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  I have previously written about picking a first line therapy, but my post from 2013 has become quickly outdated.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.

Frontline Survival Benefit for Ibrutinib

NEWSFLASH:

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 naïve 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.

Take your pills - ibrutinib dosing matters!

When we are investigating new drugs that have never been tested before, we start with what's called a phase 1 study.  Historically, the goal of a phase 1 study was to define the "maximum tolerated dose." In the era of traditional cytotoxic chemotherapy, you knew you had arrived at that dose when patients simply couldn't handle any more - it was just to much. Perhaps they had too much nausea or vomiting, or the liver couldn't handle it anymore, kidneys failed, or some other toxicity made it clear that you had reached the limits of human tolerance.  As researchers, we just hoped we could get the drug levels high enough without causing too much damage.  If we achieved blood levels that we expected to kill the cancer cells without irreparably harming the patient in the process - that was victory.

Many of the new drugs challenge that paradigm.  When treatments effectively target the specific molecular abnormality with a cancer cell we can see considerably more efficacy while at the same time reducing toxicity.  This has led to the concept of "optimal biologic dose."  Instead of pushing the dose to the max, you only increase the dose as far as you need to - often with substantially less side effects than the traditional therapies.

Unfortunately, "optimal biologic dose" is much harder to define than "maximum tolerated dose."  It presumes that we have effective and accurate means of actually measuring what were trying to do.  While it may come as a surprise to many patients, the unfortunate reality is that there is an enormous amount of human judgment as well as a paucity of clear data involved in early clinical trials. Things are not as scientifically certain in early trials compared to the level of data we have later in a drugs like cycle.  Furthermore, we often need to generalize to the larger population from a very small subset of patients that are appropriate for a phase I study.

There is new data regarding the dosing of Ibrutinib that I think is really important to consider.

Most drugs inhibit enzymes in what we call a "reversible" fashion.  This means that the particular target is turned off only when you have high enough levels of the drug in the blood.  Ibrutinib is a little bit different, it is what we call a "covalent" inhibitor.  When you swallow a pill of Ibrutinib it gets into the bloodstream and either quickly binds to the BTK protein or it gets eliminated from the body.  Within just a few hours of taking a pill there is virtually no free drug in the blood.  Instead, it is all bound to the BTK protein - completely shutting down that signaling pathway until the cell makes more BTK.  This is very different than most oral drugs where we are trying to make sure the levels are still high enough right before you take your next dose.

When you had a sore throat as a kid, the doctor always said to be sure to take all your pills so that the bacteria didn't become resistant.  It is virtually a scientific paradigm that exposing bacteria to inadequate antibiotic dosing creates resistance.  The same is probably true in leukemia and lymphoma with some of the new drugs.  A CLL cell that has its B-cell receptor signaling pathway completely inhibited has a hard time escaping that inhibition.  If that same pathway is only partially inhibited however, it will try to find ways to escape.   This is why the discovery of mutations in the BTK protein that confer resistance to Ibrutinib or so important. These can only arise in cells that have survived the BTK inhibitor long enough to figure out how to thrive under the suppressive influences of Ibrutinib.

Dose intensity can be measured in two key ways.  The first is how many days you take it out of how many days you are supposed to take it.  We already know in other chronic leukemias like CML, adherence to Gleevec (imatinib) is the biggest predictor of treatment success.  Heck, it is even true in breast cancer with hormonal agents.  Now it looks like the same is true in CLL.  Sometimes side effects force you to hold therapy - but prolonged drug holds are undesirable.  Patients who had drug holds in excess of 8 days were almost three times more likely to experience a disease progression (link to ASCO 2015 abstract here).  

The second way dose intensity is measured reflects what dose you take daily compared to the "optimal biologic dose."  There was a very compelling presentation at AACR a few months ago  (I am still trying to figure out how to link to the actual poster, but here is link to the session).  The study title was "Population Pharmacokinetic-Pharmacodynamic (PKPD) Modeling of Ibrutinib in Subjects With B-Cell Malignancies" by Poggesi et al. (prize to the first person who figures out how to find the actual poster).  I need to get a little technical for a minute - stick with me.

As I wrote above, ibrutinib has a cool property that is unique compared to most drugs.  Since it covalently (or irreversibly) binds to BTK, we can do a blood draw, isolate the CLL cells, purify the BTK protein, and look to see how many molecules of the BTK protein are "bound" to a molecule of ibrutinib.  This is what we call, "receptor occupancy."  The higher the occupancy, the more drug is bound to the protein, and the more the pathway is shut off.

You can then ask how many people have how much of their BTK protein "occupied" or inhibited by ibrutinib at different doses.  If we set the bar pretty low at 75% occupancy, any dose above 280mg (two pills) is pretty effective.  96% of patients achieve that level of occupancy at any of those doses.  that may seem good but unfortunately, that low bar means that the pathway is only 75% "turned off."  It is more like a dimmer switch on the lights instead of an on/off.  75% occupied means that there is a lot of room for cells to try to discover ways to become resistant.  If you set the bar much higher at 90% occupancy, the standard CLL dose of 420mg (three pills) can accomplish that in 86% of patients but only 75% of patients who take two pills and 53% of patients taking on pill.  In short - dose matters.  You get more complete pathway inhibition with higher doses of ibrutinib.

What we don't really know what level of pathway inhibition is optimal for CLL treatment.  It is tempting to think that 100% occupancy in 100% of subjects might be much better at preventing eventual resistance - but honestly, we do not know if that might mean higher levels of side effects. How could we get there?  Well, perhaps we didn't actually define the "optimal biologic dose" correctly in the original phase I study.  We pretty much stopped escalating dose because it seemed to be doing what we wanted it to do in the relatively small population of patients we were studying.

I would be curious to go back and do a "dose optimization" study to see if we could modify either the dosing schedule or the actual dose taken to see if we could make ibrutinib work better than it already does.  I also worked on another BTK inhibitor that is no longer in development called CC-292.  We never really got it to behave as well as ibrutinib until we started giving it to patients twice daily. Other BTK programs are looking at this as well.  Another way of potentially addressing such drug limitations is by adding a second drug that acts through different mechanisms.  This should ONLY be done in the context of a research study.  We have three such studies within the US Oncology network of sites (and here as well) including the addition of ublituximab (an updated version of rituximab), the combination of a BTK and PI3K inhibitor, or even BTK in combination with one of the new immune checkpoint inhibitors - pembrolizumab. 

Doctors tend to reduce doses when there are problems.  It is how we think about so many different clinical problems, that we tend to assume it is smart decision making.  In my own patients, I am concerned that dose reductions or prolonged dose interruptions may be causing ibrutinib to be less effective than if we can maintain the dose intensity.

To leave a comment, click on the title of this blog post.  It will open up the blog post in a separate window with a comment field at the bottom.  All comments are reviewed by myself before being allowed to be posted - be patient, I'm a busy guy.

Thanks for reading.

Rituximab monotherapy in CLL

I expect this blog post is going to ruffle some feathers. I can’t wait to see the responses in CLL forum, ACOR and elsewhere.

Patterns of care databases report that during the course of CLL approximately one third of patients will receive mono-therapy with rituximab (ie. rituximab with NO OTHER CHEMOTHERAPY). In fact, it is one of the most commonly utilized therapies in the management of CLL but should almost completely disappear in light of new clinical trial data. Based upon information published within the last 6 months, I think any treatment recommendation for single agent rituximab should he held to some additional scrutiny.

I will admit that I have given this therapy a limited number of times in CLL/SLL before under circumstances where I thought it might be appropriate. In CLL/SLL I think rituximab monotherapy is mostly outdated as of late 2014. Newer drugs such as obinutuzumab and Ibrutinib or new combinations such as idelalisib with rituximab have taken the place of rituximab monotherapy and I have changed my practice patterns as a result.

I recently blogged about rituximab monotherapy in follicular lymphoma and highlighted several key papers published that show how well this immunotherapy drug works. I also blogged about how the addition of lenalidomide may alter the landscape of front line treatment in follicular / indolent lymphoma. Indeed, rituximab monotherapy in indolent NHL (follicular, marginal zone) is a good treatment and definitely appropriate in many circumstances - particularly low tumor burden disease. But what is true for some indolent lymphoma isn’t necessarily true for ALL indolent b-cell disorders.

Small lymphocytic lymphoma and chronic lymphocytic leukemia are often considered two different manifestations of the same disease. Indeed, they are often referred together as CLL/SLL and lumped in with the rest of the indolent lymphomas. But different lymphomas have different behaviors and the response to rituximab is one key difference. Unfortunately, many doctors don’t pay too close attention to this distinction.

Rituximab is often a very easy drug to administer (some uncommon exceptions apply). In most indolent lymphomas and even CLL, you can see things get better and everyone seems happy.  Both doctors and patients can be lulled into a sense that they are getting good therapy when they see things going the right direction – but good can sometimes be the enemy of better and may not be best in long term. 

When rituximab first came out as a new drug it was noted that it had fairly modest activity in the management of chronic lymphocytic leukemia. Response rates were lower than in follicular lymphoma and didn’t last as long. Two key papers were published in the Journal of Clinical Oncology in 2001 authored by John Byrd (linked here) and Susan O’Brien (linked here). Both of them looked at ways to increase the dose of rituximab in order to get a better response in patients with relapsed disease. Dr. Byrd's paper looked at more frequent dosing and Dr O’Brien’s paper looked at giving mega-doses. Despite these efforts the overall response rates were between 35-45% and generally lasted 8-10 months.
 
Two key caveats though should dampen even that modest efficacy. The first is that this was in a population that had largely not been exposed to rituximab previously. Rituximab works better in patients who have never received it before. Nowadays virtually all patients get rituximab added to their first line therapy. When their disease relapses, a sizable population is getting rituximab mono-therapy and it is less likely to work when used a second time. The second caveat is that in 2001 we had different criteria for response assessments and CT scans were not used the same way they are today. Since lots of patients have enlarged lymph nodes hanging out in their chest or abdomen that cannot be detected by physical exam, looking more closely with CT scan would influence the determination of response and progression.

To get a good estimation of how well rituximab or even ofatumumab actually works, I would suggest looking at the control arm of the recently reported studies that led to the approval of idelalisib and Ibrutinib (linked here and here respectively). In these studies patients were randomly assigned to one of the “tried and true” or one of the new drugs but looked at rituxan exposed patients and used CT scans to determine progression. In the rituximab alone arm of the idelalisib study, the lymph node response rate was only 6% and the median progression free survival was under six months. Those response rates are really lousy. In the ofatumumab alone arm of the ibrutinib study, patients didn’t fare much better.

CLL researchers look at the patterns of care data and look at the utilization of rituximab monotherapy with a measure of disdain. While in the past I might have argued back that CLL patients treated in academic centers are fundamentally different from those seen in community practice (an assertion which has good data to support). Indeed, community patients are on average older, have more medical issues, and less good baseline organ function, and several other key differences compared to patients seen in academic medical centers. In the past, I think you could have used that logic to support some utilization of rituximab monotherapy but new data sets strip that away.

So what are the key new data sets?

In previously untreated CLL, obinutuzumab is better than rituximab. These are both CD20 antibodies but obinutuzumab has a number of key modifications that make it more effective than rituximab. In a paper published late last year (linked here), the German group performed a three arm study comparing chlorambucil to chlorambucil in combination with either rituximab OR obinutuzumab. From progression free survival perspective these came in at 11, 16, and 26 months respectively with obinutuzumab the clear winner. If you only compared the chlorambucil arm to the obinutuzumab arm, you even saw an overall survival benefit (second paper to ever show this in CLL). I have heard some people argue that the better performance of obinutuzumab was just based on differences in dosing in the study.  I believe that is an argument made by people who are unfamiliar with obinutuzumab (gazyva).  Clinically, it is a very different drug and the differences in dosing are pretty minimal.

This study was in CLL patients that are more typical for the disease (average age 71). Of course chlorambucil is somewhat of a pariah in the US and many have asked whether it is even a necessary part of the regimen. I was recently at the International Myeloma, Lymphoma, and Leukemia conference in NY where this topic was the subject of a one hour debate (hot Friday nights in the CLL research world). Hard to debate the topic given the lack of published data in this space but our group led a large study of obinutuzumab monotherapy that was presented at ASCO (link here) and will hopefully be published soon. My take on the data: you get a little more bang for the buck when you add the chlorambucil but not clear it is worth the cost, particularly with the agents available now in the relapsed setting.

Two years of average benefit in this disease can be meaningful. It will even be more meaningful if we can apply molecular data to pull out the patients less likely to benefit as well. There is new data from two studies that suggest the presence of NOTCH1 mutations makes CD20 antibody therapy considerably less effective (FC vs FCR and Chlorambucil vs chlorambucil-ofatumumab). Not sure if it applies yet to obinutuzumab yet, but hopefully that data will come out soon. You can test for NOTCH mutations here.

The second key data set (linked here) led to the approval of idelalisib. In this study, patients received either rituximab alone or in combination with idelalisib – a twice daily, non-chemotherapy pill. The difference was striking. Instead of a nodal response rate of 4% it was 96% and the difference in progression free survival was improved by 82%. In fact the difference was so striking the study had to be terminated for ethical reasons because the difference in overall survival started becoming too obvious to ignore (which we were not expecting to be different for technical reasons attributable to cross-over study design). This was the third study ever reported to show that there could be a survival difference in CLL with a new regimen.

I fundamentally believe that there is a significantly sized population of CLL patients who are not appropriate for an aggressive chemotherapy regimen. Let’s face it, the average age at first treatment in CLL is between 71-74 years old. Many are much older. Tack on heart and lung disease or multiple other medications, arthritis, etc which is entirely common in the population and things like FCR are absolutely prohibitive and even bendamustine-rituximab can be a stretch. If a CLL patient TODAY received the recommendation for rituximab therapy alone, I think it would be hard to justify why idelalisib isn’t included (note, I do not put rituximab or ofatumumab in combination with ibrutinib outside of a clinical trial as there is some suggestion that the ibrutinib may make the antibody work less well).

The third data set (linked here) compared Ibrutinib pills to ofatumumab infusions. Here too, the differences were so striking the study had to be terminated before it was planned to do so. In clinical research you set out to conduct studies when there is a sense of “equipoise.” That means there is an honest uncertainty about the difference between two therapies that you need to prove. The difference between ofatumumab and Ibrutinib in this particular study shatters the possibility of equipoise – the differences are too overwhelming.  Response rates, progression free survival, and overall survival for patients treated with ibrutinib absolutely trounced ofatumumab.

So between these three papers the justification for rituximab monotherapy in either front line or relapsed CLL disappears. In front line, obinutuzumab is better than rituximab and in relapsed disease either adding idelalisib or swapping the two for Ibrutinib improve outcomes enough to fundamentally change the paradigm.

The remaining setting where CD20 antibody therapy such as rituximab or ofatumumab is used in CLL is as a “maintenance therapy” following some other chemotherapy. There have been several recent updates in this space and I think you could make a rational argument in support of maintenance though I’m not sure this is widely adopted in CLL treatment. I have provided a few links (here and here) but will leave this discussion for another time.

To summarize:

In previously untreated CLL, I think obinutuzumab has demonstrated sufficient clinical superiority over rituximab (either monotherapy or in combination with chlorambucil) to justify the swap in most cases - there is some debate about this point but I think the argument is settled.  To date, there is not enough published data to routinely combine obinutuzumab with drugs like bendamustine or fludarabine outside of a clinical trial.  

In patients with relapsed CLL, adding idelalisib to rituximab makes it work a whole lot better and Ibrutinib monotherapy trounces ofatumumab. Neither rituximab nor ofatumumab look nearly as good as single agents as we had believed in the past.

I anticipate the next several years of research will be about swapping out the various parts and putting them together again. Newer antibodies will be combined with newer pills and newer pills will be used earlier and earlier in the disease. It is a new era and we are quite fortunate to be in a time period where many of the “rules” are being re-written. Patients will live longer than our standard “prognosis” dictums and maybe we will even begin see a disease once considered incurable to be curable. Throw in BCL-2 inhibitors, CAR-T cells, bi-specific antibodies, and immune checkpoint inhibitors and I hope all patients will look to join in research studies so we can move the needle more quickly.

Thanks for reading

Can CLL be cured?

Question for you -

What is better, 10+ years free of CLL in exchange for 6 months of chemotherapy or 10 years of a pill taken daily?  Go one step further: what if the chemo not only got rid of the disease for 10 years but actually cured some patients?

We are incredibly fortunate that there are new therapies approved by the FDA that are non-chemotherapy based - but we should be careful before abandoning something that can be extremely effective for some patients just because it is called "chemo."

Everyone desperately wants to find a cure for CLL so we need to be vigilant and avoid excessive optimism.  The idea of "curable CLL" is debatable among the researchers who study the disease.  For the purposes of this post, I need to be very clear that the difference between very long term remission and cure can become a little blurry.  At what point is a patient with no signs of leukemia considered "cured?" 

I am always careful to define "remission" when I am in the clinic.  To me, it means, "we can't see the cancer but we know that it is there."  That is very different from a cure, where one would assume it isn't.  The only thing that really distinguishes between the two is the test of time.  How much time needs to pass before you say it is no longer a remission but indeed a cure.  In CLL we have never really talked about cure before, so I guess the answer is "a long time."

When carefully identified patients are treated with FCR chemo-immunotherapy, a decent fraction of them may not have any evidence of their CLL for over a decade.  Two studies have now shown statistical outcomes to suggest that some of these patients may be cured (link here and here).  

Frequent readers of my blog likely know that I have periodically taken a skeptical view of the FCR regimen.  The multitude of new drugs such as ibrutinib and idelalisib have forced us to fundamentally re-think the best ways to treat the disease.  After the widespread introduction of bendamustine and rituximab followed by the newer agents, the enthusiasm for FCR has been steadily diminishing.  Database analysis would indicate that it is only utilized in the front line management of patients with CLL in about 20-35% of patients,

I think it is human nature to embrace things that are new and exciting - especially when that means moving away from chemotherapy.  Yet as pendulums swing away from FCR 14 years after it was initially introduced, we may be ignoring some of the most impressive arguments in favor of the regimen that are only just now becoming evident. 

The "chemoimmunotherapy regimens" such as FCR and Bendamustine-rituxan have constituted our treatment backbone for a number of years.  Please see my prior blog post about choosing between the two.  With the new non chemotherapeutic targeted drugs that are coming, there is likely to be quite a "turf war" over what regimens are right in which circumstances.  While the new drugs are primarily approved in patients with relapsed disease, there will be considerable interest in moving them to the front line setting.  Indeed, I've already had quite a few patients ask me if starting with one of the new drugs up front makes more sense than chemotherapy.  I think that in some cases the answer may be yes, in other cases no.  In many cases it is too early to tell.

So where is all this going?

CLL is biologically heterogeneous.  Two patients who look very similar can have very different outcomes with treatment.  Understanding that biologic heterogeneity is essential if you want to make the best choices on behalf of the patient.  At the extremes, I think there are some patients where we need to make every effort to give effective chemoimmunotherapy and others where starting with a targeted agent makes more sense.  Between those two extremes there is a lot of uncertainty.  Over the next several blog posts, I hope to make that spectrum clear.

Let me start by coming back to the question that I began this post with:  If you could get six months of chemotherapy and have 10 years free of disease and not require any treatment, would that be better than taking pills every day for ten years?  What if I upped the ante and asked if that same six months of therapy cured a decent proportion of molecularly defined patients?  Would chemotherapy be preferable to pills in that circumstance?   What fraction of patients would need to be cured?  Would 20% be enough?  What if it was 60%?  If 80% could be cured, would that make chemotherapy better than pills that are not thought to result in cure for anyone (yet)?

Let's start by defining "cure."

When we evaluate the performance of a new drug or a regimen, we plot the efficacy on a "Kaplan Meier" curve.  On the "Y axis (up and down)" is a variable such as overall survival, or progression free survival.  On the "x-axis (left to right)" is time.  At time point zero the curve should be at 100% but then it keeps going down every time someone has an "event" such as disease progression or death.  If a disease is really bad or a treatment really ineffective, the curve goes down very quickly toward the  x-axis.  If a disease is mild, or the treatment very effective, the curve stays very "flat" and doesn't drop from 100 much. 

People who look at Kaplan Meier curves a lot get really excited when they see a "plateau."  A plateau happens when you do some sort of treatment that is likely to cure a subset of patients.  As time goes on, all those patients who are not cured either relapse or die until you are left with those patients who no longer have the disease and the events stop happening.  When this happens, the curve may start at 100, slowly drop down to the percentage of cured patients (20%?-40%?) and then stays flat - or reaches a "plateau."  If a plateau persists with updates of the data, researchers start to ask if those patients who are no longer relapsing are cured of their disease - particularly if you test them with MRD testing and they remain negative for CLL.  Of course if you follow all patients long enough, it will always go down to zero as patients die of other causes, but few studies follow patients that long and a prolonged plateau is suggestive of something very important when considering a treatment.

At ASH 2012, the MDAnderson group put out an abstract entitled, "Is CLL still incurable?"  This provocative question was asked in response to an apparent plateau in their long term follow up of the original 300 patient sample treated with FCR.  After following their original group of patients treated back in 2000-2003 for thirteen years, a group of them still appear to have no evidence of any active CLL.  That is a very impressive result for a therapy that only lasts six months.

Many researchers however regard data from MDAnderson with a degree of skepticism.  It says a lot about a patient if they get on a plane and fly down to Houston for an opinion.  It says even more if they do that every month for six months to get treated.  Such patients necessarily have a degree of affluence, fitness, and education that makes them different from the average CLL patient.  Multiple different studies have shown that such variables strongly influence outcome.  It ends up being a biased sample set.  Indeed, the average age of patients in the study was 57 years old while the average age of a patient requiring treatment for CLL in the United States is typically 74 years.  That is a massive difference.

I have to admit, I was somewhat dismissive of the 2012 abstract on that basis - until the Germans gave an update of the CLL8 study which compared FC (fludarabine / Cytoxan without rituximab) versus FCR and evaluated outcome on the basis of molecular risk factors.  They show that after six years of average follow up, several groups of patients start to achieve a plateau.  Over the ensuing two years of follow up, if a patient has not already experienced a progression, very few such patients appear likely to do so.

Is this a cure?  It is still probably too early to tell for sure.  All Kaplan meyer curves are prone to becoming "unstable" the farther out in time that you go.  Since fewer patients of the original cohort have been followed that long, single patient changes in status can have disproportionately larger effects on the curve than happens earlier in the follow up.  Furthermore, bias influences become larger if there is a subset of patients with "better" follow up data.  I am very interested though to see if this curve remains flat with subsequent follow up.  It appears to mirror the single center MDA experience but in a multicenter population where the data is more reliable.

So who are these patients? It is interesting to know after the fact that some patients do very well, but it is far more helpful if we know before selecting a therapy if a cure is within reach.  It would likely influence how you think about treating such a patient. 

I previously wrote a post about the mutation status of the B-cell receptor, so called IgVH mutation analysis.  The new update from the German CLL8 study did an impressive job looking at the multitude of new prognostic markers in CLL.  They showed that patients with unmutated IgVH (bad), had a substantially higher rate of other negative prognostic markers (such as NOTCH, SF3B1, TP53 mutations) compared to those patients with mutated IgVH (better) to the tune of about 43% vs 24%.  We also know from recent publications that newer technologies (next generation sequencing) can find a much higher frequency of adverse markers as it is a lot more sensitive to lower levels.  These lower levels appear to be very important because they appear to confer similar overall prognosis.  I wouldn't be surprised if "next-gen" could identify an even larger split between the IgVH mutated and unmutated groups.

Turns out that those patients with the mutated IgVH did MUCH better long term than those with unmutated IgVH.  Indeed if the plateau in their data holds, it may occur in as many as 60% of patients with mutated IgVH whereas no clear plateau is seen in patients with unmutated IgVH. 

Is 60% chance of long term disease control (maybe cure) good enough to take FCR?  It is abundantly clear that not all patients are sufficiently "fit" to receive FCR and NCCN guidelines draw the line for full dose FCR at age 70.  Are there other variables that you can look at to remove "bad actors" within this subset of better risk patients?  If you focus on the "good risk" patients with IgVH mutated BCR and then exclude the patients with 17P or 11Q or bad molecular markers such as TP53, NOTCH1, SF3B1 mutations what is the long term disease control rate in that group - certainly a lot higher than 60% - probably closer to 80-90% chance of long term disease control - possible cure in this subset of patients.

These findings are very similar to those seen by the MD Anderson group.  In their study just under 40% of patients had not experienced any progression at the 10 year point. If you look at the associated table however, it was strongly skewed in favor of those patients IgVH mutated BCR 49% vs 11%.  They did not have access to FISH or molecular markers so that information is not available.  I find it compelling though that the numbers were very similar between the two studies.  It is also interesting to note that the change in the shape of the curve occurred right around the 6-7 year mark in both data sets.  This implies that if you fit this highly favorable profile and make it that far out, your chance or progression over the next few years seems very unlikely.

The point I wish to make is this.  The new drugs are very "sexy."  It is very appealing to think of  taking a non-chemo pill rather than chemotherapy, but if I am ever a patient with CLL and IgVH mutated BCR lacking 17P/11Q/TP53/NOTCH1/SF3B1 abnormality, I will absolutely take chemoimmunotherapy because there is a VERY GOOD chance I will not have to think about my CLL for many years, and based upon these two studies, I think he plateau in the survival curve is very provocative.   

This blog post was originally intended to also talk about what I would do if I had 17P deletion, IgVH unumtated BCR, or other high risk markers but the post became too long and unwieldy.  I will tackle those possibilities in upcoming posts. 

Thanks for reading.

ASH 2013 Video WIth Andrew Schorr

This was a video we did at ASH in December prior to the approval of ibrutinib.  At the time, we didn't know the terminology the FDA would use to describe its "approval."

The main topic of discussion in this video is primarily how a patient goes about choosing a therapy in CLL.  In many cases patients will feel comfortable with a physician recommendation, in other cases they may want to educate themselves about all their options and make their own choice.

In the midst of new treatments like ibrutinib, idelalisib, ABT-199, Gazyva etc. that can be bewildering. Not sure if this video helps sort it out or not, but it is short and hopefully worth your time

Nutritional Supplements

This post was originally posted in February 2013 but I've read several recent articles that shed additional light on the topic so clearly that I felt an encore was necessary with specific links to the articles.  The original post was one of the most widely read on my blog so perhaps a re-post is in order anyhow.  I've added the links at the bottom of this article and embedded them in the text as well.



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Here is my original post:

I recognize how frightening cancer can be for a lot of patients.    One day you are cruising along in life taking care of business, the next day you are confronted with a life threatening diagnosis.  For many patients, it is a journey with unfamiliar terms, clouded along the way by scary thoughts of chemotherapy, illness, and death.

For some patients, fully embracing the health care system and trusting that it will provide the best care possible is too much to swallow.   Suspicion may even be healthy.  Does my doctor know what is best for my case?  Has my doctor adequately explained why we are taking the steps we are taking?  Add in the cost of getting ill and the craziness of navigating a broken healthcare system and just about anyone could go nuts.

In a situation that feels so out of control, I can completely understand why patients may want to take control of some aspect of their care.  In many cases that can be educating themselves to engage in the decision making, in some cases it may be traveling to see a “specialist.”  One of the more common manifestations I encounter is the use supplements.  I think self-treatment through use of supplements can often provide an aura of control that really appeals to quite a few patients or their loved ones.

Maybe it is because I practice in the Northwest where complementary alternative care competes with “western medicine” in the minds of many, but it comes up as a discussion point with the majority of patients I take care of.  I suspect quite a few patients never even tell me what they are taking.  Patients often bring the topic up somewhat sheepishly – as though they know they are doing something a “western” doctor would never endorse.

So let’s talk about what we know and what we don’t know and I will share my opinion.  I recognize this is a “near-religious” topic for many so I have no doubt I will offend a number of readers.  My apologies in advance – my intent is not to offend but to try to make sense of a topic that a lot of patients want to know more about.

Let’s start with the admission that EVERYTHING that we encounter is a “drug.”  Every so often, some uber-athlete dies in a marathon from drinking too much water.  Yes – water can be fatal!  If you sweat too much, lose a lot of sodium, and replace your fluids without the salt, you can have seizures and die.  Oxygen is clearly important, but give too much to a person with emphysema and their brain forgets to breath.  We are complex biologic organisms and things need balance.  Introduce ANY variable and the body has to adapt.  For MOST things we encounter day to day the body is up to the task – but start mixing lots of variables and sometimes you get unexpected results.

Another misconception is that if you are taking a “natural” product, it is somehow less likely to be harmful.  Interestingly several important chemotherapies came straight out of nature. Taxol was isolated from the bark of the Pacific Yew tree, adriamycin was discovered from soil samples near an Italian castle, and vincristine comes from the Madagascar periwinkle plant.  I’m not sure how that fits the idea that “natural” products are somehow safer than chemotherapy – in some cases they ARE chemotherapy.  While you may be tempted to conclude that naturopathic clinicians are therefore onto something, I would also point out that these compounds were then subjected to many years of intensive, focused research and clinical development that refined and re-refined the precursor compounds into validated effective therapies.  When you take one of these drugs, you know what you are getting.

There is also a near mystical belief that if it comes out of a culture that has practiced medicine for thousands of years it is likely to either be extra effective or maybe very safe.  Try telling that to thousands of Taiwanese who developed bladder canceror renal failure from Aristrlochia.  Before I sound too negative though, I should point out a favorable example too.  There is a rare form of very dangerous leukemia called “Acute Promyelocytic Leukemia.”  Perhaps the single most effective drug ever identified for this condition is actually arsenic.  Yes, arsenic has literally saved the lives of thousands of people.  It is approved for this use by the FDA – and guess where it was discovered…. traditional Chinese medicine.

So if we can agree that everything can be a drug, the lines between “natural” and “synthetic” are more blurry than we would like, and “traditional medicine” has its highs and lows I think most readers would agree that we are best off if we can really sort out fact from fantasy.

The sad reality however is that we know VERY LITTLE about the interactions between supplements and chemotherapy.  This link references a good description of the problem.  I wish there was a more rigorous scientific effort to understand these things but it has always been too close to “fringe science” for grant driven academic researchers to risk taking their careers.  Once you start publishing about astragalus effects in lymphoma, research funding may start to dry up.  There have been several laudable exceptions such as curcumin, resveratrol, and green tea, but unfortunatley very few of these have made it far enough for human clinical testing. Things can look very compelling in laboratory experiments but until you do the human subject testing you really do not know much at all. 

So let’s consider some examples that might surprise you.

Grapefruit juice should seem harmless enough right?  Actually grapefruit is one of the worst things out there for just about anyone who takes drugs.  Grapefruit shuts off a set of liver enzymes that are responsible for clearing drugs out of the bloodstream.  I remember hearing about a colleague’s patient on a cholesterol lowering drug who decided to go on a grapefruit juice diet.  Unfortunately this resulted in toxic levels of the cholesterol drug.  The subsequent muscle tissue injury caused kidney failure.  It is so well recognized that when companies are developing drugs sometimes the FDA mandates that they study the interaction with grapefruit juice (another reason drug development sometimes takes so long).

Most of us would agree that smoking is bad – but did you know that the metabolic byproducts of tobacco can mess with the same liver enzymes as grapefruit juice but in the opposite direction?  Ironically (and sadly) this can rev up the metabolism of drugs such as erlotinib which we use to treat lung cancer.  There have been some publications suggesting that smokers taking erlotinib need much higher doses to get the same effect as lung cancer patients who have given up on smoking. 

Green tea is quite the rage these days.  There have actually been a number of good quality studies that have looked into its anti-cancer properties.  The “polyphenols” contained in green tea may indeed possess important anti-cancer properties – but just like water and oxygen, context is everything.  Green tea also contains ECGC.  Unfortunately a very important drug for treating myeloma called bortezomib (aka. Velcade) gets metabolically inactivated by green tea.  Not too long ago one of my myeloma patients on velcade having a suboptimal response to treatment informed me that she had been started on Green Tea by a local naturopathic practitioner.  While I don’t know if it was the green tea or just a bad case of myeloma you can imagine how we all felt.  Other green tea supplements have recently been linked to liver failure.  

Take st. john’s wart for depression?  You might be particularly depressed if it causes cataracts or gets you a horrific sunburn.  More freightening still is that it alters metabolism of quite a few different drugs.

The point of these examples is to highlight the dangerous interactions between things that we might not expect to interact.   If we agree that we know very little about the majority of supplements, the interactions that we DO know about give me reason to be VERY careful putting unknown drugs into the system.  I believe these examples should give us pause before launching into a twenty supplement regimen to “strengthen our immune system.”

I know one very reputable academic doc with a fantastic career who simply refuses to take care of patients if they engage in using supplements during chemotherapy.  While I don’t go that far, I do tell patients it introduces a level of uncertainty and risk that I cannot predict.  I often tell patients to try to avoid supplements during chemotherapy though I don’t so much mind them doing whatever they want when chemo is not in the mix.  On the other hand, if it seems like a patient is going to be doing a lot of supplements no matter what I say, I may not offer them participation in a clinical trial.  It isn’t fair to blame unpredictable side effects caused by a supplement / drug interaction on a research medication.  It could potentially slow down the development of a lifesaving drug.

By now, I've blurred the distinction on natural vs non-natural, traditional vs western, side effects, interactions, and so forth - but that is just the start of it!  In the nutritional supplement business there is comparatively little oversight.  Supplement manufacturers do not have to submit their processes to the same regulatory scrutiny as traditional drugs.  There can be big variations in dose between different manufacturers - as if we even knew what dose mattered in the first place.  Add in a pretty sophisticated science in pill manufacturing which influences how much drug even gets into your system and it is really impossible to know if you are even taking what you think you are taking.

With all that in mind, I ask my patients to avoid suplements during chemotherapy.  I don't get all upset if they ignore the recommendation - some people are going to look at the same information and make a different judgement.  I tell patients they are paying me for my opinion.  After eight years in the UC system, three at Harvard, and three at Stanford, hopefully it is worth the money.  They can disagree with me and choose a different path but it isn't one I would take for myself. 

There are a few things about the "supplement industry" that irritate me and one that makes me extremely mad.

I occasionally hear the assertion that there is some enormous conspiracy to keep a cure for cancer under wraps.   Sometimes the drive for supplements has a distinctly "conspiratorial" overlay.  If there is a huge conspiracy I must really be a dope because I am smack dab in the middle of it and I had no idea.

Two things that bother me about the "supplement industry" are the ridiculously false claims you occasionally see or the claims that have some truth at their basis but takes it far beyond what the data supports.  Yes glucose is an important nutrient for cancer cell survival but you cannot really get your sugar levels low enough to kill the cancer without having a serious brain injury at the same time.  Yes pH is important but the body very tightly regulates pH so try making yourself more acidic or alkaline and you are either wasting your time or risking serious injury.

What really makes me furious though is the occasional exploitation of really sick patients.  I have seen a number of patients exploited by the “alternative care industry” when they are at their most vulnerable time.   Not a week goes by where I am not asked about some form of alternative care and some cost huge amounts of money.  Many times thesetreatments are dressed up to look like real science.  Sometimes I have a hard time at first glance sorting out the real from the fake but if I take the time, I can usually tell them apart.  

But what about the desperate mother of a dying child whose treatment has failed at the hands of “Western Medicine?  I can’t blame her for grasping for hope – but what makes me furious are the charlatans out there ready to take her money knowing full well they are selling crap (see this amazing 60 minutes documentary for point of reference).   

There are MANY well-meaning alternative care providers out there who try their hardest to help their patients and sincerely believe their interventions will help.  I am not writing about them.   My advice: if they are both recommending and selling the product - and it costs a lot - ask them where else you can buy it - and how the other products compare to theirs.  If the answer is “nowhere” or “the others are not as good” I would be concerned.

One last thought.  The American diet is truly awful.  I was shocked when taking a human anatomy class in medical school how fat we all are.  Even people who look "average" often have inches of goey yellow fat padding huge areas of the body.  Our fast / quick food culture undoubtedly leaves our bodies wanting something different.  I like to eat organic when possible.  I've watched Food Inc and realized that corporate agriculture introduces things into my diet that I want to avoid.  For me, eating at McDonalds is truly an act of desperation.

The first time "chemotherapy" was tried in children with acute leukemia should serve as a grave warning though about trying to replace "missing nutrients."  Sydney Farber - the American "father" of chemotherapy was studying pernicious anemia and had found that some patients responded to folic acid - a common additive in multivitamins.  His first experiment involved giving children with acute leukemia large doses of folic acid.  Unfortunately, this was a "missing ingredient" for the cancer cells and they immediately started growing faster and the children died.  Sydney almost got ran out of Harvard for it, but after deciding what he really needed was an "anti-folate" he started work on methotrexate -  a drug that we still use today.  60 years later the Dana Farber cancer institute in Boston still gives tribute to his early discoveries.

I need to wrap this up. 

I think a lot of patients or their loved ones seek out supplements to try to make a bad situation better.  Sadly, I think it is possible to accept some myths about alternative care and get yourself into a worse situation.  For most alternative care providers, I don't question their intent - most are good people who want to help.  Cancer is an incredibly savvy enemy though and I  believe there are extremely few magic bullets out there to be discovered amongst the supplement aisle.  If you are going to do supplements, it is probably safest to do it when chemotherapy is not in the mix.  If you are in watch and wait or some remission, it is probably fine in most cases - just beware that you can hurt yourself with supplements and the claims are not regulatred by the FDA. 

That is my opinion.

Herbal Supplements Are Often Not What They Seem

Herb-Drug Interactions in Oncology

The Quackish Cult of Alternative Medicine

Common US Supplements linked to liver failure

Watch and Wait (AKA: Watch and Freak Out)

Nothing can make a patients head spin faster than the two juxtaposed statements, “you have cancer” and “we’re not going to treat it right now.”

Huh?

“Watch and wait” has been a mantra for patients with asymptomatic CLL and indolent lymphoma for quite a few years and sometimes no explanation is enough to comfort a patient who is understandably worried about their new diagnosis (see: when to treat CLL, choosing first treatment in CLL, and how I treat follicular lymphoma part 1).  Quite a few people have dubbed this “watch and worry” instead of watch and wait.  There is an avalanche of messaging out there about early detection and early treatment saving lives in so many cancers that watch and wait can sound more like medical quackery than good science.  For some patients, taking a nutritional supplement and avoiding chemotherapy is an easy sell – but for others, the thought of living with untreated cancer is too much.The short answer is that CLL and low grade (indolent lymphoma) are different than a lot of solid tumors – but this blog is about the long answers – so here goes.

Historically, the argument in favor of watch and wait was that our treatments did not impact overall survival – so why take chemotherapy unless you needed to get rid of some bothersome symptom.  We would argue that chemotherapy was a steep price to pay if it didn’t do you any good in the long run (see risk stratification in CLL).  Admittedly, those conclusions were based on studies from the 80’s and 90’s that used fairly ineffective treatments or drug combinations with moderate to significant side effects of their own. 

But science continuously evolves.  Several recent studies have shown that IF you are going to treat CLL, certain treatments may improve survival compared to others (FCR better than FC, Fludarabine better than chlorambucil).  While this later observation does not indicate that treatment is better than NO treatment, now that we know we can improve survival with some of our treatments those old assumptions need to be retested.

In follicular lymphoma (which is a model for many of theindolent diseases), an ongoing study already presented at ASH compared rituxan to observation.  Not surprisingly that has shown that patients who get rituxan are generally able to wait longer until their next treatment compared to the folks who were randomized to observation – not necessarily an earth shattering observation.  Whether this approach influences how long patients actually survive remains to be seen as that will take quite a few years for the study to collect data.  While the data from that study continues to evolve, others have pointed to the SAAK study in which eight doses of rituxan were given over nine months (weekly x4 then every other month x4) and note that nearly 40% of patients have not required any more treatment over the next ten years.  It is possible that early intervention may be better, but we really still do not know.  I suspect the data will look different from those old studies now that we are using drugs like rituxan that are both effective and well tolerated – but whether that means you live longer has yet to be seen.

In CLL however, single agent rituxan doesn’t pack the same punch as it does in follicular lymphoma.  There is less of the CD20 target on the surface of CLL cells than there is in follicular lymphoma.  Furthermore, CLL has some tricky ways of lulling T cells to sleep (anergic).  Interestingly revlimid may help wake those T cells up (not FDA approved for this indication and should be done very carefully as there have been reports of tumor lysis syndrome).

Along comes a new paper though that I think has profound implications on how we thing about managing ANY of our patients with ANY lymphoid cancer.  I’ve written several times on clonal evolution (here and here) because I think CLL highlights this principle better than just about any other cancer and may actually have lessons for metastatic breast cancer or other solid tumors.  I realize that I’ve probably been trying to write about watch and wait in these posts but never really put it into the right context – so here goes.

Consider the following hypothetical experiment.  You are welcome to try this at home though I would not recommend it.  Plant a lawn but make sure you have a few weed seeds included in the mixture.  Let that lawn grow but resist the temptation to pick the dandelions.  Once you have a nice back yard scattered with a few weeds here and there go down to Home Depot.  Pick up a big bottle of round-up and spray your entire back yard.  Make sure the entire lawn is covered well enough so that you will have a completely brown mess in two weeks.  Now wait……

Ok, so you have waited twelve months without doing anything to the brown mess.  Go out back again and tell me what is growing.  Is it a lush green yard with a few scattered weeds or is it a mess of ugly weeds.  Chances are, you will have a bunch of mutant dandelions that have totally taken the place over.

In SOME cases – that example MAY illustrate the effect of chemotherapy on CLL on the “clonal architecture” surviving cells.  In evolutionary biology terms, we may refer to effective chemotherapy as a “mass extinction event” – think asteroids and dinosaurs.  Any time you have a mass extinction event in a biologic system you may see “survival of the fittest” play out right in front of your eyes.  In our example above, the reason the dandelions didn’t run amok before the round-up was that there was a lot of grass competing for the soil, water, etc.  You could say that the grass was the dominant (incumbent) clone holding the dandelions back.  Once you cleared out the grass though, the weeds had plenty of room to take over (boy with weed and grass both in this post – really curious to see what sort of google searches land on this page).

In this prior post, I highlighted a paper that followed a single individual at several time points and showed how there were three separate subclones at the time of diagnosis.  Before FCR chemotherapy there was a small subclone (1% of total cells) with a bad mutation.  After chemotherapy, that clone which was the “fittest” took off and became the dominant clone and ended up being the one that caused the patient to pass away.  This example has been replicated in a few other papers too so I think it has some validity to it.

Now – it is really important to stress the things we DO NOT KNOW.  If we go back to our analogy of the backyard, would we expect the dandelions to take over if we used napalm instead of round-up?  What if we just turned on the hose and let it flood the backyard for a month – would that select for the dandelions?  Or is it possible that may cause the crabgrass to run wild.  Perhaps we could just put a bunch of biblically hungry locusts in the back yard.  After they ate everything in sight – maybe it would be the grass that came back instead of the dandelions or the crabgrass.  In other words – does the nature of mass extinction event select for different types of “fittest” to come back?  Maybe the extinction has no bearing on what comes back in some cases.  Put into chemotherapy terms – does bendamustine have different outcomes for clonal selection than fludarabine?  Is rituxan different than chemotherapy?  Do the new drugs like ibrutinib and idelalisib have any effect on clonal selection?  We DON’T KNOW the answer to that question BUT we do know that treatment DOES exert a selection pressure on cancer cells and gives me an argument to consider “watch and wait” that I believe is more sophisticated than just saying, “our treatments don’t keep you alive longer.”

I often tell patients, “bad” may be a good enemy of “worse.”  Yes, having indolent lymphoma or CLL may be a bummer, but it may be better than having a super mutant, chemotherapy resistant, transformed beast come back at you.  I have often been puzzled by studies that show a dramatic improvement in “progression free survival” that have zero impact on “overall survival.”  In other words, treatment “x” does a better job keeping your disease away than treatment “y” but ultimately you both pass away at the same time – huh?  Maybe the better treatment is beating the disease back further – but also selecting for a more resistant set of cells to come back when it does come back.

In the paper I referenced above that shows how “clonal architecture” can change over time, one of the most interesting findings to me was that the presence of a “subclonal driver mutation” generally predicted for a shorter remission duration and the emergence of resistance.  “Subclonal driver mutations” are a lot of the bad markers we’ve been describing in other posts such as BIRC3, NOTCH, SF3B1,P53 etc. but that these mutations are in a very small population of the cells.  In other words, you may only have 3% of your cells that are really smart (ie P53 mutated) and 97% of your cells that are generally dumb (del 13q), but that 3% of cells are the dandelions.  Your chemo may make your numbers look a whole lot better and even make you feel better, but now you’ve traded the devil you know for the devil you don’t know – and that second devil might be really nasty.

Newer sequencing technologies are about to enter the clinic and help us find these “subclonal driver mutations” with vastly better skill (though there will still be limitations on how well we can look).  I HYPOTHESIZE (though this is absolutely conjecture and should not be taken as settled science) that in 5-10 years knowing the full clonal architecture will influence our recommendations surrounding watch and wait.

With all this in mind, I think it is easy to take the "watch and wait" strategy too far.  Some folks will do anything possible to avoid treatment and get themselves into a deeper hole than they need to.  Sometimes with a slow disease, it can feel like you can just wait it out a "little bit longer."  For low grade lymphoma there are criteria for treatment.  In CLL, I've written about "when to treat" which is my summary of the IWCLL guidelines.  The caution here is that you can get yourself a lot sicker than you need too if you hold things off for too long.  I would wager that it is even quite possible to feel a lot sicker from the disease than from some of the treatments available.  I've seen quite a few patients literally feel A WHOLE LOT BETTER after starting treatment that they had delayed longer than they should have.

So a few key take home points

1)      Watch and wait was historically based on ineffectiveness of therapy

2)      Newer treatments have led scientists to revisit #1 but the answers are not in yet

3)      One risk of treatment is the emergence of resistance but not all patients experience this

4)      We may be able to begin measuring a patients risk for resistance based upon “subclonal driver mutations” soon

5)      To date, we do not have much insight into what sorts of therapies influence emergence of resistance

6)      Watch and wait is not crazy in appropriate patients – there may have been benefit to it for a long time that we are only just now starting to figure out.

7)    Patients should not wait too long otherwise they just feel lousy when they could have been feeling better with treatment.

Thanks for reading

Selecting a therapy in CLL

CLL is unique because there is often a significant lag in time between when the diagnosis is made and the first treatment is needed.  Since complete blood counts (CBC's) are fairly routine, and CLL sticks out like a sore thumb, patients can often watch their disease for a long time before needing to start on treatment.  This can create a dangerous "paralysis by analysis" situation where careful consideration of all options leaves a patient unable to decide on what to do - the downsides of ANY treatment can look really big when they are staring you in the face.

When it comes to treatment decisions, I need to make one an argument for "watch and wait."  We are so conditioned to believe that early treatment improves outcomes in cancer that watch and wait feels very counterintuitive.  I have been really struck by several recent publications that evaluate "clonal evolution" in CLL.  I've written about them in two prior posts linked here and here. 

I could quickly sumarize by saying that CLL may start as only one clone, but it can often give rise to several clones over time.  If some of the clones that evolve over time are "smarter" (ie. have chemotherapy resistance, faster growth, predisposition to transform - see my post on the "new markers" and "CLL Prognosis") - it may be to your advantage to leave the "stupid" clone alone.

Treatment often eliminates the "stupid" clone and gives more room for the "smarter" clone to take over.  In CLL, we take it for granted that high risk markers like 17p, 11q, BIRC3, P53 mutations are more common in relapsed disease.  What we haven't considered until recently is that our treatment may be selecting for these higher risk markers.

So I am a big fan of "watch and wait" until treatment is needed.  Please see my post on "when to treat CLL" for more of a discussion about when watch and wait is no longer indicated.

But sometimes - we can't wait any longer.....

I've had a fun time serving on a leadership team for a large registry study called the "Connect CLL Disease Registry" sponsored by Celgene.  Other leaders on the study include Neil Kay, Michael Keating, Ian Flinn, Mark Weiss, Nicole Lamana, Chris Flowers etc.  We've collected a lot of data about how patients with CLL are treated throughout the United States.  We've reported some of our data at American Society of Hematology but we've really only just gotten started. 

In the United States, most patients treated off of a clinical trial are going to receive either FCR (Fludarabine, Cyclophosphamide, Rituxan), FR (get rid of the cyclophosphamide), or BR (bendamustine, rituxan).  Chlorambucil is a respectable option for the elderly population with other medical issues but is generally reserved for patients you just can't treat with chemotherapy (editorial - I think chlorambucil is underutilized as a treatment option in elderly patients - just telling you what the patterns are out there).  There is also a surprising amount of single agent rituximab use out there. 

Thus far, there have been NO PUBLISHED REPORTS that compare FCR to BR in a prospective randomized study (Gold standard for evidence).  The study is being done by the Germans but we don't expect data from that study soon.  Chaya Venkat did a very thoughtful evaluation on her blog CLL Topics looking at the data from the single arm phase II study of BR in the front line.  I would direct the motivated reader to her post. 

To be very clear - when evidence is lacking - opinion abounds.  Right now in 2013 we do not know what the best front line therapy actually is.  FCR has been the leader of the pack for a number of years, but there are a lot of reasons FCR isn't always the right answer for all patients. 

Without a clear answer - opinion is fair game - I will share mine.  My first choice for therapy is to consider participation in a clinical trial.  That is the "standard answer" in the NCCN guidelines, but it is more true in CLL today than just about any other disease.  New investigational treatments like ibrutinib, idelalisib, GA-101, ABT-199, TRU-016 are exploiting the biology of CLL and bringing forward a new generation of treatments for patients with CLL that are currently only available in clinical trials.

The Germans have wonderful terminology that segregates patients into different groups of patients called the "go-go" population, the "slow go" population and the "no go" population for the patients who are young and fit vs the patients in whom you need to have more caution, vs the patients that have a ton of medical issues and the goal is to do no harm.  They use a tool called the "cumulative illness rating scale" aka CIRS which has actually been around for quite a few years but gives you a tool to mathematically quantify how many medical problems other than CLL a patient has.  The sicker you are - the less intensively you can treat the CLL.

I look at a patient and ask myself if they are "fit" for a fludarabine based regimen.  Fludarabine is a good drug - but it has some potential draw backs.  It is cleared by the kidneys, so if the kidneys are less than ideal - problems start to increase.  Since kidney function declines with age, and CLL is more common in the elderly, the kidneys often guide my decision making.  Kidney function can be measured by the "creatinine" which is a standard measure on a chemistry panel.  Take age, gender, creatinine and you can calculate a "glomerular filtration rate" or GFR.  When that number dips below 60, my caution level goes up quite a bit.

So what problems can fludarabine cause?   It can lower the immune system, cause prolonged supression of the bone marrow, and worsen a hemolytic anemia.  Therefore, in a patient with bad lungs from smoking (COPD) who has had pneumonias, has a GFR well under 60, or maybe already has signs of the immune system attacking the red blood cells or the platelets - I avoid fludarabine based chemo and lean toward bendamustine based treatment.

If a patient is "fit" for fludarabine, the choice is either FR or FCR.  There is no question that the addition of the cyclophosphamide adds a punch - both to the CLL and to the patient.  The Germans have published a study looking at F vs FC (pre-rituximab era).  This was also studied in the US by the Eastern Cooperative Oncology Group.  The English also looked at this in the CLL4 study.    The English did a good job looking at biomarkers in their effort and came to the conclusion that patients with the 11q deletion did a better when they had the cyclophosphamide added to fludarabine.  There has been some debate whether the cyclophosphamide is necessary in the absence of 11q deletion.  I tend to reserve it for the particulary fit younger patient or the patient with the 11q but I acknowledge this is an opinion and there are plenty of bright CLL docs that would disagree and give it more broadly.  It goes without saying that any regimen would include rituxan as shown to us by the German CLL study group. 

If a patient is "unfit" for a fludarabine regimen the decision in my mind comes down to Bendamustine versus chlorambucil.  Bendamustine is more effective than chlorambucil but perhaps a little more intensive.  Bendamustine does not require the kidneys for elimination - so when GFR is a little lower, this can be a good option.  For an elderly patient, chlorambucil may still be a good option and should not be disregarded completely.  Our patterns of care study indicated that it is the treatment decision of only about 10% of patients over the age 75 and much less common in younger individuals.  If I give bendamustine, I virtually always give it with rituximab.

There are some special populations to consider.  The biggest one in my mind is the 17p deleted group.  We know that cells with the 17p deletion don't respond well to DNA damaging chemotherapy (FCR, BR, etc).  I always want to know, "how many 17p deleted cells they have?"  Keep in mind that FISH testing gives you a rough percentage of cells with a particular marker.  A patient with 5% 17p deleted cells is very different to me than a patient with 85%.  The first patient is likely to respond reasonably well to treatment but relapse earlier with a disease that is predominantly 17p deleted.  The latter patient is likely to respond very poorly to FCR (short duration of response or limited response at all).Pretty soon we will also be looking at SF3B1 and BIRC3 in this setting and asking the same questions.

For a patient with a large population of 17p deleted cells, there are regimens out there now that use high doses of steroids in combination with either rituximab or campath.  We know that campath is one of the few drugs that largely ignores the 17p deletion status but it is not a drug that is easy to use.  It definitely lowers the immune system quite a bit and you need to be careful about infections with things that you don't always consider (PCP, CMV, shingles, etc.).  Most docs who use campath give preventative antibiotics for each of these - which can definitely be a mouthfull of pills.  Campath has recently been taken off the market - but you can still get it.  It is a little cumbersome (ie. given three times per week for 12-16 weeks) but it can be quite effective in this setting.  Frankly, if I can buy a patient a year or two without really messing up their genome, I think I will be able to get them some of the research drugs that appear quite effective against 17p deletetion CLL including ibrutinib or ABT-199.

Of course, not many patients are appropriate for allogeniec stem cell transplant, but these might be the folks.  I am also really intrigued by the "engineered T-Cell" therapies being developed that may be a good option for these patients that don't respond well to typical chemotherapy.

That is the basics of my thinking for patients with untreated CLL that need some form of treatment.  This is no substitute for the advice of your own doc, but at least how I think through the issue.  There are a number of modifications to what I wrote that would be entirely acceptable.  With any luck this will all be outdated in a few years as new options come on line. 

 Hope that helps.