Friday, December 30, 2005

Revlimid

Revlimid is an analogue of thalidomide that has been developed as part of a research programme to separate the evil effects of thalidomide from the beneficial effects. Are there any beneficial effects?

Well, in multiple myeloma, in patients who had failed even the so called "total therapy" use in Little Rock, there was a 37% response rate when treated with thalidomide. It has also been used in some other cancers, producing remissions where there was previously no hope. Thalidomide has also been useful in some forms of Leprosy and in some types of Graft-versus-Host disease. Even without the birth defects, thalidomide is still an unpleasant drug. It cause a peripheral neuropathy, severe constipation and sleepiness. In myeloma it increases the rate at which venous thrombosis and pulmonary embolus occur. But, of course, the major reason for being wary of it are the birth defects that it caused, babies born without arms or legs (known as phocomelia). This was perhaps the greatest drug scandal ever.

Does Revlimid have the same side effects?

Not surprisingly it has never been given to pregnant women. Thalidomide was never tested in pregnant animals before it was used, but after the birth defects were found, it turned out that it was possible to reproduce them in pregnant animals. The pregnant animal test is now a must for all drug testing. In pregnant animal tests that produce the birth defects with thalidomide, it has not been found that Revlimid is free of this side effect. Developmental toxicology studies were conducted in rats and rabbits to examine possible teratogenic effects of lenalidomide. The rabbit study contained a thalidomide arm as a positive control, as the New Zealand White rabbit is known to be sensitive to thalidomide’s teratogenic effects. Teratogenic effects were not seen in either study with lenalidomide. However, the rat is
not sensitive to thalidomide and thus is not considered a useful model for evaluating
thalidomide-like effects. The highest dose used in the pivotal rabbit teratogenicity study did not meet the level of being sufficiently maternally toxic, a standard endpoint in teratogenicity studies to assess appropriate dosing. Maternal toxicity was observed in rabbits at higher doses in the dose-range finding study. It has been given to pregnant rats at 600 times the dose to be used in humans and no fetal abnormalities were found. In mice, doses of 100 times that to be used in humans killed the embryos. But there was no phocomelia.

Thalidomide is a well-known teratogen, but the mechanism of teratogenicity is not established. It is not known whether thalidomide itself, degradation product(s), or both are responsible for teratogenicity. Thalidomide derived products have been identified in animals and humans; lenalidomide derived products have been identified in animals but not searched for in humans. It is likely that both compounds share similar metabolic or degradative pathways. Modeling suggests that the intermediates and final products would be structurally similar, but chemically unique, for each drug.

Does that mean that it is safe to use in pregnant women? By no means. I doubt that any thalidomide analogue will ever be licensed to be used in pregnancy. Indeed the conditions of the license are that special precautions must be taken to avoid it being given to pregnant women inadvertently.

What about the other side effects?

It does not cause sleepiness, neuropathy or constipation. But clinical trials have uncovered other problems. It causes diarrhea, though this can be overcome by appropriate treatment. Most important, in MDS it causes bone marrow suppression. This does not seem to be a major problem in multiple myeloma, where there is a lot of experience of using a larger dose, but in MDS the bone marrow cells are damaged to start with, whereas in myeloma the marrow is occupied by the myeloma, but the normal bone marrow cells are not themselves damaged.

The license is for MDS with deletion 5q. The clinical trial involved 148 MDS patients who all had a part of their long arm of chromosome 5 missing. Now there is confusion about this condition. Not everyone with MDS and a missing 5q has the 5q minus syndrome. 5q minus syndrome is a fairy benign form of MDS occurring mainly in older females, who have macrocytosis and a normal or high platelet count, and in the marrow, mononuclear megakaryocytes. The patients in the trial included some of these, but many who just had low or intermediate grade MDS with a missing 5q. 34.5% were males, 25% had other chromosomal abnormalities as well, 48% had RARS, RAEB, or CMML, all had a transfusion requirement. So in evaluating the results it is wrong to think that this was the rather benign 5q minus syndrome that often does require therapy.

In all clinical trials of effective chemotherapy in MDS marrow suppression is expected. Although Revlimid has many other effects, in MDS it seems to act primarily as a cytotoxic drug, rather than a supportive care drug like erythropoietin (EPO). EPO will produce relief from the need for transfusion in 30-50% of low and intermediate grade I MDS, but it will not get rid of the abnormal clone. On the other hand in this trial Revlimid relieved the need for transfusion in 67% and got rid of the abnormal clone in a substantial proportion of patients. Cytotoxic drugs produce severe cytopenias lasting in excess of 3 weeks in MDS, and in MDS Revlimid caused severe neutropenia or thrombocytopenia in 53.4% and 50% respectively. Febrile neutropenia (getting a high temperature while the patient has low white cells) occurred in 5.4%, which is very low for a cytotoxic drug. 11.5% got pneumonia. There were 11 deaths in the trial. 2 of these were attributed to the Revlimid. Now you may argue that these deaths have not been independently evaluated and that the other 9 that were attributed to the disease might have been contributed to by the drug. All I can say that the FDA had more information than we have on that and they have licensed it for this use. The FDA is very touchy on thalidomide analogues, and it seems to me that they would be unlikely to approve one that relied on camouflaged data.

So how does this relate to CLL?

Revlimid has not been licensed for use in CLL and neither has thalidomide. However in small phase II trials both have been shown to have some activity in CLL. Do not be persuaded to take either of these drugs unlicensed, except in the context of a clinical trial. Clinical trials have to be assessed by ethical committees. They will regard any trial as unethical if the risk to the patient is greater for taking the drug rather than avoiding it. Therefore there will be strict entry criteria for these trials, and patients entered into the trials will be closely monitored. Ideally these trials should be randomized phase III trials. If we had these for MDS we would know for certain whether the 11 deaths were caused by the disease or the treatment.

3 comments:

Jenny Lou said...

Dr. Hamblin,
Thank you so much for this blog. I find on the rare days that you don't post a new topic, I am sad. It is such a pleasure to read your advice and insights into cll and life. I have enjoyed every bite of information and feel priveledged to read it.

Jenny Lou Park
Austin TX

Terri said...

Just came across your blog. My mom has MDS/deletion 5q and has been taking Revlimid for nearly three months. She is the hospital right now having her 7th transfusion since beginning this drug. Not exactly what the doctor said would happen. She had the rash which was dismissed yet I jsut read an article that said the rash could be fatal and would be added to the label. She's been admitted several times for fevers and now possible pneumonia. This all a result of chemo for breat cancer five years prior. Needless to say ...concerned and anxious. Terri K

Terry Hamblin said...

Terri
It sounds like your mom has treatment related MDS. Deletion of bits of chromosomes 5 and 7 are the commonest findings in these, but despite having a 5 deletion these cases are often more severe than the free-standing 5qminus syndrome, I'm afraid.