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Alert Number 292

Revlimid (aka lenalidomide) in the news

Date: September 6, 2008, 2008

I am baaaack!

The last couple of years have seen a lot of research papers devoted to the use of “Revlimid” (scientific name lenalidomide) in CLL.  Most researchers agree that Revlimid acts in a way that is different from the mechanism of action of most other CLL drugs, hence the hope that it gives us a valuable new “bullet”. There is also hope that Revlimid may synergize with Rituxan, and that the “R&R” combination will prove to be better than either drug by itself. Several clinical trials have commenced or are about to open looking at this combination.

I have to admit, I was not a big fan of Revlimid (certainly not the hype that surrounded it), but when push came to shove and Harvey proved to be fludarabine refractory from the get-go, Revlimid was a welcome option that managed to reduce his swollen lymph nodes ahead of his stem cell transplant.  For patients who have “graduated” from single agent Rituxan and requiring something a bit stronger to control their disease - but not willing to go all the way to RFC or PCR (Rituxan + cyclophosphamide, with fludarabine or pentostatin) - the combination of Rituxan plus Revlimid may be an attractive choice.  But Revlimid has some unusual side effects that may be worrisome, including the so-called tumor flare syndrome.  For that reason, I strongly urge patients to try this drug either in the context of a clinical trial, or under the supervision of a physician familiar with its behavior pattern.

When was anything to do with CLL an open and shut case? I just came across two different publications that once again raise my concerns about Revlimid + Rituxan combination.  The first is a paper in “Blood” (abstract below, write me if you want to read the full text article) – authored by no less than John Byrd of Ohio State. Bear in mind this is a cell study, cells obtained from CLL patients, and not a live patient clinical study.  Nevertheless, Revlimid seems to have the unfortunate habit of decreasing the number of CD20 units expressed on the surface of the CLL cell, thereby making them less attractive as targets to Rituxan.  It appears that CLL cells treated with Revlimid “internalize” or tuck into their interior the CD20 markers so necessary to anchor Rituxan.  As it is CLL cells express CD20 only sparsely, as compared to lymphoma patients – one reason why Rituxan is less effective in CLL as compared to lymphomas. Bad news for the synergy argument, if Revlimid makes for even lower expression of CD20 and therefore reduces the oomph of Rituxan.

The second piece of information is even more troublesome.  The FDA has just announced a list of 20 drugs that the agency is watching for possible adverse effects. The appearance of a drug on this list does not mean that FDA has concluded that the drug has the listed risk. It means that FDA has identified a potential safety issue – no more and no less.  Revlimid (lenalidomide) is on the list, with the potential safety risk of Stevens Johnson Syndrome. The link to the FDA citation is given below, as well as the write up in WebMD.

(For those of you with inquiring minds, Stevens-Johnson syndrome (SJS) is an immune-complex–mediated hypersensitivity that can cause severe angry looking red skin rash. Most authors and experts consider SJS and toxic epidermal necrolysis (TEN) two faces of the same disease, and for that reason you may see it referred to as SJS/TEN. Stevens-Johnson syndrome typically involves the skin and the mucous membranes. Sometimes SJS can be mild, but sometimes it can cause significant involvement of oral, nasal, eye, vaginal, urethral, GI, and lower respiratory tract mucous membranes. SJS can be a serious systemic disorder with the potential for severe morbidity and even death).

What concerns me is that one of the side effects of Revlimid is a red rash.  “Harvey” had it, while he was on Revlimid. Will local oncologists with limited experience of Revlimid (and perhaps even SJS) be able to tell the difference between generic garden variety Revlimid rash that needs nothing more than large doses of Benadryl to treat it, and the more dangerous tell-tale signals of incipient SJS?  I repeat my caution: Revlimid should be used in the context of clinical trials, or under the care of an experienced physician, or a physician willing to take guidance from one of the Revlimid experts.

Revlimid to the Rescue?

Harvey Does Revlimid

Be well,



Blood. 2008 Sep 4. [Epub ahead of print]

Lenalidomide down-regulates the CD20 antigen and antagonizes direct and antibody-dependent cellular cytotoxicity of rituximab on primary chronic lymphocytic leukemia cells.

Lapalombella R, Yu B, Triantafillou G, Liu Q, Butchar JP, Lozanski G, Ramanunni A, Smith LL, Blum W, Andritsos L, Wang DS, Lehman A, Chen CS, Johnson AJ, Marcucci G, Lee RJ, Lee LJ, Tridandapani S, Muthusamy N, Byrd JC.

Hematology-Oncology, Department of Medicine, The Ohio State University, Columbus, OH, United States.

Lenalidomide, an immunomodulatory agent that enhances antibody dependent cellular cytotoxicity (ADCC), is currently being investigated as a therapy for chronic lymphocytic leukemia (CLL). The anti-CD20 antibody rituximab is active in CLL and represents a rational agent to combine with lenalidomide. We therefore examined if lenalidomide combined with rituximab enhances direct apoptosis and antibody dependent cellular cytoxicity (ADCC) in CLL cells. In contrast to previous reports using CD20-positive lymphoma cell lines, lenalidomide down-regulated CD20 surface antigen expression in CLL patient cells via enhanced internalization, without influencing transcription. The CD20 surface antigen internalization enhanced delivery of an oligonucleotide incorporated into anti-CD20 immunoliposomes. In addition, CD20 surface antigen down-modulation by lenalidomide in CLL was accompanied by diminished rituximab-mediated apoptosis and ADCC. These observations suggest a need for alternative sequencing strategies to avoid antagonism between lenalidomide and rituximab therapy in CLL. Additionally, they suggest that lenalidomide therapy might be useful to enhance targeted delivery of RNAi-based therapies using CD20 immunoliposomes in B-cell malignancies.

PMID: 18772452


Potential Signals of Serious Risks/New Safety Information Identified by the Adverse Event Reporting System (AERS) January - March 2008

Lenalidomide (Revlimid)   Stevens Johnson Syndrome


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