FCR: The Empire Strikes Back

I'm not really a huge Star Wars guy, but the title seemed appropriate for the content.  For web savvy CLL patients FCR is a lot like the "evil empire."  With two new papers on this regimen, FCR is making a strong push in selected patients.

If a patient was offered a huge likelihood of long term disease control (as in just about every patient would be disease free at 7-8 years post treatment) AND many of those long term remissions were actually looking a lot like cures - would you take FCR?

In today's CLL climate, web informed patients are rebelling against FCR - and in many cases, I think it is for good reason.  FCR is a tough regimen.  Even in the German CLL8 study, about 4% of patients die in the first 12 months after starting therapy.  In the MD Anderson data set, it appears that unusual infections are increased as far out as two years from therapy.  The long term risk of marrow compromise and secondary cancers is real.

But....  In appropriately selected patients, it is probably all worth it.

Two new data sets shed important new data on this regimen that is now almost 15 years old.  An update from the MD Anderson group shows that patients with IgHV mutated CLL have impressive median progression free survival in excess of 12.8 years and that no relapses happened in any patients who made it to 10 years (in other words - if you made it 10 years, you appear to be free and clear). The numbers were comparatively poor however for those patients with IgHV unmutated CLL.  This test should be absolutely CENTRAL to the management of CLL patients being considered for aggressive chemoimmunotherapy - but unfortunately we have data to show that the test is woefully underperformed.

The German group has updated their analysis of the FC vs FCR study with a focus on cytogenetic risk groups with best outcomes.  They validate the role of IgHV status with incredible rates of long term disease control in patients with IgHV mutated CLL particularly those lacking 17P.  For those patients with trisomy 12 not a single patient experienced progression and the del 13Q folks did extremely well too.  I talked with Stilgenbauer recently and he is still reticent to use the word CURE, but I think these subgroups (IgVH mutated WITH either Trisomy 12, or Del 13Q) have high likelihood of super long term disease control if not cure.

None the less, FCR is clearly not for everyone.  If you look at inclusion criteria for FCR studies, only a small number of "typical" CLL patients would be considered eligible.  Furthermore, from the German CLL10 study, we know that the benefit of FCR over BR is primarily in those patients less than age 65.  The median age of frontline treatment in the US is closer to 72.   I will be eager to see subsequent analysis looking at FCR in patients above age 65 who have the favorable marker profile - that remains a question mark for me.

SO... to summarize

For patients with CLL who need therapy, it is imperative to test for FISH and for anyone considering intensive chemoimmunotherapy - IgHV mutation analysis is a must.  For patients less than age 65 with IgHV mutated CLL and either trisomy 12 or del 13Q, should seriously consider FCR as these groups have exceptionally high rates of progression free survival (like about 90% and I believe many of these will prove to be cured).

While FCR has been pushed back in the minds of many following the introduction of novel agents, this small subgroup has results that may help best define the "home" for FCR.

That doesn't answer what to do for those patients with IgHV unmutated CLL, but in my own mind, the long term outcome of FCR in this population (provided there is no 17P deletion) is considerably less favorable and I tend to prefer bendamustine based regimens.  While FCR may still have better "frontline" outcomes than BR in patients less than age 65 according to CLL10, BR is clearly a lot easier to tolerate and I expect lower long term toxicity.  Because our options in relapsed CLL are so darn good, not sure you need the incremental benefit of FCR in the frontline if it really beats up your marrow for the future.

The German "GREEN" study of Bendamustine with obinutuzumab has reported really excellent results with the swapping of rituximab for obinutuzumab and is something we are researching within US Oncology.  Obviously any opportunity to add a novel targeted agent (BTK, PI3K, BCL-2) to this regimen would be great, but currently those combinations have not been approved and are not available outside of a clinical trial.

Anyhow, wanted to get a blog post up.  It has been way too long.  Lots of stuff happening in my own life that has me busier than ever.  Getting an hour here and there for a blog post is a rarity these days. Hopefully this is still valuable.


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