Monday, December 7, 2015

Trial in relapsed "high risk" CLL

There is no question that ibrutinib represents one of the greatest advancements in the management of CLL.  This drug has fundamentally changed our understanding of the biology of the disease and opened up new vistas moving forward.

But there is still room for improvement!

It is like we just unlocked a door and now we have a whole new area to explore.  What strategies make most sense moving forward?  Does ibrutinib work best alone or in combination with other drugs?  Do we have the correct dose and schedule of ibrutinibCan we create a better version of a BTK inhibitor?

One of the earliest questions to emerge is the role of adding CD20 antibodies (rituximab, ofatumumab, ublituximab).  There was some debate that ibrutinib might interfere with CD20 antibodies, but that was speculative.  Now clinical trial data is emerging to help answer this question.

I made a video with PatientPower (great site for all things CLL), to describe one such study looking at this question directly: Does adding CD20 antibody to ibrutinib improve outcomes over ibrutinib alone.

In the video we talk a little about "high risk" CLL, FISH, TP53, 17P, 11Q and so forth.  I hope you find it educational.

As always, you can leave a comment below by clicking on the title of this post then scrolling to the bottom.

Sunday, November 8, 2015

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.

To leave a comment, click on the title of this post then scroll down to the bottom.  There should be a place to enter comments.

Thursday, June 4, 2015

Frontline Survival Benefit for Ibrutinib


Resonate-2, the randomized phase III study comparing frontline ibrutinib against chlorambucil met its primary endpoint of progression free survival (how long you are both alive AND without progression) and ended early.  More importantly, the secondary endpoint of overall survival was improved as well

Meeting the primary endpoint was a virtual certainty.  Everybody knew this study would be positive - but the study had to be done in order to get FDA approval for frontline ibrutinib.  Single agent chlorambucil is a dead dog.  It has served as the control arm that has been beaten up by just about every new drug in CLL in the last ten years (including campath, bendamustine, fludarabine, obinutuzumab, and now ibrutinib).  

Meeting the secondary endpoint is a little more provocative.  This study was built with a crossover design - meaning if you were randomized to chlorambucil and experienced disease progression, they gave you ibrutinib at that point.  If there is an overall survival benefit, it means that early ibrutinib saves lives compared to ibrutinib after progression.  This was also true in the Resonate study comparing ibrutinib to ofatumumab and the Gilead study that led to approval of idelalisib in combination with rituximab.  That is three studies that show that patients die faster when they get ineffective therapy compared to novel agents.  It remains to be seen if that is true with standard  regimens that actually work like bendamustine-rituximab or FCR where the bar will be much higher than chlorambucil.

Presumably this will be presented at ASH if it isn't already published by then.  It will also lead to FDA approval of frontline ibrutinib but that is probably still a ways off and the exact prescribing "label" will determine who can get it in the frontline.  I have no particular insight, but suspect that is still 4-8 months away.

There will be several key details I want to see in the presentation:

1) In this "elderly" subset of patients - how well was ibrutinib tolerated?  In most clinical trials it appears that about 5-10% of patients discontinue drug for poor tolerance.  Age has also been shown to be biggest variable leading to drug discontinuation - and the median age in this study is likely to be a fair bit higher than other studies due to the nature of the control arm

2) How good is good?  Our group helped contribute to the "frontline ibrutinib" data published in the Lancet.  In that cohort of about 40 patients, only one patient experienced disease progression and several others discontinued for intolerance.  In this larger - multicenter study, it will be the largest to date of previously untreated patients to go on ibrutinib.  Is the progression rate still that good?  Are there more progressions or is it still in the low single digits?

3) What happens to patients who discontinue ibrutinib?  In the relapsed / refractory setting, patients who discontinue ibrutinib have been extremely sick and many have died very quickly.  There has been a fair bit of discussion about "ibrutinib discontinuation syndrome."  Some have argued that these patients had already failed every other therapy which is why they died so quickly.  In this treatment na├»ve cohort - that excuse cannot hold.  If the overall survival curve looks like the progression free survival curve - I will be worried.

4) Dose intensity.  Do patients start 3 pills per day and stay on three pills per day without dose reduction or interruption?  The ASCO data just presented really gives me considerable apprehension about big dose interruptions.  As a patient, I would be trying to keep skipped doses to a minimum.  Obviously you may need to do that for surgery etc. but if I had the choice, I would not want to do that early in a treatment course when there are a lot more CLL cells running around.

5) Cytogenetics and high risk markers:  While chlorambucil is such a dog it really isn't worthy of a comparison arm, it will be interesting to look at the subgroups treated on ibrutinib.  While comparing across trials is always dangerous, we have expectations for the outcomes of patients with markers like TP53, 11Q, and IgHV mutated/unmutated.  This will serve as some interesting food for thought with those higher risk populations.

This news release follows two positive randomized phase III trials presented at ASCO for ibrutinib in combination with bendamustine/rituximab and idelalisib in combination with ofatumumab.  These latter two studies are important but may not have as much practice impact as the study discussed above.

With a frontline indication for ibrutinib likely available within a year, it begs the question who to treat with chemotherapy and who to treat with targeted agents.  I've attached some slides from a talk I recently gave on this topic but please note that these reflect my approach and guidelines are rapidly changing in this disease.

Thanks for reading.  To leave a comment, click on the title of this post and it will open up the post in a new window with a comment section at the bottom.