MMF and ITP a talk by Dr Terry Gernsheimer, this was first shown at the ITPSA Convention in May 2022.
Hello i’m dr terry guernsheimer i’m a professor of medicine and hematology at the university of washington in seattle in the beautiful pacific northwestern united states this is our beautiful city and mountain i want to thank the itp support association for the invitation to speak about treating itp with mycophenolate and i’ll refer to mycophenolate as mmf frequently
I have to note first that mmf is not an approved treatment for itp nor are some of the other medications i’ll be discussing and these are my disclosures for many years our understanding were was that antibodies were the sole cause of itp coding platelets and leading to destruction of platelets in the blood by spleen and mac and cells called macrophages um here
You can see um in the white arrow a platelet that’s been engulfed by a macrophage another one being pointed to by the black arrow that that has now getting surrounded by an by a macrophage due to its being coded by antibody these antibodies are produced by a type of lymphocytes b cells and decreasing antibody production or how well those antibodies work are very
Important ways to treat itp for example using rituximab by decreasing numbers of b cells about 40 years ago we began to understand that these antibodies also attack megakaryocytes which are the bone marrow cells that make platelets and that production of platelets in itp is also impaired and the typo receptor agonist targets target this impaired production another
Type of lymphocyte t cells also turn out to be very important in the mechanism of itp studies have shown that t cells from patients with active itp those shown here in this orange color can actually destroy platelets in a culture but when itp is in remission shown here in these green dots those t cells act more like the t cells from control individuals in these
Red dots and these t killer cells can also directly attack megakaryocytes so it can affect both destruction of platelets and again production of platelets we also know that there are different subpopulations of the t cells and that some t cells actually help to regulate the inflammatory response these are called t-rex and when the t-regs increase in activity
The platelet count goes up because they’re better regulating the immune response and and suppressing the autoimmunity if you will so a more complete picture of itp is that antibodies that are made by b cells cause platelet destruction and also affect the bone marrow but also that t cells can directly destroy platelets and megakaryocytes but are also responsible
For a regulatory function on the other components of the immune system mycophenolate is a powerful inhibitor of cell turnover but especially lymphocyte proliferation both b and t cells it also can inactivate the t cell response to inflammation and can cause the death of activated t cells mmf has been used since the early 1990s for prevention of acute rejection
Of liver cardiac and kidney transplants because both b cells and antibody formation and a direct t cell killing of the transplanted tissues can be important in rejection some of the patients who were receiving liver transplant also had a history of autoimmune hepatitis and it was observed that this also came under control with the mmf and so the principle of
Inhibiting both t and b cells was applied to other severe autoimmune disease and it’s been reported to have activity in the treatment of lupus autoimmune kidney disease and autoimmune hemolytic anemia when other treatments have failed there’s a very long list of potential side effects that need to be reviewed before starting mycophenolate treatment including heart
Liver skin others but the main side effect that can make it intolerable is gastrointestinal discomfort specifically diarrhea and although this usually gets better over time even without a change in dose some patients will just not tolerate it because it inhibits cell division and production of new blood cells of new cells especially in the bone marrow it can
Lower blood counts especially platelets and we see this fairly commonly when mmf is used to treat transplants so it may seem like a bad idea to treat itp with mmf but there is a bigger effect on the immune system and if it works the platelet count comes up mycophenolate is a powerful immunosuppressive drug and with that comes an increased risk of malignancy but
Especially a significant increased risk of infection and we’ll talk more about that in a few minutes um but i also want to make note that mycophenolate should not be given to pregnant women women who are trying to become pregnant or women of child bearing age who are not using proper birth control the first patient i ever treated with mycophenolate was a 42 year
Old engineer he had been healthy all his life until february of 2000 and at that time he developed nosebleeds and bruising his platelet count at that time was 10 000 and a bone marrow examination which was commonly done back then was also normal he did respond to ivig and prednisone but they could not get him off prednisone without his platelet count falling
And him starting to bleed again his disease got worse and after getting very high doses of steroids he developed something called acute hypnosis which is sometimes seen with high dose or prolonged steroid use this shows what this can look like the black arrows are showing narrowing of the hip space of the joint space the white arrows are showing the fracture
In what we call the head of the femur here um and you can imagine how very painful this actually was for him he had quite a limp he was treated with rituximab and he did respond with a platelet count that increased to more than a hundred thousand but his count fell again after two years and he didn’t respond a second time and then he was treated with cyclosporine
A drug that’s commonly used to treat uh to treat graft versus host disease and bone marrow transplant patients and rejection and kidney transplants and it also can inhibit t cells after three years on cyclosporine he moved to seattle and i met him for the first time and he responded to the cyclosporine at this point with a platelet count of greater than three
Hundred thousand when he saw me i was concerned that he had been on cyclosporine for such a long time and that it was potentially affecting his kidneys the risk of infections so i suggested to him seeing how he would tolerate tapering the dose within three weeks of tapering his cyclosporine his platelet count fell to below 5000 and then despite increasing the dose
To the previous level his platelet count did not increase at that time we did not have typo receptor agonists but i did try multiple other treatments including ivig ritoximab cyclophosphamides steroids but his platelet count did not increase he had clear evidence of bleeding with blisters in his mouth bruising patiki on his legs hands and face and i was becoming
Frantic he was quite stoic and began to refuse any treatment with ivig or steroids because he felt it just didn’t help at that point we began treatment with mycophenolate starting a bit slowly but increasing to one gram twice daily over a month and within a month of that his platelet count began to increase and remained above 300 000 for almost two years at that
Point i suggested to him that perhaps we should try tapering off the drug and actually very nicely he didn’t tell me that i was crazy and walk out of my office he thought that maybe this was a good idea and he agreed to try despite remembering what happened the last time when he stopped the cyclosporine when he left seattle five years later to move back to the east
Coast his platelet count was greater than 300 000 and he just wrote me last month when he moved back to seattle and he is still in remission eight years after starting the drug off all treatment this is a visual of his course to just show how dramatic his response was here’s where we stopped with cyclophosphamide his platelet counts sorry cyclosporin his platelet
Count fell rather rapidly restarting it did not help ivig and steroids would give him short bumps he got a course of rituximab which helped for a very minimal amount of time and also received cyclophosphamide and then we started the mycophenolate you can see where his platelet count increased significantly and then after a time we tapered off and you can see
His plate account remained and it does remain greater than 300 000. we don’t have a lot of reported data on cases like the one i just presented to you in this report by taylor and colleagues the patients that are reported generally have very severe disease they’ve been treated with several different therapies you can see here some of them had secondary itp that
Was due to other autoimmune diseases or had hiv and in this case report about half of the patients had some response in my experience about two thirds to three three-quarters of patients have had some response but i don’t think we’ve done a carefully an enough controlled study of this although we are going back um and doing a more careful look at this to get a
Better sense of how well patients are actually doing on treatment the flight trial which was reported last year was different from most reports in that it was the first one where patients had acute itp this being the first therapy they got when they presented to their physician and needed treatment and also that it was randomized although not blinded the patients
Were randomized to receive steroid therapy alone or steroid therapy with mmf the steroids were tapered after about six to eight weeks um the mmf if they were on that arm continued for about six months and could be tapered if the platelet count was greater than a hundred thousand at that point and the primary endpoint was the time to treatment failure so when the
Platelet count was less than thirty thousand or if they never increased above thirty thousand there’s no great question that more patients who received mycophenolate responded within the first two months those are in the the blue areas and they continue to respond up to two years later although those numbers tend to get very small there importantly though was no
Difference in between the two groups in the occurrence of bleeding rescue treatment or treatment side effects including infections and also i think of note many of the patients continue treatment with mmf as their platelet counts were not greater than 100 000 and therefore weren’t eligible to taper or stop it the other thing that’s very important here is that the
Patients in the mmf group reported worse quality of life outcomes regarding their physical function and fatigue than those that were getting steroids alone so they um a lot of this was due to the gi side effects but they had more fatigue they just overall felt worse all of the potential mechanisms in itp can be responsible in a greater or lesser way in how severe
The disease is and any of one of these are a potential target for therapy and indeed we sometimes need to combine therapies as they work better than either does separately so we might want to combine steroids with with a typo receptor agonist or with a t cell inhibitor the list of patients who are considered to be at increased risk of developing severe
Complications of coca-19 either due to lack of response to the vaccine for example after rituximab or who might have decreased responsiveness to the vaccine or an inability to fight the infection such as people on high dose or prolonged steroids or patients who have had a splenectomy all are considered to be at increased risk and mmf would be included in this
Category immunosuppressive agents i’d also add that some patients with itp also have an inherited immunodeficiency and therefore may also be at an increased risk and so recommendations for combined monoclonal antibody evusheld include all of these categories considering our ability to raise the platelet count with relatively few and uncommon side effects either
With a short course of steroids or ivig if it’s acute or with a typo receptor agonist and especially at a time of great concern around new variants of soros kobe 2 in my opinion mmf should be reserved for patients with severe disease who are refractory to a typo receptor agonist alone or who cannot tolerate one or who doesn’t respond to one with a small addition
With an addition of a small amount of steroids i’ve used mmf successfully in lots of patients most of them have tolerated it well but i think we need to learn more about how best to use it in itp and i’m hoping to see more clinical trials so we can learn more about it and with that i’d like to thank you for your attention and wish you all good safety and health
Transcribed from video
MMF and ITP a talk by Dr Terry Gernsheimer By The ITP Support Association UK