Increased Risk of Cardio-Cerebrovascular Disease After Hematopoietic Cell Transplantation in Patients with Previous History
Hematopoietic cell transplantation (HCT) is a well-established treatment for hematologic malignancies. Over the past decades, the safety of HCT has significantly improved due to advancements in supportive care practices and the careful evaluation of comorbidities before transplantation. However, the impact of pre-existing cardio-cerebrovascular disease (pre-CCVD) on HCT outcomes remains poorly understood. Patients with pre-CCVD are often considered poor candidates for HCT, but recent studies suggest that these patients can still benefit from the procedure. This article provides a comprehensive overview of a retrospective study that investigated the impact of pre-CCVD on transplant outcomes, focusing on the incidence of post-transplant cardio-cerebrovascular disease (post-CCVD) and its implications for non-relapse mortality (NRM) and overall survival (OS).
Background and Study Objectives
Cardio-cerebrovascular comorbidities are recognized risk factors for NRM following HCT. These comorbidities are included in the HCT-specific comorbidity index (HCT-CI), which is used to assess the suitability of candidates for transplantation. However, the physiological status and organ function of patients with pre-CCVD can vary significantly at the start of conditioning, making it challenging to predict outcomes accurately. The study aimed to evaluate the impact of pre-CCVD on transplant outcomes, particularly the incidence of post-CCVD and its effect on NRM and OS.
Methods
The study was conducted at the Department of Hematology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China. A retrospective analysis was performed on patients who underwent allogeneic or autologous HCT between November 2013 and January 2020. The study compared the outcomes of 23 HCT recipients with pre-CCVD to those of 107 patients without pre-CCVD, matched for age and disease status. The primary endpoints were post-CCVD and NRM, while secondary endpoints included engraftment, overall survival, and relapse rates.
The study population included adult patients with hematological malignancies who underwent HCT during the specified period. Patients were excluded if they lacked a pre-specified dataset comprising disease characteristics, history of pre-CCVD, cardiovascular risk factors (CVRFs), pre-transplant risk assessment, and information on transplantation. The last follow-up was recorded on July 18, 2020.
Patient Characteristics
The median age of patients in the pre-CCVD group was 51 years (range: 30-65), compared to 45 years (range: 27-63) in the control group. There were no significant differences in the distribution of primary diseases, disease risk, disease stage before HCT, total cycles of chemotherapy, HCT-CI, conditioning regimen, graft source, or the number of graft cells infused. However, patients in the pre-CCVD group had a higher prevalence of CVRFs (78.3% vs. 30.8%, P < 0.001) and abnormal electrocardiography (ECG) before HCT (47.8% vs. 22.4%, P = 0.019) compared to the control group.
Definitions of CCVD
Pre-CCVD was defined as a history of cardiac or cerebrovascular disease before transplantation. Cardiac disease included symptomatic arrhythmia, cardiomyopathy, congestive heart failure, valvular heart disease, or coronary artery disease (CAD). Cerebrovascular disease included transient ischemic attack, cerebrovascular event, or cerebral artery stenosis. Post-CCVD was defined according to the Common Terminology Criteria for Adverse Events version 5.0, including grade ≥2 cardiac complications, intracranial hemorrhage, and cerebrovascular ischemia.
Statistical Analysis
The primary endpoints were NRM and post-CCVD. Secondary endpoints included neutrophil and platelet engraftment, length of stay in the laminar flow ward, relapse, and overall survival. Cumulative incidence curves with competing risks were used to estimate the incidence of post-CCVD, NRM, and relapse. The Kaplan-Meier method was used to estimate overall survival, and the log-rank test was used to compare survival curves. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for each outcome.
Results
Transplant Outcomes
There were no significant differences in the median days of neutrophil engraftment (14 vs. 12 days, P = 0.269) or platelet engraftment (14 vs. 14 days, P = 0.395) between the pre-CCVD group and the control group. The length of stay in the laminar flow ward was similar in both groups (45 vs. 47 days, P = 0.569). At the time of the last follow-up, there were no significant differences in overall survival (67.00% vs. 67.90%, P = 0.983), relapse rates (29.78% vs. 28.26%, P = 0.561), NRM (14.68% vs. 17.08%, P = 0.670), or disease-free survival (66.20% vs. 69.70%, P = 0.485) between the two cohorts.
Post-Transplant Cardio-Cerebrovascular Disease
The study observed 30 post-CCVD events in 18 patients, including 21 cardiac events, seven cerebrovascular events, and two severe vascular events. The most common post-CCVD was arrhythmia (36.67%), followed by heart failure (26.67%). The 2-year cumulative incidence of the first post-CCVD was significantly higher in the pre-CCVD group than in the control group (42.26% vs. 9.67%, P < 0.001). Multivariable analysis showed that pre-CCVD was the only independent risk factor for the occurrence of post-CCVD (HR: 12.50, 95% CI: 3.88-40.30, P < 0.001).
Correlation Between Post-CCVD and Outcomes
The development of post-CCVD was independently associated with high NRM (HR: 10.29, 95% CI: 3.84-27.62, P < 0.001) and inferior overall survival (HR: 10.29, 95% CI: 3.84-27.62, P < 0.001). Subgroup analysis revealed that post-CCVD remained a strong risk factor for inferior OS and high NRM in allogeneic HCT recipients but was not significant in the autologous HCT subgroup.
Discussion
The study’s findings suggest that pre-CCVD does not directly increase mortality but may exacerbate the toxicity of the transplantation procedure, leading to an increased risk of post-CCVD. Post-CCVD was identified as a powerful predictor of high NRM and inferior OS. The study highlights the importance of early identification and intervention for post-CCVD in HCT recipients, particularly those with pre-existing cardiovascular conditions.
The study’s limitations include its retrospective nature and the small sample size, which may limit the generalizability of the findings. Additionally, the study did not include patients with multiple myeloma, who may have different cardiovascular risks due to cardiac amyloidosis. Future research should focus on larger, prospective studies to confirm these findings and refine risk stratification for pre-CCVD in HCT candidates.
Conclusion
Patients with pre-CCVD can tolerate HCT well but are at an increased risk of early post-CCVD. Post-CCVD may be promoted by the combined effects of pre-CCVD and transplant toxicity and is a powerful predictor of high NRM and inferior OS. Further risk stratification of pre-CCVD is needed to reduce NRM in various transplantation settings. Early identification and intervention for post-CCVD are crucial for improving outcomes in HCT recipients with pre-existing cardiovascular conditions.
doi.org/10.1097/CM9.0000000000001569
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