Is this the thud of the second shoe dropping?
As we discussed in an article just a couple of weeks ago, reactivation of JC virus can cause PML (progressive multifocal leukoencephalopathy, a viral infection of the brain). PML carries a huge mortality risk: as much as 90% of the patients die within a month or two. PML has been noted when patients with deeply suppressed immune systems (such as AIDS patients) have been treated with drugs that further suppress the immune system. But the citation of PML as a risk factor for NHL / CLL patients treated with Rituxan has been very, very sparse – up to now.
I was taken aback when I saw this article in Blood, a pre-publication online version. The abstract of the article is given below. Sneak a look at the list of authors and institutions, that should give you a sense of its credibility. If you wish to read the full text of the article send me a personal email and I will try to help you locate it.
Blood First Edition Paper, prepublished online March 5, 2009
Progressive multifocal leukoencephalopathy following rituximab therapy in HIV negative patients: a report of 57 cases from the Research on Adverse Drug Event and Reports (RADAR) project
Kenneth R. Carson, Andrew M. Evens, Elizabeth A. Richey, Thomas M. Habermann, Daniele Focosi, John F. Seymour, Jacob Laubach, Susie D. Bawn, Leo I. Gordon, Jane N. Winter, Richard R. Furman, Julie M. Vose, Andrew D. Zelenetz, Ronac Mamtani, Dennis W. Raisch, Gary W. Dorshimer, Steven T. Rosen, Kenji Muro, Numa R. Gottardi-Littell, Robert L. Talley, Oliver Sartor, David Green, Eugene O. Major, and Charles L. Bennett*
Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO, United States
Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
Department of Hematology, Mayo Clinic College of Medicine, Rochester, MN, United States
Division of Hematology, University of Pisa, Pisa, Italy
Division of Haematology and Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, East Melbourne, Victoria, Australia
Dana Farber Cancer Institute, Boston, MA, United States
Division of Hematology/Oncology, Stanford University School of Medicine, Stanford, CA, United States
Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, United States
Division of Hematology/Oncology, New York Presbyterian Hospital-Cornell Medical Center, New York, NY, United States
Section of Hematology/Oncology, University of Nebraska Medical Center, Omaha, NE, United States
Division of Hematology/Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, United States
VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, University of New Mexico, Albuquerque, NM, United States
Pennsylvania Hospital, University of Pennsylvania Health System, Philadelphia, PA, United States
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
Kansas City Cancer Center, Kansas City, MO, United States
Tulane Medical School, New Orleans, LA, United States
Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutues of Health, Bethesda, MD, United States
VA Center for the Management of Complex Chronic Conditions, Jesse Brown VAMC, Chicago, IL, United States* Corresponding author; email: cbenne@northwestern.edu.
Rituximab improves outcomes for persons with lymphoproliferative disorders and is increasingly used to treat immune-mediated illnesses. Recent reports describe two patients with systemic lupus erythematosus and one with rheumatoid arthritis, who developed progressive multifocal leukoencephalopathy (PML) following rituximab treatment. We reviewed PML case descriptions among patients treated with rituximab from the FDA, the manufacturer, physicians, and a literature review from 1997 to 2008. Overall, 52 patients with lymphoproliferative disorders, two patients with systemic lupus erythematosus, one patient with rheumatoid arthritis, one patient with an idiopathic autoimmune pancytopenia, and one patient with immune thrombocytopenia developed PML following treatment with rituximab and other agents. Other treatments included hematopoietic stem cell transplantation (7 patients), purine analogues (26 patients), or alkylating agents (39 patients). One patient with an autoimmune hemolytic anemia developed PML following treatment with corticosteroids and rituximab and one patient with an autoimmune pancytopenia developed PML following treatment with corticosteroids, azathioprine, and rituximab. Median time from last rituximab dose to PML diagnosis was 5.5 months. Median time to death after PML diagnosis was 2.0 months. The case-fatality rate was 90%. Awareness is needed of the potential for PML among rituximab-treated individuals.
Viral reactivation is a potential risk factor for Rituxan
This article makes it clear that Rituxan therapy carries some risk of viral reactivation in patients with non-Hodgkin’s lymphoma, a very close kissing cousin of CLL. A 2006 mandatory change in the labeling information for Rituxan confirms this point. While the number of cases is small (52 patients), the nature of the risk is so very high (90% fatality risk!) that I think we need to sit up and take notice. I also have this sneaking suspicion that we are only seeing the tip of the iceberg.
There is some evidence in this paper (you have to read the full text version to get the details) that patients who had severely depleted T-cell counts (CD4+ T-cell counts less than 500) or out of whack CD4/CD8 T-cell ratio were more likely to be in the at-risk group. Simple blood tests are now available for monitoring T-cell counts of this variety, courtesy of the AIDS epidemic. But tell me, how many of you have ever had T-cell counts monitored? As our beloved Terry Hamblin is fond of pointing out, CLL patients are not that far from AIDS patients when it comes to T-cell deficiencies, especially after their CLL has progressed and they have been through chemotherapy to treat it.
It is well known that Campath therapy depletes T-cells and many different T-cell populations do not recover even 12 months after completion of therapy. Lack of adequate T-cell function is a major reason for viral infections and viral reactivations, since T-cells are the front-line troops when it comes to killing viruses. Campath therapy now carries a Best Practices recommendation for active anti-viral prophylaxis.
Until recently it has been assumed by most of us that since Rituxan targets CD20 marker carried by mature B-cells only, the cell kill is limited to B-cells only. The further assumption is that since there is no damage to T-cells (we assume), there is no risk of viral infections of viral reactivations due to Rituxan therapy. Some of these assumptions may need to be reexamined in view of recent articles such as this one.
Mechanism for JC viral reactivation during Rituxan therapy
Like the familiar Epstein-Barr virus (think mononucleosis) many viruses maintain small traces of themselves in our bodies, often for the rest of our lives, once we have been infected by the little buggers. These trace elements of the viruses can come back as full blown viral infections during periods of immune dysfunction when the virus makes full use of the window of opportunity. CLL can present that window of opportunity, especially when the disease has progressed and patients have had therapy for controlling it. Almost all of the drugs used to treat CLL are immune suppressive, making a bad situation even worse.
One of the mechanisms proposed for JC virus reactivation after Rituxan therapy is interesting. It seems pre-B-cells (these are baby cells that are destined to become adult B-cells when they grow up, you can think of them as wannabe B-cells waiting their turn in the limelight) may harbor traces of JC virus for many years in anyone who has ever been infected with this virus. It is estimated that roughly 80% of our population has been exposed to JC virus at some point and therefore carries traces of it in their bodies.
The whole point of Rituxan therapy is to kill as many of the adult B-cells in your body as possible. These adult B-cells carry the CD20 marker, the target that attracts Rituxan attack. The seeds of potential JC virus infection may lie in the very success of Rituxan in killing vast numbers of adult B-cells.
Our bodies have a built in mechanisms to correct any kind of imbalance. When there are very few adult B-cells left after Rituxan therapy, the message goes out to get new B-cells out into blood circulation as quickly as possible. The result is that all those baby pre-B-cells get a chance to grow up really fast and get kicked out of the bone marrow and into blood circulation as replacement troops. If they were harboring traces of JC virus to begin with, they bring with them this tell-tale viral load into general circulation. If at that point in time the patient is also a little low on his T-cell defenses, the trace levels of JC virus circulating in the blood can quickly bloom into a full blown infection.
Ongoing drug surveillance: how effective is it?
Here is how it is supposed to work. After the FDA approves a new drug (such as Rituxan, in this instance) for commercial availability, the company is asked to maintain rigorous ongoing surveillance of all adverse effects reported by community oncologists who treated their patients with the drug.
The concept of ongoing surveillance makes sense, in theory. There is no way any company can do enough testing and with sufficiently large number of patients to identify, document and quantify all potential adverse risks associated with their new drug roll-out. The hope is that over time as thousands and thousands of patients are exposed to the new drug we will get a more complete picture of the risks and rewards.
This paper identified a huge gaping hole in the supposed safety net of ongoing adverse effecr surveillance of newly approved drugs. Most of the reported cases of PML came from expert centers. It makes sense to me, only institutions which are very familiar with PML and therefore able to diagnose it accurately are likely to catch the connection.
Here then is the crux of the problem: the vast majority of CLL patients are treated locally. How many cases of PML has your local guy seen? Would he know how to diagnose it, would he be able to connect the dots quickly enough, and would he take the extra time to document and report the potential link he has seen between Rituxan therapy and JC virus reactivation? Definitive diagnosis of JC virus requites careful neuroimaging scans, detailed experience with clinical findings and confirmed by brain tissue biopsy (Right. We need brain tissue biopsy like we need a hole in the head – literally.) Delicate pcr testing has been proposed to help with the diagnosis, but not too many commercial labs are competent in doing this test and certainly very few doctors request it.
As some of you may remember, my husband PC developed hypersensitivity to Rituxan. At that time I asked our local oncologist who was supervising his use of Rituxan if we can report the incident to the manufacturer’s adverse effect surveillance program. We were told that without a lot more documentation and paperwork it is not possible to do so, and the doctor was certainly not interested in taking on the additional work involved.
Something tells me this is the norm and not the exception, that a very large percentage of potential adverse effects are never reported because they are encountered at the local health-care setting. This article confirms that suspicion, most of the PML / JC virus reactivation reports came from experts centers – very few reports originated at your friendly overworked and under trained local oncologist.
Is this article reporting only the tip of the iceberg, are viral reactivations a lot more common than we had assumed thus far with respect to Rituxan therapy? I will confess I do not know the answer to that question and it bothers me.
What should we do?
First and most important, it is important not to throw the baby out with the bathwater. Rituxan has proven itself to be a very important drug in our fight against CLL. While it is not very effective as a single agent, its combination with other drugs such as fludarabine and cyclophosphamide has improved response and remission statistics significantly. We would be foolish to forswear Rituxan under any circumstances.
Having said that, I wish there was some way we can improve the present post-marketing surveillance system we have. I guess neither the manufacturer nor busy local oncologists have much interest in capturing most of the adverse effects. But that just means the adverse effect profile stays hazy at best and we are groping in the dark.
Do you have a long history of viral infections? Do you break out in Herpes sores at the drop of a hat? Have you had a lot of immune suppressive therapy to control your CLL? If the answer to most of these questions is “yes”, you might want to ask your local oncologist if it is worth getting your T-cell counts tested. If indeed your T-cells are not what they should be (look for CD4+ T-cell counts and the CD4/CD8 T-cell ratio), you may be more at risk of viral reactivation. You might be among the patients that should get prophylactic anti-viral protection ahead of therapy, even if it is just good old Rituxan therapy.
One other thing you can do is learn a bit more about PML. Early warning sign of PML include:
- Dizziness
- Loss of Balance
- Vision difficulties
- Difficulty speaking
- Difficulty walking
- Confusion
If you notice any combination of these symptoms and they seem to be getting worse rapidly, you should bring them to the attention of your medical team.
All in all, we really do not have a good handle on the adverse effect profile of Rituxan, not yet. We can only hope that the profile will get less hazy over time. So far we have heard of the following potential adverse effects:
- Delayed onset neutropenia
- Hypersensitivity that can become dangerous in a subset of patients.
- Potential risk of JC virus reactivation
I don’t know about you, but what bothers me most is stuff I don’t know about, it is the curve ball coming in from left field that knocks me for a loop.
RSS Feed
28 comments on "Rituxan in the news – again"
Chaya – I am so very grateful to you for grabbing us by the lapels and aiming our attention at a problem that we might otherwise have ignored, if indeed we had known about it. I failed PCR in 2005 and then Revlimid in 2008, and now have been turned down for the ABT-263 trial because of advanced aortic valve stenosis. The best available therapy for me has seemed to my excellent oncologist and me to be Bendamustine + Rituxan. In fact, I would have started it already has it not been for the cardiologist’s concern that I am likely to need aortic valve replacement surgery right away, a decision that awaits the outcome of an angiogram next week. Yes, the information you have made known to me does complicate my situation, but will make decisions better informed ones. Thank you! RAA
Chaya,
Again you are the “firstest with the mostes”. Thanks a million for your wonderful work which benefits so many of us in the CLL community.
Dan Hill
Chaya,
This news does raise many questions. My quick response is wondering if this might be another reason for SOME subsets of patients to consider Rituxan monotherapy more in the light of being less damaging to the T-cell function or does it not matter in some cases because of dysfunctional T-cells (T-cell anergy)? It would make sense that the right immunomodulators could make Rituxan as a frontline therapy safer by avoiding T-cell damage. Managing most CLL patients perhaps should replace the “cure” goal as an interim solution.
I am not convinced that Rituxan is being used in the best way for CLL given the seemingly contradictory studies which show that Rituxan given at 20mg/m2 or less can rapidly deplete B-cells in the peripheral blood avoiding CD20 shaving yet other research indicates high dose R at 500mg/m2 gives a superior response. All these questions cry out for more trials to pry out efficacy for defined subsets of patients.
WWW
Chaya,
Thanks so much for pointing this out. Last year I had Rituxan because they thought that I had tumor fevers. Well, long story but it turned out to do nothing for the fevers but a rule out identified toxoplasmosis that was treated but means anti viral drugs now. When I get closer to treatment for CLL I will discuss this with my medical team, particularly getting the T cell count.
Jerry Mohatt
I am glad my rituxan infusions are over. I am still on oral chlorambucil.
Rita Horwitz
Hey Guys
I am new to CLL Topics.. I am being treated at MD Anderson by Dr Keating as well as by my local Oncologist here in Birmingham Alabama –I am having soft tissue pain……….and Dr Keating — nor my local doc have ever seen CLL present itself in this way.
The pain is in foot — forearm…leg –etc. never in the same spot for more than 24 to 36 hours – then moves. Just finished my second round of Clinical trial – Chemo — and the pain goes away after the Oxilaplatin. Trying to see if other CLL patients have ever expereince soft tissue pain from thier CLL?? Its bad enough to keep me home bound…hurts like crazy.
CLL – diagnosed 2003 —— FCR in Fall of 2007 — CR until fall of 2008 — 17 p deletion – Fall of 2008. Preparing for transplant in Summer of 2009.
AU1981
After very successful RFC I went through a terrible year of neutropenia until eventually my spleen had to go.
During this time I suffered acute mouth ulcers which really were terrible, and a mass of cold sores, so there were obviously a lot of viral “Awakenings” going on.
However I can gladly report that everything is fine now, don’t get mouth ulcers, and only the occasional cold sore, no worse or more frequent than they have ever been pre- CLL. I am enjoying a very good C.R. working hard and enjoying life to the full!
FCR and splenectomy have given me back my life. I have no more frequent or worse infections than other healthy friends around me, fewer if anything. perhaps i am just lucky, but this is just to tell people that is isn’t all bad!
Good luck everyone!
Michael
Iceland
Excellent as usual ! Thanks Chaya.
I had rituximab last year (FCR Therapy) and altho it did the job, I did get Shingles (aka herpes reactivation) on top of it.
I wouldnt now accept Ritux without antivirals…
Thanks again
Lawrence Hanney
Cornwall, UK
Thanks Chaya – I’m getting my Rituxan (FCR) today… I was debating whether I should open this before I left the house! I’ll have something to bother my oncologist about at least. Thanks for the heads up.
Tim
Chaya-
I just got back the results of Tom’s CD4 counts.
You stated “who had severely depleted T-cell counts (CD4+ T-cell counts less than 500) or out of whack CD4/CD8 T-cell ratio were more likely to be in the at-risk group.”
Tom’s absolute CD4 positive counts is 259UL (229-1448) His CD3+CD8+ cells is 40.1(H) (10.8-36.3)
His CD3+/CD4+cells at 26.2%(L) (32.3-63.8)
Do these counts have anything to do with this paper?
Thanks
Jenny Lou
Dear Chaya,
You are a gem. Thank you so very much for keeping us updated as you have.
At age 73, Kelly, my dear husband, completed 5 rounds of FCR, and a BMB revealed that he is in CR. He had been scheduled to have 6 rounds, but his platelets were becoming an issue, hence the early BMB.
Throughout his FCR treatments, Kelly had been taking valacylovir and still is. Kelly and I have already discussed our desire that he remain on the valacylovir and plan to discuss this with Kelly’s oncologist at his next appointment. Our reasoning is that while in CR, he (of course) still has CLL plus his immune system has been further embattled by chemo+. In addition, shingles, et al, can be more a concern the older one gets. Your latest update confirms my feeling that the benefits of continuing valacylovir may out-weigh the risks by a long shot.
Warm wishes,
Jan
I had FCR two years ago and am doing fine. Except from the usual unpleasant problems with the infusions, I’ve had no problems to speak of, only 2-3 weeks of diarrhea a few months after treatment. They gave me an antibiotic, Valtrex, allopurinol, iron pills, and some stuff for nausea. My counts are good, except that my absolute lymphocyte count is still below normal, 0.61 in Jan.
Still, I’m glad to see that I’m well past the median 5.5 mos for getting PML.
Dear Chaya,
The points raised in your discussion are all relevant. I have not been able to download the complete “Blood” article, so I can not be certain of all of the characteristics of the CLL patients identified with PML in the RADAR study and all of the the CLL related therapy that they received. Still, I am struck by several things:
PML was initially identified in AIDs patients with particularly low CD4 counts.
Such patients have occasionally been observed to undergo “arrest” of the progression of the PML when appropriate anti-retroviral therapy has been successfully given to them and their CD4 counts have risen. (they actually may develop localized worsening or ongoing involvement in certain brain sites already affected by the PML, indicating attack by an active immune system).
Numerous monoclonal antibodies which have been used to treat various autoimmune/inflammatory and malignant diseases have now been associated with PML. These patients have not been uniformly similar and I am not aware that there has been a good effort to characterize specifics about their global immune status (both before and after whatever therapy they received), but the salient point seems to be that they have some immune system abnormality to begin with and then receive a therapy (be it rituximab, infliximab, nataluzimab, etc) that further impairs one or more aspects of the immune system (principally something involving T cell function) prior to the onset of the evidence of PML.
There seems, in general, to be a prevalence of the problem when autoimmune disease (or presumably the predisposition for it) is present in the patient who receives whatever treatment is subsequently linked to the PML.
Testing for CD4 counts and CD4/CD8 ratios is frequently and easily done for patients with HIV infection, but there has not yet been any clinical reason to do this in the general CLL patient population. I can not recall with certainly, but don’t believe that it was part of the protocol for the study that I had initially hoped to enter which employed rituximab and alemtuzumab simultaneously (though I believe that there was a recommendation to test the CD4 counts at the end of 6 months before ceasing prophylactic therapies).
My impression has been that there is a woeful absence of uniformity as regards protocols to provide prophylaxis following therapy for CLL and that many patients do not receive appropriate prophylaxis or monitoring post-treatment.
There are a few references in the literature (mainly in post solid organ transplant patients) suggesting that antiviral prophylaxis by itself may provide some measure of protection against other sorts of infection, presumably because CMV infection (the main culprit prophylaxed) may impair immune function in a general way. This, of course, would not preclude other prophylaxis for PCP and fungal infections.
I think that it may be reasonable for all patients with CLL to discuss prophylaxis carefully with their physicians, including the advisability of prolonged anti viral prophylaxis (let us be clear that there is no known good prophylaxis against JCvirus reactivation at this time), and at least raise the flag about testing and following CD4 counts when certain therapies such as alemtuzumab or purine analogs are used or when autoimmune disease such as ITP, AIHA, SLE, etc is already present.
After the food fights we had on our earlier Yahoo groups site I was a little gun shy about making Updates an interactive site. You guys have proved me wrong. This discussion thread is terrific!
To address some of the points made in the comments above:
Rick, you are absolutely right, there is no good known prophylactic anti-viral drug that can prevent JC virus reactivation. Unlike broad spectrum anti-bacterials that can handle a wide swath of bacteria, we do not have broad spectrum anti-virals (or anti-fungals!). My comments on exploring use of an ti-virals as prophylaxis is with reference to stuff like valtrex (valacyclovir) to control Herpes (think shingles).
As for the safety of taking anti-herpes drugs such as acyclovir, valacyclovir etc over long term, I am told people have been on daily doses of these drugs for years at a time (as a prophylaxis against genital herpes – a very transmissible STD) with little harm. Thank providence for small mercies.
Let me repeat an important point here: Rituxan continues to be a very important drug in treating CLL. Please do not throw the baby out with the bathwater. But we do need to treat it with respect, just as we need to treat all cancer drugs with respect.
And we need to have meaningful discussions with our doctors about protecting ourselves against opportunistic infections and viral reactivations while we are going through therapy. As Rick pointed out, this is perhaps the one area where expert Best Practices are not followed as often as they should be by local oncologists.
It is not just local healthcare providers that do not follow Best Practices. Many patients do not seem to do a good job of exercising commonsense either. I am talking about “social distancing” during periods of deep immune suppression, more emphasis on staying away from crowds etc. It is a fine balance, living your life to the fullest in spite of cancer and not taking foolish chances.
Jenny Lou, the T-cell counts you report for your husband would put him in the category of someone with significantly reduced T-cell protection. But I am sure his doctors know this and they probably have him on all sorts of medications to keep him protected.
Dear Chaya,
If the t-cells are tested, and the cd4 counts are followed, that is a good thing. My question is can a cller be tested for that minute amount of virus that they may be harboring?
Best Reguards!!
Raymond Parker
Raymond:
No, I do not believe there are tests that can confirm or deny trace levels of JC virus present in patients who have ever been exposed to it.
From a statistical point of view, the fact that 80% of more of our population has been exposed to JC virus at some point in their lives, and the virus survives in the host as traces for the rest of their lives, suggests that majority of us need to be aware of the risks of viral reactivation.
Same logic holds for the far better known Epstein-Barr virus. Most people do not even know that they have been exposed. In some the infection can get severe and then it is clinically diagnosed as mononucleosis. EBV is easily transmissible. It is not called the “kissing disease” for no reason.
There have been several very interesting articles on the subject of prior history of clinically diagnosed mononucleosis and subsequent CLL prognosis. In fact, EBV has been suggested as the culprit that actually causes several types of cancer. Is it linked to CLL? I do not know of any article that links EBV and CLL initiation. But several literature articles (including several from M. D. Anderson) suggest there may be a connection between mononucleosis and aggressiveness of subsequent CLL.
There are a couple of full length reviews / Alerts on the subject on our flagship website CLL Topics. You can find the articles by searching for the key phrase EBV in the search box at the top right hand side of the home page of the website.
My mother was on IV rituxan treatments regularly. She has inflamation of the visual cortex and is now legally blind. They believe the vision loss is due to a medicinal insult, and therefore they have taken her off rituxan. They were hoping the inflamation would reverse itself, but so far it has not. She is only on two other medicines, one of which they also took her off of (Prozac). The did consider this virus as a potential at first, however this is a very fast acting virus and she has not exhibited any other symptoms.
I am very sorry to hear about your mother’s situation. vision problems are among the symptoms of PML. But I will be the first to admit PML diagnosis is not easy and something that can be missed by physicians who have not had experience with it. What makes JC virus dangerous is the speed with which it can grow and become dangerous.
Dear Chaya,
I was tested for the EBV at first diagnosis, to the compliment of my local. I am 47 now and was diagnosed at 43. I am one of the first to come thru with all of the shots for most of the communicable diseases,
therefor i have never had the measles, mumps, chicken pox, or any of the other goodys. That was the reason for the test question, because I seem to be clear for all of the rest. There does seem to be some question of the effectiveness of the vascines after this amount time has passed in my life. My local is checking. Dr. Keating will get this question on my next visit.
Many Thanks!!
Raymond
Chaya was kind enough to mail me the article from the 3/5/09 issue of “Blood” and I realized that I was incorrect about one important thing.
PML was described almost 20 years before AIDS was recognized in (you guessed it) patients with lymphoproloferative disorders such as CLL.
I was mistaken principally because AIDS was the context on which I learned about it.
Dear Chaya,
May I please express a caveat about CD4 counts.
As part of the CLL207 trial in the UK I received Campath for minimal residual disease following 6 cycles of FC.As expected my total lymphocyte and CD4 counts remained depressed for about 12 months. Then last November my CD4 count staggered over the magic ‘200’ level below which prophylaxis against pneumocystis is advised.I stopped prophylaxis and in Jan my CD4 count had risen to 240.Then in February I was hospitalised with Pneumocystis pneumonia.
Curiosity drove me to the literature where I discovered the following:
1)advice about prophylaxis is derived from clinical experience with Pneumocystis in AIDS.
2)CD4 cells perform a range of functions. The FUNCTIONAL defecit in CLL as a consequence of CD4 depletion is different from the functional defecit in AIDS.This is probably because different populations of T cells are compromised in each condition.
In other words an’adequate’ number of CD4 cells (as determined from AIDS studies)does not mean adequate function by the CD4 population in CLL patients.
3)I understand this to mean that following treatment which exacerbates the immune defects of CLL it is not possible to make reliable statements about risks of viral or fungal infection in any individual.There appears to be inadequate published data on which to assess risk of common viral infections (eg influenza) and clinical outcome in relation to cell counts or tests of immune function.
I do appreciate that Rituxan has different influence on immune function from Campath.However Chaya’s comments make it clear that T cell function is impaired even though Rituxan targets B cells.
So it seems to me that reliance on cell counts,while better than nothing,should be coupled with a high degree of patient awareness and clinical suspicion.
Adrian
Adrian is spot on.
The recommendation to continue prophylaxis in CLL patients until CD4 counts exceed 200 is based on data/experience in AIDS patients on anti- retrovirals. Initially the goal was to get the CD4 counts above 400, but the 200 “limit” was noted to be associated with a decreased incidence of infections such as PCP in AIDS patients who remained on anti-retrovirals.
Unfortunately, there is data to suggest that if anti-retrovirals are given “on demand” when CD4 levels fall below certain levels (and then are stopped after the CD4 levels rise) the incidence of opportunistic infections remain high.
There is no good data on the utility of this “limit” of 200 CD4 cells in patients in CLL, but this level has been empirically adopted because of the data in patients with AIDS.
I agree that lymphoproliferative disorders are intrinsically different from HIV infection. We know that there are abnormalities of signaling between T cells and B cells in patients with lymphoproliferative disorders and that T cell function is abnormal in varied ways.
Interestingly, in some patients with advanced AIDS there has occasionally been demonstration of the HIV virus invading B cells as opposed to just CD4 cells (the cells usually involved with HIV infection). Clearly no one knows as yet what this means.
Personally, I plan to continue prophylaxis against PCP until my CD4 count exceeds 400 as I’ve heard too many accounts similar to Adrian’s of PCP pneumonia developing in patients many months after completing alemtuzumab when their CD4 counts were above 200.
I also intend to remain on valacyclovir indefinitely to suppress CMV, EBV and herpes viruses. Certainly the development of side effects from the valacyclovir may alter my plans. This is the joy of CLL, the disease which keeps on giving.
Good luck, Adrian
Rick
Immune deficiency in CLL patients is hardly a question for debate any longer, especailly if they have been through chemotherapy or used drugs such as Campath that kills T-cells. I am more than willing to agree that we do not understand exactly how to characterize this immune deficiency and that it may follow a different pattern than in those with AIDS.
What should we monitor to try and get ahead of the curve? B-cells? Hardly, they are mostly dysfunctional in CLL patients. Neutrophils? Yes, and patients are warned to be aware of the risks of long lasting neutropenia (including delayed onset neutropenia following Rituxan therapy in some patients). T-cells? Which ones? There are many different varieties of T-cells, including cells called “Tregs” or regulatory T-cells that we wrote about in earlier articles on our website.
I wish we had better handles, better ways of monitoring exactly how at-risk people are, so that we can better protect them. For now, the best we can do is monitor absolute neutrophil counts, someting that most patients do when they get their regular CBC blood test.
I guess I am raising the question that perhaps CD4 T cell counts and CD4/CD8 ratio might be worth monitoring too. These tea leaves (ahem) may not give us the whole story or even an important part of the story. But anyone knows a better way of trying to predict who is more at risk of viral reactivation?
In the absence of definitive tests that can shed light on level of risk of viral infections, I agree with Rick the best thing to do may well be to stay indefinitely on antivirals like valacyclovir and pneumonia prophylaxis.
But there is always the concern that overuse of anti-viral drugs leads to drug resistant forms. Bummer. As an example, this year we have seen major percentage of flu strains circulating in this country are now resistant to Tamiflu.
Chaya
Thank you so much for everything you do to educate us CLL’ers. You are a very important part of our lives.
BG
Dear Chaya,
I have or had rheumatoid arthritis, mononucleous and tuberculosis over my lifetime. My doctor tried to give me a rituxan treatment for CLL but I got the rigors (which lasted 30 minutes) and I stopped breathing. This was after about 15 minutes of Rituxan or 2 percent of the dose to be given. The doctor considered this a normal reaction to Rituxin and wanted to begin again, but my wife refused to let the session continue. Days later I began to experience loss of balance, confusion and difficulty walking. My wife says my mental focus has never been the same since the treatment. I have had 2 MRI’s and no one found anything abnormal in the brain. So I do not know what really happened. But with your article I am going to be pretty careful if I ever use Rituxan again. Thanks for all your hard work.
Richard
Rituxan use appears to be a contentious topic. While the standard dosage of 375mg/m2 for CLL use was adopted from the protocol for Follicular Lymphoma we have interesting research by Ron Taylor concerning CD20 shaving (that I learned from CLLTOPICS) and the fact that low dosage 500mg/m2 studies indicating better responses than low or standard dose use. I suppose all of these observations could be valid depending on what mechanism of cell kill is involved.
For the purpose of this topic involving reactivation of viral pathogens my attention was grabbed by last comment in an abstract which read: “Use of high doses of Rituximab in CLL can avoid T-cell dysfunction and neutropenia, and is associated with humoral immunorestorative effects.” Source – Comprehensive Cancer Center, NY medical college 5 Jan. 2008
Another puzzle to me in the discussion of prophylactic drugs with treatment came from the response by Dr. J. Byrd to my question as to what he uses in his RF protocol. “nothing” accept allopurinol for the first treatment. I was remiss in not asking him the appropriate follow-up questions but it got me wondering (once I got home) how anti-viral or anti-biotics might affect the efficacy of the tx. It is reasonable to assume that a doc might pre treat with antimicrobials if the patient were clinically prone to infections or had low neutrophils at the time of first tx – but still???
Musings on the learning curve.
WWW
Is PML always fast acting or can it be slow moving also ?
As stated above my mother’s vision has become very bad, but I believe the doctors feel that since nothing else has appeared to deteriorate within the last few months, that it is not PML. They think PML can take its’ toll in 5 months.
smartino:
The honest answer to your question is that I do not know if PML always progresses fast, whether there are always multiple symptoms. I will look around and see if I can find the answers.
But I think your mom will be well served by going to one of the expert centers where they are more likely to have broad experience with PML
This must be frustrating to you and your family. Sorry I cannot help more than this. But I think it is important for all of us to recognize our own limits, not do harm with incorrect or ambiguous information.
Leave a Comment