ISSN 1662-4009 (Online)

ESPE Yearbook of Paediatric Endocrinology (2019) 16 9.5 | DOI: 10.1530/ey.16.9.5

Total body irradiation for hematopoietic stem cell transplantation during early childhood is associated with the risk for diabetes mellitus

Nakagawa R, Hosokawa-Tsuji A, Aoki Y, Takasawa K, Maru M, Nakajima K, Sutani A, Miyakawa Y, Tomizawa D, Kashimada K & Morio T

To read the full abstract: Endocrine. 2018 Jul; 61(1):76

Hematopoietic stem cell transplantation (HSCT) is a curative treatment for life-threatening malignancies. However, late HSCT adverse effects cause substantial morbidity among long-term survivors. Metabolic complications, such as diabetes mellitus and hyperlipidemia, are the major late effects of pediatric HSCT, but the pathogenesis of these complications is unclear. Different mechanisms leading to insulin resistance have been implicated, including TBI related muscular damage leading to secondary muscular insulin resistance and a chronic systemic inflammatory state.

This retrospective study evaluated general clinical conditions and metabolic complications of a small group of HSCT survivors. Among 22 participants, 4 developed diabetes mellitus and 9 hyperlipidemia. All patients with diabetes mellitus also developed hyperlipidemia. No patient with diabetes mellitus was obese, but all showed substantial insulin resistance. Ten participants had received total body irradiation (TBI), including the four participants with diabetes mellitus and 5/9 participants with hyperlipidemia, revealing that TBI may be an independent risk factor for diabetes. The age at TBI of patients with diabetes was significantly lower than those without diabetes; all patients with diabetes had received TBI before 6 years of age.

These results suggest that weight control is not enough to prevent metabolic complications and body weight is not predictive of metabolic complications. Therefore, close monitoring of metabolic biomarkers, such as fasting blood glucose, HbA1c, immunoreactive insulin, seems to be essential. This is the first study to report TBI during early childhood as a significant risk factor for diabetes mellitus. The authors recommend a conditioning regimen without TBI for patients younger than 6 years of age, whenever possible, and close monitoring of metabolic status in patients who underwent TBI before the age of 6.

TBI has been widely employed as a conditioning regimen of HSCT, especially for high risk malignancies. TBI regimens have been described as significantly superior to Busulfan regimens without TBI, with disease-free survival being 57% for TBI and 20% for Busulfan (2). These results suggest that innovative therapies are required to avoid TBI, including novel technologies like T-cell therapy (3). Such treatments could represent a future option to avoid TBI, and we expect that these novel therapies will be greatly beneficial for young children with cancer, not just for what concerns their anti-tumor effects, but also in reducing severe late effects of TBI.

References: 1. Kavanagh K, Dendinger MD, Davis AT, Register TC, DeBo R, Dugan G, Cline JM. Type 2 Diabetes is a Delayed Late Effect of Whole-Body Irradiation in Nonhuman Primates. Radiat Res. 2015; 183: 398–406.

2. Bunin N, Aplenc R, Kamani N, Shaw K, Cnaan A, Simms S. Randomized trial of busulfan vs total body irradiation containing conditioning regimens for children with acute lymphoblastic leukemia: a Pediatric Blood and Marrow Transplant Consortium study. Bone Marrow Transplant. 2003; 32: 543–548.

3. Hartmann J, Schüßler-Lenz M, Bondanza A, Buchholz CJ. Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med. 2017; 9: 1183–1197.