SUN-174 Severe Insulin Resistance and Diabetic Ketoacidosis after Brentuximab Vendotin and Cyclosporin Treatment

Abstract

Introduction: Brentuximab Vendotin(BV) is antibody-drug conjugate that selectively delivers cytotoxic agent, monomethyl auristatin E, targeting cells expressing surface CD30, treatment approved for refractory Hodgkin’s lymphoma. Previous research suggested MDR1 inhibition (cyclosporine) can overcome BV resistance. Case: 23 year old male with relapsed and refractory classical Hodgkin lymphoma underwent clinical trial with BV and Cyclosporin( CyA). He was given one dose of BV( 1.8mg/kg) and CyA ( 725mg 2 times a day for 5 days). A week after BV and 3 days after the last dose of CyA, patient had acute onset of hyperglycemia and ketoacidosis; glucose 435 mg/dL, bicarbonate 14 mmol/L, anion gap 14( 8-14), beta hydroxybutyrate 40.3 mg/dL (0.0-3.0 mg/dL), urine ketone +3, C-peptide 9.0 ng/ml (0.8-3.5 ng/ml). Serum cyclosporine level was high as 453 ng/ml (150-300ng/ml) at the time of presentation, which was reduced to 116 ng/ml within a week. He had no previous diabetes history. His severe hyperglycemia and metabolic acidosis persisted after aggressive hydration and multiple daily insulin injections. He was started on modified intravenous insulin infusion protocol. Within 24 hours, his glycemic control was improved at goal requiring average 34 units/h of regular insulin with NPO status. This was transitioned to U500 regular insulin divided dose injection every 8 hours with holding criteria. 10 days after initial clinical presentation, patient's insulin requirement was abruptly reduced and eventually discontinued. Patient was discharged and glucose level remained within reference range (80-128 mg/dl) without additional medical management from follow-up. Patient had completed given clinical trial with reduced dose of BV and CyA, and there was no further similar episode. During the hospital course, underlying endocrine disease related to insulin resistance was ruled out including thyroid, glucagon, cortisol, catecholamine, or growth hormone excess. Autoimmune workup was negative except elevated ESR. Insulin autoantibody panels were negative. Pancreatitis and infections were also ruled out. Lymphocytes were reduced and monocytes were increased in CBC during the episode. Peripheral blood mononuclear cell (PBMC) analysis by flow cytometry showed that absolute B and T cell counts were low but in the residual CD4+ and CD8+ T cells, expression of CD25 and PD-1 was increased. Major portion of the PBMC did not stain with our standard immune phenotype panel, which may include plasma cells, NKT, or dendritic cells. Discussion: Adverse events ≥ Grade 3 hyperglycemia (12%) has been reported with BV treatment. On the other hand, CyA is known to be related to insulin resistance as well. This is the first case report of a patient who developed rare condition of severe insulin resistance and diabetic ketoacidosis in the context of hyperinsulinemia likely due to impaired insulin signaling induced by BV and CyA.