.15, 95% CI 1.06 to 4.36, P = .034) were independently predictive of 1 year-NRM. Accordingly, we combined the two factors to develop a composite risk model stratifying patients in low, intermediate, and high-risk groups: 111 (55.8%) patients were considered low-risk, 76 (38.2%) were intermediate and 12 (6%) were high-risk. Compared to patients in the low-risk group, the intermediate (HR 2.38, 95% CI 1.31 to 4.33, P = .005) and high-risk (HR 5.77, 95% CI 2.31 to 14.39, P < .001) groups were associated with a significantly inferior 1-year OS. Multiorgan failure (MOF) was among the common causes of NRM (14/32, 43.8%) particularly among patients with prior pulmonary comorbidities [7 (50%) patients]. Our study shows that EASIX score is predictive of survival after PT-Cy. The novel EASIX-HTN composite risk model may stratify patients prior to transplant. MOF is a common cause of NRM in patients receiving PT-Cy, particularly among patients with pulmonary comorbidities.
