Ofatumumab‐associated acute respiratory manifestations: clinical characteristics and treatment

Ofatumumab is a humanized monoclonal antibody (mAb) that binds the membrane–proximal epitope of the CD20 molecule in B cells [1] Together with its homologues rituximab and ocrelizumab that bind different segments in the large loop of CD20, ofatumumab is being more largely utilized in the treatment of several clinical conditions resistant to other treatments including multiple sclerosis [2], haematologic [3] (e.g. chronic lymphocytic leukemia, lymphoma) and rheumatologic [4] (e.g. rheumatoid arthritis) diseases. Similarly to the other anti-CD20 antibodies, infusion of ofatumumab is associated with typical respiratory symptoms such as dyspnoea, throat irritation and pharyngolaryngeal pain whose occurrence seems dose-correlated. At the concentration of 700 mg 1.73m dissolved in 1 l saline, respiratory side effects of ofatumumab are reduced to the minimum or are prevented by a pre-medication that is now consolidated in a multidrug association of methylprednisolone, cetirizine and paracetamol. This schedule has been extensively utilized with success for preventing side effects due to infusion of rituximab and it was utilized also as standard approach for ofatumumab. More recently, the use of ofatumumab has been extended to nephrotic syndrome with a main indication for those cases resistant or requiring prednisone and calcineurin inhibitors [5, 6]. In the former case, multiple infusions with high drug dosages of 2000 mg 1.73 m each, have been shown to modify proteinuria and reverse the clinical outcome. In patients with dependence to steroids and calcineurin inhibitors, a clinical trial has been designed and is currently in progress at our Institution that compares the long term effect of one or more ofatumumab doses (1500 mg 1.73 m) with rituximab (375 mg 1.73 m). For practical reasons, ofatumumab was diluted in 1 l saline and the infusion rate was steadily increased in order to be completed in 12 h (12 ml h for the first 60 min followed by 24 ml h 61–120 min, 48 ml h 121–180min and 96ml h up to the end). This allows the reduction in the flow rate in case of clinical problems and to be completed in 24 h that is the stability term of the drug. In the preclinical study [7] as well as in the first part of the clinical trial, the premedication schedule utilized for infusion of rituximab (i.e. methylprednisolone, cetirizine and paracetamol) has been utilized without modification. Respiratory symptoms that very often occurred at the passage from the first speed of infusion to the second (i.e. from 12 to 24 ml h) were initially treated with a second dose of cetirizine and/or steroid (with the dose reduced to 50% of the initial dose). Additionally, the infusion rate was slowed down. However, both the frequency and clinical impact of respiratory side effects increased in a relevant way in those patients receiving increased amounts of drug due to high body surface area and they required hospitalization in the emergency room in some cases. Inclusion of salbutamol in aerosol immediately before ofatumumab infusion prevented these symptoms and now represents a basic step in the pretreatment schedule.