THU295 The Role Of Imatinib In Pediatric Diabetes

Abstract

Abstract Disclosure: K. Lavelle: None. C. Chamberlain: None. M.S. Anderson: None. M.S. German: None. A. Nip: None. S.E. Gitelman: None. Background: A growing body of evidence suggests that imatinib may attenuate or even reverse diabetes in both mice and adults. In children, however, this has not been reported yet. Clinical Case: A 14-year-old previously healthy Black male presented to the hospital with a 2-week history of polydipsia, polyuria, and weight loss. He had no family history of diabetes. On admission, he was underweight (weight 45th percentile, Z=-0.11; BMI 1st percentile, Z=-2.33) and was found to be in DKA (serum pH 7.15 [7.31-7.47], glucose 560mg/dL [65-99 mg/dL], HCO3 9.7 mEq/L [20-28 mEq/L], urine ketones 4+, Hgb A1c 12.3%, C-peptide <0.2 ng/mL [1.1-4.4 ng/mL]) as well as COVID-19 positive and G6PD deficient with hyperleukocytosis (WBC 137.8 TH/mm3 [5-10 TH/mm3]). He was requiring 0.6u/kg/day insulin upon discharge and went home on glargine 10 units daily, aspart insulin-to-carbohydrate ratio 1u:10g at breakfast, 1:12 at lunch, and 1:15 at dinner with insulin sensitivity factor 1u:50 mg/dL. After discharge, autoantibodies (GAD-65, IA-2, IAA, ZnT8) returned negative. Oncologic testing returned positive for myeloid neoplasm, and he was readmitted for initiation of imatinib 400mg/day 2 months post-discharge. Over the next 3 months, his Hgb A1c decreased from 6.3% to 4.9%. The following month, he had gained weight (weight 83rd percentile, Z=0.95; BMI 61st percentile, Z=0.27) and was requiring only 0.2u/kg/day insulin on a non-restricted diet. His Hgb A1c was down to 4.6% without hypoglycemia 6 months after starting imatinib. Conclusion: Imatinib is a tyrosine kinase inhibitor first approved for treatment of chronic myeloid leukemia. In vivo studies have demonstrated that it targets anti-diabetic pathways as well: imatinib inhibits c-Abl in pancreatic beta cells, thereby blunting endoplasmic reticulum stress responses and reducing apoptosis. It also inhibits platelet-derived growth factor receptors, thereby increasing adiponectin and improving insulin sensitivity. Mouse studies have shown prevention of Type 1 diabetes (T1D) and reversal of both T1D and Type 2 diabetes with imatinib. A phase 2 trial in adults with new onset T1D treated with imatinib for 6 months showed preservation of beta cell function out to 12 months (Gitelman et al, Lancet Diabetes 2021). While receiving imatinib, participants also saw lower Hgb A1c, less insulin use, higher adiponectin and lower proinsulin:C-peptide, and improved beta cell glucose sensitivity when compared to the placebo group. This case suggests that imatinib might similarly benefit children, as our patient experienced a 1.7-point reduction in Hgb A1c% and a 67% reduction in insulin requirement on therapy. It is the first case to describe imatinib use in an adolescent with diabetes and poses two important questions: what is the etiology of diabetes in this patient, and how might imatinib impact the natural course of disease? Further studies are underway to clarify these issues. Presentation: Thursday, June 15, 2023