Late-occurring venous thromboembolism in allogeneic blood or marrow transplant survivors: a BMTSS-HiGHS2 risk model

Abstract

Background: Allogeneic blood or marrow transplant (BMT) recipients are at risk for venous-thromboembolism (VTE) because of high-intensity therapeutic exposures, comorbidities and a pro-inflammatory state due to chronic graft vs. host disease (GvHD). The long-term risk of VTE in allogeneic BMT survivors remains unstudied. Methods: Participants were drawn from the BMT Survivor Study (BMTSS), a retrospective cohort study that included patients who underwent transplantation between 1974 and 2014 and survived ≥2y after BMT. The BMTSS survey collected information on sociodemographics, health behaviors and chronic health conditions along with age at diagnosis. Details regarding primary cancer diagnosis, transplant preparative regimens, type of transplant and stem cell source were obtained from institutional databases and medical records. We analyzed the risk of VTE in 1,554 2y survivors of allogeneic BMT compared to 907 siblings. Using backward variable selection guided by minimizing Akaike's information criterion, we created a prediction model for risk of late-occurring VTE. Results: Allogeneic BMT survivors had a 7.3-fold higher risk of VTE compared to siblings (95%CI: 4.69-11.46, p<0.0001). After a median follow-up of 11y (inter-quartile range: 6-18y), and conditional on surviving the first 2y after BMT, the cumulative incidence of late-occurring VTE was 2.4% at 5y, 4.9% at 10y and 7.1% at 20y after BMT. Older age at BMT (hazard ratio [HR]=1.02/y, 95%CI=1.01-1.04, p=0.002), use of immunosuppressive medications (HR=2.28, 95%CI=1.41-3.38, p=0.0008), obesity (HR=1.06/unit increase in body mass index, 95%CI=1.02-1.10, p=0.002), history of stroke (HR=3.71, 95%CI=1.66-8.27, p=0.001), chronic GvHD (HR=1.62, 95%CI=1.00-2.60, p=0.049), and use of peripheral blood stem cells (PBSCs) as source of stem cells compared to bone marrow (HR=2.73, 95%CI=1.65-4.50, p<0.0001) were associated with increased VTE risk. The final model for VTE risk applied at 2y post-BMT ("HiGHS2") included History of stroke, chronic GvHD, Hypertension, Sex (male vs. female) and Stem cell source (PBSCs vs. other) (corrected C-statistics: 0.73; 95%CI=0.67-0.79), and was able to classify patients at high and low VTE risk (10y cumulative incidence 9.3% vs. 2.4%, p<0.0001). Conclusions: The BMTSS HiGHS2 risk model when applied at 2y post-BMT can be used to inform targeted prevention strategies for patients at high risk for late-occurring VTE.

International Recommendations for Screening and Preventative Practices for Long-Term Survivors of Transplantation and Cellular Therapy: A 2023 Update

“…Survivors of both autologous and allogenic HCT are at increased risk for VTE [ 34 – 37 ], and long-term HCT survivors with a history of VTE have greater nonrelapse mortality [ 38 ]. Risk factors include indwelling catheters, acute GVHD (aGVHD) or cGVHD, infections, prolonged immobilization, HCT for malignancy, endothelial damage from conditioning, and prior history of VTE [ 34 – 36 , 39 , 40 ]. Patients receiving immunomodulatory drugs for myeloma also are at higher risk.…”

Long-term health outcomes of allogeneic hematopoietic stem cell transplantation

“…One found that risk for venous thromboembolism at 2-years or more post-HCT was 7.3 times higher in survivors compared to siblings. Cumulative incidence of late VTE was 2.4% at 5 years, 4.9% at 10 years, and 7.1% at 20 years ( 67 ). This study was used to build a clinical risk rule using history of stroke, cGVHD, hypertension, sex, and stem cell source.…”

Sex-Specific Cardiovascular Risks of Cancer and Its Therapies

“…In contrast, among long-term allogeneic survivors, male sex has been associated with VTE, although no difference by sex was seen in autologous HCT survivors. 84,94 The reason for these differences is not entirely clear but may be based on a different set of risk factors for thrombosis in the immediate post-HCT setting (eg, immobility, central venous catheter), compared with longer-term survivors (eg, chronic GVHD, lifestyle factors), as well as lower overall rates of thrombosis in long-term autologous survivors. As thrombosis is clearly linked to worse outcomes in HCT patients, further investigation into sex-based differences is warranted.…”

“…73,95 In addition to myocardial damage, radiation may also cause direct vascular injury, which is characterized by endothelial dysfunction, smooth muscle cell proliferation, fibrosis, and lipid deposition. 94 Immunosuppressive drugs such as corticosteroids, calcineurin inhibitors, and mTOR inhibitors used to prevent and treat GVHD can increase risks of insulin resistance, hypertension, and dyslipidemia.…”