Background

Ocrelizumab, an anti-CD20 monoclonal antibody similar in action to rituximab, has demonstrated efficacy in relapsing and primary progressive MS. Late onset neutropenia (LON) is a rare, but serious side-effect of rituximab occurring in 1.3% of patients. There only 2 reported cases of LON related to ocrelizumab. A single case of grade 4 LON occurred during the phase three studies.

Objectives

Increase awareness of the features of late onset neutropenia and improve risk management of disease modifying treatments.

Methods

We discuss a case series of 3 treatment naive patients with active RRMS who developed severe LON (grade 4) after ocrelizumab treatment in MS specialist centres in the United Kingdom.

Results

A 31y female presented with neutropenic sepsis (neutrophils 0.0) 115 days after her third ocrelizumab infusion, requiring treatment with intravenous antibiotics and granulocyte colony stimulating factor (G-CSF). Subsequent multiple episodes of recurrent grade 4 neutropenia (neutrophils 0.0-0.2) occurred over the next 6 months, often requiring G-CSF treatment. Bone marrow aspiration demonstrated normocellular granulopoiesis.

A 35y male developed neutropenic sepsis (neutrophils 0.2) 119 days after the first ocrelizumab infusion which recovered rapidly with G-CSF. He received the 2^nd and 3^rd ocrelizumab doses with no recurrence of neutropenia.

A 22y female developed fever and cough with neutropenia (0.28), 150 days after initial treatment with ocrelizumab. She was treated with IV antibiotics and the neutropenia recovered spontaneously.

Conclusions

The 3 cases demonstrate the spectrum of LON with ocrelizumab. The aetiology of LON is poorly understood, but hypothesised to be mediated by autoimmune destruction, neutrophil apoptosis or failure of release from the bone marrow. The normal bone marrow aspirate suggests peripheral consumption. The cases are important to raise the clinical suspicion of this life threatening complication of disease modifying therapy and the need for serial blood monitoring. Further experience is required to understand risk of recurrence and when it is safe to re-challenge with ocrelizumab.

Background

Ocrelizumab is one of the most effective disease-modifying drugs for MS. As a potent immunosuppressor, ocrelizumab carries significant infection risk and its long-term effects on immunocompetence are not fully understood. Although ocrelizumab is given as a regular six-monthly infusion, it shares several characteristics with immune reconstitution therapies, such as alemtuzumab and cladribine. Alemtuzumab and cladribine deplete circulating lymphocytes and ocrelizumab specifically depletes circulating B-cells, with reconstitution of cells occurring from bone marrow. It is not known whether the therapeutic effect of ocrelizumab outlasts the administration period. Giving ocrelizumab in a time-limited fashion could reduce both short- and long-term side effects, as well as provide a substantial cost reduction.

Objectives

Share experience of a case in order to stimulate investigation into ocrelizumab as an immune reconstitution therapy.

Methods

1. Consent was successfully obtained to present the patient's case.

2. Case details were collated, including radiological and laboratory data.

Results

A 24-year-old female patient was diagnosed with MS following subacute onset left hemiparesis, positive CSF oligoclonal bands, exclusion of mimics and MRI showing multiple T2 lesions in the periventricular areas, corpus callosum and juxtacortical areas. Her baseline MRI performed immediately prior to treatment commencement showed five new T2 lesions with new enhancement. She was treated with five doses of ocrelizumab at six-monthly intervals between 2012-14 as part of a clinical trial. She then decided to withdraw from the study to travel, but returned to the UK in 2020. Despite cessation of all disease modifying treatment for six years the patient reported no clinical relapses, and in comparison with the MRI at treatment cessation in 2014 there were no new lesions or enhancement. Lymphocyte subset analysis showed reconstitution of B-cells (578 x 10⁶ cells/L; normal range 50-500 x 10⁶ cells/L). The patient is fit and well and suffered no side effects of treatment.

Conclusions

A patient treated early with a limited course of ocrelizumab for two years demonstrated no evidence of disease activity (NEDA2) after six years without treatment. Caution is recommended in extrapolation from a single case, however investigation of ocrelizumab as an immune reconstitution therapy is warranted. Limited duration ocrelizumab treatment could have substantial benefits in terms of side effects, cost and patient convenience whilst maintaining efficacy.