Personalized Medicine - turning drug development upside down!

American Society of Clinical Oncology is meeting in Chicago this weekend.  That means that you will be hearing about a bunch of important developments in cancer medicine. 

I am very fortunate to serve as the medical director for the US Oncology Hematology Research Committee.  Leading the largest network of community practice based research sites in the world gets me access to senior leadership of many of the major pharma companies.  Spending a day with the decision makers at Novartis, Genentech, Celgene, Janssen, and Gilead makes it pretty clear what will be happening in the next several years for patients with CLL/NHL (see posts about why it takes so long and costs so much).

So what is making me so excited?  I think I can now say that drug development is getting turned upside down.  We are entering a new era where therapies are rationally designed and deployed.  This creates hope for treatments that are far more effective and far less toxic.  That "double benefit" is part of the enthusiasm behind drugs like ibrutinib, idelalisib, and the antibody drug conjugates.

If you are not aware of the book, The Emperor of All Maladies I highly recommend you purchase a copy of it and read it cover to cover.  It was written by one of my classmates from residency and was awarded the Pulitzer Prize.  The book details the history of cancer medicine in a way that keeps you awake and burning through the pages.  I gave a 4 part you tube lecture series that is a broad overview of the book that doesn't do justice to Sid's book, but can hit the highlights pretty quickly.  Furthermore, my version is probably a good antidote to the insomnia you are suffering currently that has you reading my blog in the first place.

One theme that comes out clearly through the book and is forcefully validated in all of my pharma meetings is that the old way of developing drugs is running out of steam and a new era is starting to take shape.

So what is the old way?

In the old way, you might take a "compound library" which was merely an inventory of random chemicals.  Sometimes these came from sources like the pacific yew tree or the indian sea hare (not kidding).  You then grew some cancer cells in a laboratory dish and looked to see if you would wipe them out with your chemical of interest.  If that worked, you gave it to mice.  If the mice died from cancer - you abandoned the effort.  If they died from the horrible toxic brew that you just gave them, that was a bad sign too.  If the mice somehow survived the treatment and you saw ANY improvement in the mouse's survival - you took it to a phase I clinical trial.  In the old model, the likelihood of deriving clinical benefit in a phase I trial was less than 5% and many ethicists debated if such trials were fair to the patient.

Provided you could demonstrate that you could get the drug into patients, you then tested it on just about every type of cancer there was.  If you got lucky, most patients survived the treatment and you saw a few cancers shrink.  If that was "successful," you then did a randomized phase three study in a population of patients with a specific type of disease (perhaps you had seen patients with breast cancer respond in earlier studies).  You crossed your finger that the patients treated with drug x did a little better than patients with drug y.  If that difference was big enough, or you proved it in a large enough sample of patients.... you had a drug.

I am sure I have just thoroughly offended a bunch of medicinal chemists and drug developers with my grossly oversimplified version of the story - but that was the general theme.  There is a reason why people dread cancer so much.  For years, we made a bunch of drugs toxic enough to wipe out the cancer cells but often wiped out the patient in the process.  Provided the patient was able to get through the process, they might have been marginally better off for going through it.... feeling miserable the whole time.

The whole process was very empiric.  It wasn't based so much on good science as much as it was the remarkable strength of so many patients who wanted to live a day longer no matter what the cost.  I call it a "drug led process" meaning we had drugs - we didn't necessarily know why they should work, or who they should work in - but give it to enough people and you could often figure it out.

What is the new model?  I think we are entering a "diagnostic led" era.  Some have called this "precision oncology" others have called it personalized medicine.  What it means is that we are leaving the "drug led" process into a "diagnostic led" period.  We are several years into a remarkable transformation in cancer medicine that is only picking up speed.  We are matching drugs the appropriate mutations and doing a vastly better job helping patients live longer - WHILE FEELING BETTER!

The human genome project has unleashed an unbelievable set of discovery tools in cancer medicine.  This gave way to the cancer genome atlas which has systematically categorized the fundamental causes of a bunch of different cancers.  Now you can go to a single webpage like COSMIC (which stands for catalog of somatic mutations in cancer) and look up a single type of cancer and figure out what the important mutated genes are.

What you find is that there are really only a small handful of really bad mutations that cause a bunch of different types of cancer and the same mutations crop up in a bunch of different diseases.  Mutations in RAS, B-RAF, P53, Notch and others keep popping up just about everywhere you look.  In total there are about 100-150 really important targets (out of a genome of 4 billion base pairs).

If you take a disease like lung cancer - just a few years ago we looked into a microscope and said it was either small cell lung cancer or non-small cell lung cancer.  By the time I was in medical school, it was helpful to figure out if the non-small cell lung cancer was adenocarcinoma (gland like) or squamous cell (like the skin).  By todays standards that would be grossly insufficient in many cases.

Today you have to know their RAS mutation status.  If that is negative, you might like to know if their EGFR is normal or not, their ALK translocation status, and maybe even their ROS status.  If they are EGFR mutated, you need to know where the mutation is because exon 19 mutations might be predict sensitivity to erlotinib but T790M mutation mean erlotinib won't work yet afatinib will. 

This story is evolving right in front of our CLL focused eyes with a new understanding of ibrutinib resistance and a bunch of other unique prognostic markers / mutations.

At the same time a bunch of the new drugs may inhibit several of these important enzymes with a single drug.  Take a drug like gleevec (imatinib).  This drug inhibits the key protein in chronic myelogenous leukemia, but it also inhibits different enzymes that drive the growth of some intestinal cancers, skin cancers, and even rare melanomas.  In fact, the drug is approved in 10 different cancer settings where it is truly revolutionary in most of them.   

So we have two parallel developments going on at the same time.  We can find out what makes a patients cancer actually tick and in many cases we can give a drug unique for their profile.  That is personalized medicine and it is happening now.  Today my organization announced a joint effort with a company called Foundation Medicine to do tumor profiling on thousands of patients in order to get them into appropriate clinical trials.

So why is drug development "upside down?"

The traditional model to get a drug approved was to test it in a bunch of patients with a single disease and hope it worked.  Now we can find patients with specific mutations (regardless of what sort of cancer they actually have), give them specific drugs and the results can be dynamite.... but there is a problem.... a bunch of these mutations are uncommon in a single disease (2-10% of cases) which makes it REALLY HARD to do the sort of clinical trials to prove a point.

Let me give an example.

I was taking care of a patient with multiple myeloma.  He had some of the truly most awful myeloma I've ever seen.  His disease was way off the charts in terms of severity.  He didn't respond to two different types of powerful treatment.  Finally a super potent regimen got him into remission.  He got a stem cell transplant and within two months his disease was exploding once again.  In the process, he fractured several bones, became virtually bedbound and slept 16-18 hours per day. 

I was able to get him tested with one of these fancy diagnostic tests and found he had a specific mutation that is only seen in 2% of all myeloma cases (not going to say which one because the next part of the story gets a little more adventurous than I would typically recommend).  Amazingly there is a drug approved by the FDA for a totally different cancer that targeted his particular mutation.  Even more amazingly, I was able to get his insurance to cover the drug. 

His response was unbelievable.  His blood markers rapidly improved, his transfusion dependence ended, he felt better, he was able to get back to doing home repairs, etc. He survived several extra months, feeling MUCH BETTER (until the cancer came back in his brain where the drug couldn't get to).

So here is the challenge.  An individual patients cancer may have a small and unique number of critical mutations that make the disease grow.  Another patient with the exact same type of disease has a different set of mutations.  Take 100 patients with the same disease and you begin to see patterns to suggest that there may only be 10-20 important mutated genes for a single type of cancer  and 2-4 important ones for a single patient.

The challenge is that they can be in various combinations for different patients - but fortunately a drug from an unrelated type of cancer might work provided the right mutation is there.  Instead of studying a single disease to get a drug approved - we need to study a single mutation in a bunch of different types of cancer.  For a bunch of reasons that is really hard to do but companies like Novartis, Seattle Genetics, and Genentech are starting to figure it out and that makes me really excited.

Now we have tests that can tell us what an individuals profile is and in many cases we have research drugs that might work in their unique profile.  We are no longer in a "drug led" era but we are in a "diagnostics led" era.  We can make a pretty informed decision about what sort of therapy might work in a particular patient - even if we have to borrow a drug from melanoma or kidney cancer to treat a patient with leukemia.

I hope I've made this complicated subject actually make sense.  If I've failed, I encourage you to pick up a copy of "The Emperor of All Maladies" - Sid is far more clear about the subject than I am.

Thanks for reading.
Jeff

Finding a clinical trial

I use the website clinicaltrials.gov almost every day.  It is something I turn to so frequently that I periodically have to catch myself when I explain it to a patient because it isn't completely obvious how to get a good search result.  I thought I would offer a small tutorial.

The trick is to make a search narrow enough to find what you are looking for without getting overwhelmed by the tidal wave of possible studies.  The second task though is a lot more challenging - figuring out the good studies from the bad ones.  That is a lot harder and often something good to review with your own doc or other patients who are aware of the trial.

Step 1: Go to the webpage clinicaltrials.gov

Step 2: Bypass the front page and go directly to the "advanced search" which is a hyperlink immediately beneath the search box (or click my hyperlink)

Step 3: Enter your search terms - this is where you want to be able to focus your search so there are a few hints.

a-  For search term, I like to either use lymphoma or chronic lymphocytic leukemia.  If I don't get the results I am looking for, I might further clarify, "follicular lymphoma" or "diffuse large B cell lymphoma."  Sometimes you may wish to enter trials for a specific drug like ibrutinib or idelalisib.

b-  On the recruitment tab - I normally recommend clicking on the "open studies... recruiting." Expanded access studies are typically only open for a brief window between the time it becomes clear that a drug is going to gain approval and when it actually gets approved. Those may be available soon for both ibrutinib and GA-101 (obinituzumab).

c-  On the "study type" tab - you pretty much want the "interventional" option - i.e. it has a research drug.  This can cut down on some of the excess studies.

d-  Narrowing down the states you would be willing to travel to can also help a ton.  While some Oregon patients are going to be mobile enough to get to Texas for a study - many wouldn't consider doing that for a study that requires an infusion once per week.  On the other hand, if you live in western Massachusetts, it is pretty easy to get to a lot of major medical centers with a relatively short drive.  While "top flight" medical centers (MD Anderson, Dana Farber, Mayo) are always likely to be loaded with studies - they can be slow centers to activate a trial.  Don't exclude the community practice site with an affiliation to US Oncology or Sarah Cannon.  Major pharma likes those centers because of their speed of opening studies.

That should normally get you to a list that isn't ten pages long.  The next task though is to figure out if any of the studies might fit your situation.

a-  The biggest distinction in this situation is trials for previously untreated patients versus patients with relapsed or refractory disease.

b-  Next- ask yourself it is a randomized trial - if it is randomized, are there any placebos in the study  - randomization is most common in phase III, but can happen in phase II.

c-  What phase is the study
        1. phase I studies are about finding out the safe dose
        2. phase II studies are about figuring out if the safe dose has any meaningful efficacy
        3. phase III studies are whether the new therapy is any better existing therapies.


Once you find a list of studies, and you have figured out if you fit one or two of them, then figuring out if it is a good option for you is the hardest part.

a-  It helps here to talk to people who have been on the trial.  Chat groups like cllforum.com or lymphoma.com can be very helpful in this situation.  You can often find people who have already tried the drug and know what it is like.

b-  Your doc may or may not be all that useful - sadly.  A lot of docs are simply unaware of the incredible advances in CLL/NHL.  I've put together a list of a bunch of good ones who may be better able to guide you than others (ACOR is another great source).
      1.  It may depend upon what standard options you have available
      2.  It may depend upon what you have already had
      3.  It may depend if the new drug has a totally different mechanism of action

c-  When you look at the list of studies and the sites available, often there is a contact person.  Don't hesitate to actually contact that person.  Often they can tell you if a visit would be worth your time.  The docs participating in the study should be able to help you figure out if it is a good option for you.

Anyhow, those are some of the things I think that can help you figure out if a clinical trial is available for you and whether you want to go for it.

Medicare killing personalized medicine....?

Just when you thought we might see some enormous breakthroughs in CLL/NHL molecular testing (see my posts on CLL prognosis, prognostic marker definitions, molecular prognosis in DLBCL) Medicare comes along and squashes progress....

Two recent articles by Scott Gottlieb spell out how new molecular tests get started and the important role Medicare plays in setting policies that apply to ALL insurance (yes - even if you don't have medicare, when they make a change, so does Blue Cross etc)

Medicare Has Stopped Paying Bills For Medical Diagnostic Tests. Patients Will Feel The Effects

Medicare Nixes Coverage For New Cancer Tests

 
In CLL, we are on the cusp of new molecular testing strategies that will help inform the optimal treatment for an individual patient, clarify their prognosis like never before, and even help identify patients where watch and wait may be a particularly beneficial strategy.

When Medicare makes a ruling, it can be very difficult to turn things around unless patients step up and make noise.  Not sure how this one will play out in the end but hopefully such testing will be able to move forward.

Inotuzumab sinks....

Inotuzumab flops in DLBCL

I am very excited about a new class of investigational therapies called "antibody drug conjugates (AKA. ADC's".(see my prior post on these fascinating drugs).  In essence these are "smart bombs" compared to old school chemotherapy that goes after just about everything. 

An ADC is an antibody loaded up with powerful chemotherapy.  Once infused, the expectation is that the antibody will help deliver the chemotherapy directly to the tumor cells sparing healthy tissue.

Scientists have been playing with this concept for many years.  In fact Paul Ehrlich initially proposed the idea in the late 1800's before we even knew that antibodies existed (visionary!).

The first drug ADC approved was myelotarg for acute myeloid leukemia (a much more aggressive disease than CLL/NHL).  Unfortunately, the drug had some significant side effects including liver damage and the drug was pulled off the market although recent studies may bring the drug back to life.

The team at Seattle Genetics extensively studied the science of how to use an antibody to deliver chemotherapy specifically to cancer cells and came up with brentuximab.  This has been a quantum leap in the management of Hodgkin's lymphoma.  Once the science of the linker and chemotherapy was solved - solving a new disease was simplified to finding the right surface marker on the cancer cells.  That is a science that is pretty advanced in CLL/NHL and now a host of companies are developing drugs in these diseases.

Genentech just got another such drug approved in breast cancer called traztuzumab-emtansine (T-DM1).  This is a big step forward in patients with breast cancer and a particular marker on the surface of the cancer cells.

Meanwhile, Pfizer (who made myelotarg) continued development using the "myelotarg technology" but turned their attention on B cell cancers.    Inotuzumab used a different antibody but the same drug and "glue" (the linker that attaches the drug to the antibody).  The drug looks very active in acute lymphoblastic leukemia and development continued in DLBCL.  Unfortunately - in a press release out today it looks like the drug failed to improve outcomes sufficient to justify continuing the trial.

We are fortunate however that a number of companies have seen the success of brentuximab and are looking to make their mark on B cell cancers.  I can think of about a half dozen drugs that are being studied in NHL. While inotuzumab didn't pan out, I think it used the most primitive technology out there.  The remainder of the research drugs out there use the 2.0 technology (smarter linker / drug).  It will be exciting to see how these influence outcome!

GA-101 aka. obinutuzumab in CLL

I love it when a drug comes out of nowhere to suddenly become the hottest thing around...  The latest recipient of that distinction is obinutuzumab.

The annual mega-conference ASCO (american society of clinical oncology) starts up in the last few days of this month.  There are a few big papers for CLL/NHL patients.  I hope to capture the highlights over the next few weeks as I put out updates.

One thing to be VERY careful about is the misuse of the term, "significant."  There is a huge difference between something that is "statistically significant" (ie. a comparison in which the results are unlikely to have occurred by chance) and "clinically significant" (ie. this makes a genuine difference for patients with the disease).  Read my prior post about how things get mischaracterized as "significant."

So what are the big updates this year?

Ibrutinib is in a data lull between the mature reports of the early studies and the ongoing registration studies that have not yet reported.  There is a fantastic piece about ibrutinib resistance that I put up a few days ago.  Idelalisib is still reporting out the mature results of early studies.  Phase III trials are ongoing.  I've been after them to get their phase I studies published but they have been quite slow getting those out the door.

GA-101 (also named obinutuzumab) has a very important presentation.  Rituxan comes off patent pretty soon - hopefully that would lower drug costs (although in this case - maybe not so much).  While the regulators and industry are all tied up in knots over how to make a generic antibody - Roche has set out to make a better version of the drug - see my post on building a better CD20 antibody.

Our first peak into the "efficacy" of GA-101 came last year at ASH where it was compared straight up head to head with rituxan in relapsed indolent non-hodgkin's lymphoma.  Patients got a dose of either drug once per week then once every two months for two years.

There was a suggestion that patients in the GA-101 arm had a higher response rate compared to rituxan.  Unfortunately when you figured out how long the responses lasted it was pretty equal for both groups.  It was interesting to watch the response.  I think the sponsors were excited to see the increased response rate but a lot of investigators sort of yawned.... yup, just another CD20 antibody - not much to see here.

That is why this ASCO presentation of GA-101 in patients with CLL is so exciting - there is something really different here!

GA-101 was studied in the German CLL 11 study.  This was a three arm study in which chlorambucil was compared to chlorambucil in combination with either rituximab or GA-101.  The study included elderly (average age 73) individuals with decreased kidney function (necessary for fludarabine elimination from the body), or a bunch of other medical problems as defined by the Cumulative Illness Rating Scale (CIRS). 

Addition of either rituxan or GA-101 thumped chlorambucil doubling the overall response rate from 30 to 60-70%.  Complete response rate with chlorambucil came in with a whopping 0%, adding rituxan took it to 8%, and GA-101 got it to 22%.  While the increased response rate was encouraging you could say that was the same in the other study listed above that wasn't quite as exciting.

The key to this being something really new was that the progression free survival went from 10 months with chlorambucil to 15 months with rituxan and 23 months with GA-101.  To me that indicates that GA-101 is really doing something new / better than the stalwart rituximab.  Infusion reactions were a bit more significant with GA-101.

For a variety of statistical considerations they did not directly compare the rituxan group to the GA-101 but looking at the raw numbers things look good for GA-101.  In fact Genentech looks pretty happy with the data and sounds like the drug has been labeled "breakthrough drug" with the FDA indicating a fast track for approval in near future!

GA-101 has been circling around under the radar for a little while.  While the stories of patients on the new B Cell receptor inhibitors have been very exciting, I don't think there was quite the buzz out there for this drug.  I love it when we get a nice surprise!

Drug Costs - By State?

I already put up a post explaining why drugs cost so much.  Essentially it has to do with an enormously expensive process of drug development, the high rate of drug failure, the frequency of the diagnosis, and good old fashion profit.

One out of four patients walks away from the pharmacy counter without their medications when they are told the co-payment is $500 or more.  For new CLL/NHL drugs (lenalidamide, ibrutinib, idelalisib, etc.) lots of people will be encountering that sort of bill. 

Under new health-care regulations the price you pay may vary considerably based upon the state you live in and the rules imposed upon insurers on account of their individual exchange policies.

Look for patients in California to find another reason to leave the state (like I did).  New York on the other hand looks pretty good.  Can't wait to see what states like Texas and Oregon do (on either end of the political spectrum).

Once again, the law of unintended consequences makes things harder on quite a few people. 

Ibrutinib Resistance

ASCO abstracts are out.  It feels like Christmas Morning and I am 5 years old (that is probably a very sad commentary about myself).

I'm part way through the CLL stack and Abstract 7041 jumps out at me as a MAJOR discovery:

They took CLL cases treated with ibrutinib and sequenced the entire exome in patients who became resistant (an exome sequence is not as comprehensive as a genome but it is still pretty dang impressive).

In resistant cases, they found that the binding site for ibrutinib on BTK had been mutated in two cases and in a third case, an enzyme downstream of BTK acquired a mutation that turned the protein on.

This is big because it can tell us why patients become resistant to the drug.  It is always a good sign that you have hit a very important target when the mechanisms of resistance show how important the pathway actually is.  In other words, you know the BCR is important because the CLL cells that become resistant have discovered a way to reactivate the BCR.  The next step is figuring out  how to get those patients to be sensitive again (perhaps using idelalisib?)

The other significant finding of the paper is that ibrutinib does not result in a bunch of new genetic changes in the same way FCR might.

Stereotypes

One aspect of B cell receptor (BCR - aka antibody) physiology that I think is really remarkable plays out in several types of lymphoma (mantle cell and marginal zone lymphoma) but is most striking in CLL.  It is called BCR “stereotyping.”

You make antibodies to fight off flu, e. coli, salmonella, etc.  In fact you can make an enormous number of different antibodies to fight of just about any sort of invading micro-organism imaginable.  People who study this have determined you can actually make about 1,000,000,000,000 different antibodies (one trillion).  Recall that DNA is the master plans for RNA and RNA is the template for making proteins (such as an antibody).  Even though we have a TON of DNA in each and every cell (4 billion base pairs), if you had to have a different DNA segment for every antibody you could make, you wouldn’t have enough DNA (almost sounds like the federal budget type of numbers)!

So how do we possibly get one trillion different antibodies out of four billion base pairs and still have enough DNA left over for the rest of the things our cells need to do?  The answer is best illustrated in the childhood game of Mr. Potato Head.  Recall that brown kidney bean shaped doll where you could put different arms, different hats, and different legs on it to make an infinite number of different Potato Heads?  B cells do the same thing – except instead of a trademarked game from Hasbro, it involves a process called VDJ recombination.

On chromosome 14, you have a relatively small segment of DNA where most of the BCR gets made.  In order to make an antibody, the cell has to pick a “V=variable” a “D=diversity” and “J=joining” segment sort of like picking a set of arms, legs, and bow ties for Mr. Potato Head.  I forget the exact numbers but there is something like 70 V’s to choose from, 40 D’s to choose from, and something like 10 different J segments.  The smart math guy in the back of the room would quickly point out that can only give you 28,000 different possible combinations.  The B cells have some special tricks up their sleeves though and can add in additional base pairs between the segments that they  produce out of thin air (non-templated base pair addition) and in the process called “somatic hyper-mutation” can swap out base pairs (this same process may actually cause lymphoma in the first place).  It takes three base pairs to select an amino acid (the building blocks of proteins) but if you add one to the chain it can cause a “frame shift” so that everything moves to the right and now you have one base pair from one amino acid partnering up with two base pairs from another amino acid to give you a totally different amino acid.  Everything downstream is also messed up too so you get a chain reaction.

With those sorts of tricks – you get to one trillion different antibodies.  No two people should EVER have a case of CLL where their BCR looks anything like another patients BCR.  Heck, there are something like 6 billion people on planet earth.  Even if every single one of them had CLL you would only have a 1/166 chance of having the same BCR as another CLL patient.

BUT about 1/3 patients with CLL have a BCR that looks functionally identical to somebody else – what gives?

Turns out CLL is really strongly driven by signaling through the BCR.  In the routine processing of cellular debris, some of the "cellular junk" can stimulate the B cells into action when they should probably just look the other way.  When cells die, they may expose proteins such as vimentin, myosin, etc.  Sometimes those proteins can stimulate a B cell when it shouldn’t.  Since lots of our cells are always dying there is a persistent stimulus for those B cells.  Leave that stimulus on long enough and those B cells keep growing and growing and growing trying to fight off what it thinks is an invading micro-organism when in fact it is just some cellular debris that your body will never actually get rid of.

Since we all have the same myosin, vimentin, etc. we can stimulate BCR’s that look pretty much the same.  Therefore we can make, “stereotyped” B cell receptors.   

So what you ask?

The “why it all happens” is far less interesting than what it means in the clinic.  If you accept that 1/3 patients with CLL have similar receptors, they break up into very distinct subgroups and those subgroups can behave in very characteristic ways.  Knowing about stereotypes can have a big impact on prognosis. It may help to review my prior post about new prognostic markers.


Subgroup 1?  These patients typically need treatment very soon after they walk into clinic the first time.  If you compare the typical BCR mutated/unmutated status, these guys blow them both out of the water.  They may also have a higher frequency of NOTCH mutations and trisomy 12 or other high risk abnormalities like p53 mutations.

Subgroup 2?  They are bad actors.   It is clear that they have a high frequency of SF3B1 mutations which indicate that fludarabine won’t work very well.  They tend to progress early and may also have a higher frequency of del 11q.

Subgroup 4?  The average age of a patient with subgroup 4 is actually 43 years old (whoa nelly – I thought CLL was average 71).  Furthermore, these patients have exceptionally slow growing CLL.  I recently met a young woman with CLL in her early 30’s who was pregnant at the time.  In my mind I bet she is subgroup 4 and I would love to know that because it might put her at ease that she is likely to see her baby grow up.  Their BCR is typically IgG subtype instead of the customary IgM variety.

Subgroup 8? They have an extremely high rate trisomy 12 and Notch mutations.  We know Notch is a bad thing to have – but it is really bad in this subgroup because 75% of these patients will experience Richter’s transformation within 5 years - and those patients destined to transform all have the Tri12/Notch combo.

All told, about 1/3 of patients will have a particular stereotype but there are a ton of different stereotypes someone can have.  About 1/10 CLL patients will have one of the frequent ones  (subgroups 1-8).  As we get to know these subgroups more, I think it will add quite a bit of value to knowing if you are stereotyped or not.

Some of the relationships get really interesting.  We know that certain lymphomas arise as a response to an infection.  In fact, you can sometimes cure gastric marginal zone lymphoma by treating the bacteria that causes stomach ulcers.  Subgroup 4 often has evidence of a viral infection with either CMV or EBV.  Another subgroup looks like it is trying to fight off certain types of yeast.  It is really not that farfetched (THOUGH NEVER FORMALLY TESTED – don’t try this at home) that you might be able to treat some of these cases of CLL with either anti-viral drugs or anti-fungals. 

The problem is that we don’t currently test for stereotypes. Darn!  Sort of like Notch, SF3B1 and other new markers – testing for stereotypes is not part of current CLL management.

I think we will be testing for these soon enough though and it will be interesting to see how these markers get utilized into clinical practice.  Ask most general oncologists and they are totally unaware of this topic.  Even a lot of hematology oriented docs are aware of the topic but may not have much familiarity with the different subgroups.

Frankly, the Europeans have been kicking the Americans backside on this topic.  It is the Greeks and the Italians who have been the champions of the topic. 

Anyhow – hope you find it as interesting as I do.  My flight is coming in for a landing – have to turn this off now….

Dying

What is the absolute worst thing about being diagnosed with CLL or NHL?  I would wager for most patients it is coming face to face with their mortality and having to confront that fear every day.  With CLL and NHL - that daily reminder can last many years.

I know most readers have been drawn to the upbeat, positive, research oriented posts I've put out there. I am surprised though that there is very little written about a process we ALL must encounter - particularly one as scary as dying.  I don't think this post is for everyone - might be good to come back to it when you are in the right headspace.  I want to illustrate the two most common ways I see people pass away and encourage readers to know what their choices are and what they can control.  Hopefully staring the topic in the eyes gives you knowledge to make choices that work for you and your family.

In a world where we have "sterilized" dying into a process that frequently happens inside a hospital - many of us have no clue what dying even looks like.  Add the existential crisis that death often heralds and it is no wonder that being diagnosed with cancer is one of the most frightening experiences around.  Lost among the considerations of watch and wait, when to treat, prognosis, and choosing a treatment there is an underlying fear of the unknown.

I've been present at the deaths of quite a few people.  Sadly, the things that patients put themselves through at the end of life can create a lot more suffering for themselves than is necessary.  I think most patients are unaware of how their decisions and communication about end of life issues with their medical team can result in dramatically different experiences that ultimately lead to the exact same outcome.  With some thoughtful consideration and willingness to talk things through, patients have a lot of power to avoid unnecessary pain.

You cannot go through medical training without being called to innumerbale "code blues" where a patients physiology has entered the "final common pathway" where restoring a beating heart and breathing lungs in the next several moments will determine if that exact moment is the end or not.

Typically a frazzled nurse has been working an increasingly desperate situation for a number of hours.  Once the "code blue" has been called the patient gets turned over to a team of residents or ER physicians eager to run their "code algorithms."  Whoever is running the code is often completely unfamiliar with the patients history, but has a set of interventions designed to bring the patients physiology back from the brink that apply to just about anyone.

Large IV's are hastily inserted into the neck or groin, chest compressions are administered, ribs pop, somebody holds an airway mask connected to an oversize pill shaped plastic bag squeezing air into the patients lungs until anesthesia shows up and intubates the patient.  Often after ten to thirty minutes it is obvious that the efforts are not going to succeed and the "code is called."  Housekeeping is left to clean up a situation that has instantaneously turned into a battlefield and the body is removed from the room.  The frenetic activity settles down and life on the hospital floor quickly returns to normal although family members may linger for a while processing the sudden departure of a loved one. 

In some cases the patient survives the resuscitation only to transfer to the ICU where events slip out of control and the patient dies hours or days later - sometimes after several rounds of CPR are given.  If the process goes on for several days, family members are often confronted with the choice of "removing life support."  I hope to God I never have to make that decision - it is often incredibly painful for surviving family members.

This is the "default" pathway for anyone who has not made it clear they want something more peaceful.

I can tell you - it is rarely like what you see on TV.  In fact, only 0-5% of patients who have advanced cancer who require CPR survive until hospital discharge.  Unfortunately the fact that ANYBODY survives often convinces a number of patients that they have to "do everything possible."  I can also tell you it is not how I want to check out of planet earth.  Fortunately it does not have to be this way.

Determining when to go full speed ahead and when to pull back on interventions requires a lot of judgement. Communicating that balance and guiding a patient appropriately is an art that no doctor has mastered.  Every patient is unique and brings their own perspective on their life and death.  Some patients approach death with a calm exterior, while others want to cling to every single day available, some even greet the end of a "long fight" with a sense of relief.  Working with patients through those issues can be incredibly rewarding but sometime very difficult.

When it comes to determining how hard to push with chemotherapy, I often ask myself two main questions; how "healthy" is the terminal patient. A 42 year old patient with refractory DLBCL is different from a 82 year old with the same relapse. The diabetes, heart disease, strokes, etc that accumulate with age greatly influence how much more therapy a patient can take. I also ask myself how effective the remaining therapies are. If there are very effective, well tolerated drugs that can control the disease, I am much more willing to keep pushing than when the options are few, innefective, or really hard on the patient. Unfortunately the perspective of patients and doctors may differ considerably as to where this line actually is. Sometimes even doctors can suffer from the "cancer of optimism" thinking that the next treatment may just turn things around.

Setting limitations on care most commonly comes up in an oncology practice when you bring up the topic of a patient's "code status."  A code status or "advanced directive" defines what sort of interventions a patient wants if they are unable to communicate for themselves.

It can be really hard to know when to discuss this with a patient.  You hate to introduce the topic when you meet a patient for the first time because invariably they walk away thinking they have been given a death sentence from their cancer.  I also hate to bring it up when somebody's disease has progressed because they may never remember the treatment options we discussed.  Anytime there is bad news - bringing up a code status can make a patient think you've told them they are dying.  So often I am left to bring it up when things are going well - in fact sometimes the best time to bring it up is after a good CT scan (of course then they question if you were telling them the truth about the scan).  Having the patient bring it up on their own would be GREATLY APPRECIATED.  As doc's we are human too.  It is easy to get really connected to a patient whose life is slipping away.  Sometimes I don't want to inflict the emotional chaos I know the discussion will bring.

Keep in mind, a formal "advanced directive" can be totally useless in an emergency if it is filed away in a filing cabinet.  In the event of an emergency - your doctor needs to know of your preferences well in advance.  Once I have had a conversation with a patient, I copy it into each subsequent visit note so that I can keep it in mind and and my office partners can quickly reference through our electronic medical record.  Oregon has a program called  POLST which stands for "physician orders for life sustaining therapy."  I think it is wonderful because it allows us to give the patient a very easy / portable document that is a medical order in the event the paramedics ever get sent to the house.  This document can be used in a bunch of states - I highly recommend it.

It is important to discuss code status early, but when a patient has crossed that gray line where I don't think additional therapies are going to give more benefit than harm - it is essential to be clear on expectations.  I often tell patients that when you are 24 years old and you are in a motor vehicle accident, full court press life support makes a lot of sense.  Whatever actually happened was a one time event and you just need to get physiology back on track.  When you have an advanced incurable cancer though, life support becomes a lot more difficult to support.  It is nearly universal that patients with an incurable cancer who experience a sudden turn of events never recover to a level that is actually very meaningful.  Yes there are bound to be exceptions and anecdotes but for the vast majority of such patients - such life support is merely time spent with tubes and lines, and hospital lobbys for family members nervously awaiting favorable updates that never really come.

So what is the alternative? 

What does it actually look like to die without all the crazy interventions that modern medicine can offer (but probably shouldn't in many cases).  I think many people would be relieved to know that in the substantial majority of patients it can actually be a very peaceful experience.  There are a lot of different medical pathways that lead to a common set of terminal physiologies.  Whether it is bone marrow failure leading to infections, or a pneumonia just taking advantage of a compromised host, or even some cancerous growth that causes a lot of pain requiring ever increasing doses of pain medications - the final few days can often be very peaceful.

Death can happen at home or in the hospital.  I think most patients would prefer the former but that is not always possible.  Some people are pretty confused about what hospice actually is.  I tell patients that accepting hospice is a transition where we focus first and foremost on a patients comfort instead of life preservation.  Typically this is at home although it can happen in a skilled nursing facility if necessary.  In hospice, trained staff come to you instead to provide necessary care instead of the patient coming to the clinic for a 15 minute visit.  Often as docs, we stay involved.  We still get medical updates, get asked to sign orders, etc.  Fortunately, the patient doesn't have to do nearly as much work as they do when they are still schlepping into clinic once per week.  Some of the most wonderful people I've ever met are hospice nurses.

Regardless of the setting, as death gets closer, you generally you observe a balance that shifts from awake and alert to more time spent sleeping and less periods of actually being fully coherent of circumstances.  Hopefully this is in the home environment on Hospice, but sometimes it is in the hospital.  Frequently narcotics are required for the treatment of either shortness of breath or pain.  When you are 29 years old and you break your arm, a shot of dilaudid in the emergency room relieves your pain and probably doesn't put you into a prolonged restful sleep.  When you are 69 years old and you've been through a ton of different treatments though that same shot of dilaudid may make you sleep for a few hours.  Add to that the decreased kidney and liver function patients accumulate after lots of treatment and you may get to a place where keeping them comfortable requires enough medication that they really are not awake all that much.

Eventually the patient decreases their dietary intake, and their fluid consumption drops off.  While you could fight that with IV's and tube feeds that only prolongs the situation until another problem arises.  Once the patient isn't taking in any food because they are sleeping most the time they are often quite comfortable.  Hunger is rarely an issue and thirst can be helped with swabs.  As a doc, often it seems to me that the care provided at that point is really to support the family and keep the patient comfortable.  As a doc, I try to set expectations about how long the process may last.  I try to get families to agree to turn off the medical monitors so that they are focused on the patient instead of a device that is destined to alarm every hour of the night.

Breathing becomes more shallow as the diaphragm weakens.  If the patient has been on IV fluids they often get an uncomfortable "rattle" that reminds me why I always encourage patients to forego that intervention.  Eventually the breathing stops.  The heart stops shortly thereafter.  Sometimes the body gives up one more groan.  It often has less to do with pain as it does with the effect of the diaphragm tensing up at the very end.  The patient has died.  In the substantial majority of patients I've taken care of who have elected not to go through all of the craziness that health care can do - it is often very peaceful.  Unbearable pain is pretty uncommon.

I am amazed how "will" can influence things at the very end.  Just about every family will tell me at some point, "he is a fighter."  Sadly, I don't think that really influences much in the final days.  That said, I've seen a number of situations where "will" can profoundly influence the final moments.  Sometimes a family says their final "goodbyes" only to have the patient die moments later.  Some sort of release allows the patient to let go.  I've seen patients who hold out until a particular loved one shows up.  Once they are present, the patient lets go and surrenders to the end.  I've seen where a family gives a loved one, "permission to let go" and even after seemingly having been asleep for a few days then end comes quickly.  Even when a patient seems totally out of it, I tell family members to tell their loved ones the things they want them to know.

As a believing Christian, I've often observed the spiritual journey that is associated with it all - sometimes even hoping that my own faith will give me strength to face my final days. I've seen patients of faith (any faith for that matter) approach the end with quite a few different attitudes.  I've seen some really sweet individuals face the end joyfully.  I've seen others really struggle with it all.  Interestingly a recent study shows that where a patient draws spiritual support (ie. discusses terminal care with doctor versus their faith community) influences how they approach death. 

I recognize that it is hard to write a broad post and have it reach everyone who reads it.  I know that some people will have personal stories that differ greatly from what I've written - sometimes quite painfully.  For those readers who are struggling with painful loss - I am sorry if what I've written causes you any fresh pain.

So what are the take home points on this one?

1)  As a patient, you are in control of more than you think.  When it comes to terminal care - take the initiative to talk to your doctor about it.

2)  Try to find out what is realistic in your situation.  Don't let blind optimism put you and your loved ones into a process that really makes everyone suffer.

3)  Ask you doctor, "Is my survival measured in days, weeks, weeks to months, or months to years?"  Docs are horrible with crystal balls.  We tend to speak in averages.  No individual is an average.  While my projections are likely to be innacurate when death is a long way away, I can get pretty good when it is really close.   I can often give an estimate like the one I encourage you to ask above.

Thanks everyone - you all inspire me.  I know this is a tough journey but I hope this can help you to think with a clear mind about a very difficult topic.

When bad ideas go badly....

I've written previously about the impact of the Sequester on community oncology practice.  In short it is REALLY HURTING cancer patients access to affordable care.  Ironically it is also increasing the cost of delivering the exact same care.

Here are the results of a survey that shows the extent of the impact.

Please contact your local representative and let them know your concerns about access to care.  This is a big deal and a bunch of colleagues I know around the country are making significant changes to their practice.

How expensive are new drugs?

Ibrutinib, idelalisib, GA-101 (aka obinatuzumab - if I got that right), ABT-199, etc.  The tidal wave of new drugs is exciting because we will soon be treating the disease with therapies that are very effective and lack many of the side effects of chemotherapy. These are some of the exciting new drugs coming soon for patients with CLL and NHL.  Unfortunately they will probably also break the bank.  I bet that ibrutinib costs about $150k per year... that is my prediction.

CML is a leukemia that has a lot in common with CLL.  It is a slow cancer that affects about 10k new patients per year.   Historically (before the year 2000) patients lived a number of years (3-5) with the disease and put up with a bunch of lousy chemotherapy drugs that didn't do much.  Eventually the disease took on a nasty personality (like richter's transformation) and the patient died of "blast crisis."

That all changed in 2000 when a new "wonder pill" called Gleevec made the disease vanish from patients blood.  A single, once a day medication literally changed overnight what it meant to hvae the diagnosis of CML.  Newer, more sensitive molecular tests were required to even detect the disease that could no longer be seen by standard tests like, "cytogenetics."  Sounds familiar right?

Gleevec cost about $40k/year when it first came out (we can talk about how much that price has risen later).  While that number seems extremely high - it is inexpensive compared to many of the new drugs for cancer. 

Why so high?

I have a prior post about why drug development takes so long.  It might be a good read for starters because it can help explain why the process is long and expensive.  A landmark study from 2002 estimated that the total research and development costs of a new drug was about $800,000,000 (eight hundred million dollars).  That is the price for a drug that actually gets approved.  Then you need to take into account all of the drug failures.  There are a ton of drugs that get made that never even enter human clinical trials.  Of the ones that enter phase 1 testing, somewhere between 5-20% will ever see a successful phase 3 trial and get approved. 

Join the high cost of drug development and the high rate of failure and you have a formula for expensive drugs - but that still misses one critical ingredient - what is the frequency of the disease?  If you are making a new drug for cholesterol, you can treat just about everyone in America.  If you are making a drug for angioimmunoblastic T cell lymphoma - you have to recoup your costs on the backs of the 1000 patients per year that get the diagnosis.  The formula goes something like: (drug development costs divided by number of patients = drug price). 

One irony is that the number of new patients diagnosed with CML per year hasn't changed, now that patients are living much longer, CML has actually become quite common.  Every oncologist probably has a handful of CML patients in their clinic because instead of living 3-5 years, they now all live almost normal lives.

Ok, I think most readers at this point can agree that drugs for CLL and NHL will be expensive.  Many readers will agree that the drug developers should be rewarded for taking enormous risk and bringing new effective drugs to patients with cancer.  Some would say that we should just have government funded research and that would make drugs more affordable.  Unfortunately, I've seen both government supported research and pharma research up close.  If we relied on government based research to bring new drugs, I think we would still be stuck with chlorambucil. 

But at what point does a drug price go from being a fair reward for innovation to profiteering off vulnerable cancer patients?  In the last ten years we have seen remarkable breakthroughs in cancer treatment but it doesn't always seem like price and effectiveness are totally linked.  Some new drugs are small incremental improvements while others are truly revolutionary.  What is odd is that the difference between a "single" and a "homerun" have no impact on cost.  Any new cancer drug is more than $100k/year.  Academic thought leaders have taken note and for the first time we are seeing organized pushback. 

One clue to me that we are in an era of profiteering is that the price of a new drug seems more linked to what the price of the most recently approved drug was rather than how effective the new drug is.  In the case of Zaltrap - a newly approved drug for colon cancer that didn't move the needle too far in terms of effectiveness (ie. new mechanism but not a whole lot more effective) the price was right on mark with other recently approved drugs (over 100k per year).  Fortunately the organized rebellion of academic thought leaders has resulted in a decreased price for this drug. 

I believe that market forces are able to result in fair prices in most situations.  The problem with medical care is that it isn't a normal market.  When you go to buy a car, you figure out what something is worth and you decide if the dealer is selling it for a fair price.  If not, you walk away.  In medicine though, how do you put a value on keeping your hair?  Staying at your job instead of taking sick leave?  How do you decide the value of an additional year of life.  Is that the same for a 25 year old as an 85 year old?  Value determinations are difficult.  Furthermore, in medicine you may have your co-payments but chances are some anonymous third party is paying the lion share of the cost.  Who wouldn't want the latest and greatest if they don't have to foot the bill.  Add to that the lack of choice.  You can't just go down the street to a different car dealer when it comes to picking a therapy in lymphoma.  Without market forces, drug prices get all out of whack.

If we come back to the price of Gleevec it is interesting that the price has risen over the years.  Two newer drugs came along (sprycel and tasigna) that had prices set around the going rate when those drugs were approved.  Oddly enough, Gleevec rose too.  The drug didn't get better, it's peers got more expensive and they were able to rise closer to their peer group.  This has drawn the focused criticism of many CML docs as well as a rebuttal from the maker of two of these drugs.  It will be interesting to watch what happens to all three drugs when Gleevec goes generic soon.  A generic drug can sometimes drop in price by 90% overnight.  Sprycel and tasigna are better than Gleevec but I bet the price of all three drop considerably.

I think most patients who see these prices for their care experience some disbelief and anger.  It is hard to know where to place that anger and sometimes that falls upon the drug companies, sometimes the insurance companies, and sometimes even the doctors caring for the patient.  I can tell you as a docs are not the ones making much money - in fact some docs are closing up shop or refusing to see Medicare patients because they can't deal with the costs anymore.  Any simple answer probably misses a lot of complexity.

It is clear to me that the current trajectory is unsustainable.  I watched in amazement as Peter Hillman gave an analysis of the impact of new CLL drugs on the overall spending of the British Health Service.  New CLL drugs alone could tank the British cancer funding system.  I credit the British for having a system that also takes into account the cost of drug in determining coverage.  In the US it is strictly about safety and efficacy.  Drug prices are not a factor in determining approval.

I am not sure I can offer solutions without getting too political. We all want new drugs but in a broken marketplace you cannot expect "fair prices" to sort themselves out.  I'm not even sure that a "single payor system" could afford the innovation we are seeing now.  I think the best thing we can all do right now is get involved in clinical trials so that there are a bunch of new BTK or PI3K inhibitors out there to restore some degree of choice.