Pancreatitis in patients treated with brentuximab vedotin: a previously unrecognized serious adverse event

To the editor:

Brentuximab vedotin (BV) is a novel anti-CD30 antibody drug conjugate that gained accelerated regulatory approval¹  after studies demonstrating impressive efficacy in relapsed Hodgkin lymphoma and anaplastic large cell lymphoma.^2-4  The cytotoxic component is monomethylauristatin E, a potent inhibitor of microtubule assembly. Although abdominal pain has been reported in up to 18% of patients treated with BV, pancreatitis is a previously unidentified serious adverse event (while this report was under review, an additional case of BV-associated pancreatitis was reported in which the patient was successfully retreated⁵ ). After a fatal case of pancreatitis in a patient receiving single-agent BV in an ongoing clinical trial (NCT01476410), we identified an additional fatal case and 6 nonfatal cases of pancreatitis associated with single-agent BV therapy. Cases were collected from collaborating investigators and colleagues at other lymphoma programs, including adverse events reported to the US Food and Drug Administration Adverse Event Report System from June 2011 to July 2013. Institutional review board or ethics committee approval, as required, was obtained in all cases. Collected data were centralized through the Research on Adverse Drug Events and Reports project at Northwestern University in Evanston, Illinois. Immunohistochemical staining with the anti-CD30 antibody BER-H2 (Dako) was performed on residual normal pancreas from 1 of the fatal cases and on 2 normal control pancreas specimens and was analyzed by routine microscopy and the Nuance multispectral imaging system (PerkinElmer).⁶ 

Demographic, treatment, and laboratory data for all 8 cases are summarized here (Figure 1). Notably, no patient had antecedent exposure to alcohol, had biliary pathology diagnosed during their ensuing hospital course, or had a history of hypertriglyceridemia. The median time to presentation was 26 days from the first BV exposure and 12 days from the most recent treatment, with all cases occurring by the third cycle of therapy. All patients had clinical presentations consistent with pancreatitis, as manifested by severe abdominal pain and nausea along with biochemical evidence, with an elevated lipase. Two patients were retreated with BV after their initial episodes of pancreatitis, including one patient who developed recurrent pancreatitis and one who never redeveloped symptoms. Two patients experienced progressive multiorgan dysfunction as a consequence of pancreatitis, leading to death.

On pathologic assessment, neither our patient’s autopsy pancreas specimen nor normal pancreas controls showed CD30-positivity with routine immunohistochemistry. However, using multispectral imaging, the patient’s routine immunohistochemistry pancreas sample and 2 normal pancreas controls showed variable low-level CD30 expression that was significantly higher (P < .0001, Student t test) than mouse immunoglobulin controls (Figure 1), suggesting that unintended targeting of low-level pancreatic CD30 by BV may underlie this complication of therapy. Other mechanisms postulated for the observed toxicity include circulating unconjugated monomethylauristatin E, the presence of isolated CD30-positive malignant cells in the pancreas of some patients, or host factors such as mutations predisposing patients to the development of acute or chronic pancreatitis.⁷ 

BV offers a promising therapeutic advance for the treatment of CD30-positive lymphomas, with limited toxicity. This series demonstrates an uncommon, previously unreported, and potentially life-threatening adverse event. Pancreatitis should be considered in the differential diagnosis of abdominal pain after BV therapy.