MON-619 - Polatuzumab-Induced Diabetes Mellitus - A Case Report

Introduction:
Targeted immunotherapy has improved outcomes in aggressive lymphomas compared with conventional chemotherapy. Polatuzumab, an antibody–drug conjugate targeting CD79b, a key component of the B-cell receptor complex, is now used as frontline therapy for diffuse large B-cell lymphoma (DLBCL). Unlike immune checkpoint inhibitors, immune-related adverse events have not been reported with polatuzumab. We present a case of diabetic ketoacidosis in a patient without prior diabetes following completion of six cycles of polatuzumab with rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP).

Case Description:
A 61-year-old man presented to the emergency department with a three-day history of fatigue, generalized weakness, polyuria, and polydipsia. Medical history notable for non-Hodgkin's lymphoma, diagnosed in 1997 and treated with radiation and chemotherapy, stage III right-sided colon cancer in 2022 status-post right hemicolectomy, and active stage III DLBCL diagnosed six months prior to presentation, for which he completed six cycles Pola-R-CHP. He denied any personal or family history of diabetes mellitus.

On presentation, laboratory evaluation demonstrated severe hyperglycemia (glucose 450 mg/dL), elevated anion gap (23), metabolic acidosis (pH 7.26), and elevated beta-hydroxybutyrate (6.28 mmol/L), consistent with DKA. Hemoglobin A1C was 12.4%. He was admitted to the medical intensive care unit and treated with intravenous fluids and continuous insulin infusion. After resolution of metabolic acidosis and ketosis, he was transitioned to a basal-bolus insulin regimen.

Evaluation for autoimmune diabetes revealed negative zinc transporter 8, glutamic acid decarboxylase, and insulin antibodies; however, C-peptide was low at 0.4 ng/mL, consistent with insulin deficiency. Despite initial therapy, glycemic control remained suboptimal, requiring escalation of his basal-bolus insulin regimen. He was discharged on insulin glargine 26 units daily and insulin aspart 8 units three times daily with meals, with close outpatient follow-up in endocrinology.

Discussion/

Conclusion:
Endocrinopathies are well-recognized adverse effects of targeted immunotherapies, arising from loss of immune tolerance due to dysregulated T-cell activation. This process can cause thyroiditis, adrenalitis, and hypophysitis, ultimately leading to hormonal deficiencies from tissue destruction. Although polatuzumab targets B cells via CD79b, inducing endocytosis of antibody–drug conjugate and intracellular release of the cytotoxic agent monomethyl auristatin E (MMAE), we hypothesize that the resulting tumor cell apoptosis triggers a downstream inflammatory response that promotes aberrant T-cell activation. This immune dysregulation may result in pancreatic beta-cell injury, leading to insulin deficiency and diabetes mellitus.

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