Thursday, October 23, 2014

Lenalidomide and Rituximab in Lymphoma

In a recent post I outlined some of the important historical milestones of how we arrived at current standards of care in lymphoma.  I ended my list with the advent of “immunotherapy.”  Last week there was a paper published (link to article here) that helps lay the groundwork for a paradigm change in indolent (slow/follicular) lymphoma – and I want to highlight it here.

I think patients are instinctively drawn to the idea of immunotherapy when they understand it.  Most clinicians use the term to describe some intervention that helps shape the immune system to fight off a cancer rather than traditional chemotherapy.  Just about every patient I meet asks me if there are some nutritional supplements that can “boost the immune system.”  While maintaining healthy Vitamin D levels is a good candidate some of the new treatments that are being developed are pretty fantastic.

At the most simple level, rituximab is an example of immunotherapy.  I have blogged about CD20 antibodies previously.  You naturally make antibodies to fight off bacteria and viruses.  Rituximab is merely an antibody that we give to you that fights off lymphoma and CLL.  When you give the medicine, it binds to the outside of cancer cells and alerts the remainder of the immune system to eliminate the cancer cells – no chemo involved.

For the last 15 years we have shown in study after study after study that adding rituximab to just about any other sort of chemotherapy makes that chemotherapy work better.  I have also recently blogged about giving rituximab by itself (link here).

There have also been a lot of other studies that have tried to make better versions of rituximab.  We now have FDA approval ofatumumab and obinutuzumab which are all “CD20 antibodies.”  In the case of obinutuzumab it has been shown to definitively work better than rituximab in chronic lymphocytic leukemia.  There is also a huge list of CD20 antibodies that are lingering in development or have been killed off all together because they weren’t any better.

A different approach might be to ask if adding a second drug can make rituximab work better.  One interesting theme that has evolved in research is the concept of “T cell pseudo-exhaustion.” Lymphocytes primarily come in three flavors (T cells, B cells, and NK cells).  Rituximab works in part by recruiting the T/NK cells to kill the B cells.  But B cells are crafty – they are able to use cell surface receptors and micro-hormones to lull the T/NK cells to sleep – aka – pseudo-exhaustion.  It is as if the T/NK cells identify a problem, but they have  a post thanksgiving turkey coma and can’t do anything about the problem.  We call it “pseudo” though because it is entirely a reversible biochemical process.  Give those T/NK cells a jolt of biochemical “coffee” and now they can wake back up.

It has now been well shown in multiple laboratory studies that lenalidomide can reverse T/NK cell pseudoexhaustion.  Lenalidomide is a pill that is FDA approved for treatment of multiple myeloma , another blood disorder called MDS, and even mantle cell lymphoma but a handful of studies have shown it has substantial activity in both follicular lymphoma and DLBCL.  More impressively when you give those T/NK cells a medicinal jolt and then the rituximab helps tell them where to go, the results are pretty spectacular.

The article I referred to at the start of this is (linked here).  It reports the activity of lenalidomide (revlimid) in combination with rituximab for previously untreated indolent NHL.  Here is the punch line, it works extremely well.

When you use rituximab with chemotherapy for untreated follicular lymphoma (like R-CHOP or R-Bendamustine), the overall response rate is a health 90+% and the rate of “complete response” is about 35%.  Somewhere between 50-60% of patients have their disease still in remission at the 3 year mark (link to key article here).

When you use rituximab in combination with lenalidomide toe overall response rate is also a healthy 90+% but the rates of complete response are an astounding 87% in follicular lymphoma.  Furthermore the rates of three year remission are closer to 80%.  If you look at rates of PET negative scans at end of treatment (an important prognostic marker) it is virtually everyone and looking at markers like “complete molecular response” they are extremely high.

All without chemotherapy! 

A few caveats to note.  This study was a “single institution study” from the MD Anderson.  In multiple prior studies things that came out of MD Anderson didn’t pan out when tested in more diverse treatment settings (selection bias, patient comorbidity, etc.).  That said, this looks like it could herald a paradigm change in low grade lymphoma.

So what does it take to change the status quo?  For starters, insurance typically wouldn’t cover lenalidomide in this setting because it is not yet approved for frontline treatment.  Some patients may be able to get it paid for but it is extremely expensive so without coverage few will probably take it.  Fortunately a prospective randomized multicenter phase III study that compares lenalidomide and rituximab to either R-CHOP / R-Bendamustine (link here) has nearly completed accrual and if the results from that study hold up, the drug will likely be approved in this setting and insurance will have to cover it.  If that happens, I think you will see a large change in practice patterns as patients ask / push for non-chemo treatments that may be better than chemo treatments.

In the meantime, there are still studies patients can join.  In PREVIOUSLY TREATED lymphoma (including follicular, marginal zone, mantle cell) there is a study going on where EVERYONE gets the combination of these two drugs and then there is a randomization for the duration of lenalidomide treatment (link here).

There are also a handful of other studies using lenalidomide in lymphoma in a variety of combinations (see clinical trials webpage linked here)

When you can get the immune system to do its job, it can be a fabulous thing.

Thanks for reading

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