National Cancer Institute–National Heart, Lung and Blood Institute/Pediatric Blood and Marrow Transplant Consortium First International Consensus Conference on Late Effects After Pediatric Hematopoietic Cell Transplantation: Long-Term Organ Damage and Dysfunction

Abstract

Long term complications following hematopoietic cell transplantation (HCT) have undergone comprehensive study. Although virtually every organ system can be adversely affected after HCT, the underlying pathophysiology of these late effects are incompletely understood. This manuscript describes current understanding of the pathophysiology of late effects involving the gastrointestinal, renal, cardiac, pulmonary systems along with a discussion of post-HCT metabolic syndrome studies. The patient’s underlying disease, pretransplant exposures, transplant conditioning regimens, graft versus host disease (GVHD) and other therapies contribute to these problems. Because organ systems are interdependent, long term complications with similar pathophysiology often involve multiple organ systems. Current data suggest that post-HCT organ complications occur as a result of cellular damage that leads to a cascade of complex events. The interplay between inflammatory processes and dysregulated cellular repair likely contributes to end-organ fibrosis and dysfunction. Though many long term problems cannot be prevented, appropriate monitoring can lead to detection and organ-preserving medical management at earlier stages. Currently, management strategies are aimed at minimizing symptoms and optimizing function. There remain significant gaps in knowledge regarding pathophysiology of therapy-related organ toxicities disease following HCT. These gaps can be filled by closely examining disease biology and defining which patients are at highest risk of adverse outcomes. In addition, strategies should be developed for targeted disease prevention and health promotion efforts for individuals at high risk because of their genetic makeup or specific exposure profile.

Long-term Cardiovascular Toxicity in Children, Adolescents, and Young Adults Who Receive Cancer Therapy: Pathophysiology, Course, Monitoring, Management, Prevention, and Research Directions

“…Intensive chemotherapy and acute or chronic graft-versus-host disease often result in permanent glomerular injury, chronic kidney disease, and related hypertension. 399 Total body radiation may also cause a radiation-induced nephropathy, as noted with abdominal radiotherapy above, and it commonly causes insulin resistance and metabolic syndrome, and consequently, hypertension. 316,[400][401][402] Given these multiple pathways to elevated blood pressure, it is not surprising to find that 70% of 180 allogeneic hematopoietic cell transplant recipients became hypertensive within 2 years after transplantation.…”

GVHD-associated chronic kidney disease after allogeneic haematopoietic cell transplantation

“…Our results are in line with recent data from other studies. [18][19][20] The pathogenetic mechanism of GVHD-associated CKD that was proposed by the National Cancer Institute consortium, 21 involving not only CKD but also other late complications and end-organ damage postHCT, is endothelial injury-related. Injury of the endothelium, the principal target tissue of cGVHD, may initially lead to inflammation, cytokine cascade through tumor necrosis factor-a (TNF-a), IL-6 and transforming growth factor-b (TGFb) and later to fibrosis and organ failure as a result of the immune intolerance of cGVHD.…”

Pulmonary Function after Treatment for Childhood Cancer. A Report from the St. Jude Lifetime Cohort Study (SJLIFE)

“…Therapeutic interventions that may impair pulmonary function include surgical procedures in which lung tissue is removed or the structure of the bony thorax and/or respiratory muscles is modified; radiation therapy that includes part or all of the lungs and chest wall; and/or chemotherapeutic agents such as 1,3-bis(2-chloro-ethyl)-1-nitrosourea (carmustine, BCNU), bleomycin, busulfan (6, 7), or 1-(2-chloro-ethyl)-3-cyclohexyl-1-nitrosourea (lomustine, CCNU) (8) that may cause parenchymal lung damage. In addition, patients who undergo hematopoietic stem cell transplants may develop pulmonary dysfunction following graft-versus-host disease, which is strongly associated with restrictive and obstructive lung disease (9,10).…”