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!