Rituximab May Cause Late-onset Low Neutrophil Count in Rare Cases

Late-onset neutropenia increases risk of serious infection

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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An illustration of white blood cells, part of a person's immune system.

In rare cases, people with neuromyelitis optica spectrum disorder (NMOSD) can experience low blood levels of neutrophils, a type of immune cell, a few weeks after receiving anti-CD20 therapy.

Researchers have reported the case of a NMOSD patient who developed the uncommon side effect, called late-onset neutropenia, four weeks after her third dose of rituximab. The effect was also reported for a patient with multiple sclerosis (MS) who was receiving another anti-CD20 therapy, called ocrelizumab (sold as Ocrevus).

“Patients and clinicians should be aware of this entity, including the propensity for delayed presentation and the potential for serious outcomes especially in patients presenting with infective symptoms,” researchers wrote.

The study, “Late-onset neutropenia following anti-CD20 therapies in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders: A report on two patients,” was published in Neuroimmunology Reports.

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What are CD20 inhibitors?

CD20 inhibitors are increasingly being used for inflammatory and autoimmune conditions. They act by blocking the activity of CD20, a protein on the surface of immune B-cells, leading to their depletion. B-cells are the immune cells responsible for producing antibodies, including the self-targeting antibodies that drive autoimmunity in conditions like NMOSD.

Rituximab is an antibody treatment that is sometimes used off-label in MS and NMOSD to control the abnormal inflammatory attacks. Ocrelizumab is another anti-CD20 therapy that’s approved for MS.

Because these therapies suppress the immune system, they are associated with some side effects, with the biggest safety concern being a greater risk of infections. But other rare effects have also been reported.

A rare effect of anti-CD20 antibodies is late-onset neutropenia, which is defined as an unexplained low neutrophil count (levels below 1500 million cells per liter of blood) that emerges more than four weeks after the last treatment dose. Neutrophils are immune cells that act as the body’s first line of defense in response to a perceived threat, like a virus or bacteria.

In the report, researchers in Singapore described two cases of late-onset neutropenia that occurred after anti-CD20 therapy.

The first was a 65-year-old Chinese woman with NMOSD who developed neutropenia about four weeks after her third rituximab infusion.

The woman had first come to the clinic in 2017 with symptoms of spinal cord inflammation. Despite treatment with methylprednisolone and plasma exchange, the patient failed to improve, becoming bed-bound and dependent on a ventilator.

Because mycophenolate mofetil also failed to prevent new disease relapses, the patient was switched to rituximab. She received her first two doses (1000 mg each) two weeks apart, without adverse effects. But about one month after the third dose (600 mg), the woman developed a fever, breathing difficulties, and higher levels of white blood cells in her urine.

She began treatment with antibiotics but her symptoms persisted. Mild neutropenia (1400 million cells/L) was identified when she went to the hospital six days later, and continued to worsen over three days, reaching a low of 890 million cells/L.

Respiratory cultures also revealed bacterial infections, for which she was given treatment with into-the-vein antibiotics. She was also given a single dose of granulocyte colony stimulating factor, a treatment used to boost the production of neutrophils and other white blood cells. Her neutropenia subsequently resolved.

After discharge, the woman restarted rituximab and received another four cycles of treatment without neutropenia recurrence. The patient died in 2021 due to complications associated with advanced NMOSD.

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The Consequences of Rare Side Effects

The team also described another case of late-onset neutropenia in a 40-year-old woman with relapsing-remitting MS, which occurred 14 weeks after her third ocrelizumab infusion. After neutropenia resolution, the woman restarted ocrelizumab without further incident.

The researchers reviewed data from people who received anti-CD20 therapies at their institution in Israel from 2015 to 2021. There were a total of 67 patients, including 41 with MS — nine on ocrelizumab and 32 on rituximab — and 26 with NMOSD on rituximab.

The case report documents the only two cases of late-onset neutropenia found in the data. This corresponds to an incidence rate of 3% over the seven-year period — 1.7% for rituximab and 11% for ocrelizumab.

Overall, late-onset neutropenia “following anti-CD20 therapies is an uncommon adverse event and its incidence may not necessarily be high enough to warrant close full blood count monitoring,” the researchers wrote.

“Nevertheless, we wish to highlight the importance of this entity — firstly for patient education, and secondly, to alert clinicians to its propensity for delayed presentation, sometimes even after many months from the last infusion,” they added.

The mechanisms underlying late-onset neutropenia following anti-CD20 therapy are not fully understood, the researchers noted.