Summary
Introduction: Significant advancements in the supportive care and better conditioning regimens have led to improved survival in HCT recipients. Concurrently, an increase in the late complications have been observed in these groups compared to controls. Late effects affect almost every organ and lead to both morbidity and mortality in the HCT survivors.
Risk factors of the effects: Both clinical and genetic risk factors play a role in the development of late effects in HCT survivors. Among clinical risk factors, receipt of irradiation, certain chemotherapies (e.g. cyclophosphamide) and lifestyle factors (e.g. smoking, alcohol intake), significantly increase the risk of both cardiovascular complications and subsequent cancers. GVHD and its associated treatments (immunosuppressants) also contribute to the risk of many late effects. Among inherited risks, a genetic predisposition to enhanced toxicity (e.g. cardiotoxicity due to anthracyclines) and inherited DNA defects leading to increases in oral carcinomas in Fanconi Anemia are some examples.
Late effects: Late effects in HCT survivors may include acute and chronic infections (including HHV6, fungal and mycobacterial infections), cutaneous complications (e.g. vitiligo, carcinomas), oral cavity complications (particularly squamous cell carcinomas), hepatic complications (including cirrhosis), GI complications (e.g. malnutrition), genital complications (vaginal stenosis, phimosis etc.), renal complications (leading to chronic kidney disease), ocular complications (e.g. retinopathies, dry eye syndrome etc.), endocrine complications (diabetes and hypothyroidism), hypogonadism, fertility loss, dental complications, musculoskeletal and bone complications (including avascular necrosis and contractures), pulmonary complications (including BOS), neurologic complications (neuropathies, strokes), psychological and social complications (including financial toxicity and PTSD), sexual dysfunction, cardiovascular complications (particularly ischemic heart disease and HTN), subsequent solid malignancies, and subsequent hematologic malignancies.
Future directions: Existence of multidisciplinary clinics for the early detection and comprehensive management of these late effects is warranted given their effect on mortality and morbidity. Prospective studies with translational elements (e.g. biomarker discovery, metabolomics, microbiome assessments, etc.) are urgently needed for these HCT survivors.
References
1 1. Majhail NS, Rizzo JD, Lee SJ, et al. Recommended screening and preventive practices for long‐term survivors after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2012; 18(3):348–371.
2 2. Martin PJ, Counts GW Jr, Appelbaum FR, et al. Life expectancy in patients surviving more than 5 years after hematopoietic cell transplantation. J Clin Oncol. 2010; 28(6):1011–1016.
3 3. Hammond C, Abrams JR, Syrjala KL. Fertility and risk factors for elevated infertility concern in 10‐year hematopoietic cell transplant survivors and case‐matched controls. J Clin Oncol. 2007; 25(23):3511–3517.
4 4. Littley MD, Shalet SM, Morgenstern GR, Deakin DP. Endocrine and reproductive dysfunction following fractionated total body irradiation in adults. Q J Med. 1991; 78(287):265–274.
5 5. Cust MP, Whitehead MI, Powles R, et al. Consequences and treatment of ovarian failure after total body irradiation for leukaemia. BMJ. 1989; 299(6714):1494–1497.
6 6. Corson SL, Sullivan K, Batzer F, et al. Gynecologic manifestations of chronic graft‐versus‐host disease. Obstet Gynecol. 1982; 60(4):488–492.
7 7. Practice Committee of the American Society for Reproductive Medicine. Smoking and infertility. Fertil Steril. 2004; 81(4):1181–1186.
8 8. Buchbinder D, Brazauskas R, Bo‐Subait K, et al. Predictors of Loss to Follow‐Up Among Pediatric and Adult Hematopoietic Cell Transplantation Survivors: A Report from the Center for International Blood and Marrow Transplant Research. Biology of Blood and Marrow Transplant. 2020; 26(3):553–561.
9 9. Blazar RB, Murphy WJ, Abedi M. Advances in graft‐versus‐host disease biology and therapy. Nat Rev Immunol. 2012; 12:443–458.
10 10. Epstein O, Thomas HC, Sherlock S. Primary biliary cirrhosis is a dry gland syndrome with features of chronic graft‐versus‐host disease. Lancet. 1980; 1(8179):1166–1168.
11 11. Wenzel J, Lucas S, Zahn S, et al. CXCR3<–>ligand‐mediated skin inflammation in cutaneous lichenoid graft‐versus‐host disease. J Am Acad Dermatol. 2008; 58(3):437–442.
12 12. Kawasaki H, Takayama J, Ohira M. Herpes zoster infection after bone marrow transplantation in children. J Pediatr. 1996; 128:353–356.
13 13. Atkinson K, Meyers JD, Storb R, et al. Varicella‐zoster virus infection after marrow transplantation for aplastic anemia or leukemia. Transplantation. 1980; 29:47–50.
14 14. Wainwright MS, Martin PL, Morse RP, et al. Human herpesvirus 6 limbic encephalitis after stem cell transplantation. Ann Neurol. 2001; 50(5):612–619.
15 15. Shiroshita K, Mori T, Kato J, et al. Clinical characteristics of human herpesvirus‐6 myelitis after allogeneic hematopoietic stem cell transplantation and its favorable outcome by early intervention. Bone Marrow Transplant. 2019; 55:939–945.
16 16. Youssef S, Rodriguez G, Rolston KV, et al. Streptococcus pneumoniae infections in 47 hematopoietic stem cell transplantation recipients: clinical characteristics of infections and vaccine‐breakthrough infections, 1989–2005. Medicine (Baltimore). 2007; 86:69–77.
17 17. Hoyle C, Goldman JM. Life‐threatening infections occurring more than 3 months after BMT. 18 UK Bone Marrow Transplant Teams. Bone Marrow Transplant. 1994; 14:247–252.
18 18. Sheridan JF, Tutschka PJ, Sedmak DD, Copelan EA. Immunoglobulin G subclass deficiency and pneumococcal infection after allogeneic bone marrow transplantation. Blood. 1990; 75:1583–1586.
19 19. Kulkarni S, Powles R, Treleaven J, et al. Chronic graft‐versus‐host‐disease is associated with long‐term risk for pneumococcal infections in recipients of bone marrow transplants. Blood. 2000; 95:3683–3686.
20 20. Alonso CD, Treadway SB, Hanna DB, et al. Epidemiology and outcomes of clostridium difficile infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2012; 54(8):1053–1063.
21 21. Joseph RW, Couriel DR, Komanduri KV. Chronic graft‐versus‐host disease after allogeneic stem cell transplantation: challenges in prevention, science, and supportive care. J Support Oncol. 2008; 6:361–372.
22 22. Creamer D, Martyn‐Simmons CL, Osborne G, et al. Eczematoid graft‐vs‐host disease: a novel form of chronic cutaneous graft‐vs‐host disease and its response to psoralen UV‐A therapy. Arch Dermatol. 2007; 143:1157–1162.
23 23. Sullivan KM, Shulman HM, Storb R, et al. Chronic graftversus‐host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression. Blood. 1981; 57(2):267–276.
24 24. Jacobsohn DA, Kurland BF, Pidala J, et al. Correlation between NIH composite skin score, patient‐reported skin score, and outcome: results from the Chronic GVHD Consortium. Blood. 2012; 120:2545–2552.
25 25. Patel AR, Turner ML, Baird K, et al. Voriconazole induced phototoxicity masquerading as chronic graft‐versus‐host disease of the skin in allogeneic hematopoietic cell transplant recipients. Biol Blood Marrow Transplant. 2009; 15(3):370–376.
26 26. Rizzo JD, Wingard JR, Tichelli A, et al. Recommended screening and preventive practices for long‐term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2006; 12:138–151.
27 27. Schubert