2.5. Cellular Therapy and Hematopoietic Stem Cell Transplantation
Many childhood diseases, malignant and otherwise, are seeing improved survival rates as a result of allogenic or autologous bone marrow transplantation. The cardiotoxicity experienced in this population of children varies according to the risk factors they carry prior to transplant as well as their experiences post-transplant. Among patients transplanted for malignancies, many children are placed at a higher risk for developing cardiotoxicity due to pre-treatment with high doses of anthracyclines to induce a remission prior to their consolidative transplant
[61][40]. Patients transplanted for non-malignant conditions, such as sickle cell disease or thalassemia, often receive repeated red blood cell transfusions and are thus at higher risk for iron overload. Iron can deposit in the myocardium, increasing this population’s risk for eventual heart failure
[61][40]. Finally, malignant and non-malignant patients alike may receive total body irradiation as a part of their preparative regimen for bone marrow transplantation, increasing their risk for cardiotoxicity for the reasons mentioned previously
[61][40].
A number of factors that arise post-bone marrow transplantation increase the risk for cardiotoxicity as well. Patients are most often treated with calcineurin inhibitors (e.g., cyclosporin) as prophylaxis for graft versus host disease (GVHD). Calcineurin inhibitors are associated with systemic hypertension, and if blood pressures are not adequately managed, can increase the risk for development of heart failure
[61][40]. If GVHD does occur, it is often treated with corticosteroids, sometimes for long periods of time. The side effect profile of corticosteroids includes hypertension, hyperglycemia, and weight gain, which are all risk factors for heart disease
[61][40]. Finally, there is a higher incidence of metabolic syndrome in the post-transplant population, which compounds the risk factors that are already present
[61][40]. While development of heart failure as a consequence of these modifiable risk factors can take years or even decades to develop, the appropriate identification and treatment of these issues in the childhood years are critical to mitigate future cardiovascular risk and improve longer term outcomes.
Cellular therapy is an evolving field for treatment of childhood cancers. Most promising thus far is the development of chimeric antigen receptor (CAR) T cells. To engineer a CAR-T cell, a patient’s T cells are collected via leukapheresis, injected with a genetically engineered receptor to target antigens on the surface of tumor cells, expanded, and infused back into the patient. This was first used in pediatric pre-B acute lymphoblastic leukemia (ALL), where CD-19 on the surface of B cells was targeted by CAR-T cells
[62][41]. Patients treated with CAR-T therapy are at risk for cardiotoxicity both because of treatment they may have seen in the past (e.g., anthracyclines) in addition to acute risks associated with the CAR-T cells, most notably cytokine release syndrome (CRS).
CRS is a phenomenon in which the infused CAR-T cells stimulate both the innate and adaptive immune system, releasing supraphysiologic levels of cytokines leading to systemic inflammation
[63][42]. CRS ranges from mild to severe, with signs and symptoms ranging from fever and tachycardia to hypoxia, hypotension, and, in the worst case, organ failure and death. IL-6 is an important mediator of CRS and is released by antigen presenting cells (APCs) and activated endothelial cells
[50][39]. The dysfunction of endothelial cells then contributes to vascular leak and disruption of the blood brain barrier, leading to CAR-T cell induced neurotoxicity (i.e., immune effector cell associated neurotoxicity/ICANS). IL-6 is thought to be secreted at the same time CAR-T cells are recognizing antigenic targets on tumor cells, not as a direct result of CAR-T cells engaging APCs or endothelial cells
[50][39]. The role of IL-6 in CRS is further supported by the rapid improvement seen with the initiation of tociluzimab, a monoclonal antibody against the IL-6 receptor
[64][43].
Acute cardiotoxicity in the setting of CAR-T cell therapy occurs almost exclusively in the setting of CRS and most closely resembles cardiomyopathy associated with sepsis
[50][39]. IL-6 is largely to blame for cardiotoxicity in this context, which is consistent with previous work showing this cytokine to be implicated in myocardial depression in both inflammatory and infectious states
[65][44]. Supraphysiologic levels of this and other pro-inflammatory cytokines can lead to tachycardia, hypotension, troponin elevation, reduced left ventricular ejection fraction, pulmonary edema, and cardiogenic shock
[50][39].
Finally, metabolic derangements can play a role in CAR-T cell associated cardiotoxicity. When CAR-T cells engage target antigens on the surface of tumor cells and induce cell lysis, intracellular electrolytes such as potassium, phosphate, calcium, and uric acid spill into the extracellular space in a phenomenon known as tumor lysis syndrome. These metabolic derangements may lead to arrythmia and renal failure if left unchecked
[50][39].