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Case study: switching from ocrelizumab to cladribine
This patient wants to switch from an anti-CD20 therapy to oral cladribine in the hope that it is going to allow him to make an antibody response to the COVID-19 booster.
I am 38 years old and have been on ocrelizumab for just over 4 years. I have been double-jabbed with the Moderna mRNA COVID-19 vaccine and I have not seroconverted. I have been offered a booster dose, but I am not sure when to have it. My last ocrelizumab infusion was in July. Another worrying development is that I have recently developed hypogammaglobulinaemia; my IgG level has just fallen below the lower limit of normal. My neurologist has suggested a switch from ocrelizumab to oral cladribine. Do you agree? If yes how do you suggest this is done? Thank you.
Prof G’s opinion
Your scenario is not unique. Many people on anti-CD20 therapy are not making an antibody response to the COVID-19 vaccines. This however doesn’t mean you are not immune as pwMS on anti-CD20 therapies have been shown to have T-cell responses to SARS-CoV-2 and this immunity is likely to be sufficient to protect you from getting severe COVID-19. The latter is based on theoretical considerations and has yet to be shown at a population level. In the UK we have seen several patients on ocrelizumab, who have been vaccinated, develop severe COVID-19 and sadly one of our patients passed away recently from COVID-19 pneumonia. This patient had other risk factors for severe COVID-19 so it is impossible to blame his ocrelizumab treatment entirely. However, I have little doubt it was a contributing factor.
As you have developed hypogammaglobulinaemia this does put you at increased risk of developing infections and severe infections in the future. How you manage this is up for debate. In some clinical situations when there are no other treatments clinicians are beginning to give patients immunoglobulin replacement therapy. In the NHS the latter is only done when patients are having recurrent infections. However, in MS we have the option of offering you an alternative therapy. I note you have been offered oral cladribine and this makes sense, but there are other DMTs not associated with immunosuppression that could also potentially be used in this situation. Please read my newsletter on ‘Switching from an anti-CD20: the why and the how’ (7-Aug-2021) for further details.
Cladribine has many pros when it comes to managing MS during the pandemic.
Cladribine is a high-efficacy DMT therefore it potentially allows you to flip the pyramid and offer a high-efficacy DMT first-line.
Cladribine is an oral therapy; hence no visits to COVID-19 hot hospitals or institutions.
Cladribine kills cells gradually by a process called apoptosis. Cells dying from apoptosis are phagocytosed or swallowed by macrophages and as a result, there is no cell lysis or bursting open of the cells and the release of their contents that causes a cytokine release syndrome. This means there is no need to pre-treat patients with steroids. At the moment we are trying to avoid high-dose steroids because they increase your chances quite dramatically of getting severe COVID-19.
Cladribine does not deplete monocytes and neutrophils and other innate immune cells. Its impact on the so-called natural killer or NK cells is moderate. As the innate immune system is left intact there is a low risk of bacterial and other infections during the depletion phase and the innate cells can help fight viral infections, such as SARS-CoV-2. Innate cells are also important as antigen-presenting cells in vaccine responses.
T lymphocytes are in general depleted by about 40%-50% and most patients don’t drop their counts below 500/mm3. In the phase 3 cladribine trial programme about a quarter of patients had a grade 3 or 4 lymphopaenia, but this tended to occur after the second course in year 2 in subjects who were redosed when their lymphocyte counts had not recovered to above 800/mm3. We have used the trial data to model grade 3 and 4 lymphopaenia. I.e. less than 500/mm3, and estimate that ~5% of cladribine treated subjects will develop lymphocyte counts less than 500/mm3 if we stick to the redosing guidelines. This is very important as lymphopaenia is probably the most important risk factor for viral and severe viral infections.
In the T-cell compartment, the CD8+ T-cells are less affected than CD4+ T-cells. This is important because CD8+ T-cells are the cells responsible for fighting viral infections. This probably explains, apart from a small risk of herpes zoster reactivation, why we didn’t see an increase in viral infections compared to placebo in cladribine treated subjects in the phase 3 trial programme. The viral infections that did occur tended to be non-specific upper respiratory tract infections and were mild to moderate. The infection profile on cladribine, including the zoster signal, is much more similar to that which we see with ocrelizumab compared to alemtuzumab. However, cladribine is not associated with the development of hypogammaglobulinaemia. In a small series of patients in Australia who switched from ocrelizumab to cladribine their immunoglobulin levels actually increased slightly over the next 12 months. I suspect this is why your neurologist has recommended switching to oral cladribine.
Cladribine-treated pwMS who get COVID-19 are not at increased risk of getting severe COVID-19. Unlike, pwMS on ocrelizumab. However, as the effect of ocrelizumab on B-cells last many months this risk is likely to persist for many months after stopping ocrelizumab.
Cladribine is a remarkably good depleter of B-cells. B-cells numbers drop quicker than T-cells numbers; i.e. within days to weeks. In addition, B-cells are depleted by about 85-90% and importantly memory B-cells are severely depleted and to a similar level that we see with alemtuzumab. Importantly, when the B-cell numbers return these are so-called naive B-cells, which come from the bone marrow and are not memory B-cells. These are the B cells that you need to make vaccine responses and explains the data showing excellent seroconversion rates to COVID-19 vaccines in cladribine treated patients.
Please note that because ocrelizumab is given as maintenance or continuous therapy there is a small increase in the incidence of serious infections over time and the development of hypogammaglobulinaemia. This is not seen with cladribine. Once the immune system reconstitutes post-cladribine it can fight infections, immune survey the body for cancers and mount immune responses to new viral infections, such as SARS-CoV-2, and vaccines.
The other important thing about cladribine is the monitoring requirements are low. Once you have had a course you only need a full blood count to be done at months 4 and 7 in each treatment year. The rationale for this is that the 4-month time-point is where the nadir occurs and the 7-month time point is to check for recovery of lymphocyte counts.
When you look at how cladribine works, i.e. it needs to be activated by an enzyme call DCK (deoxycytidine kinase) and broken down by an enzyme called ADA (adenosine deaminase), the profile of cells expressing the correct ratio of these enzymes matches the B-cell population that expresses CD19 and CD20 and explains why B-cells are more susceptible to the effects of cladribine than T-cells.
Another advantage of cladribine is that as a small molecule it penetrates the CNS. Cerebrospinal fluid (CSF) levels are about 25% of what is found in the peripheral blood and at a level that would target B- and T-cells within the brain and spinal cord. I think this property of cladribine is very important and is one of the reasons why we are exploring cladribine as a treatment for progressive MS in the CHARIOT-MS trial.
I am not saying cladribine is entirely safe. It has a well-defined risk-benefit profile that is less risky than what has been suggested by many people. These risk-benefit profiles simply allow you to counsel patients with active MS about their treatment options. Clearly, the issues highlighted by the COVID-19 pandemic make this decision a lot more difficult than it used to be.
Oral cladribine is cost-effective. NHS England has negotiated a value-based pricing deal with the manufacturer for a rebate if anyone treated with cladribine switches to another agent within 4-years of starting treatment. This makes cladribine a very good option; you are only paying for the drug if it is effective.
I have addressed the question of vaccine readiness in another MS-Selfie Newsletter; ‘COVID-19 vaccines and DMTs’ (16-July-2021). However, I would only have your booster vaccine once you have some peripheral B-cell recovery, i.e. you want to have more than 10 CD19+ B-cells per millilitre of blood. The latter seems to be the threshold for vaccine responses. I would therefore wait until January before checking your B-cell levels and if they have not recovered to do monthly counts until they are >10/mm3 before having the booster. I would then wait for 4-weeks before starting cladribine. The latter will depend on you all the cladribine-related baseline checks being fine.
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.