Revlimid

May 2005

Thanks for the LIST member who sent me this abstract about the Roswell Park
study of Revlimid in CLL which was presented recently at ASCO
This Phase II trial evaluated the clinical benefits of REVLIMID in patients
with relapsed or refractory CLL. Eighteen relapsed or refractory CLL patients,
 median age of 66 years (range: 58-74) were enrolled in the trial with all
patients available for toxicity and fourteen patients available for response
evaluation. REVLIMID was given at 25mg orally every day for 21 days followed by
 7 days of rest on a 28-day cycle. Absolute lymphocyte count at days 0, 7 and
30  were taken to determine direct anti-CLL effect of REVLIMID. Response was
assessed at day 30, and then monthly using the National Cancer Institute
-Working Group criteria. CLL patients with SD or better response continued on
therapy for a maximum of one year while those with PD will receive Rituximab at
(375mg/m2) added to REVLIMID. Twelve out of fourteen patients responded, at
day  30, with a decrease of 61% in absolute lymphocyte count, (range: 55-70%).
Three  patients achieved CR; one CR and two Cytopenic CR (bone marrow biopsy
pending),  two patients achieved PR and nine patients achieved SD. One patient
withdrew  consent and was not available for evaluation. Progressive disease
has not been  observed in any patient and therefore Rituximab has not yet been
administered to  any of the patients.
Toxicity profile was predictable and manageable. The most common side effect
was fatigue and rash in six patients. Flare reaction (tender swelling of
lymph  nodes) was noted in 73% of the patients while 2 patients were reported to
have  tumor lysis syndrome. Grade 3 / 4 toxicities included thrombocytopenia,
anemia  and neutropenia. Further follow-up and analysis will ascertain the
durability of  these responses and establish the role of REVLIMID as a potential
treatment of  patients with CLL. Accrual is ongoing and updated results of this
phase II study  are expected to be presented at the American Society of
Hematology meeting in  December 2005.

May 2005

Following the Roswell Park report there has been a sudden enthusiasm for Revlimid. One of the main reasons for this has been the desire to avoid chemotherapy.

Revlimid is one of a number of drugs that have been derived from thalidomide. Apart from the well known effect on developing babies, the main side effects of thalidomide are neurologic. It causes sleepiness and sedation and it stops the nerves working in the limbs and bowel, so that patients get constipation and numbness. Revlimid is free from all these complications. It can cause diarrhea though. Thalidomide itself does not work in CLL, but the trial at Roswell Park is encouraging researchers to try it in a wider group of patients. At first these trials will be in patients who have already received other treatments.

On the other hand chemotherapy has been spectacularly successful in CLL. Granted that it has side effects. However, it is the rule that most patients have improvements in their disease following chlorambucil. Fludarabine gives more responses, the combination of fludarabine and cyclophosphamide more yet and the FCR combination even more, many of which are complete responses and in some no disease can be detected even after PCR testing. There is now a suggestion that adding mitoxantrone to this combination might produce even better results.

The possibility of cure following a remission obtained with chemotherapy certainly exists, though almost certainly this will require further treatment, possibly with Campath or a reduced intensity condition allograft.

Now this approach to treatment is hazardous with the risk of important side effects. It should only be attempted in patients who are likely to eventually die from their CLL unless it is effectively treated.

This is why it is important to test for prognostic markers before embarking on treatment. For patients who are destined to survive a very long time, this approach to treatment is likely to be inappropriate.

Although this approach seems to be encouraging for poor risk patients, we have yet to see a trial that shows an improvement in overall survival for the newer treatments. Better and longer remissions - yes, but overall survival remains to be tested. Very few patients have stratified patients according to the new prognostic markers. And those that have are tioo immature to have followed enough patients for long enough. This is not to say that these treatments will not lead to an overall improvement, just that they haven't been around long enough for us to tell.

Whether Revlimid will eventually find a place in the treatment of CLL remains to be determined.