A fatal case of bortezomib-induced lung toxicity in a young adult heart transplant recipient

Bortezomib is approved for the treatment of multiple myeloma but increasingly used in heart transplant (HTx) recipients with antibody-mediated rejection (AMR). Severe pulmonary toxicity is a rare complication in multiple myeloma patients treated with bortezomib, but has not been described in a solid organ transplant recipient. A 20-year-old man 7 years post-HTx presented with acute rejection with hemodynamic compromise. Endomyocardial biopsy showed mixed rejection (ISHLT grade 2R-3R acute cellular rejection (ACR) and pAMR 1 (I+) with diffuse C4d staining). Two new high MFI circulating MHC class-II donor-specific antibodies (DSA) were detected. Treatment included corticosteroids, antithymocyte globulin, plasmapheresis, IVIG, rituximab, and bortezomib (1.3 mg/m(2)). Due to rebound in DSA, a second course of bortezomib was started. Thrombocytopenia and peripheral neuropathy prompted a 50% dose reduction during the 2nd course. Shortly after the 3rd reduced dose, the patient developed hypoxemic respiratory failure. Bronchoscopy revealed pulmonary hemorrhage with negative infectious studies. Chest CT showed bilateral parenchymal disease with bronchiectasis and alveolar bleeding. Despite treatment with high-dose steroids, severe ARDS ensued with multisystem organ failure. The patient expired 23 days after the final dose of bortezomib. Post-mortem lung histology revealed diffuse alveolar damage, pulmonary fibrosis, and hemorrhage. Cardiac histology showed resolving/residual ACR 1R and pAMR 1 (I+). While rare, bortezomib-induced lung toxicity (BILT) can occur in HTx recipients and can carry a high risk of mortality. Drug reaction and immediate drug withdrawal should be considered in patients who develop respiratory symptoms, though optimal management of BILT is unclear.