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Alert Number 293

Rituxan in the news

Date: September 13, 2008, 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.
http://www.fda.gov/medwatch/safety/2008/rituxan_DHCP_Final%209411700.pdf

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.

I have also reproduced below another “Dear Doctor” letter from 1998. (The highlighting is mine, not the company’s). 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

 

http://www.fda.gov/medwatch/SAFETY/1998/rituxa.htm

December 5, 1998

Important Prescribing Information

Dear Doctor:

It is important that Genentech, Inc. and IDEC Pharmaceuticals Corporation inform you of eight post-marketing reports of severe infusion-related adverse events associated with the use of RITUXAN (rituximab) that resulted in fatal outcomes. These adverse events represent an increase in the severity of infusion-related symptoms. Since its approval in November 1997, for the treatment of patients with relapsed or refractory low-grade or follicular, CD20 positive, B-cell non-Hodgkin's lymphoma, approximately 70 cases of serious infusion-related events have been reported out of an estimated 12,000 to 14,000 patients that have been treated with rituximab worldwide. The labeling for RITUXAN (rituximab) will be revised to reflect this new information.

In seven of the eight fatalities, severe symptoms occurred during the first RITUXAN (rituximab) infusion. The cause of death was not reported or remains unknown for two of the eight cases. In most cases, death was preceded by severe bronchospasm, dyspnea, hypotension, and/or angioedema. Severe respiratory events, including hypoxia, pulmonary infiltrates, and adult respiratory distress syndrome, contributed to six of the eight reported deaths. In some cases symptoms worsened over time, while in others initial improvement was followed by clinical deterioration. Therefore, patients experiencing any of the severe infusion-related symptoms mentioned above or in the labeling (see ADVERSE REACTIONS section of the enclosed package insert) should be monitored closely until complete resolution of their symptoms occurs.

Review of the reports for these eight patients did not reveal a common pattern of predisposing factors. However, it appears that patients with a high tumor burden or with a high number (>50,000/mm3) of circulating malignant cells may be at higher risk. Therefore, these patients should be treated with extreme caution and be closely monitored throughout each infusion. The package insert was revised in September 1998 to include additional information in the WARNINGS section regarding tumor lysis syndrome and the management of patients presenting with tumor lysis syndrome.

Please consult the WARNINGS section of the enclosed RITUXAN (rituximab) package insert for information on monitoring and handling patients experiencing hypersensitivity reactions or other infusion-related symptoms.

This new safety information will help in the management of your lymphoma patients who receive RITUXAN (rituximab) therapy. Should you have any questions regarding the use of RITUXAN (rituximab), please call our Medical Information Department at 1-800-821-8590.

Healthcare professionals should report any serious adverse events suspected to be associated with the use of RITUXAN (rituximab) to Genentech at 1-8000-626-3553, extension 57541. Alternatively, this information may also be reported to FDA's MedWatch reporting system by phone (1-800-FDA-1088), facsimile (1-800-FDA-0178), or mailed to MedWatch using form FDA 3500 to HF-2 5600 Fishers Lane, Rockville, MD 20852-9787.

Sincerely,

Susan D. Hellmann, MD, MPH
Senior Vice President
Chief Medical Officer
Genentech, Inc.
1 DNA Way
South San Francisco, CA 94080-4990
650-225-1000

Antonio J. Grillo-Lopez, M.D.
Senior Vice President
Medical and Regulatory Affairs
IDEC Pharmaceuticals Corporation
11011 Torreya Road
San Diego, CA 92121
619-850-8500

 

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