New Onset Persistent Hyperglycemia with Initiation of Brentuximab Treatment
Authors: Quintas Joseph B. , Mowatt Kelley B. , Mullally Jamie A. , Steinberg Amir 
Published: November 2021

Abstract
Brentuximab is a CD-30-directed antibody-drug conjugate. The addition of brentuximab vedotin (BV) to adriamycin, vinblastine, and dacarbazine (AVD) has become a standard-of-care approach for advanced stage Hodgkin Lymphoma. BV has well known toxicities including peripheral neuropathy and infusion reactions. One emerging toxicity that is beginning to be recognized is new-onset hyperglycemia and diabetes mellitus. This case describes a rare presentation of new-onset diabetes mellitus one month after initiation of BV+AVD therapy in a patient with Hodgkin Lymphoma.
A 41 year old previously healthy woman presented initially with complaints of chest and back pain. Cardiac etiology was ruled out, and lymphadenopathy was noted on chest imaging. Subsequent pathologic report from a robotic-assisted excision of a mediastinal mass and level five lymph node revealed Classical Hodgkin Lymphoma, nodular sclerosis type. Her baseline Hba1c was 5.8% at time of diagnosis. BV+AVD therapy was initiated about five weeks later.
Six weeks after initiating treatment, she was admitted for abdominal pain secondary to constipation, at which time her blood glucose was noted to be 357 mg/dL. A repeated Hba1c was 8.1%. She required rapid acting insulin, and her glucoses ranged from 132-263 mg/dL. After discharge, a fasting glucose of over 250 mg/dL deemed her ineligible to have a PET/CT performed to assess disease status after completing cycle 2. She was referred urgently to the endocrinology clinic. She had been receiving dexamethasone 12mg every two weeks in conjunction with her chemotherapy, as well as additional lower doses for chemotherapy induced nausea. Thus, there was some thought she could have steroid-induced diabetes mellitus. However, her last dose of dexamethasone was given more than ten days prior to her most recent FSBG reading of 220 mg/dL, so steroid-induced diabetes was deemed less likely. The more likely etiology considered was BV-induced hyperglycemia. The patient was started on basal insulin, a DPP4i, and a meglitinide analog. Since initiation of this therapy, her glucose levels are now better controlled with readings consistently under 200 mg/dL. Furthermore, her lymphoma is in remission after three cycles of BV+AVD therapy, with a plan to complete six cycles.
For many years, the standard of Hodgkin Lymphoma treatment consisted of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD). In 2017, the results of the ECHELON-1 phase 3 clinical trial demonstrated that a regimen with BV in conjunction with adriamycin, vinblastine, and dacarbazine (BV+AVD) has superior modified progression-free survival for patients with stage III/IV classical Hodgkin Lymphoma when compared to ABVD (Connors, NEJM, Jan, 2018). In a subsequent 3-year follow up study published in Blood, the authors demonstrated superior 3-year PFS for BV+AVD relative to ABVD.
While BV has been a preferred treatment option to bleomycin, and one that avoids the dreaded complication of pulmonary fibrosis, we are learning more about other emerging toxicities related to its use. When the drug was first approved in 2011 for use in relapsed/refractory Hodgkin Lymphoma, the toxicity of hyperglycemia was not noted in the side effect profile. As the drug has now been in use for ten years, emerging data on other toxicities have been noted in trials and reported to the manufacturer. Hyperglycemia is a listed adverse effect in the prescribing label with an incidence of up to 8% of patients experiencing any grade hyperglycemia, and 6% experiencing Grade 3 or 4 hyperglycemia.
The pathophysiology of hyperglycemia with BV administration is currently unclear. Interestingly, there is a paucity of literature describing this toxicity of the drug, and most incidence reports may be related to clinical trial data or post-approval reporting. An extensive literature search revealed only one other case report of new onset diabetes mellitus in patients receiving BV (Chiang, AACE, 2020). The authors suggest a general decrease in immune surveillance while on the drug leading to autoimmune conditions. Regardless of the mechanism of action, the above case report demonstrates a need to monitor blood glucose levels carefully during the initiation of BV therapy, especially in those individuals who have risk factors such as obesity or pre-diabetes mellitus. Future studies may further address the mechanism of hyperglycemia from BV and if the resultant diabetes is reversible.

Disclosures
No relevant conflicts of interest to declare.