This post explains why I have started to refer to cladribine as a small molecule anti-CD20/CD19 therapy and why oral cladribine should be part of the exit strategy to treat MS during the tail of the COVID-19 pandemic.
Although we use cladribine as an immune reconstitution therapy and often compare it to alemtuzumab it is, in fact, closer to anti-CD20 therapies in terms of its immunodepletion profile. This distinction is particularly important during the COVID-19 pandemic because it has allowed us to classify cladribine in an intermediate risk DMT, which allows us to treat MS with an IRT when we can’t use alemtuzumab.
Cladribine is an oral therapy; hence no visits to COVID-HOT hospitals or institutions.
It 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, which we are trying to avoid at present.
Cladribine does not deplete monocytes and neutrophils and has a moderate impact on so-called NK cells. 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.
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 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 less 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 were less effected 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. In fact, the infection profile on cladribine, including the zoster signal, was much more similar to that which we see with ocrelizumab compared to alemtuzumab.
Cladribine is a remarkably good depleter of B-cells. B-cells number drop quicker than T-cells numbers; i.e. within days to weeks. In addition, B-cells are depleted by about 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. Interestingly, when you stop an anti-CD20 therapy such as ocrelizumab or rituximab and allow B-cell reconstitution they are also naive and are not memory B-cells that return in the short-term. In other words cladribine, alemtuzumab and ocrelizumab have similar effects on B-cells.
Please note that because ocrelizumab and rituximab are given as maintenance or continuous therapy there is a small increase in the incidence of serious infections over with 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. In relation to vaccines both live and inactivated component vaccines can be given after cladribine.
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 3 and 7 months after starting treatment. The rationale for this is that the 3-month time-point is where the nadir occurs and the 7-month time point is to check for recovery of lymphocyte counts. What this means during the COVID-19 pandemic is that if you are treated with oral cladribine and at 3 months your lymphocyte counts is above 500/mm3, which will be the vast majority of treated patients, you don’t need to self-isolate. In the 3-4% who have a lymphocyte count below 500/mm3 at month three, you will need to continue to self-isolate until your counts go above 500/mm3. To find out the latter you could wait another three months for the next blood test our you could ask your GP or MS team for an earlier test.
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 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.
In a similar way to ocrelizumab, I think cladribine has been hard done by COVID-19 guidelines that have stated not starting or not redosing cladribine during the COVID-19 pandemic. Why? Where is the science to support this position?
Now that we can see the pandemic is not going to end anytime soon and with a vaccine 18 or 24 months away I think we should reconsider using oral cladribine as it addresses many of the issues of treating highly active MS in these troubling times and it has the added advantage of leaving people with MS with a reconstituted vaccine-ready immune system if and when a SARS-CoV-2 vaccine arrives.
Please note that I am not saying cladribine and/or anti-CD20 therapies are safe. They have well-defined risk-benefit profiles that are less risky than what has been proposed by many people in terms of developing severe COVID-19. These risk-benefit profiles simply allow you to counsel patients with active MS about their treatment options during the COVID-19 pandemic.
I personally think both anti-CD20 therapies and cladribine are two highly effective therapies that allow a treatment exit strategy during the long tail of the SARS-CoV-2 pandemic.
Do you agree?