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.