Venous Thromboembolism in Blood or Marrow Transplant (BMT) Survivors: A Report from BMT Survivor Study (BMTSS)
Authors: Gangaraju Radhika , Chen Yanjun , Hageman Lindsey , Wu Jessica , Francisco Liton F. , Kung Michelle , Ness Emily , Parman Mariel , Weisdorf Daniel J. , Forman Stephen J , Arora Mukta , Armenian Saro H. , Bhatia Smita 
Published: October 2019

Abstract
BACKGROUND: Patients undergoing BMT are uniquely vulnerable to venous thromboembolism (VTE) due to high-intensity therapeutic exposures, prolonged hospitalizations (and attendant immobility), a high burden of comorbidities, and the pro-inflammatory state induced by graft-versus-host disease (GvHD) in allogeneic BMT recipients. An assessment of the long-term risk of VTE in BMT survivors and subsequent cause-specific late mortality remains unstudied. We used the BMTSS to address this gap.
METHODS: In patients with hematologic malignancy treated with BMT at 3 sites in US, had survived ≥2y after BMT, were alive and ≥18yo at BMTSS survey completion, we examined: i) incidence/risk factors for VTE; ii) subsequent mortality by VTE status. The survey covered sociodemographics, tobacco use, diagnosis by a healthcare provider of specific chronic health conditions, including VTE, relapse, or development of new cancer and medication use. The outcome of interest (VTE) was defined as self-report of VTE diagnosed by a health care provider, supplemented by history of anticoagulant use. BMTSS survey was administered over two time periods: i) Survey completed between 2000 and 2004: 1,022 patients transplanted between 1974 and 1998 and survived ≥2y (original BMTSS cohort; participation rate: 63%). This cohort was followed for a median of 15.1y (range: 0.04-17.9) after survey completion, to determine the association between VTE and subsequent mortality using National Death Index; ii) Survey completed between 2014 and 2017: 1,711 patients transplanted between 1974 and 2010 and survived ≥2y (expanded BMTSS cohort; participation rate: 68%) - this cohort was used to determine demographic/clinical variables associated with VTE risk. A cohort of 644 siblings also completed the survey and served as a comparison group. Human Subjects Committee at participating sites approved the protocol.
RESULTS:
Risk of VTE: Of the 1,711 participants, 891 (52.1%) had received an allogeneic BMT; 53.5% were males and 78.8% were non-Hispanic whites; median age at BMT was 48y. The cohort was followed for a median of 10.9y (3.8-40.6). BMT survivors were at a 2.8-fold higher risk of VTE as compared to siblings (95%CI:1.7-4.5, p<0.0001), after adjusting for sociodemographics. Conditional on surviving ≥2y after BMT, the cumulative incidence of VTE was 6.9±0.9% at 10y (Fig 1), with similar rates in autologous (6.1±1.1%) and allogeneic BMT recipients (7.5±1.5%%, p=0.5).
Risk of VTE in allogeneic BMT recipients: History of chronic GvHD (HR=3.6, 95%CI:2.2-6.0, p<0.0001), primary diagnosis of acute myeloid leukemia/myelodysplasia (HR=1.9, 95%CI:1.0-3.7, p=0.05) or non-Hodgkin lymphoma (NHL) (HR=2.3, 95%CI:1.1-4.8, p=0.02) (ref: chronic myeloid leukemia), male sex (HR=1.6, 95%CI:1.0-2.6, p=0.05), and older age at BMT (HR=1.03/y, 95%CI:1.0-1.1, p=0.002), were associated with increased VTE risk.
Risk of VTE in autologous BMT recipients: Diagnosis of a plasma cell disorder (HR=2.4, 95%CI: 1.3-4.2, p=0.004) (ref: NHL) and annual house hold income <$50,000 (HR=2.0, 95%CI 1.2-3.6, p=0.02) (ref: income >$50,000) were associated with increased VTE risk. Of note, relapse of primary disease or development of new cancer were not associated with increased VTE risk in either autologous or allogeneic BMT patients.
Subsequent mortality: In this cohort of 1,022 BMT survivors, median age at BMT was 34.9y; 55% had received allogeneic BMT. The overall survival among patients with and without VTE was 50.4% vs. 72.3%, respectively at 15y from survey completion, p<0.0001 (Fig 2), yielding a higher risk of subsequent mortality in VTE patients when compared to those without VTE (HR=1.6, 95%CI:1.1-2.3, p=0.02) after adjusting for relevant clinical/demographic predictors, relapse of primary cancer and development of new cancer. The VTE-associated mortality risk was primarily due to non-relapse mortality (NRM: HR=1.7, 95%CI:1.1-2.5, p=0.02) and not due to relapse (HR=0.7, 95%CI, 0.2-1.8, p=0.5). Leading causes of NRM among those with VTE included infection (15.5%), cardiac (8.5%) and subsequent neoplasms (7%).
CONCLUSION: BMT survivors are at a 2.8-fold increased risk of developing VTE when compared with a non-BMT sibling comparison group. Those with VTE are at an increased risk of subsequent NRM. Development of risk prediction models to identify BMT survivors at highest risk would facilitate targeted thromboprophylaxis.

Disclosures
Weisdorf: Equillium: Consultancy; SL Behring: Consultancy; Seattle Genetics: Consultancy; FATE: Consultancy; Pharmacyclics: Consultancy. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.