Long-term management considerations in patients treated with antiCD20 agents

Topics for discussion

AntiCD20 agents are now the most commonly prescribed disease-modifying therapies in the UK because of their high efficacy, excellent tolerability and convenience. While long-term follow-up studies have been reassuring about the overall safety profile of antiCD20 agents common management problems include hypogammaglbulinemia and infections, managing patients with concomitant autoimmune diseases and cancer, and family planning. Data is also lacking on when to consider stopping treatment, or de-escalation. The webinar will explore these issues through a series of case studies and a review of the latest available data.

Objectives:

• Review latest data on long-term safety of anti-CD20 agents
• Discuss management problems in patients treated with antiCD20 agents including neutropenia, hypogammaglbulinemia and infections, comorbidities and family planning using case-based examples
• De-escalation in stable patients on antiCD20 agents

Webinar summary

Anti-CD20 therapies are arguably the most commonly initiated treatment for MS in the UK, and often the “go to” choice when switching treatments.

The reason for this is clear, said Dr Wallace Brownlee, consultant neurologist, National Hospital for Neurology and Neurosurgery. There are now more than10 years of data, he explained, to show the agents can significantly reduce relapses and gadolinium-enlarginglesions on MRI, and, particularly for those who are treated early, slow progression.

“Anti-CD20 therapies are our standard of care, and if you are initiating patients on less effective therapies, then you really need a reason for that,” he said.

Despite the clear benefits, however, the long-term use of anti-CD20 therapies carriesimportant management considerations. These include hypogammaglobulinemia (HCG), neutropoenia, autoimmune complications, comorbidities, malignancy

Infection considerations

A 2019 study found that patients on the anti-CD20 agent rituximab were almost 2.5 times more likely to develop a serious infection than those on beta interferons.

IgG levels can fall during treatment with rituximab and ocrelizumab, though there is conflicting data on whether this is associated with an increase in frequency or severity of infections. Another consideration is comorbidities, which a 2022 study of ocrelizumab-treated patients found were the biggest risk factor for infection.

A recently published paper has proposed an algorithm for managing HCG. It suggests MS teams measure serum IgG levels at least annually. If they are normal, anti-CD20 therapy can continue. If HCG is present without infections, teams can monitor for infections and increasing IgG monitoring to six monthly, while also reassessing disease modifying therapy (DMT) choice in line with clinical and laboratory risk factors. If the patient has HCG with infections, the paper recommends reassessing the DMT choice, considering IVIg supplementation, and checking for B-cell immune competence via vaccination.4

The panel agreed that this was a useful and pragmatic approach, but also said that management decisions should be made on a patient-by-patient basis, considering all the pertinent circumstances and risk factors.

Another infection consideration is neutropenia, which is a known complication of anti-CD20 therapies used to treat B cell malignancies and autoimmune disorders. The complication tends to be transient and self-limiting, though the risk of recurrence appears to be up to 20%.The risk appears to be higher in those on high-dose, pulsed treatment, such as ocrelizumab,than those in low-dose, subcutaneous therapy, such as ofatumumab, but the causativemechanism is unknown.

The speakers said management should be tailored to the individual. Some patients, for example, had recovered with no change to treatment, while others had been switched from ocrelizumab to ofatumumab.

Counselling and monitoring is important, they went on. Dr Gillian Ingram, consultant neurologist, at Swansea Bay University Health Board, said she explained the higher risk of infection to patients and advised they have a “have a low threshold” for seeking medical attention if they develop a fever or other symptoms.

Autoimmune complications

There has been much discussion around whether anti-CD20 treatment can cause autoimmune conditions such as psoriasis and colitis.

CD20+ cells play a regulatory and protective role in the gastrointestinal system and in the skin, said Dr Ingram. “It may be that when we reduce the B cells we trigger abnormal T cell regulation via reduced IL-10,” she went on, adding that IgA and IgM, which anti-CD20 therapies can reduce, may protect the mucosal barrier. However, while there are a number of case reports linking the drugs to IBD, the “jury is still out” on whether there is a causative link.

Management of patients with comorbid colitis and MS should be conservative, said Dr Ingram. Teams may recommend steroids and think about withdrawing the anti-CD20 treatment, but should be aware of the prolonged washout period. Biologic therapies, such as natalizumab, can be considered as an alternative, particularly for those who are DMT naïve.

Malignancies

While there were concerns around malignancies in the OPERA 2 and ONTARIO studies of ocrelizumab, seven-year follow up data have shown that there is no significant increase in risk, when compared to the general population., This is reassuring, said Dr Kate Petheram, consultant neurologist, South Tyneside and Sunderland NHS Foundation Trust.

Likewise, there is no additional cancer risk with fingolimod, natalizumab, or rituximab. Data is still relatively limited for ofatumumab, though at this stage there does not appear to be asignal significantly increased risk.

People with MS being diagnosed with cancer, however, is not uncommon, and many MS teams will discontinue ocrelizumab at this point. It is worth noting, Dr Petheram went on, that the treatment is likely to have persistent efficacy while the patient undergoes chemotherapy.

Long-term treatment dilemma

There is an increasing clinical dilemma around how to manage people who are doing well on anti-CD20 therapy as they age and develop the co-morbidities that can leave them more vulnerable to infection, said Dr Waqar Rashid, consultant neurologist, at St George’s University Hospitals NHS Foundation Trust. As the risk/benefit profile evolves, he said, deciding whether to maintain, deescalate, or discontinue treatment can be challenging.

“We know the agents have a prolonged effect on lymphocytes,” he said, pointing to data that show sustained suppression of CD19 and CD20 levels well beyond six months or three courses of ocrelizumab. This appears to translate into prolonged clinical benefit, with, albeit small, real world series suggestion that extended dosing intervals or reduced dosing can be achieved without an increased risk of relapse., There is, however, a lack of evidenceregarding the safety of treatment discontinuation in older people. “It is a really complex issue,” said Rashid.

“We do not have the evidence and people across the country are doing very different things,” said Dr Petheram. Whether the approach is de-escalation or a treatment holiday, “it has to be very dependent on the patient in front of you”, she went on. “Having a ‘one size fits all’ is going to be challenging. I think we need to try and collect the outcomes of how these people are doing clinically and use that to inform our treatment choices going forward.”