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 pharyngo‐laryngeal pain whose occurrence seems dose‐correlated. At the concentration of 700 mg 1.73m^{– 2} 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^{– 2} 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^{– 2}) with rituximab (375 mg 1.73 m^{– 2}). 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^–1 for the first 60 min followed by 24 ml h^–1 61–120 min, 48 ml h^–1 121–180 min and 96 ml h^–1 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^–1) 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.

Case report

Thirty‐two patients (M15 F17, age 4–18 years ) affected by nephrotic syndrome dependent to prednisone (>1 mg kg^–1) plus ciclosporin (4 mg kg^–1) or tacrolimus (0.1 mg kg^–1) were treated with ofatumumab 1500 mg 1.73 m^{– 2} (Table 1). The drug (final dose between 550 to 1900 mg) was diluted in 1 l saline and infused at constant rates from 12 ml h‐1 to 96 ml h^–1 in 24 h. The study was approved by the Ethics Committee Regione Liguria and was published in Clinical Trials.gov (NCT02394119 and NCT02394106). All patient parents gave the informed consent to the study. At the beginning of the study, 19 patients received ofatumumab infusion preceded by i.v. methylprednisolone (2 mg kg^–1), oral cetirizine 0.2 mg kg^–1 and paracetamol 0.15 mg kg^–1. Respiratory symptoms mainly throat irritation, cough, dyspnoea and bronchospasm occurred in all but three patients of this series at the start of the 24 ml h^–1 speed infusion that required to slow down and stop of infusion when the symptoms persisted. Ofatumumab infusion was completed in the emergency room in six patients. SaO₂ decreased under the limit of 95% in five patients. All these symptoms occurred in almost all cases infused with doses higher than 800 mg l^–1. Based on this observation and being impossible to reduce ofatumumab concentration (e.g. at the speed required, 1000 ml is the maximum to complete infusion within 24 h that is the limit of the stability of the drug) we modified the pretreatment scheme by adding salbutamol (0.1 mg kg^–1 up to a maximum of 3.75 mg) administered by nebulizer immediately at the start of ofatumumab infusion. Thirteen new patients received ofatumumab with the modified pretreatment scheme, maintaining drug concentration and infusion rates as before. We obtained a clear improvement consisting in complete absence of respiratory symptoms. As a consequence, no patient required to be assisted by an anaesthesiologist and all completed the infusion in less time without any consequence.

Table 1.

Characteristics and main clinical features of 23 patients treated with ofatumumab for nephrotic syndrome dependent on both steroids and calcineurin inhibitors. The dose of ofatumumab was in all cases 1.5 g/m² diluted in 1000 ml of normal saline. (A) Nineteen patients received a pre‐treatment with i.v. methylprednisolone (2 mg kg^–1), oral cetirizine 0.2 mg kg^–1 and paracetamol 0.15 mg kg^–1 and 16 presented respiratory symptoms, mainly dyspnoea, throat irritation and pharyngo‐laryngeal pain that required repetition of steroids and cetirizine. (B) Following this observation, 13 patients were pre‐treated with salbutamol (0.1 mg kg^–1 up to a maximum of 3.75 mg) administered by nebulizer immediately at the start of ofatumumab infusion which minimized the impact of respiratory symptoms.

A	Gender/Age	m 2	Ofatumumab (mg l –1 )	Clinical features	SaO 2 %	Emergency
1	F/6.68	0.78	680	No	100	No
2	M/6.3	0.80	700	No	100	No
3	M/6.51	0.84	730	Cough	100	No
4	M/6.53	0.99	860	Abdominal pain, rash	99	No
5	F/9.97	1.00	870	Throat irritation, cough	94	No
6	M/12.12	1.02	880	Throat irritation, dyspnoea	93	No
7	F/6.51	1.04	900	Throat irritation, cough	100	No
8	F/10.17	1.21	1050	Headache, nausea, abdominal pain	100	No
9	M/10.69	1.24	1075	Throat irritation	99	No
10	M/9.54	1.33	1150	Cough, rash	100	Yes
11	M/11.53	1.35	1170	Throat irritation, cough	98	Yes
12	F/13.26	1.35	1170	Throat irritation, rhinitis, conjunctivitis	99	No
13	M/14.64	1.39	1200	Dyspnoea, bronchospasm	93	No
14	F/13.87	1.43	1240	Throat irritation	100	Yes
15	F/13.97	1.46	1270	No	97	No
16	F/15.43	1.48	1280	Dyspnoea, bronchospasm	80	Yes
17	F/14.81	1.70	1470	Bronchospasm	96	Yes
18	F/15.67	1.84	1600	Throat irritation, cough	98	No
19	M/16.34	2.17	1880	Throat irritation	98	Yes
B	Gender/Age	m 2	Ofatumumab (mg l ‐1 )	Clinical features	SaO 2 %	Emergency
1	M/4.4	0.64	560	No	95	No
2	F/8.7	0.84	730	No	100	No
3	M/7.1	1.03	890	No	99	No
4	F/7.1	1.04	900	Rash	98	No
5	F/10.9	1.11	960	No	98	No
6	F/10.6	1.15	990	No	97	No
7	M/12.7	1.25	1000	Throat irritation	98	No
8	F/15.2	1.29	1120	No	99	No
9	M/15.2	1.46	1270	No	99	No
10	F/15.7	1.5	1300	No	99	No
11	M/14.7	1.6	1390	Throat irritation	98	No
12	M/18	1.65	1400	No	96	No
13	F/15.9	1.66	1440	No	99	No

In conclusion, we propose to include salbutamol in an aerosol as a key pretreatment step in patients receiving ofatumumab for nephrotic syndrome.

Competing Interests

All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.

Funding/Support

The study on ofatumumab was supported by Istituto Giannina Gaslini deriving from ‘Cinque per mille of IRPEF‐Finanziamento della ricerca sanitaria’, the Italian Ministry of Health, The Renal Child Foundation, and the ‘Fondazione La Nuova Speranza’ (‘Progetto integrato per la definizione dei meccanismi implicati nella glomerulo sclerosi focale’).

Bonanni, A. , Bertelli, E. , Moscatelli, A. , Lampugnani, E. , Bodria, M. , Ravani, P. , and Ghiggeri, G. M. (2016) Ofatumumab‐associated acute respiratory manifestations: clinical characteristics and treatment. Br J Clin Pharmacol, 82: 1146–1148. doi: 10.1111/bcp.13029.