Selecting Therapy in CLL

The CLL landscape continues to change very quickly.  I have previously written about picking a first line therapy, but my post from 2013 has become quickly outdated.

I recently had the opportunity to participate with a group called "Clinical Care Options" on a decision support tool that allows you to plug in a variety of variables that are central to picking out a treatment regimen and then seeing what therapy would be selected by a handful of experts.

To use the tool, you have to register for an account - but I thought it would be worth it for a number of patients who are at the point of picking out a particular therapy.

Here is a link to the tool

I also serve on the CLL Steering Committee for Medscape.  We have recently conducted several taped interviews discussing how to pick therapy in both the front line and relapsed / refractory setting.  Here again, you need to sign up for an account - but worth it if you want more color commentary regarding the tool outlined above.

Here is the link for the frontline video with me and Steve Coutre

Here is the link for the the relapsed / refractory video with Stephen Schuster, Matthew Davids and Amy Goodrich

I would like to predict that these will remain relevant tools for the foreseeable future but I am happy to report that they will only be valuable for another 12-24 months before the world changes again.

I tried to embed these tools directly on the blog but unfortunately was not able to do so.  I hope you find them helpful.

Thanks for reading / viewing / tooling.

FCR versus BR in frontline CLL

The abstract I have been most eager to review in this years ASH meeting details the results of the German CLL10 study in which FCR (fludarabine, cyclophosphamide, rituximab) is compared to BR (bendamustine, rituximab) in the front line management of patients with symptomatic CLL.

Here is a link to the data

The data is based upon a planned interim analysis and concludes with the statement, "In light of these results, no firm recommendation of one regimen over the other can be given at the present time"

Why the balance?

It looks like FCR is better than BR in terms of depth of response.  While the overall response rate was identical between the two arms, the CR rate favored FCR (47% versus 38%) and MRD negativity (71% versus 66%).  This translated to a more durable progression free survival (85% versus 78%) at two years of follow up but not surprisingly the overall survival at this early time of follow up are equal.

While that may lead you to conclude that FCR is better than BR, it comes with a price.  4% of FCR treated patients died during treatment as opposed to 2% of patients who received BR.  That was in part because 90% of FCR treated patients versus 78% of BR treated patients had side effects rated grade 3-5 in severity (the higher the worse).  This was particularly evident in the rates of severely low blood counts which translated into a considerably higher rate of severe infections (40% vs 25% in favor of BR).

Not surprisingly, the outcome seems to have an age effect.  In the population less than age 65 with good performance status the progression free survival more strongly favored the FCR over BR but above age 65 it was a wash - totally equal.

One tragedy of this study was that there was an imbalance in the randomization that resulted in considerably more patients with an unmutated BCR ending up in the BR group.  This less favorable group may have handicapped the BR arm of the study making it appear worse when perhaps it was just that that arm had patients destined to do worse genomically.

Keep in mind that the average age at diagnosis is 72 and average age at first therapy is 74 years old.  I think a lot of the bias against FCR comes from experiences docs have treating patients with FCR that probably should have never had the combination of drugs because they were never likely to handle it well in the first place.

FCR is also pretty close to the limits of what a person can tolerate while BR seems to be a good platform for adding new drugs.  Drugs like idelalisib and ibrutinib combine very well with BR.  I suspect GA-101 would also be a good partner with bendamustine.  I wouldn't be surprised if some of the new combo treatments make BR much better while maintaining the better tolerability.

This study sheds very important new light on selecting first line therapy for patients with CLL.  How will I handle the data?  For patients above age 65 I will probably favor the BR therapy - particularly if I can do it in a clinical trial that adds a novel agent.  Below age 65 I will look very closely at parameters like renal function and medical comorbidities.  In the very healthy sub-65 year olds FCR will probably get my nod (unless I have a trial with BR with a new drug).  If I have concern about marrow or renal function, I would probably go with BR in this group.  Of course a close discussion with the patient will be very important.

Thanks for reading