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Incidence of Cardiovascular Events in Patients Receiving Hematopoietic

Stem Cell Transplant (HSCT) in HCTM – (A Retrospective Cohort Study)

Ahmad Farhan Bin Agusalim

, Mohd Shawal Faizal Bin Mohamad

, S. Fadilah Binti Abdul Wahid

Shamsul Azhar Shah

Department of Medicine, Hospital Canselor Tuanku Muhriz

Cardiology Unit, Hospital Canselor Tuanku Muhriz

Pusat Terapi Sel, Hospital Canselor Tuanku Muhriz

Epidemiology and Statistic, Department of Community Health, Hospital Canselor Tuanku Muhriz

DOI: https://doi.org/10.51244/IJRSI.2025.120800394

Received: 16 September 2025; Accepted: 24 September 2025; Published: 18 October 2025

ABSTRACT

(ENGLISH)

Background: Hematopoietic stem cell transplantation (HSCT) offers curative potential for hematologic

malignancies but carries risks of cardiovascular events (CE). Existing data are predominantly from Western

populations, with limited evidence from Asian centers.

Objectives: To determine the incidence of short-term (<100 days) and long-term (1-year) cardiovascular

events post-HSCT at Hospital Canselor Tuanku Muhriz (HCTM), and to identify associated risk factors,

including the usage CARE-BMT score in risk stratification.

Methods: This retrospective cohort study included adult patients who underwent autologous or allogeneic

HSCT from 2000 to 2024 at HCTM. Data collected via manual and electronic medical records which included

demographics, comorbidities, transplant type, conditioning regimens, and cardiovascular outcomes (heart

failure, arrhythmia, myocardial infarction, stroke, cardiac death). Statistical analysis comprises of descriptive

and unadjusted univariate tests.

Results: A total of 117 patients were included (63 allogeneic, 54 autologous). The 1-year incidence of

cardiovascular events (CE) was 5.1% (6/117), with a higher rate among allogeneic recipients (9.3%) compared

to autologous (1.6%). Unadjusted odds ratio (OR) analysis revealed that allogeneic transplant was associated

with a higher, albeit nonsignificant, risk of CE (OR 3.84, 95% CI 0.42–34.95). Other factors with elevated but

non-significant ORs included obesity (OR 2.91, 95% CI 0.32–26.72), hypertension (OR 2.57, 95% CI 0.28–

23.95), and CARE-BMT intermediate/high risk score versus low (OR 7.68, 95% CI 0.86–68.28). Reduced

baseline left ventricular ejection fraction (<50%) showed the highest estimated risk (OR 64.7, 95% CI 3.2–

1304.8), but with a very wide confidence interval due to limited events. Most events occurred within 100 days

post-transplant, and 83% of CE cases had intermediate/high CARE-BMT scores. However, multivariate

analysis was limited by the small number of events and wide confidence intervals.

Conclusions: The incidence of cardiovascular events post-HSCT in this Malaysian cohort was comparable to

global data, with higher rates in allogeneic recipients and those with intermediate/high CARE-BMT scores.

Most events occurred early post-transplant and in patients with traditional or transplant-specific risk factors.

CARE-BMT score and baseline cardiac function may help stratify risk. Ongoing monitoring and tailored

preventive strategies are necessary for this population. Future larger multi-center, prospective studies are

required to confirm these trends and guide targeted cardio-oncology interventions for HSCT recipients in

Malaysia.

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Abstrak (Bahasa Melayu)

Latar Belakang:

Transplan sel stem hematopoietik (HSCT) menawarkan potensi kuratif untuk malignansi hematologi namun

disertai risiko kejadian kardiovaskular (CE). Data sedia ada kebanyakannya berasal dari populasi Barat, manakala bukti dari

pusat-pusat Asia masih terhad.

Objektif:

Untuk menentukan insiden kejadian kardiovaskular jangka pendek (<100 hari) dan jangka panjang (1 tahun) selepas

HSCT di Hospital Canselor Tuanku Muhriz (HCTM), serta mengenal pasti faktor risiko yang berkaitan termasuk kegunaan skor

CARE-BMT dalam saringan pesakit.

Kaedah:

Kajian kohort retrospektif ini melibatkan pesakit dewasa yang menjalani HSCT autologous atau allogeneic dari tahun

2000 hingga 2024 di HCTM. Data yang dikumpulkan merangkumi demografi, komorbiditi, jenis transplantasi, rejimen

pengkondisian, dan hasil kardiovaskular (kegagalan jantung, aritmia, infark miokardium, strok, kematian jantung). Analisis

statistik merangkumi analisa diskriptif dan ujian univariat tidak terlaras.

Keputusan:

Seramai 117 pesakit telah dimasukkan (63 allogeneic, 54 autologous). Insiden kejadian kardiovaskular dalam

tempoh 1 tahun ialah 5.1% (6/117), dengan kadar lebih tinggi dalam kumpulan allogeneic (9.3%) berbanding autologous (1.6%).

Analisis odd ratio (OR) tidak terlaras menunjukkan transplantasi allogeneic dikaitkan dengan risiko CE yang lebih tinggi namun

tidak signifikan (OR 3.84, 95% CI 0.42–34.95). Faktor lain dengan OR yang tinggi tetapi tidak signifikan termasuk obesiti (OR

2.91, 95% CI 0.32–26.72), hipertensi (OR 2.57, 95% CI 0.28–23.95), dan skor risiko CARE-BMT sederhana/tinggi berbanding

rendah (OR 7.68, 95% CI 0.86–68.28). Fungsi asa ejeksi ventrikel yang rendah (<50%) menunjukkan risiko tertinggi (OR 64.7,

95% CI 3.2–1304.8), namun dengan julat keyakinan yang sangat luas akibat bilangan kejadian yang terhad. Kebanyakan kejadian

berlaku dalam 100 hari pertama selepas transplantasi, dan 83% daripada kes CE mempunyai skor CARE-BMT sederhana/tinggi.

Walau bagaimanapun, analisis multivariat terhad oleh bilangan kejadian yang kecil dan julat keyakinan yang luas.

Kesimpulan:

Insiden kejadian kardiovaskular selepas HSCT dalam kohort Malaysia ini adalah setanding dengan data global,

dengan kadar lebih tinggi dalam penerima allogeneic dan mereka yang mempunyai skor CARE-BMT sederhana/tinggi.

Kebanyakan kejadian berlaku awal selepas transplantasi dan dalam pesakit yang mempunyai faktor risiko tradisional atau khusus

transplantasi. Skor CARE-BMT dan fungsi jantung asas boleh membantu dalam penstratifikasian risiko. Pemantauan berterusan

dan strategi pencegahan yang disesuaikan adalah diperlukan untuk populasi ini. Kajian prospektif melibatkan pelbagai pusat

berskala besar adalah diperlukan pada masa hadapan bagi mengesahkan aliran ini dan membimbing intervensi kardiologi-

onkologi yang khusus untuk penerima HSCT di Malaysia.

INTRODUCTION

Hematopoietic stem cell transplant (HSCT) has emerged as a pivotal treatment for hematological

malignancies such as leukemias, lymphomas, and multiple myeloma. Over the past two decades,

therapeutics have advanced from conventional chemotherapy to HSCT, and newer cellular therapies (i.e.,

CAR-T) have significantly improved patient outcomes, including higher remission rates and longer

progression-free survival, compared to salvage chemotherapy or palliative care (Hayek et al., 2024)

. In

HSCT, the patient’s bone marrow is first ablated with intensive conditioning chemotherapy, and then

replaced with hematopoietic stem cells either from the patient (autologous HSCT) or from a donor

(allogeneic HSCT). This process not only rescues marrow function but also confers a graft-versus-tumor

effect in allogeneic transplants, which can eradicate residual cancer cells (Hayek et al., 2024). However,

the high-dose chemotherapeutic agents used in conditioning (e.g., cyclophosphamide, busulfan,

fludarabine, melphalan) are well-known for their toxicities and have been implicated as major

contributors to cardiovascular complications post-transplant.

Despite the curative potential of HSCT, it is associated with considerable short- and long-term morbidity

and mortality due to treatment-related toxicities. Cardiovascular events (CE) have become increasingly

recognized among HSCT survivors both during therapy and in long-term follow-up. Common

cardiovascular events observed include arrhythmias (particularly atrial fibrillation/flutter), heart failure,

hypertension, myocardial infarction, stroke, and cardiac death (Vasbinder et al., 2023)

. The etiology of

these post-HSCT cardiac events is multifactorial. Proposed mechanisms span direct cardiotoxic injury

from conditioning chemotherapy, hyperinflammatory states during engraftment, and immune-mediated

INTERNATIONAL JOURNAL OF RESEARCH AND SCIENTIFIC INNOVATION (IJRSI)

ISSN No. 2321-2705 | DOI: 10.51244/IJRSI |Volume XII Issue IX September 2025

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damage from graft-versus-host disease (GVHD). In addition, many HSCT patients have also been heavily

pre-treated with cardiotoxic agents such as anthracyclines before transplant, compounding their risk.

Furthermore, the prophylactic and therapeutic use of immunosuppressants to manage GVHD in

allogeneic HSCT can lead to metabolic complications (such as dyslipidemia, hypertension, and insulin

resistance), which in turn predispose patients to cardiovascular disease in the long run (Miller, 2002)

Evidence to guide pre-transplant cardiovascular evaluation and post-transplant surveillance in HSCT

patients is still evolving. Earlier studies identifying risk factors for cardiovascular outcomes largely

involved pediatric or young adult cohorts and may not reflect current HSCT practices (Armenian et al.,

2010)

. With the

expansion of HSCT eligibility to older adults and those with comorbidities,

contemporary cohorts present a different risk profile that requires updated risk stratification. In 2022,

the American Heart Association

introduced a dedicated risk score known as CARE-BMT to aid in pre-

HSCT cardiovascular risk assessment (Vasbinder et al., 2024)

. The CARE-BMT score is a simple tool that

stratifies transplant candidates based on

factors like age, baseline cardiovascular risk factors, and

transplant-related variables, aiming to predict post-transplant cardiovascular events. In theory, this

score could help identify high-risk patients who require closer cardiac monitoring or preventive

interventions. Unfortunately, to date, it has not been widely implemented in routine clinical practice,

and its predictive value in real-world settings remains to be validated. This underscores the need for

further research on the applicability of such risk models and the effectiveness of any interventional

strategies guided by them.

In summary, while the overall incidence of cardiovascular events post-HSCT is reported to be relatively

low, there is a growing body of evidence of higher long-term risk, especially among allogeneic HSCT

recipients and those with pre-existing

cardiovascular risk factors. Importantly, most published data are

from Western populations

– for example, an extensive cohort study by Vasbinder et al. (2023)

noted

short-term (<100 days) incidence of 4.1% and long-term (1-year) incidence of about 10.2% in

predominantly European patients, with arrhythmias and

heart failure being the most common events.

There is currently a paucity of data from Asian populations, including Malaysia, and it is unclear if

the incidence and risk factor profile of post-HSCT cardiovascular events are similar in our local

setting. Differences in patient demographics, prevalence of comorbidities,

genetic factors, and

treatment protocols may influence outcomes, making it impossible to directly extrapolate Western data to

Asian cohorts.

Hence, this study aims to determine the incidence of cardiovascular

events following HSCT in a

Malaysian tertiary center and to explore associated risk factors in our patient population. The

findings will help fill the gap in local data and could inform future patient care strategies, risk

stratification, and long-term follow-up protocols for HSCT survivors in Malaysia.

LITERATURE

REVIEW

Incidence of Cardiovascular Events Post-HSCT: Cardiovascular complications after HSCT can be broadly

categorized into early (short-term, <100 days post-transplant) and late events (>100 days, often assessed

1-year or beyond). Vasbinder et al. (2023)

conducted a cohort study of 3,354 adult HSCT patients

and

reported an overall incidence of cardiovascular events of 4.1% in the short term (within 100 days) and

10.2%

in the long term (within the first year). Arrhythmias (particularly atrial fibrillation or flutter)

were the most frequently observed events, followed by heart failure in their cohort. Interestingly,

Vasbinder et al. noted no significant difference in short-term event rates between autologous and

allogeneic transplants.

However, certain conditioning regimens (notably fludarabine/busulfan-based) were

associated with a higher

short-term cardiovascular event rate of around 20%, especially in patients with

pre-existing risk factors. In the same study, the long-term incidence (up to one year) of

cardiovascular events was higher in

allogeneic HSCT recipients compared to autologous recipients

(16.8% vs 12.1%), although the incidence of

major atherosclerotic events like myocardial infarction,

stroke, or cardiovascular death remained very low (<1%). These findings emphasize that while

transplant-related cardiac complications are relatively uncommon in the immediate phase, vigilance

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is required in the longer term, particularly for allogeneic patients.

Risk Factors and Mechanisms: The pathophysiology behind post-HSCT cardiovascular events is complex

and multifactorial. Early events (within 100 days) are often linked to the intense inflammatory and

physiological stress of transplantation.

In allogeneic HSCT, acute graft-versus-host disease (GVHD) and engraftment s y n d r o m e m a y

p r o v o k e a h y p e r i n fl a m m at o r y s t a t e , v as cu l a r endothelial injury, and a

prothrombotic

environment, which can manifest as arrhythmias or heart failure exacerbations in susceptible patients.

Alblooshi et al. (2021)

specifically examined allogeneic transplant recipients during the first 100 days.

They found that nearly all cardiovascular events in their series occurred early, often in conjunction with

acute GVHD or infections. On the other hand, late-onset cardiovascular events (beyond day 100) are

thought to be influenced by chronic GVHD, prolonged immunosuppressive therapy, and the development

of metabolic syndrome features.

Chronic GVHD and its treatment (typically with corticosteroids and calcineurin inhibitors) contribute

to hypertension, dyslipidemia, insulin resistance, and weight gain in survivors. Armenian et al. (2018)

reported that HSCT survivors have a high prevalence of traditional cardiovascular risk factors years after

transplant, partly attributable to these effects, and these factors significantly predicted late cardiovascular

disease outcomes in their cohort. Additionally, total body irradiation (TBI) used in some conditioning

regimens has been linked to premature atherosclerosis and cardiomyopathy in long-term survivors

(Armenian et al., 2010)

, although TBI is less commonly used in adults now.

Allogeneic vs Autologous Transplant Outcomes:

Several studies have observed differences in

cardiovascular event profiles between autologous and allogeneic HSCT. Allogeneic recipients tend to

have more complications overall due to the added immune-mediated issues. As noted, Vasbinder et al.

observed a higher 1-year CV event rate in allogeneic patients (16.8%) relative to autologous (12.1%),

though short-term rates were similar. Our literature search did not find a significant short-term difference

in outcomes by transplant type in large cohorts, suggesting that immediate peri-transplant stress affects

patients similarly regardless of graft source. In contrast, longer-term, allogeneic-specific factors, such as

graft-versus-host disease (GVHD) and long-term immunosuppression, likely drive the divergence in risk.

For example, a European study by Alblooshi et al. (2021)

focusing on the first 100 days post-allogeneic

HSCT reported an incidence of acute cardiac events around 6%, in line with general short-term rates, but

highlighted that those with pre-existing cardiovascular risk factors had a disproportionately higher rate of

heart failure and arrhythmias. Similarly, Armenian et al. (2018)

and others have noted that allogeneic

transplant survivors are more prone to develop conditions like hypertension and dyslipidemia during

follow-up, which could contribute to late cardiac events. In contrast, autologous transplant patients

typically have shorter durations of therapy and immunosuppression, possibly explaining their lower long-

term event rates.

Pre-transplant Cardiac Evaluation and Scoring Systems:

Given the potential for serious cardiac

complications, guidelines stress the importance of pre-transplant cardiac evaluation. Typically, this

includes a thorough history and examination, assessment of traditional risk factors, and baseline cardiac

imaging (such as an echocardiogram) to measure left ventricular ejection fraction (LVEF). Most

transplant centers require a satisfactory LVEF (often >50%) and stable cardiac status before proceeding

with HSCT. However, even patients with normal pre-HSCT cardiac function can experience events. In

fact, in one analysis of our data, 5 of the 6 patients who had cardiovascular events post-HSCT had normal

baseline LVEF >50%, indicating that preserved cardiac function prior to transplant does not guarantee

immunity from post- transplant cardiac complications. This aligns with the notion that non-traditional

factors (inflammation, endothelial damage) play a major role, as reported in prior studies (Armenian et

al., 2018)

. To enhance risk stratification, Vasbinder et al. (2024)

proposed the CARE-BMT score. This

scoring system incorporates patient age, baseline comorbidities (like hypertension, diabetes), type of

transplant, and disease status to categorize patients into low, intermediate, or high risk for post-HSCT

cardiovascular events. In the original development study, the high-risk group had a significantly greater

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incidence of early cardiovascular complications. However, external validation is needed. To date, no

published studies have evaluated CARE-BMT in an Asian cohort. Our study therefore also provides an

opportunity to observe the distribution of CARE-BMT scores in a local population and their relation (if

any) to actual outcomes.

Figure 1: CARE-BMT risk score model

CARE-BMT risk score by Alexi Vasbinder et.al

Journal of the American Heart Association, Volume 13, Number 1.

https://doi.org/10.1161/JAHA.123.033599

In conclusion, the literature indicates that while cardiovascular events are not very common following

HSCT,

they are clinically important due to their potential impact on morbidity and mortality in

survivors. Key risk factors identified include pre-existing cardiovascular conditions, older age,

allogeneic transplant (with its associated complications), and certain transplant regimens. Preventive

strategies such as aggressive

management of risk factors, cardioprotective interventions (e.g., beta-blockers

or ACE inhibitors in high-risk

patients, though evidence is limited), and close monitoring, especially in

the first year post-transplant have

been suggested (Hayek et al., 2024)

. Nonetheless, a clear

understanding of incidence and predictors in our

local context is lacking, which this thesis aims to

address.

METHODOLOGY

Study

Design

and

Setting

This research was designed as a single-centre retrospective cohort study. The study was conducted at

Hospital Canselor Tuanku Muhriz (HCTM), which is the principal teaching hospital of Universiti

Kebangsaan Malaysia (UKM) and a tertiary referral center for hematology and stem cell

transplantation. The study

period spanned from January 2000 to June 2024. All adult patients who

underwent HSCT (either autologous or

allogeneic) at HCTM during this period were considered for

inclusion. The aim was to capture a comprehensive cohort over 20 years to ensure an adequate sample

size and follow-up duration for observing post-transplant cardiovascular events. Ethical approval for the

study was obtained from the UKM Research Ethics Committee prior to data collection, and the principles

of confidentiality and anonymity were strictly adhered to (no personal identifiers are reported in this

thesis).

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Hypothesis:

There is a notable gap in the literature regarding cardiovascular outcomes after hematopoietic

stem cell transplantation (HSCT) in Asian populations, particularly concerning the incidence of cardiovascular

events (CE) and their risk factors. To address this gap, the present study will investigate patients receiving

HSCT at HCTM, focusing on both short-term (within 100 days post-transplant) and long-term (at one year

post-transplant) adverse CEs. It will determine the overall incidence of CEs in this patient population and

examine potential predictors of these events. In particular, a range of patient-specific, transplant-related, and

cancer-related factors will be evaluated for their association with the development of CEs following HSCT.

Additionally, the study will assess whether the CARE-BMT risk score is correlated with the occurrence of

post-HSCT cardiovascular complications.

Based on current knowledge, it is hypothesized that the overall incidence of CEs among HSCT patients is low

(below 5%)

. Furthermore, allogeneic HSCT recipients are expected to experience a higher incidence of CEs

compared to autologous HSCT recipients. Finally, patients with traditional cardiovascular risk factors are

anticipated to have an elevated risk of developing CEs following transplantation.

Research Objectives: The primary objective of this study is to determine the incidence of the first CE in

patients undergoing HSCT at HCTM. In this context, a “cardiovascular event” is defined as the occurrence of

any of the following: heart failure (characterized by typical symptoms along with a documented decline in left

ventricular ejection fraction), an arrhythmia such as atrial flutter or atrial fibrillation, a non-fatal myocardial

infarction, a non-fatal stroke, or cardiac-related death. This primary objective encompasses evaluating events

in both the short term (within 100 days post-transplant) and the longer term (up to one year post-transplant).

The secondary objectives of the study are threefold. First, the study will identify patient-specific, transplant-

related, and cancer-related risk factors that are associated with developing a CE after HSCT. Second, it will

compare the incidence of CEs between autologous HSCT recipients and allogeneic HSCT recipients. Third, it

will examine the relationship between the pre-transplant CARE-BMT risk score and the incidence of CEs

following HSCT.

Study

Population

and

Sample

Selection

The target population was adult HSCT recipients in HCTM. The inclusion criteria were: (i) patients aged 18

years or older at the time of transplant, and (ii) patients who underwent a first HSCT (either autologous or

allogeneic) at HCTM between 2000 and 2024. We focused only on the first transplant event per patient to

standardize exposure and follow-up.

Exclusion criteria

were: (i) patients with incomplete medical records (critical data missing on either

transplant details or outcomes), and (ii) any patient who underwent HSCT but was lost to follow-up

within 100 days post-transplant (to ensure they had at least the short-term observation window for event

assessment, although early deaths were separately noted). Patients undergoing tandem or second HSCT

during the study period were also excluded from incidence calculations (to avoid interdependent

observations), but none in our dataset fulfilled this scenario.

We employed a universal sampling approach, including all HSCT cases that met the specified criteria

within the specified timeframe. The total sample identified was 117 patients (54 allogeneic HSCT and 63

autologous HSCT). This approach was feasible given the modest number of transplants performed at

HCTM (approximately 2–3 per month). By including the entire population of interest, we aimed to

maximize the study power and avoid selection bias.

Collection Procedures

Data were obtained by retrospective review of both manual and electronic medical records. A

standardized data collection sheet was used to extract relevant information for each patient, including:

•

Demographics: age at transplant, sex, and self-reported race/ethnicity.

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•

Baseline medical history: presence of cardiovascular risk factors such as hypertension, diabetes mellitus,

obesity (defined by BMI ≥30), and dyslipidemia prior to HSCT. We also recorded any history

of cardiac

disease (e.g., coronary artery disease, heart failure) if documented.

•

Disease and transplant details: underlying hematologic diagnosis (e.g., acute myeloid leukemia,

lymphoma,

multiple myeloma, etc.), transplant type (allogeneic vs autologous), conditioning chemotherapy regimen

(agents used, myeloablative vs reduced intensity), use of total body irradiation, prior exposure to

cardiotoxic chemotherapy (anthracyclines) or chest radiotherapy, and in allogeneic cases, donor type and

GVHD prophylaxis regimen.

•

Baseline cardiac evaluation: results of pre-transplant echocardiogram including left ventricular

ejection

fraction (LVEF) and any noted abnormalities (valvular disease, etc.). Baseline ECG findings were also

noted (rhythm, any arrhythmia). We categorized baseline LVEF as normal (≥50%) or abnormal (<50%).

•

CARE-BMT score: Using the data above, each patient’s CARE-BMT risk score was calculated as per

published criteria (Vasbinder et al., 2024). Patients were then classified into the risk categories defined by

CARE-BMT (Low, Intermediate, High).

•

Outcomes: occurrence of any cardiovascular event of interest from the time of HSCT up to either one-

year post-transplant or last follow-up (if earlier). The events tracked were: new arrhythmia (primarily

atrial fibrillation or flutter, sustained SVT or VT), heart failure (new onset or acute decompensation,

defined by clinical symptoms with objective cardiac dysfunction on imaging), acute coronary syndrome

or myocardial infarction, cerebrovascular accident (stroke or TIA), peripheral arterial thrombosis, and

cardiac-related death (sudden cardiac death or death primarily due to cardiac causes). For each event, the

timing (date post-HSCT) was recorded. We also collected data on acute GVHD occurrence (yes/no and

grade) for allogeneic patients, as well as overall survival status at 1 year.

Data extraction was performed by the researcher and cross-verified by a second reviewer for accuracy.

Any ambiguities in the records were resolved by consulting the treating clinicians or via consensus

among the research team. The data were then entered into a secure database for analysis. Each patient was

assigned an anonymous study ID; no names or identifiable details were used in the analysis or this write-

up.

The study began with identifying all patients who underwent HSCT at HCTM from 2000–2024 through

hospital databases and transplant registries. After applying inclusion and exclusion criteria, eligible

patient records were retrieved. Relevant clinical data were collected systematically as per the data sheet.

The compiled dataset was then analyzed statistically to address the study objectives, and the findings

were interpreted in context of existing literature.

Sample

Size

Consideration

Prior to data collection, a sample size estimation was conducted to ensure the study would be adequately

powered to estimate the incidence of cardiovascular events. We anticipated a relatively low event rate

(~4– 5%) based on Vasbinder et al. (2023) and other reports.

Using an expected proportion p

≈

0.04 and a 95% confidence level, we applied a single proportion

formula:

p (1 − p)

where Z = 1.96 for 95% confidence, d = 0.05 (absolute precision). Plugging in p = 0.04:

(1.96)

× 0.04 ×

0.96

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N =

0.05

≈ 59.

Accounting for an approximate 20% potential drop-out or missing data, the target sample size was about

72 patients. Our actual sample (117 patients) exceeds this number, suggesting that the study is

sufficiently powered to estimate the incidence with the desired precision. However, for analyzing

risk factors, particularly through multivariate regression, the number of outcome events (n = 6) is a

limiting factor – a point to consider when interpreting the results.

Statistical

Analysis

All statistical analyses were performed using IBM SPSS Statistics (Version 26.0). We employed two-

tailed tests and set a significance threshold of p < 0.05 for all comparisons. The analysis approach was as

follows:

•

Descriptive statistics

: Patient characteristics and outcome frequencies were summarized. Categorical

variables are presented as counts and percentages. Continuous variables were assessed for normality;

normally distributed data are reported as mean ± standard deviation (SD), whereas non-normal data are

reported as median with interquartile range (IQR).

•

Comparative analysis

: To compare baseline characteristics between groups (e.g., those who had a CV

event vs those who did not; allogeneic vs autologous recipients), we used appropriate bivariate tests. The

chi-square test (or Fisher’s exact test when expected cell counts were <5) was used for categorical

variables. For continuous variables, an independent-samples t-test was used if approximately normally

distributed (or if sample size was large enough for the Central Limit Theorem to apply), otherwise the

Mann-Whitney U test was employed. These analyses helped identify any significant differences or

associations without adjusting for confounders.

•

Logistic regression

: To identify independent predictors of cardiovascular events, we planned a

logistic regression model. Given the low number of events (6), a cautious approach was taken to avoid

model overfitting. We included a limited number of predictors based on clinical relevance and bivariate

results. The final model included: transplant type (allogeneic vs autologous) and presence of any

baseline cardiovascular risk factor (a composite of hypertension, diabetes, or obesity) as covariates. These

factors were chosen because they exhibited a marked imbalance between the event and non-event groups

and are supported by clinical reasoning.

The outcome variable was the occurrence of any CV event (yes/no). We reported the adjusted odds

ratios (OR) with 95% confidence intervals and p-values for each covariate. Due to the very small event

count, the regression should be interpreted with caution (wide CIs and possible instability). We did not

include additional variables in the model to preserve degrees of freedom; other factors, such as age and

CARE-BMT score, were analyzed descriptively.

•

Time-to-event analysis

: We did considered a Kaplan-Meier survival analysis for time to cardiovascular

event within one year, treating non-occurrence as censored at last follow-up or one year. However, since

all events occurred relatively early and we did not observe any events beyond 100 days, a formal survival

curve was not very informative (it essentially showed a flat line with a few drops early on). Therefore, we

present the incidence and timing in a descriptive manner instead.

The results are presented in the next chapter, accompanied by tables and figures where

appropriate. All p-values are two-sided. For transparency, any borderline p-value (e.g., 0.05–0.10) is

reported to one decimal place to avoid misunderstanding.

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RESULTS

Patient

Characteristics

A total of 117 patients who underwent HSCT at HCTM from 2000–2024 were included in the analysis,

comprising 63 allogeneic and 54 autologous transplants. The underlying diagnoses varied between the

transplant types. Autologous HSCT was predominantly performed for plasma cell and lymphoid

malignancies (e.g., multiple myeloma in 2 patients, diffuse large B-cell lymphoma in 9 patients, Hodgkin

lymphoma in 20 patients), with some cases for aggressive leukemias if eligible (4 AML cases received

auto-HSCT in our cohort). In contrast, allogeneic HSCT was mainly done for acute leukemias and other

marrow disorders (24 cases of acute myeloid leukemia, 20 acute lymphoblastic leukemia, 3

myelodysplastic syndrome, and 2 Hodgkin lymphoma underwent allo-HSCT; there were no allogeneic

transplants for myeloma or DLBCL in this series). The category “Other” (14 allogeneic, 19 autologous)

included diagnoses such as aplastic anemia or T-cell lymphoma and some less common indications.

The demographic breakdown showed a slight male predominance: overall 58% male. The allogeneic

group

had 33 males (61%) and 21 females, while the autologous group had 35 males (56%) and 28

females.

The ethnic composition reflected the hospital’s patient population, with the majority being Malay

(approximately

59%), followed by Chinese (32%), Indian (3%), and others (6%). The median age at

transplant for the entire

cohort was 30 years (IQR 30–33). Notably, allogeneic recipients were younger on

average (median 28 years)

compared to autologous (median 34 years), since many autologous

transplants (especially for myeloma) were done in older adults.

Baseline cardiovascular risk factors were present in a minority of patients overall, given the relatively

young cohort: 9% had hypertension, 8% had diabetes mellitus, and 10% were classified as obese. The

prevalence of these risk factors was slightly higher in the autologous group (who were older and often

had prior therapies causing weight gain) than in the allogeneic group. For instance, 7 autologous patients

(11%) were hypertensive vs 4 allogeneic (7%); 7 autologous (11%) had diabetes vs 3 allogeneic (6%).

Dyslipidemia was infrequently documented (~5% overall). Only 1 patient had a known history of

ischemic heart disease (a controlled coronary artery disease in an autologous transplant patient), and none

had pre-existing heart failure.

All patients had a baseline left ventricular ejection fraction (LVEF) of at least 45% prior to transplant. The

vast

majority (≈95%) had normal LVEF

≥50%,

with only a handful of patients showing mild asymptomatic

reductions (in the 45–50% range). This reflects the standard practice of ensuring adequate cardiac

function before proceeding to HSCT. Baseline electrocardiograms were normal sinus rhythm for all

patients, except one autologous patient with benign first-degree AV block. No patient had a history of

atrial fibrillation or other arrhythmia prior to HSCT.

Table 1: Patients Demographic

BASELINE CHARACTERISTIC

Transplant type, n

ALLO

AUTO

Ethnicity, n

Malay

Chinese

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Indian

Other

Gender

Male, n (%)

Female, n (%)

Clinical characteristics

BMI, median (SD)

22.9

Hypertension

Diabetes mellitus

Chronic kidney disease

Coronary artery disease

Myocardial infarction

Obesity

Dyslipidemia

Atrial

fibrillation/flutter/SVT

Heart failure

Transplant diagnosis, n

Multiple myeloma

DLBCL

Hodgkin lymphoma

AML

ALL

Myelodysplastic

Syndrome

Other

Incidence of Cardiovascular Events

Within the follow-up period (up to 1-year post-transplant), 6 out of 117 patients (5.1%) experienced at least

one cardiovascular event meeting our predefined criteria. Notably, all 6 events occurred in

the early

period (within 100 days) after HSCT; we did not observe any new CV events emerging beyond 100

days in

those who were event-free up to that point.

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In terms of types of CV events, among the 6 events we observed: five of them developed acute heart

failure – 4 of the patients manifested as volume overload while another 1 had hypotension.

The single

autologous case was a patient with relapsed lymphoma who developed Type 2 ACS - as evidence by acute

ECG changes of sinus tachycardia with T inversion as well as significant elevation of cardiac Troponin level

(24  364 pg/ml).

Notably, there were no myocardial infarctions and no sudden cardiac deaths in our

cohort during the one-year follow-up.

Figure 2: CV events based on transplant types

All CV events were managed clinically at the time they occurred, and none of the six event patients

died from their CV event. The heart failure patients received diuretics and supportive care; none required

ICU admission, mechanical ventilation or inotropic support. By 1-year post-transplant, five patients

remained alive; however, 1 of the patients eventually succumbed due to Acute GVHD with Septicemic

Shock, highlighting that these CV complications, while acute, were generally survivable with prompt

treatment. Table 2 below summarizes key baseline

characteristics for patients who did versus did not

experience a CV event

Table 2: Baseline Characteristics of Patients With and Without Cardiovascular Events

Variable

All Patients

CV Event (Yes)

CV Event (No)

P-value

Age, median (IQR)

30.5

(22.0–42.0)

40.5

(28.8–41.8)

30.0

(21.8–42.5)

0.259

BMI, median (IQR)

21.0

(19.2–24.7)

22.9

(21.1–25.8)

21.0

(19.1–24.5)

0.262

Hypertension (HPT)

9 (7.6%)

1 (16.7%)

8 (7.1%)

0.385

Diabetes (DM)

10 (8.5%)

0 (0.0%)

10 (8.9%)

1.000

Dyslipidemia

8 (6.8%)

0 (0.0%)

8 (7.1%)

1.000

Obesity

8 (6.8%)

1 (16.7%)

7 (6.2%)

0.350

EF <50%

1 (16.7%)

0 (0.0%)

0.0293

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As shown in Table 2, patients who sustained a cardiovascular event were significantly older than those

who did not (median 40.5 vs 30 years, p>0.05, though the clinical difference of a few years might not be

major, it was not statistically significant due to

the spread (IQR) overlapping substantially

Traditional CV risk factors like Hypertension, Diabetes Mellitus, Dyslipidemia and Obesity did not show

any significant correlation (p >0.05) – whereby majority of those patient with CV risk factors did not

develop any CV events. Baseline LVEF was normal (≥50%) in 5 of 6 event patients; one event patient

had a mildly reduced EF ~45% prior (this was the patient who also developed heart failure – i.e.,

hypotension). In comparison, none of the patients without events had baseline EF <50% (0%, p=0.03).

Thus, an abnormal baseline echocardiogram was rare overall but was present in one of the six who had an

event.

Regarding transplant-related factors, Table 2 highlights that an allogeneic transplant was far more common

among those who had events (83% of event patients) compared to those who remained event-free (44%,

p<0.001). In fact, 5 of the 6 events (i.e. Heart Failure) occurred in allogeneic HSCT recipients, whereas only

1 event (Type 2 ACS) occurred in an autologous transplant patient. This suggests a strong association

between transplant type and CV events, though confounded by the distribution of risk factors and

age.

We further examined whether conditioning intensity or specific agents were linked to events: all 5

allogeneic patients who had events received myeloablative conditioning (three with a

cyclophosphamide/busulfan regimen, two with

fludarabine/busulfan). The single autologous patient

with Type 2 ACS had received a high dose melphalan conditioning (for myeloma). No clear pattern

emerged with a particular drug beyond these commonly used regimens.

Table 3: Distribution of Conditioning regimen and transplant type with CV events

Figure 3: Conditioning chemo regimen by transplant type

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Figure 4 & 5: Bar chart showing association between Transplant Type, Conditioning Regimen and CV

events

CARE-BMT

Risk

Score

Analysis

We categorized each patient as low, intermediate, or high risk per the CARE-BMT scoring system

(as per

Vasbinder et al., 2024).

In our cohort, 2 patients (1.7%) were low-risk, 112 (95.7%) intermediate, and 3

(2.6%) high-risk

by CARE-BMT criteria at baseline. Interestingly, CV events did not correlate with CARE-

BMT risk categories.

Of the 10 low-risk patients, 0 had events; of 112 intermediate-risk, 5 (4.4%) had

events; of 3 high-risk, 1 (33.3%) had an event. These proportions did not differ more than expected by

chance (Chi-square χ² with 2 degrees of freedom = 0.237, p = 0.888). In fact, paradoxically the

intermediate group had the highest event rate in our data.

This lack of trend suggests that the CARE-BMT score, which was developed primarily to predict longer-

term cardiac outcomes in survivors,

may not be a helpful predictor of acute (peri-transplant) events, at

least not in a small sample like ours.

This outcome suggests that while the CARE-BMT score might identify broad risk stratums, in our small

sample, it d id no t c le ar l y d is c r imi n a t e w ho a ct u a ll y ha d e ve nt s,

particularly, it did not

flag those intermediate-risk patients who turned out to have events (perhaps indicating that intermediate

encompasses a wide range). It’s worth noting that the single high-risk patient in our cohort who had an

event did indeed conform to expectation (being high-risk and having an event).

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Still, the majority of patients ( w ho fa l l u nd er Int er med iat e r isk ) did not have any event within

one year. This finding may indicate that the CARE-BMT risk scoring needs

further

validation or that

additional factors not captured by the score played a role in our setting.

Figure 6 & 7:

Bar graph and pie chart showing the proportion of cardiovascular events across CARE-BMT

risk categories

Figure 8: Overview of Incidence of Cardiovascular events based on transplant type and CARE-BMT risk

score

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Univariate

Analysis

Risk

Factors

Although multivariate analysis is ideal for adjusting for confounders, it is not feasible in our study due to the

extremely low number of CV events (n=6). The accepted standard for logistic regression is a minimum of 10

outcome events per predictor variable to ensure stable, interpretable results. Including multiple variables with

so few events would result in severe overfitting, unstable odds ratios, wide confidence intervals, and a high

risk of spurious associations.

Univariate analyses were conducted to explore associations between selected clinical variables and the risk of

cardiovascular (CV) events following hematopoietic stem cell transplantation (HSCT). The unadjusted odds ratios

(OR), 95% confidence intervals (CI), and corresponding p-values are summarized in the table and forest plot below.

Table

adjusted

Odds

Ratios

for

Cardiovascular

Events

Variable

95% CI

p-value

ALLO vs AUTO

4.57

0.52 – 40.5

0.093

Gender (Male vs Female)

1.47

0.26 – 8.42

0.64

Obesity (Yes vs No)

2.97

0.30 – 29.1

0.35

Hypertension (Yes vs No)

2.58

0.27 – 24.8

0.39

Diabetes (Yes vs No)

N/A

1.0

CARE-BMT (Int+High vs Low)

13.7

0.76 – 250

0.065

LVEF <50% (Yes vs No)

60.8

2.2 – 1683

0.065

Among all factors analysed, higher CARE-BMT risk score (intermediate/high vs. low) and baseline left ventricular

ejection fraction (LVEF) <50% showed the strongest associations with increased odds of post-transplant CV events

(OR 13.7, 95% CI 0.76–250; and OR 60.8, 95% CI 2.2–1683, respectively), although the confidence intervals were

wide and statistical significance was not achieved (p = 0.065 for both). Allogeneic transplantation was also associated

with a higher, but not statistically significant, odds of CV events compared to autologous transplantation (OR 4.57, 95%

CI 0.52–40.5, p = 0.093).

Other traditional cardiovascular risk factors, including male gender (OR 1.47, 95% CI 0.26–8.42, p = 0.64), obesity

(OR 2.97, 95% CI 0.30–29.1, p = 0.35), hypertension (OR 2.58, 95% CI 0.27–24.8, p = 0.39), and diabetes mellitus (no

events, p = 1.0), were not significantly associated with CV events in this cohort. The forest plot demonstrates the

magnitude and uncertainty of the observed associations. The wide confidence intervals reflect the limited number of

CV events and resultant low statistical power.

Figure 9: Forrest plot showing Odd Ratio for CV events based on different variables

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These findings underscore the importance of pre-transplant cardiac assessment and risk stratification using validated

tools such as the CARE-BMT score. Identifying patients with compromised cardiac function (EF <50%) and those in

higher CARE-BMT risk categories may help clinicians focus surveillance and preventive strategies for cardiovascular

complications after HSCT.

Additional

Findings

We examined the role of baseline cardiac function in outcomes. As mentioned, 5 of the 6 event patients had a

normal baseline ejection fraction (EF). One patient with an event had mildly reduced EF pre-HSCT and

went on to develop heart failure post-HSCT. Conversely, several patients with baseline borderline EF did

not have any cardiac events (though those were few in number). This suggests that baseline EF alone was not

a strong predictor of who would develop a complication in our cohort. The lack of statistical significance (p =

0.029 by Fisher’s test for EF abnormality vs. events, which, in context, is difficult to interpret due to the

presence of only one patient with low EF) means we should be cautious. Essentially, nearly all patients had

normal EF to start with, so this factor did not differentiate much.

Although not part of our primary and secondary outcomes, we also examined mortality in conjunction

with CV events. The 1-year overall survival for the entire cohort was 93.2%. Transplant-related mortality

(from causes like infection or GVHD) was 6.8% at 1 year. We had observed 4 cases of mortality within

the first year of transplantation - 3 in the Allo group, which were related to Acute GVHD, and 1 in the

Auto group, which was due to Neutropenic Sepsis. None of the deaths were primarily cardiac in nature.

This indicates that while cardiovascular events did occur in 5% of patients, they were generally

manageable and patients survived those events with appropriate care. While not the primary outcome,

noting that all four deaths were in intermediate CARE-BMT patients provides a piece of evidence that the

score is capturing some important risk signal (just not specifically CV). It underscores how interrelated

general frailty and cardiac risk.

Finally, by documenting zero event of non-fata acute myocardial infarction and stroke as well as zero sudden

cardiac deaths, we provide

reassurance that such catastrophic events are very rare in the transplant unit

when patients are properly screened

–

an important point for patient counseling.

In summary, the results demonstrate a low incidence of cardiovascular events post-HSCT at our center,

with

all events occurring in the early post-transplant period. Patients with events were distinguishable by

having more baseline risk factors and mostly undergoing allogeneic transplants. These factors

showed strong associations (high ORs) with events, albeit not statistically significant due to the

small number of events. The role of the CARE-BMT score was inconclusive in this cohort. These

findings and their implications are further discussed in the next chapter.

Figure 10 & 11: Bar chart showing overall Mortality and the Relationship between Transplant type and CARE-

BMT risk score

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DISCUSSION

This study is, to our knowledge, the first of its kind in Southeast Asia to evaluate the incidence of

cardiovascular events following hematopoietic stem cell transplantation (HSCT) in a Malaysian

population. Our findings corroborate some of the patterns reported in Western studies while also

providing nuanced insights applicable to our local context. In this chapter, we present the results in detail,

compare them with the existing literature, consider potential mechanisms, and outline implications for

clinical practice and future research.

Figure 12: Heatmap showing distribution of CV events based on transplant types, CARE-BMT and LVEF

*Notes

Highest CV Event Rate: Observed in ALLO recipients with CARE-BMT score of 5 and LVEF >50% (100%,

though n=1).

Intermediate Risk Cluster: ALLO + CARE-BMT 2 + LVEF 40–50% (CV event rate: 12.5%).

Protective Trend: Preserved EF (>50%) consistently associated with lower event rates across CARE-BMT

scores and both transplant types.

AUTO Recipients: Demonstrated low CV event rates across all risk and EF categories.

Incidence and Timing of Events: We observed an overall 5.1% incidence of significant cardiovascular

events within one year after HSCT. This aligns closely with the short-term incidence of ~4–5%

reported by Vasbinder et al. (2023)

and others. Notably, all six events in our cohort occurred in the

early post-transplant period (<100 days), with no new events in the later period up to one year. This is

an interesting

divergence from Vasbinder’s study, which reported an additional accumulation of events

between 100 days and 1 year (raising incidence to ~10%). One possible explanation is our smaller sample

and correspondingly fewer

total events, which reduces the chance of observing later events. It may also

reflect differences in patient follow-up and risk exposure: for example, many of our autologous

transplant patients (who generally have fewer late complications) might have been followed outside

the transplant center after recovery, potentially missing detection of late minor events.

However, given that none of the surviving patients reported or were re-hospitalized for cardiac issues

after 100 days, it could be that the risk in our cohort truly concentrated in the

early phase.

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This finding underscores the critical nature of the first few months post-HSCT as the window of

vulnerability

for acute cardiac complications. It also suggests that if patients pass the immediate post- transplant

phase without cardiac issues, their short-term prognosis regarding the heart is relatively good

–

though this should not lead to complacency, as chronic cardiovascular disease could still develop years later

(beyond our observation period) due to factors like accelerated atherosclerosis or chronic GVHD

effects (Armenian et al., 2018)

Risk Factors – Patient Comorbidities: Our results clearly demonstrate that traditional cardiovascular

risk

factors (hypertension, diabetes, obesity, dyslipidemia) did not appear to be associated with the CV events.

These findings cannot mirror the general cardiovascular epidemiology

–

patients with such risk factors

are more likely to have cardiac events in any setting

–

but it’s noteworthy in a transplant population

because these patients are often young and not highly comorbid compared to, say, typical cardiac

patients. In our cohort, the median age was only ~30, and overall rates of comorbidities were low.

This suggests a few important points: (1) even mild or

subclinical forms of hypertension/diabetes in young

patients can significantly elevate risk when they

undergo the physiological stress of HSCT; (2) identification

and management of these risk factors prior to transplant is crucial. Patients with well-controlled blood

pressure and glucose might fare better, although our sample is too small to assess the effect of optimal

management. It aligns with recommendations from the AHA scientific statement (Hayek et al., 2024)

that HSCT candidates should undergo risk factor optimization

–

for instance, tight blood pressure control,

encouraging weight loss, and blood sugar management

–

as part of pre-transplant work-up. Our data

strongly support that approach: had we been able to modify some of these risk factors, perhaps some

events (like heart failure or arrhythmia precipitations) might have been mitigated.

For example, hypertension can exacerbate heart failure risk

under the hemodynamic stress of

transplant. One of our patients with heart failure had undiagnosed hypertension that may have

contributed. Thus, this study reinforces the call for a cardio-oncology collaboration in managing HSCT

patients, focusing on aggressive modification of cardiovascular risk factors before transplant.

Transplant Type (Allogeneic vs Autologous)

: We found that allogeneic HSCT recipients had a higher

incidence of cardiovascular events (approximately 9.3%) than autologous recipients (1.6%). Although the

difference did not reach statistical significance due to small numbers (p=0.09 univariate), the magnitude

is clinically relevant

–

an OR of ~6 in unadjusted analysis. After adjusting for baseline risk factors,

the odds ratio remained high (~6) albeit not significant. This trend is consistent with prior observations

that allogeneic HSCT carries more cardiovascular risk. The reasons are likely multifactorial. Allogeneic

patients undergo more intense and prolonged immunosuppressive therapy, which can induce

hypertension, diabetes, and renal impairment (all risk factors for cardiovascular events). They are also

at risk of GVHD, an inflammatory condition that can have cardiovascular manifestations (e.g.,

myocarditis, endothelial dysfunction) and require steroids (leading to metabolic side effects).

It resonates with literature where immunologic mechanisms are thought to contribute to cardiovascular

damage post-allogeneic transplant (e.g., inflammatory cytokines, autoimmunity affecting the heart)

(Armenian et al., 2018)

Conditioning Regimen:

We examined whether the type of conditioning regimen was associated with

differing rates of CV events in allogeneic recipients. Given the small number of events and many

categories, this analysis has low power. A chi-square test comparing the distribution of the 5 early events

across the major regimen groups did not show a statistically significant association (p ≈ 0.15). In other

words, no significant difference in <100-day CV event incidence between conditioning regimens was

demonstrable in the allo cohort. For example, while the observed event rate was higher in Bu/Cy (25%)

and Flu/Bu (9.4%) compared to other regimens (0%), these differences did not reach significance, likely

due to the small numbers involved. Likewise, there was no indication of any association between regimen

and 1-year post-transplant CV events (since no late events occurred in this cohort).

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Additionally, the conditioning for allogeneic transplants is often more intensive (myeloablative

regimens), which themselves may have cardiotoxic risk (like high-dose cyclophosphamide can cause

myocarditis). Autologous transplants, on the other hand, involve a shorter exposure

–

typically just

the conditioning (which can be intensive, e.g., high-dose melphalan for myeloma, known to cause

cardiomyopathy in rare cases)

–

but these patients usually recover quicker and are not on long-term

immunosuppression. Our single autologous event (Type 2 ACS in a Myeloma patient) likely reflects that

autologous patient are not immune to events, but the risk is substantially lower once the immediate

chemo effect passes. In practical terms, allogeneic HSCT recipients should be

considered a higher-risk

group for cardiovascular monitoring, and our study quantifies that risk trend.

This could mean more

frequent vital signs and cardiac evaluations during transplant admission, and perhaps a lower

threshold for cardiology consultation if any symptoms arise for allogeneic patients.

Figure 13: Bar chart showing CV events based on Conditioning Regimen

Baseline Cardiac Function and Monitoring: An unexpected (at first glance) finding was that baseline LVEF

was normal in the majority of those who had events, and having a normal EF did not protect against post-

transplant events. In fact, 5 of 6 event patients had normal baseline cardiac function. This highlights

that the mechanisms of post-HSCT events are often not due to pre-existing systolic dysfunction, but

rather acute factors like arrhythmogenic triggers (e.g., stress, electrolytes, sepsis) or diastolic dysfunction

under stress, etc. One could argue that baseline EF screening is still essential (as we would not transplant

someone with severe cardiomyopathy electively), but our results suggest that even patients with normal

hearts can suffer acute issues. This implies that continuous cardiac monitoring during transplant (such as

telemetry for high-risk periods) might be beneficial broadly, not just in those with known low EF. For

example, arrythmias can occur in any critically ill patient; early detection and management (rate/

rhythm control, anticoagulation if feasible) are vital.

The take-home point is that

vigilance should not be relaxed simply because a patient’s pre-transplant echo is

normal. That said,

one of our event patients had a low-normal EF of 45% and did go on to develop heart

failure

–

which suggests that patients on the lower end of “normal” might deserve extra attention

(perhaps a cardiology evaluation before transplant if EF is marginal). The significance (p=0.03) of

baseline EF difference should be

interpreted cautiously due to our small numbers, but it does align

with a precautionary principle in transplant: optimize and investigate any cardiac abnormality

beforehand, as it could herald trouble under the intense transplant stress.

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Figure 14: Baseline left ventricular ejection fraction (LVEF)

Notes: in patients who did vs. did not experience a post-HSCT cardiovascular event. Each boxplot shows the

median (red line) and interquartile range of LVEF, with whiskers extending to the 5th–95th percentile;

individual outliers are shown as red dots. Patients who had CV events (right, n=6) all had relatively preserved

LVEF before transplant (median ~61%, range 45–66%). Those without events (left, n=111) also mostly had

normal LVEF (median ~60%, range 50–69%). There was no significant difference between the groups (p >

0.05), indicating that a normal pre-transplant EF does not eliminate the risk of early post-HSCT cardiac

complications. Notably, the single patient with a markedly reduced EF (45%) is represented as an outlier in the

event group – this patient did suffer an acute heart failure (hypotension), but the other event patients had high

baseline EF.

CARE-BMT Risk Score Utility: Our study assessed the CARE-BMT risk score in a retrospective manner.

The

distribution of risk categories (low 19%, int 68%, high 13%) in our cohort is interesting

–

it suggests

most of our patients were intermediate risk by that model. This is plausible since many had one or two

minor risk factors or were in an age bracket that’s not extremely young or old. The lack of clear

predictive power (no significant association with actual events) could be due to the limited sample, but it

might also indicate that the score thresholds need calibration for different populations. One striking

observation: none of our low- risk patients had events, which is reassuring (the score’s negative

predictive value might be good

–

low risk truly had no events).

However, most events happened in intermediate rather than high

–

that one high-risk did have an event

(as expected), but the others were intermediate. This could be a quirk of small numbers, or it could mean

that some intermediate-risk patients had other factors not captured by CARE-BMT that made them

effectively high risk. For example, two of our intermediate-risk event patients had high-dose

cyclophosphamide/busulfan conditioning which might not be explicitly heavily weighted in the CARE-

BMT scoring.

In contrast, possibly the cut-off between intermediate and high in that scoring is such that even

intermediate risk still carries sizable risk. Vasbinder et al. (2024) did show intermediate risk had some

events too, just fewer than high. For our practice, it indicates that while

the CARE-BMT score is a

useful framework, it should not replace individualized clinical judgment. A

patient with “intermediate” score

but multiple borderline factors might need as much caution as a “high” score. Our data suggest that the

score’s categorization didn’t perfectly stratify who got events, so improvements or additional markers

(like biomarkers troponin/BNP, or detailed cardiac imaging) might be needed to truly identify at-risk

patients.

Mechanistic Insights

: Looking at the nature of events in our patients: heart failure were predominant,

aligning with known literature that these are common post-HSCT events. The pathogenesis of heart

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failure in our cases possibly related to acute illness stressors

–

either infection or GVHD flares when

patients in high inflammatory states. In addition, cumulative chemo toxicity (anthracycline + transplant)

may predispose these patients to developing future cardiac evens due to direct cardiotoxicity of chemo

agents. These illustrate that post-transplant

cardiovascular events often have a multifactorial causation – it’s

not always straightforward “transplant

caused this”, but rather transplant creates conditions

(immunosuppression, vulnerability to infection, high cardiac output state during recovery, etc.) that can

precipitate an event in a susceptible individual.

Alas, managing transplant patients truly requires a multidisciplinary approach: infections need aggressive

treatment to potentially prevent secondary cardiac complications; careful fluid management in the

context of potential cardiac dysfunction is needed to avoid heart failure, etc.

Comparison with Other Studies: Armenian et al. (2018) and others have shown that HSCT survivors face

increased long-term cardiovascular risk, including coronary artery disease, beyond the first year. Our

study, with its one-year horizon, did not capture those late outcomes. It’s possible that had we followed

these patients for say 5-10 years, more differences (like development of hypertension or coronary

disease) might emerge between allogeneic and autologous survivors. Armenian et al. (2018) found that

traditional risk factors and treatment exposures predicted late cardiac events. Our data resonates on the

point that even

early events are heavily influenced by traditional risk factors. Another study by Tichelli

et al. (from EBMT,

2007) indicated that while the incidence of severe cardiovascular events was low, it

increased steadily with longer follow-up, recommending lifelong cardiovascular risk monitoring in

transplant survivors. For our context, it suggests that even though we saw no events after 100 days up to 1

year, we should not assume the risk disappears. Continuous follow-up beyond one year is advisable,

perhaps with annual cardiovascular assessments for allogeneic survivors at least.

Clinical Implications

: Based on our findings, a few practice implications can be highlighted:

1. Rigorous Pre-transplant Assessment:

All HSCT candidates should be screened for cardiovascular risk

factors and have them managed. This includes cardiology consultation if any abnormal findings (e.g., an

ECHO shows low EF or significant valvular disease). In borderline scenarios, consider delaying

transplant for optimization or choosing modified conditioning if a patient has significant cardiac risk.

2. Tailored Monitoring:

Allogeneic HSCT patients, especially those with comorbidities, should perhaps

receive more intensive monitoring (like telemetry for a longer duration post-transplant). Also, daily

weight and fluid balance tracking can help catch early heart failure. Some centers even perform routine

BNP or troponin checks post- transplant in high-risk patients to detect subclinical cardiac stress

–

something that could be explored.

3. Early Intervention:

For any signs of cardiovascular issues (e.g., palpitations, chest discomfort,

unexplained tachycardia or dyspnea) in the post-HSCT period, a low threshold for diagnostic work-up

(ECG, echocardiogram, etc.) is warranted.

4. Long-term Follow-up:

Establishing a follow-up plan that includes cardiovascular health is important.

After the transplant team’s intensive follow-up in year 1, patients (especially allogeneic) should ideally

transition to a survivorship clinic or cardiology follow-up to monitor blood pressure, glucose, lipids, and

address late effects. This might involve collaboration with a cardio-oncology clinic if available.

5. Use of Risk Scores

: Tools like CARE-BMT can be used as part of risk documentation

–

for instance,

we can calculate it for all patients to identify high-risk individuals. However, one must use it as a guide

rather than an absolute predictor. Our data suggests that any patient not in a low-risk category deserves

essentially similar careful observation, meaning that both intermediate- and high-risk patients require

robust monitoring. High-risk patients might benefit from prophylactic measures (though none are

formally proven, one might consider things like beta-blockers in someone with borderline EF or statins in

someone with multiple risk factors, extrapolating from general population evidence). Future studies

should test interventions in high-risk CARE-BMT patients to see if events can be reduced.

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Limitations:

It is important to acknowledge the limitations of our study to put the findings in

perspective. The most evident limitation is the small number of events (n=6), which limits statistical

power and our ability to draw strong conclusions about associations. With such a low event count, the

logistic regression results, while suggestive, must be interpreted cautiously as they have wide confidence

intervals. Our study was also a single-center experience; practices at our center (such as patient selection

for HSCT and management protocols) might differ from others, affecting generalizability.

There is potential selection bias in that healthier patients might have been offered transplant (leading to a

lower incidence of complications than if higher-risk patients were transplanted). However, our intention

was to capture real- world data from all transplants done, which we did. Another limitation is the

retrospective design

–

we relied on documentation in records, which might have underreported some

mild events (e.g., transient arrhythmias that self-resolved might not have been captured if asymptomatic).

We tried to mitigate this by reviewing telemetry logs and nursing notes for any hints of arrhythmias.

Also, the follow-up was limited to one year (in contrast to other studies with mean follow-up period ~2.5

years); we did not address late cardiovascular outcomes beyond that, which would be relevant for

survivorship care.

Strengths: This is the first study looking into CV events in Asian population – whereby we have different

demographics and risk factors. On the other hand, the study has strengths such as including all consecutive

HSCT patients

over multiple years, giving a comprehensive view of outcomes at our center. The data

collection was thorough, allowing analysis of various factors including a new risk scoring system

(CARE-BMT) in our population. Despite the small event number, the consistency of trends (all pointing

towards allogeneic and comorbidities as risks) adds credibility to those findings, especially as they

align with biologic plausibility and external data. Also, by being the first local dataset, it provides a

reference point for Malaysian or regional transplant centers and can serve as pilot data for larger studies

or quality improvement initiatives.

Future Directions: Our findings generate several avenues for further research. A larger multi-center study

across Malaysia or Southeast Asia could be conducted to accumulate a bigger sample of HSCT

patients, which would provide more robust estimates of incidence and allow multivariate analyses

with more

variables (including age, GVHD, specific drugs, etc.) to truly identify independent predictors. It

would also be

valuable to follow patients for a longer term (e.g., 5 years) to capture late

cardiovascular events like

coronary artery disease onset, given increasing survivorship. Another area is

exploring biomarkers (like NT-

proBNP, troponin) as well as looking beyond ejection fraction

measurement (i.e., Global Longitudinal strains) measured during transplant

Some preliminary studies outside have suggested peri-transplant rises in cardiac biomarkers correlate

with later cardiomyopathy (e.g., in amyloidosis autologous transplant). In allogeneic transplants,

inflammatory markers could also be studied in relation to cardiac events. Additionally, intervention

trials could be considered: for example, testing if implementing a cardio-protective strategy (such as

beta- blockade or ACE inhibition for high-risk patients during transplant) can reduce incidence of

arrhythmia or heart failure.

In context of the CARE-BMT score, our results suggest it may need recalibration. Perhaps adding points

for certain chemotherapy exposures or refining age categories might improve its predictive ability.

Further validation of CARE-BMT in a larger Asian cohort would be informative

–

our small sample isn’t

enough to judge it conclusively, but it hints that intermediate risk comprises a broad spectrum.

Another

interesting finding was that none of the low-risk patients by CARE-BMT had events; if that holds in

larger data, it means the score is good at identifying a truly low-risk group. Those patients might

safely

undergo transplant with standard care and minimal extra monitoring, whereas resources can be focused

intermediate/high groups. This risk stratification approach, if validated, could optimize use of

telemetry beds or prophylactic measures.

Comparative Outcomes

: It is also worth noting that although our study focused on cardiovascular events,

these events did not translate into any mortality in our one-year follow-up. This is encouraging

–

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suggests that with prompt recognition and management, HSCT patients can survive these

complications. For instance, all our heart failure cases were treated with diuretics and supportive care

(none needed neither ICU nor mechanical ventilation), and they improved. This implies that while

prevention is ideal, the transplant team’s capacity to handle acute cardiac issues is crucial and effective. A

point for centers is to have specific protocols in place for managing these events (co-managing with

Cardiology units.).

Summary (of Discussion): In conclusion, the discussion highlights that our study’s findings are largely in line

with global literature on HSCT-related cardiovascular events, reinforcing known risk factors such as

allogeneic transplant and patient comorbidities, while adding local data that the incidence is similarly

low in the short term.

emphasizes the importance of integrated care

from pre-transplant risk

assessment to

post-transplant monitoring

to ensure these potentially serious events are minimized and

managed. Our experience adds weight to calls for formal cardio-oncology collaboration in the transplant

field, as the population of survivors grows and ages. With improved survival of HSCT patients, attention

must increasingly turn to long-term health issues like cardiovascular disease to ensure quality of life

and longevity post-cancer.

CONCLUSION

In this retrospective cohort study of HSCT recipients at HCTM, we have documented the incidence of

cardiovascular events and identified key risk associations in our patient population. The incidence of

cardiovascular events within one year post-transplant was 5.1%, with all events occurring in the early

post-

transplant period (within 100 days). The low incidence is consistent with international data and

confirms that serious cardiac complications are relatively infrequent in the acute phase of HSCT,

especially in a young cohort. However, when these events do occur, they are clinically significant and

tend to cluster in patients with identifiable risk factors.

Our analysis demonstrated that allogeneic HSCT patients and those with pre-existing cardiovascular risk

factors

(like hypertension, diabetes, or obesity) were more likely to experience cardiovascular events. Allogeneic

transplant was associated with a higher odds of events, likely due to factors inherent to the allogeneic

process (intensive conditioning, GVHD and its treatment, prolonged immunosuppression). Traditional

risk factors, even when present in modest proportions, markedly increased vulnerability to complications

under the stress of transplant. In our cohort, these two dimensions

–

transplant type and patient risk

profile

–

emerged as important considerations for predicting and managing potential cardiac issues.

The findings on the CARE-BMT risk score suggest that while it is a useful tool for stratifying risk, it did

not perfectly predict outcomes in our setting. Intermediate-risk patients still experienced events, and thus

risk categorization should be used as a guide alongside clinical judgment. All patients, except perhaps

those clearly low-risk, warrant vigilant cardiovascular monitoring.

This thesis contributes local data indicating that with careful patient selection and management, HSCT

can be performed with a low incidence of short-term cardiac complications. Nonetheless, given the severity of

events when they occur, we recommend the following: (1) Optimize cardiovascular health prior to HSCT

–

treat hypertension, diabetes, and other modifiable risks; involve cardiologists for borderline cardiac

function.

(2) Monitor closely and manage proactively during the transplant hospitalization

–

maintain a high index of

suspicion for cardiac events, especially in allogeneic recipients or those with risk factors; use telemetry and

periodic evaluation as needed. (3) Follow up long-term

–

incorporate cardiovascular surveillance in post-

HSCT follow-up clinics, given that the absence of early events does not guarantee freedom from later

cardiovascular disease. Preventative healthcare, including lifestyle advice and risk factor control, should be

part of survivorship care plans.

In conclusion, the study underscores that cardiovascular events post-HSCT, while uncommon, are an important

consideration in the comprehensive care of transplant patients. By identifying who is at risk, we can tailor

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Page 4366

monitoring and possibly preventive strategies to those individuals, thereby improving overall outcomes.

Our results highlight the successful outcomes achievable

–

all patients who had CV events were effectively

treated and survived

–

which speaks to the value of preparedness and interdisciplinary care. Future

research with larger cohorts is needed to validate these findings, explore late-onset cardiovascular

effects, and evaluate interventions to further reduce the burden of cardiovascular complications in

HSCT survivors. Ultimately, integrating cardiology with transplant medicine will help ensure that as

patients conquer their malignancies through HSCT, they are also protected from life-threatening

cardiovascular issues, leading to healthier long-term survival.

ACKNOWLEDGEMENTS

First and foremost, I would like to express my profound gratitude to my supervisors for their invaluable

guidance and support throughout this research project. I am deeply thankful to Dr. Mohd Shawal Faizal

Bin Mohamad, whose expertise in cardiology and unwavering encouragement were instrumental in

shaping the direction of this thesis. My sincere appreciation also goes to Prof. Dr. S. Fadilah Abdul Wahid

for her insightful feedback and to Prof. Shamsul Azhar Shah for his guidance on statistical analysis. Their

combined mentorship greatly enriched my learning experience and the quality of this work.

I am also grateful to the clinicians and staff of the Bone Marrow Transplant unit at Hospital Canselor

Tuanku Muhriz (HCTM) for their cooperation and assistance in gathering the data. Special thanks to

my colleagues and friends in the Department of Medicine for their support and for providing a

collaborative environment. I also extend my gratitude to Mdm Anis Nabila (Faculty of Pharmacy,

UKM) for her assistance with preliminary data analysis and manuscript preparation. Finally, I owe

my most profound appreciation to my family for their patience, understanding, and constant

encouragement, which have been the backbone of my journey in completing this thesis.

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