ASH: Why Revlimid + Rituxan Works (Maybe)

 Another interesting paper to be delivered at ASH in a few weeks: "Correlative Analysis and Clinical Update Of a Phase II Study Using Lenalidomide and Rituximab In Patients With Indolent Non-Hodgkin Lymphoma," by researchers at UC-Davis.

This study looks at the combination of Revlimid and Rituxan. Revlimid is also known as Lenalidomide, which is how this paper refers to it. However, the combination is often known as R + R, or R2, or R squared, so I'm going with Revlimid, because then I can say R + R and not have to type Lenalidomide over and over because I'm both lazy and a horrible typist.

Anyway, the study provides an update on a phase 2 study of patients using R + R, but goes a little farther by also providing an analysis of what's going on in the body to give some hint as to how and why R + R works. There are several trials studying this combination, including one reported on last month that showed that Revlimid might help Follicular Lymphoma patients who have become resistant to Rituxan. But, as these researchers note, there's still little sense of why it works. Knowing why might help identify patients for whom the treatment will work best.

First, the straight numbers: It's aphase 2 trial, so there were a relatively small number of patients involved (just 30 who had been treated previously with Rituxan, with 22 of those being Follicular Lymphoma patients, and another 15 who had not received any treatment. So 45 in total.

Results: for those who had been previously treated, the Overall Response Rate was 74%, including 12 patients 44% who a Complete Response; 3 of those CRs lasted for more than 4 years. Of the previously untreated patients, the Overall Response rate was 92%, with 42% reaching a Complete Response.

Those numbers are fairly well in line with previous reports on R + R for Follicular Lymphoma patients, which is great. I expect there will be a phase 3 trial at some point.

The second part of it all was what made things so interesting. To try to figure out why the combination worked, they took blood samples and measured levels of cytokines in the blood before treatment, then at 15 days after receiving the Revlimid (and before receiving the Rituxan), and then at 30 days and 60 days.

Now, cytokines are a fairly large group of substances that do a bunch of things in the body, mostly signaling other things that they should get to work. So by measuring levels of particular cytokines in the blood, they were hoping to see if certain activities were being signaled to begin, and thus giving them some sense of how Revlimid works.

They measured for 10 different cytokines that are usually associated with immune response in some way; basically, they signal the body to defend itself. They found that six of them didn't respond in any significant way, but four other responded big time, particularly at Day 15, before Rituxan was given.

I'm not sure the specifics really matter, but these are the substances that increased so much:

• IFN-y, or Interferon Gamma, which stops viruses from multiplying, but which also stimulates the immune system to act.
• GM-CSF, or Granulocyte Macrophage Colony-Stimulating Factor, which encourages white blood cells to grow.
• CXCL10, or C-X-C Motif Chemokine 10, which binds to cells to help T cells and Natural Killer cells find their targets.
• And IL-2, or Interleukin 2, which helps to keep white blood cells in check, and helps the body figure out which cells belong there and which should be attacked.

As I said, for our purposes, the specific substances and the things they do probably don't matter much. What does matter is that the researchers found them, and can begin to consider the significance of them.

What also seems especially significant to me are two things:
First, these substances were especially present in the patients who achieved a Complete Response.
Second, the levels for these substances went up before Rituxan was given, so they might say a lot about Revlimid, rather than the combination. But that doesn't mean the combination isn't great, only that these particular substances increased with Revlimid. That might very well have prepped the lymphoma cells for the Rituxan, which is why the combination works so well.

And the combination does seem to work, at least for a specific group of patients. It will be interesting to see what a larger phase 3 trial ends up with.