In 1956, a child with leukemia received the first bone marrow transplant. This was performed by Nobel Prize winner Dr. E Donnall Thomas, who became known as the father of bone marrow transplantation and as its director, led Fred Hutch to become the pioneer bone marrow transplant institution when it opened in 1975. Since then, transplantation of blood stem cells, called hematopoietic cells, has significantly increased survival of blood cancer patients, especially children. This has resulted in a growing population of long-term cancer survivors, however it’s still unclear exactly what all of the long-term effects of these life-saving procedures are. Dr. Scott Baker, a Professor in Fred Hutch’s Clinical Research Division interested in the short- and long-term health effects of blood stem cell transplants, explained that “cardiovascular disease is one of the leading causes of mortality in long term survivors after bone marrow transplant.” For this reason, he’s had “a long-standing interest in why these patients develop these adverse cardiovascular outcomes including myocardial infarctions, strokes, hyperlipidemia and hypertension.” In a collaborative study between Fred Hutchinson Cancer Center and the University of Minnesota, Dr. Baker along with Dr. Tyler Ketterl, Medical Director of Adolescent and Young Adult Oncology at Seattle Children’s with a joint affiliation at Fred Hutch, investigated the long-term impact of hematopoietic cell transplantation (HCT) in 151 adolescent and young adult HCT survivors. In their recent study published in Transplantation and Cellular Therapy, the authors focused on cardiovascular risks related to receiving HCT by evaluating patients who received this therapy compared to a cohort of control siblings.
The patients in this study had received their most recent HCT anywhere between 2.6 and 31.5 years prior to being evaluated for this study and had received this treatment as young as 6 months of age and up to 32 years old. At the time of this study, participants averaged 26 years old but spanned 10-50 years old. To understand the potential cardiovascular effects of receiving HCT, the participants underwent a 2-day examination at either the University of Minnesota Clinical Research Center or the Pediatric Clinical Research Center at Seattle Children’s Hospital. These examinations included general body measurements, body composition assessments by DEXA (dual X-ray absorptiometry), Tanner stages of puberty assignments and various testing to measure insulin sensitivity, including conducting hyperinsulinemic euglycemic clamps. After adjusting for age, sex, race and Tanner stage, the researchers found that survivors had higher fasting insulin levels and were more insulin resistant compared to sibling controls. Furthermore, the research team found that the greatest impact on insulin levels and sensitivity was on patients who had been exposed to total body and central nervous system irradiation during treatment. Additionally, relative to siblings, survivors had significantly higher levels of total and LDL cholesterol and triglycerides which can increase the risk of cardiovascular disease.
Despite increased insulin levels, Dr. Baker described that one of the interesting things they observed “is that the patients in this study were rarely obese if you look at their body weight body mass index and waist circumference, however when we did DEXA scans which provide us with measurements of muscle mass and internal fat mass, we found that these patients overall had a significant reduction in muscle mass and an increase in visceral or internal fat mass. These changes in body composition likely contribute to these patients being resistant to the effects of insulin (i.e., insulin resistant) and this is known to contribute to the development of cardiovascular disease, diabetes and hypertension.” Dr. Baker added that “transplant survivors need to be aware of these risks and make sure that they continue to monitor their blood pressure and have annual screenings of lipid profiles and fasting blood sugars. In addition, exercise is likely to provide significant benefit and potentially reduce their risk of cardiovascular disease as we know that it does in the general population.”
Through understanding the long-term effects of HCT, this work can inform us on how “bone marrow transplant survivors need to be screened for evidence of abnormal lipid profiles, any signs of pre-diabetes such as high fasting blood sugar levels and have very close monitoring of their blood pressure on a long term basis.” Fortunately, there are a number of ways that transplant survivors can mitigate the risk of cardiovascular disease and diabetes, such as participating in physical activity. Specifically, Dr. Baker suggested that “if their care team approves of this type of exercise, then consultation with an exercise trainer to develop a plan focused on resistance training and improving their muscle mass should be obtained.” Moving forward, Dr. Baker noted that one of the first things to understand is what “the benefit of exercise, and in particular resistance training, will have on improving these abnormal cardiovascular risk factors.” Another critical factor to investigate that could not be determined in this study, is “when these cardiovascular risk factors started to become abnormal so we can find out whether these changes developed very early after transplant and then are persistent, or whether they develop over months or years after the transplant. This has an impact on screening and when it should begin after transplant.”
Dr. Baker concluded by acknowledging “the patients who participated in this study as well as their siblings who participated as it was a complex study which required a significant commitment on their part but has provided invaluable information for transplant survivors moving forward.”
This work was supported by the National Institutes of Health.
Fred Hutch/UW/Seattle Children’s Cancer Consortium members Drs. Tyler Ketterl, Scott Baker, Eric Chow and Wendy Leisenring contributed to this work.
Ketterl TG, Chow EJ, Koves IH, Goodman P, Leisenring WM, Ballard S, Dengel DR, Moran A, Sinaiko AR, Steinberger J, Baker KS. 2023. Impact of Hematopoietic Cell Transplantation on Cardiovascular Risk Factors and Insulin Sensitivity. Transplant Cell Ther. S2666-6367(23)01671-8.