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 after hematopoietic cell transplantation (HCT) have been studied in detail. Although virtually every organ system can be adversely affected after HCT, the underlying pathophysiology of these late effects remain incompletely understood. This article describes our current understanding of the pathophysiology of late effects involving the gastrointestinal, renal, cardiac, and pulmonary systems, and discusses post-HCT metabolic syndrome studies. Underlying diseases, pretransplantation exposures, transplantation conditioning regimens, graft-versus-host disease, and other treatments contribute to these problems. Because organ systems are interdependent, long-term complications with similar pathophysiologic mechanisms often involve multiple organ systems. Current data suggest that post-HCT organ complications result from 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. Although many long-term problems cannot be prevented, appropriate monitoring can enable detection and organ-preserving medical management at earlier stages. Current management strategies are aimed at minimizing symptoms and optimizing function. There remain significant gaps in our knowledge of the pathophysiology of therapy-related organ toxicities disease after HCT. These gaps can be addressed by closely examining disease biology and identifying those patients at greatest risk for adverse outcomes. In addition, strategies are needed for targeted disease prevention and health promotion efforts for individuals deemed at high risk because of their genetic makeup or specific exposure profile.

Figure 1

Proposed conceptual representation of pathogenesis of CKD in HCT recipients (aGVHD: acute GVHD, cGVHD: chronic GVHD, HTN: hypertension) From: Hingorani, S., Chapter 97: Kidney and Bladder Complications of Hematopoietic Cell Transplantation. Thomas ED, Appelbaum FR, Forman,SG, Negrin, RS, Blume, KG, editors. Hematopoietic Cell Transplantation. Fourth ed. Wiley Blackwell Science; 2009. p. 1473.

Figure 2

Cumulative incidence curves of albuminuria and non-relapse mortality from day 100 to 1 year post-transplant. N=43 for ACR <30 N=54 for ACR 30–299; N=17 for ACR≥300. From: Hingorani, S., et al., Albuminuria in Hematopoietic Cell Transplant (HCT) Patients: Prevalence and Risk Factors. Journal of the American Society of Nephrology, 2006. 17: p. 405A.

Figure 3

Kaplan-Meier curves of albuminuria and overall survival from day 100 to 1 year post-HCT. N=44 for ACR<30; N=58 for ACR 30–299; N=18 for ACR≥300. From: Hingorani, S., et al., Albuminuria in Hematopoietic Cell Transplant (HCT) Patients: Prevalence and Risk Factors. Journal of the American Society of Nephrology, 2006. 17: p. 405A.

Figure 4

Mechanisms of cellular damage and organ response