JC Virus Reactivation
In the news the past couple of days are reports of unexpected and tragic death of three (or four) patients taking an immunosuppressive monoclonal antibody “Raptiva” for psoriasis. Death was due to progressive multifocal leukoencephalopathy (PML), an infection of the brain associated with reactivation of the JC virus. According to the FDA, all 4 patients had been taking efalizumab for at least 3 years and had taken no other immunosuppressant drugs. You can read more about it below.
Medscape Alerts
Psoriasis Drug Linked to Deaths From Progressive Multifocal Leukoencephalopathy
Emma Hitt, PhD
February 19, 2009 – Three deaths from progressive multifocal leukoencephalopathy (PML) and a possible fourth case have been reported in patients taking the immunosuppressant drug efalizumab (Raptiva, Genentech, Inc), according to a public health advisory issued today by the US Food and Drug Administration (FDA). Efalizumab is an anti-CD11a antibody immunosuppressant drug indicated for the treatment of adults with chronic moderate to severe plaque psoriasis.
OK, interesting and tragic, but how does that become relevant to us as CLL patients? Here is how. Back in September 2008 we published the following Topics Alert (you can access all of our prior Alerts by going to the Alert Archive) on the subject of Rituxan and potential risk of PML.
Rituxan in the news
Alert Number 293; Date: September 13, 2008
By now most of us are aware that deeply immunosuppressive drugs such as fludarabine, Campath etc can leave us vulnerable to reactivation of viruses such as EBV (Epstein-Barr virus), CMV (cytomegalovirus), herpes, hepatitis etc. So, are there any drugs out there that are 100% safe? I am afraid not. The list of immune suppressive drugs is long, just about all the drugs used in CLL are tough on what remains of your immune system – it is a matter of degree.
What about Rituxan, the miracle biologic that has made such a difference to CLL therapy options? Many patients go for frontline therapy with single agent Rituxan, even though it is not formally approved by the FDA for that purpose and to be honest, it does not pack much of a punch in that role. Many more patients use Rituxan in various combinations with other drugs (RF, FRC, PCR, R+HDMP, R+ GM-CSF, R+Campath, R+CHOP and so on). Many patients get multiple weeks of Rituxan infusions. The original 4 week protocol has long since been overtaken by 8 weeks or even more weeks. If a little Rituxan is good for you, is a whole lot of it even better? It is important to ask the question – does use of Rituxan increase the risk of viral reactivation?
I am a strong believer of using only as much drug therapy as necessary to treat the patient, no one smidge more than that. Genentech makes enough money as it is, I don’t think they need your help on that front. There is also sufficient evidence that over-use of any drug makes it that much more likely you will stop responding to it sooner. Rituxan is a very important bullet in our battle. Why would you want to take away its potency any sooner than absolutely unavoidable? Last but not least, even our darling Rituxan is not without its list of serious adverse effects, including (admittedly rare but very dangerous) viral reactivation.
Dear Doctor…
Here is the link to the latest Genentech “Dear Doctor” letter, on the subject of Rituxan, dated September 2008.
This letter deals with a case of progressive and fatal multifocal leukoencephalopathy (PML) reported in a patient with rheumatoid arthritis who received Rituxan as long term therapy. PML has been associated with reactivation of JC virus. This particular viral reactivation is more common in populations such as HIV patients, immune suppressed cancer patients (including those with blood cancers, and that means us chickens!), transplant patients, patients with autoimmune disease who are getting Rituxan to treat it, and so on. Physicians treating patients with Rituxan are warned to consider PML as a possible scenario if there are neurological manifestations.
Here is the link to another “Dear Doctor” letter from 1998 for your information. It is important that we do not to throw out the baby with the bath water, 70 cases of serious infusion related events out of 12,000 patients is not a whole lot. But be aware that the official use of Rituxan is for a variety of lymphoma patients. Typically, lymphoma patients have most of their cancer cells residing in swollen lymph nodes, very little of the disease is seen in peripheral blood. That is exactly the reverse with CLL patients. Most of us have significant number of CLL cells swimming around in blood circulation – which brings me to the second highlighted portion, patients with high counts of CLL in their blood are at higher risk of adverse infusion related events.
Alphabet Soup
I also worry about the slippery slope of expanding alphabet soup. A little Rituxan never hurt anyone, the logic goes. And steroids like prednisone – heck, they give people that for asthma all the time, how can that be too dangerous? And drugs like Campath and Revlimid are biologics, they are not even “chemo” for heaven’s sake. So, how about months and months of Rituxan, ever higher doses of steroids, a little Campath or Revlimid to mop up remnants and just to make things interesting?
Ever heard of the perfect storm being the sum of a lot of little things, none of which are hugely dangerous by themselves, but put them all together and you are talking about serious damage? Exactly how much immune suppression can a poor CLL patient take? What levels of risk of serious adverse effects justify the potential reward of deep, long lasting remission?
I will be the first to admit, it is impossible to come up with a firm answer to the question. None of us would use any of these drugs if there was no CLL gun held to our heads. Given that we may not always have a choice about putting of high impact therapy, the least we can do is make decisions with our eyes wide open. It is important to realize there is really no free lunch out there. You pay for these drugs with your wallet and possibly increased risk of adverse effects, every time you opt for increased “oomph”. Beware of that perfect storm!
Be well, stay informed!
Chaya
Let me hasten to add, JC activation was seen only in a very small percentage of patients using Rituxan. My concern is that as we add more bells and whistles to Rituxan in an attempt to increase the potency of therapy regimens, with inevitable increased risk of deep immune suppression / dysfunction, are we also increasing the risk of life threatening viral reactivation?
People are not lab rats
Recently I have heard from a couple of patients exploring the addition of fresh frozen plasma to Rituxan therapy, based on a very small study by one (and to date, only one) research group in Israel. We brought the interesting results reported by this group to your attention in an earlier Alert.
Folks, these are early stage results! Experimenting with unproven combinations such as this on your own body can be very dangerous to your health. Going way out of the guidelines in how drugs are to be used, with little or no track record of how the combinations worked in well conducted (and reproduced!) clinical trials is truly nothing more than making a lab rat of yourself. You may luck out. On the other hand, you may also be shooting yourself in the foot and elsewhere higher up. Consider yourself warned!
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23 comments on "Fatal Viral Reactivation in the News"
Does this viral reactivation occur during the treatment only, or if after the treatment as well, how long after can the possibility of the reactivation be considered?
Harley
Harley:
The honest answer is that no one knows. We do not have enough data to define time limits.
But we do know that Rituxan lingers in the body for several weeks – this is the basis for the once monthly infusions used in most protocols. There is also evidence of delayed neutropenia in some CLL patients who have been treated with Rituxan. Bottom line, I do not believe it is safe to assume all risk is past the day after the last infusion.
It is all a matter of keeping things in perspective. Rituxan is the single most valuable drug to come through the pipeline in the last several years. It has an enviable profile of safety, compared to standard issue chemotherapy agents such as fludarabine, cyclophosphamide etc. Many CLL patients live longer and healthier lives because of Rituxan. But is it something we can assume is 100% risk free, to be used with abandon? Only if you believe in free lunches and tooth fairies.
Regarding your “stay informed” comment I am still uncertain how to assess the Best USE of many drug protocols that are multiple drug in nature. Example: For Rituxan + Fludarabine there appears to be a logic in giving F first to reduce the peripheral blood tumor load but Dr. Byrd (pioneer of R+F) published a paper indicating an increased efficacy by concurrent administration. My sense is that, where the tumor is most carried (blood , nodes or both), amount of tumor and synergy must have some important bearing on the “sequential vs concurrent” issue but I have yet to find data exploring this discussion in detail.
As we begin to see more “cocktail” approaches for multiple drug use in CLL this discussion of “best use” will become more important and I for one would love to hear more on this subject.
WWW
Wayne:
I believe longer term tracking of the R & F sequential group versus R + F concurrent group has shown a small advantage to giving the R+F at the same time.
That said, some physicians tweak the RF protocol by (1) giving the F first in order to reduce tumor load if there is concern about tumor lysis, for example (2) splitting the Rituxan dose over several days in an attempt to reduce the infusion related adverse effects some people have more than others. By infusion related adverse effects I mean the chills, blood pressure fluctuation, rash, and or slight fever. Most of these are handled by slowing down the rate of infusion of Rituxan and administering additional Benadryl.
My concern is that unlike Campath therapy (where the need for preventative anti-bacterial and anti-viral drugs is well accepted) there is not as much consensus when it comes to Rituxan based therapies. Single agent Rituxan may not need belt-and-suspenders approach to protection, but combinations such as FR and FCR may well benefit from protecting the patient ahead of time. I would like to hear from you folks out there: how many of you have had RF or FRC and your local oncologist prescribed prophylactic antibacterials and/or anti-viral drugs?
I was never prescribed prophylactic drugs for any of my rounds of RF or R. And every time I ended up hospitalized with serious infections. I have learned my lesson and I WILL have prophylactic protection with any future treatments. I am currently taking Acyclovir and Itraconazole daily (antiviral, antifungal) so I will need to add an antibiotic.
I have severe hypogammaglobulinema, neutropenia, almost absent Natural Killer Cells and very low T-Cells (CD4 and CD8). I am screened monthly for the CMV PCR antigen, and presently receive IVIg and Neupogen and treat all infections aggressively.
As for your comment about using only as much drug therapy as needed, I pressed one doctor on the ‘why’ of six cycles. The response was ‘tradition’. Not exactly confidence building. I have often felt that the pursuit of a CR had too high of a price relative to fewer cycles with a PR. Of course this is not studied.
As for me, I have had PCR, four cycles. For the first cycle, R was administered as an inpatient over 20 hours followed by P+C. Bactrim, acyclovir and allopurinol were taken, the first two for six months. Stopping at four cycles was due to deep neutropenia with a very slow recovery.
I was given Allupurinol preceding and during the first cycle of FR. I was given Bactrim and Acyclovir during my FR regimen in 2007 and continued on those drugs for another 6 months post treatment. I was also given one injection of Neulasta on day 6 (after the 5th infusion day) of each cycle for cycles 2-6. I had no infections or other complications during that period for which I consider myself very fortunate.
Well…since someone else mentioned PCR, I’ll add my two cents even though I didn’t have any Fludarabine.
I also started with the PCR treatment, which ended last January (2008) and was immediately followed with a Campath chaser. I took Bactrim, diflucan and Valtrex right from the start, and almost a year after I finished the Campath (it will be a year March 28th) I’m still taking everything but the Diflucan (actually, the generic form, fluconazole). Dr. L thought I could safely stop taking that now.
After that comment that Dr. 11Qrick made to me about checking the CD4 count instead of the ALC, and using that as an indicator of when to go off the rest of the drugs, Dr. L agreed that we should put off discontinuing the rest of the stuff until the CD4 gets up (mine was 50 at the last blood test where we included it, with an ALC of 400…my ALC is 500 now). Going slow, but I guess I’m happy that the ALC isn’t charging back unabated!
So far, I have had no infections of any kind, during or after the treatments. And, except for the ALC, and CD4 (and therefore, of course, the WBC), all the rest of the blood counts have been normal since last April.
Harley
The above comments and particularly Stacie’s caught my attention because at my June ’08 visit with Dr. Byrd I specifically asked him what prophylaxis did he recommend with his RF protocol. He said none except allopurinol.???
Another interesting and to me confusing issue with Rituxan usage is the “Low dose vs high dose” efficacy. Ron Taylor’s research regarding CD20 shaving is quite compelling yet high dose RTX appears to produce a better response. I recently came across an abstract on springerlink.com concerning the dysregulation of immunoglobulin production in CLL. I quote here the end of the abstract: “Use of high doses of Rituximab in CLL can avoid T-cell dysfunction and neutropenia, and is associated with humoral immunorestorative effects.”
Me thinks there is still a long way to go before we are using what we have in an optimal fashion!
I had one cycle of anti-viral and anti-bacterials when I got hospitalized 2 days with pnemonia that occurred after my first full cycle of RF. [That was my one and only experience with pnemonia in my life so I hadn’t a clue.] After that, I did not have any antibacterials and/or anti-viral drugs during treatment. Who knows, maybe if I had started those viral/bacterial fighting drugs at the same time I went through my first cycle of FR, I wouldn’t have gotten the pnemonia. But I do not know if taking those drugs simultaneously would reduce the effectiveness of FR? I’m guessing not. But if it does lessen the impact of FR, perhaps there would not have been any time to spare to pre-treat me with the anti v/b because I started my treatments with urgency the same day I was diagnosed.
Tom was on antibiotics and antiviral meds the whole time he was being treated with FCR…..for 6 months following treatment also. He still ended up in the hospital with UFO though.
To answer one of the questions about 6 cycles of FCR versus 3 or 4. After 2 or 3 cycles of FCR, the blood work will show what looks like a great reduction in lymphocyte % and lymphcyte absolute numbers. WBC is back in range and at first glance it looks like FCR did a great job and why keep on protocol? The reason is because the marrow does not clear CLL out at such a rapid pace as the peripheal blood. There is usually, not always, a large percentage of CLL still living in the marrow and happily dividing and making sure their home is not disturbed. 6 cycles of FCR have shown medically that the marrow is being cleared out of remaining CLL cells. The protocol has never been one of “more must be better” thinking. I personally know of 2 patient’s who stopped FCR after the third cycle because the blood work was looking like a remission. Within a year, they needed treatment again. MDACC explained the reasoning for 6 cycles to me.
Tom is on Revlimid and also on anti-viral meds for the duration. He was on allupurinol for the first 3 weeks of Revlimid also.
The problem with trying to explain the reasoning behind, for example, the number of cycles or even dosing level is that there is little or no scientific evidence only anecdotal. The medical community is only now looking at such things as a very recent article in the J Amer Med Assoc reveals. See JAMA, 2009 301(8) 831-841 for the state of cardiac treatment most of which is not based on scientific evidence by the way. The article is free.
Here is an analogy for over treatment, which has yet been defined for CLL. In your intestines lives colonies of various microbes, some of which are very beneficial to your health. There is one critter, clostridium difficile, which is nasty in abundance but whose population is kept in check by the others. Unfortunately, the others are easily killed by strong antibiotics leading to an unchecked explosion in the population of c diff. Many deaths have occurred because of this with the primary symptom being diarrhea.
Likewise, treatment with powerful combinations such as FCR do in fact kill the easy to be killed CLL cells but not all cells fall in this category. The desired goal of a CR is not the same as saying one is cured of CLL. There are always a few CLL cells lurking within tissue for example so one should view a CR as temporary. The question one can ask is this: should a treatment aim at at CR knowing full well that one suffers damage from the treatment and is exposed to unchecked populations of harder to kill cells or is there and intermediate target, yet to be defined, wherein the CLL population is driven to some level which also might reduce collateral damage. The answer to this is probably lurking within the data taken during clinical trials in terms of those patients which had to quit early. As I have found, once treatment stops there is minimal followup on an individual.
What we all hope for is a “scientific” approach toward optimal treatment of an incurable and heterogeneous disease. I would hazard a guess that the risk of more cycles of FCR vs less is tempered largely by a patient’s age, relating to marrow function and level of detectable disease at the end of cycle 3 or 4. Here in lies the importance of the Doctor-as-healer rather than Doctor-as-pharmacist who just follows the “book”.
WWW
Waynewells, I agree with you as far as you go. Unfortunately, when guidelines are followed too closely, incomplete pictures emerge which then form the basis for guidance. For example, while CT scans may be used throughout treatment, BMTs may not except at the end. So to use as you mentioned marrow data (detectable disease) as a measure one would require BMTs at say every other cycle and that is just not done.
Perhaps we have to wait for cheaper and quicker tests before the physicians have the diagnostic tools to determine when to stop or continue. Lacking that, I still think there might be sufficient data lurking in the background of the research institutions which could provide some guidance. Maybe with the increase in NIHs budget, some funds could be used for this purpose.
In addition to hoping that the decisions are being made by Doctor-as-healer rather than Doctor-as-pharmacist as Wayne points out, I fervently hope that Doctor-as-researcher does not get complete veto power.
Think about it. Most of these combinations (including the present gold standard FCR) are still part of clinical trial protocols, especially if you get treated at one of the expert centers. When they finish the trial and report the data in high profile articles, what do you think the Doctor-as-researcher wants to report? Does he want to report a substantial percentage of his test subjects dropping out of the trial before the protocol’s demands of 6 cycles? Does he want to report less than stellar CR rates and pcr negative remission rates overall for his cohort because the optimum trade between best remission and least damage from the perspective of the individual patient required less than 6 cycles?
This is an integral part of the conflict of interest between the two hats worn by most experts: the researcher looking for best solutions for the community at large and the physician looking for the best solution for the single individual patient. Being aware of this conflicting agenda is your job, so that you can influence the decision as it best suits you.
Let me give you a typical horror story that I have seen played out again and again. Just a couple of months ago I heard from a newly diagnosed patient. She had just about every bad prognostic indicator known to man, clearly a case of very aggressive CLL that will need robust therapy. As a very young patient, her case was no different than that of “Catch-22 Richard”. The tea leaves were easy to read, she needed to get her ducks in a row and get to a transplant sooner rather than later.
Guess what she was advised to do at one of our premier expert centers. She was “recruited” for a Phase-I clinical trial using a combination of chemoimmunotherapy with a vaccine type approach, a clinical trial that had yet to get on the books and begin treating patients. I have seen this happen time and time again. Patients with aggressive cancer wait too long because they are dangled sugar plums of “risk-free” and sexy therapy approaches down the road by researchers who put them at risk by this process. There is a time when a bird in hand is worth two in the bush. If you are waiting for the Starship Enterprise to land and cure you down the road, please be aware this is not cost free. There is a very real cost of passage of time during which your CLL can grow bigger fangs, become that much harder to treat.
As always, there are many agendas at play in this game. It is your business (and mine, as your spokesperson) to watch out for yours. All said and done, you have more skin in this game than anyone else.
The Doctor-as-researcher is another important distinction and useful for Chaya to point out. Doctor Researchers like Byrd and Keating who have pioneered drug protocols can be expected to want to have many patients in their data bases to better evaluate how effective their protocols are and where they fail. Patients need to be wary not from any malice on the part of doctors but of the condition of human nature.
mickey1214 pointed out the pragmatic error in my case for using marrow function/marrow-cancer-involvement for the limiting of tx cycles.
This issue raises another question: Does data exist for judging marrow reserve related to age, bone size, sex or other parameters that could bias tx and number of tx cycles toward less toxic vs more toxic protocols? I know age is to some degree an indicator of marrow function and a reason for chlorambucil use in elderly patients but how fine a point can we make for the age group approaching mid 60s & plus?
My trusted Onc who left my clinic made this remark when I was pressing him about my aggressive tumor rise and profuse lymphadenopathy in the absence of sickness or “B” symptoms – “It depends on where the disease is”
WWW
Terrific discussion folks. Lots of interesting questions, insights. I wish we had more answers.
Part of the problem is that CLL is so very different in different people. it is hard to extrapolate from the few well conducted clinical trials. The recent head-to-head comparison between FCR and PCR (reviewed in a prior Update article)showed vastly different results than one would have expected from earlier M. D. Anderson conducted FCR results – a caution for all of us not to read too much into any one study.
The researcher Doctor….well, that is Tom’s Dr. And we always have to keep the thought in our head that some will be sacrificed for the good of the all. That’s a scary thing to know, but it is reality. Tom was one of the 300 patient’s on MDACC’s Phase II trial of FCR3. The 3 stands for Rituximab infusion for all three days of infusion with FC. Before this trial, Rituximab was only infused one day out of 3. I continually read the % of CR/PR/ etc. from MDACC on how this group is faring. Tom obviously relapsing at the 2 1/2 year mark does not hit the remission status that I keep reading about. BUT–if you are involved in a clinical trial, the follow up is the rest of your life. This is trial protocol and I believe that this is the only way one can get the best follow up care. Trials demand patient’s are followed until death. Letting a single Dr. try to do this is just too much for the Dr. I remember Tom’s local oncologist saying to him that since he had already had FCR and was relapsing, he didn’t know what to do. (and this is an oncologist who is hightly touted for other cancer’s.) He basically stated to let MDACC decide.
And, Chaya is right on when she talks about researcher’s and their expectations of their personal trials. They will push a patient to the extreme edges if they think it will make the trial look better on paper. That’s my problem with Revlimid right now. so far, I wouldn’t recommend it to anyone and this is the end of cycle 3 for Tom. But, it might start showing some improvement this next cycle. If not, BYE BYE. I prefer FCR over Revlimid at this point.
Hi Chaya
The above comments are very interesting and very powerful. I have just finished my series of rituxan. I do have problems with rituxan when the fluids run in too fast. I am told most people are finished in at least 2 hours or so. Well, since I am not in the cancer center to win a popularity contest, my fluids take 5 hours. Then I can go home usually without fever, a splitting headache.
I am also on oral Chlorambucil. My wbc responded by going from 132 to 10.4. Usually my disease is in my lymph nodes but this time in my bone marrow. There was some discussion re: my treatment, as you know, because I refused Bendamustine because of the interraction with other meds.
I also refused fludara because in 2002 it left me with a horrible case of shingles, PVD and CAD. I have done relatively well on this treatment and hope to continue. Through treatment, I have walked as much as possible. And force fluids as much as I can even though I feel like I’m in electrolyte imbalance. I’m not and my veins have to share rituxan with IVIG.
I will be 76 years old in May and have had this disease for 15 years.
I look forward to your valuable information and advice.
Rita
Rita:
I think you know how much I admire your spirit. You are my kind of lady!
Most people finish their Rituxan infusion in two hours? Bull. For the present day standard dose of 375mg/m2, it generally takes 4 hours or more. I know, PC got a boatload of Rituxan (until he developed hypersensitivity to it).
And even if that 2 hour statistic is true (it is not), it is hardly relevant. The job of nurses in the infusion room is to make sure their patient’s individual needs are met, not to make their own schedules more comfortable.
All of us are so used to feeling intimidated by our healthcare system that we forget this simple truth of the marketplace: we are the customers, and the customer is never wrong!
I so much appreciate the discussion here. It is very thought provoking and helpful.
My local Doc wanted to just do R with me when Chemo starts but my Mayo doc recommended FCR3x 6 months. He suggested giving 100 mg of R the first day then dividing up the other 900 over the next 2 days. This was to be done to reduce the chills, fever, nausea symptoms that can occur I guess.
Allopurinol and Acyclovir were suggested by my local Doc but my Mayo Doc wanted to also add Bactrim(one pill three times per week for 6 months post tx)
Since I am so close to treatment(wbc 157000) hg 11.4 platelets 100,000
I feel that I can be better prepared to ask questions that are pertinant.
Regards,
Mark
Jenny,
You and Tom are a true inspiration and an encouragement for me. I was supposed to begin FCR on Feb 25th with a 191000 WBC and 10.1 Hg Platelets of 90000 when a bone marrow biopsy 3 days before tx showed that my numbers had dropped consiberably. 157000 11.4 and 100,000.
I am now going in first week of April to get tested again. Still, I feel CFR is not far away. You and Tom are in my thoughts and prayers.
Mark
I had 4 weeks of Rituxan in Dec 2005. They also put me on Alupurinal (to combat hemolytic anemia caused by the white cell proliferation). Then FCR (x6) starting in Mar 2006.
I’ve taken Acyclovier for several years to control herpes outbreaks, but due to increased outbreaks shortly before I started FCR treatment, my GYN (Yep, not my onco doc!) changed me to Valtrex instead. I take this anti-viral every day to prevent the viral breakouts and it works very well.
I’ve been in remission since summer of 2006 (Yea!!) and relatively healthy at least the last two years. I’m guessing from this article, the Valtrex has played some part in that.
MicheleB
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