Immunotherapy for Indolent (low grade) Lymphoma

An academic mentor once told me, “scientific advances are a lot like a game of baseball.”  Curious, I asked him what he meant.  He shared with me, “most advances are like getting a base hit.  Doubles happen but are not terribly common, triples are rare, home runs don’t happen all that often and genuine grand slams change the field all together.” 

As I shared with him my idea of turning off B cell receptor signaling using pills, he told me, “Jeff, it sounds like you are swinging for the fences, and for our Stanford fellows, we are happy if you just crowd the plate and get hit by a pitch…”  Oh well, I suppose everything worked out fine, and I still don't really care much for baseball.  I wanted to compile the history of home-runs in the field to highlight just where we are and point out where I think we are going.

If you look back over the last 60 years of advances cancer medicine, there are only a handful of clinical breakthroughs in low grade lymphoma (indolent) that fundamentally re-oriented our treatment strategies in the disease and upended the status quo of the time.  It hasn’t necessarily been a story of slow and steady progress.  Instead there are discrete episodes that shred through the treatment landscape and when the dust settles, the field has evolved into something new. 

Cancer is a complex beast and many discoveries have only served to show us just how little we actually know.  While the progress is now exponential, so too is the amount we realize we don’t know.  Every so often something comes along that genuinely moves the needle and patients have longer and better lives.  I am very excited about an emerging story in indolent NHL and I wanted to help put in context a story that I think we are going to hear about very soon.

Here is my short list – for the interested reader, I highly recommend the book The Emperor of All Maladies.  It was written by one of my residency training classmates at MGH and has received the Pulitzer Prize.   It is a fantastic read. 

1)  Way back in the 1940's local radiation therapy was the only treatment available.  This really didn't work well in a disease that is typically "systemic."  Since we didn't know much about radiation dosing, patients were burned and burned again until their disease became "radiation resistant" and they died of massive lymph node enlargement or complications from radiation.

 2)  In 1946 we had the introduction of "chemotherapy" which actually spun out of chemical warfare research during WWII.  (The remarkable story of America’s “Second Pearl Harbor” and the birth of chemotherapy is one of the most amazing little known stories in medicine). Patients with lymphoma were the very first to be treated with modified versions of mustard gas.  Responses were short-lived but merely 15 years after the introduction of penicillin the idea that “medicine” could treat cancer was born.

3)  In the 1950's the drug Adriamycin was isolated from a soil sample of a 13th century Italian Castle and subsequently was shown to be effective in lymphoma.  This drug became a "backbone" of many treatment strategies in lymphoma and is still commonly used today.  It is the “big red” drug that makes many lymphoma patients lose their hair but is also commonly used in breast cancer, gastric cancer, sarcoma’s and other diseases.

4)  For the next several decades, progress was built in many small steps.  New drugs were found, developed, and tested one at a time. Vincristine was isolated from the Madagascar Periwinkle, Etoposide was isolated from the “mayapple” and so forth.  Multiagent drug cocktails were assembled and tested.  When you put as many drugs together as you possibly could, you got crazy names such as M-Bacod (6 drugs), Pro-Mace-Cytabomb (8 drugs), and CODOX-M-IVAC (7 drugs).  While some of these were for more aggressive lymphomas, each had their loyal adherents and debates raged without much comparative data. That all ended however in 1993 CHOP (4 drugs) was declared the winner over several more "intensive" regimens.

5)  In 1997 we saw the introduction of rituximab in lymphoma.  This was the first time we used a therapeutic antibody (like the ones your body makes to fight the flu) to treat cancer.  Rituximab administered alone has impressive single agent activity and has become increasingly utilized as monotherapy.  It was also quickly added to CHOP to make the R-CHOP regimen.  This was the first "chemo-immuno-therapy" regimen and led to substantial improvements in long term outcome of patients with both low grade and DLBCL.  Until 2007, patterns of care data indicate that if you were going to get chemo for follicular lymphoma, 50% got R-CHOP, and another 25% got the same regimen without the Adriamycin which adds quite a punch in terms of side effects (R-CVP), and about 15% received rituximab alone.

6)  In 2008, there was a US based study of a drug that had been floating around East Germany during the entire cold war yet remained unknown to western cancer doctors.  This was the first that most US docs had heard of Bendamustine. The data was quite impressive for how effective the drug was compared to standard alternatives.   In 2009, the German lymphoma study group initially presented data at ASH comparing bendamustine-rituximab to R-CHOP in follicular lymphoma.  It was actually only published in Lancet last year.  This showed improved efficacy with bendamustine, and far reduced side effects which led to the sweeping changes in patterns of care.  Bendamustine with rituximab has upended practice patterns.  In the last two years, US patterns of care data reveals approximately 1/3 of previously untreated follicular lymphoma patients needing treatment receive Bendamustine-Ritxuximab, 1/3 receive rituximab alone, and only about 1/5 receive R-CHOP in front line treatment and virtually nobody receives it following relapse.  Fludarabine utilization is virtually gone (see attached slide presentation at the bottom of this post and my post on "How I treat follicular lymphoma). 

7)  As ASCO 2007, our lab at Stanford presented the first “pre-clinical” data showing that inhibition of B-Cell receptor signaling enzymes could have therapeutic effect in B cell malignancies.  This  theory was subsequently confirmed in a plenary session presention at ASH in 2008 utilizing the drug fostamatinib.  The discussant at the time felt that the data met the criteria for “game-changing” and put it on his list of NHL history makers.  While fostamatinib is no longer being actively developed, the proof of concept directly preceded / led to the exploration of ibrutinib and idelalisib in similar diseases.  In heavily pretreated patients, both of these drugs have approximately 50% overall response rate (size criteria for response determination, many more actually shrink and benefit – just not enough to be considered “partial response”) and average a year of benefit for responding patients.  Idelalisib was recently FDA approved in follicular lymphoma and we await data on ibrutinib in this population.  While the impact in follicular lymphoma remains an evolving story, the impact in chronic lymphocytic leukemia and small lymphocytic lymphoma is nothing short of transformative. 

8)  I believe story 8 in indolent lymphoma will be “immunotherapy."  Rarely a day goes by where I am not asked by a patient, “is there anything I can do to boost my immune system.”  While my answer has always been, “not really” a number of very important new therapies are showing that harnessing the power of the immune system to attack cancer can be extremely powerful.  Drugs have been either approved or are soon to be approved in melanoma, lung cancer, kidney cancer, and bladder cancer that help the immune system identify and destroy the cancer cells – without using chemotherapy.  Some of these are antibodies that interfere with the “on/off” switches of the immune system.  Others “re-program” T-cells using engineered viruses that can go absolutely crazy on B cells (see amazing video here).  The most accessible and perhaps most exciting of these for patients with indolent lymphoma may very well be the combination of revlimid with rituximab.  There are several very important studies that are poised to position this combination at the center of treatment pathways for patients with follicular lymphoma.

Nathan Fowler’s data from MD Anderson – link here (expecting updates at publication)

Nearly completed study in frontline follicular lymphoma Rev-Rituximab vs R-Chemo – link here

Open study of Rev-Ritux in relapsed follicular lymphoma – link here

I think of the combination of revlimid-rituximab (also called R2) as a road trip with a pot of coffee and a map.  Rituximab helps orient the immune system to go after the cancerous b cells by coating the outside of them and serving as an alarm for the T cells (like a road map).  Revlimid (lenalidomide) helps overcome what has been called T-Cell “pseudo-exhaustion” and get them to reactivate (ready for the road).  B cell cancers have a remarkable ability to “put the t cells to sleep.”  Whether though secretion of hormones, or actually manipulating the on/off switches of T cells, the cancerous B cells literally put the other half of the immune system into a post thanksgiving meal food coma.  Revlimid acts like a cold splash of water to the face for the sleepy T cells.  Not bad for a drug that really isn’t chemotherapy but is considered an “imid” for – immunomodulatory drug.

The combination has been explored in CLL.  It can be so active at times that there can be problems with tumor lysis syndrome.  The combination is not approved by the FDA in this setting and should be utilized very carefully due to the associated risks.

The combination has also been explored in follicular lymphoma with some pretty spectacular results… and that will be the subject of an upcoming post!

Thanks for reading

(Patterns of care data and a nice view of the Sisters volcanic range in Oregon from Mt Bachelor Ski area)

Treatment patterns in indolent nhl from Jeff Sharman

Relapsed Diffuse Large B Cell Lymphoma

Taking care of patients with Diffuse Large B Cell lymphoma (DLBCL) can be very satisfying (see my posts on front line therapy for DLBCL and the different types of lymphoma) because you can cure a good number of patients.  By "cure" I mean real, legitimate cure.  The disease is gone.  It never comes back.

With standard R-CHOP chemotherapy, close to 60% of patients will never have their disease return.  We use the "International Prognostic Index" or "IPI" criteria to get a little more specific for likelihood of cure in different patients that looks at several clinical variables such as age, LDH, amount of disease, functional status of the patient etc. With these details we can be a little more precise about likelihood of a cure for an individual patient.  New features such as "cell of origin," "gene expression" or mutation data can add a dimension of precision to this.

Unfortunately, some patients will not be cured by their first line of treatment - for those patients, cure remains a possibility but the odds of getting that cure the second time around is a lot harder.  Back in the days prior to rituximab when patients with DLBCL were treated CHOP alone (no rituximab) a study was done that compared regular chemotherapy to stem cell transplant.  The results of the PARMA study showed that almost half of patients who got transplants were probably cured of their lymphoma.  This was a lot better than the patients who only got chemotherapy (no transplant) and 12% were without recurrence at five years.

I strongly encourage people to read my blog post about transplants because it deserves its own discussion.  It is generally restricted to patients less than 70 years old with good health aside from their lymphoma.  For the most part, we are talking about "autologous" or giving your own stem cells.

The PARMA trial still informs most oncologists approach for "transplant eligible" patients (ie. salvage chemotherapy such as R-ICE or R-DHAP followed by transplant if patient has response to chemotherapy).  Unfortunately, the PARMA trial took place when patients were treated with CHOP instead of R-CHOP and the landscape has changed more than most oncologists necessarily appreciate.

Along came the CORAL study which set out to compare the difference between R-ICE and R-DHAP chemotherapy in preparation for transplant.  This study took place after R-CHOP had mostly become the standard for front line therapy.  As a result, the many of the patients enrolled in the study experienced relapses following R-CHOP (although there were some who had recurred after CHOP alone). This study enabled us to look at the natural history of relapsed DLBCL and contrast the differences between those who relapsed following CHOP and those who relapsed following R-CHOP - in other words it gave us important insight into how Rituxan had changed the landscape.

Patients who get R-CHOP do better than patients who get CHOP for front line therapy of diffuse large B cell lymphoma.  Unfortunately, that probably "selects" for the bad actors because relapses after R-CHOP are a lot worse then relapses after CHOP alone.   In most cases R-CHOP is the standard of care today. The CORAL study shows us that there are really two separate groups of patients who relapse following initial R-CHOP therapy - those that we call "primary refractory" and those with late relapses.

For the 1/3 of patients with late relapses (greater than 12 months following start of R-CHOP) can still be "cured" with transplant (45% of the time).  Provided the patient is young enough and sturdy enough to go through transplant.  In essence, they have already proven that their lymphoma is "sensitive" to chemotherapy because their initial "remission" lasted "long enough."  For those patients, if they respond to a chemotherapy "test" (i.e. R-ICE / R-DHAP), then giving them mega doses of chemotherapy (i.e. autologous stem cell transplant) may be a good idea.

Unfortunately, for the 2/3 of patients who relapse within 12 months (of initial diagnosis) have "primary refractory" disease and most thought leaders acknowledge that the rules established in the original PARMA study (pre-rituxan) may need to be reconsidered in these patients.  In many cases these patients have what was called "double hit" DLBCL (subject for future post).  In other cases, they may have had a mutation in a gene called TP53.  In other cases, we simply do not know why they are "refractory" to initial therapy.

If a patient experiences early relapse, it is probably a sign that chemotherapy is less likely to be  effective.  In young / sturdy patients, we often still follow the "PARMA rules" and try to get the patient to transplant but unfortunately what we have learned from the "CORAL rules" is that only 1 in 5 such patients is likely to be alive and free of lymphoma at the three year mark.  Twenty percent is a tough number.  It is high enough to want to try for it but low enough that in many cases you may have wished you went a different direction.

So what are the options if the transplant route doesn't work out or the patient is either too old or not sturdy enough to even try a transplant?

There are a handful of chemotherapies that we call "salvage regimens."  These are designed to buy the patient some time but not necessarily aim for cure anymore.  These are often given in combinations of drugs with names like, DHAP, Gem-Ox, ICE, ESHAP, CEPP, and EPOCH.  Most of the time, we throw in some rituximab as well.  Sometimes these regimens may be a little too stiff for older "transplant ineligible patients" and you may take just about any of the individual drugs and give them alone or at reduced doses.

I think that there are a number of drugs that are either available or soon to be available that may improve the outcome of patients in such situations.

I've previously written about the different subtypes of DLBCL known as "germinal center (GCB)" or "activated B cell (ABC)" DLBCL.  Interestingly, some drugs have unique activity in the ABC subtype which is often more likely to cause problems after R-CHOP anyhow.  These drugs include ibrutinib, bortezomib, and lenalidomide (links go to data in relapsed DLBCL).  Another emerging technology is known as "antibody drug conjugates" which has been subject of prior posts as well.  These drugs do not appear to necessarily be restricted to ABC subtype and may possibly work in either setting.  This includes drugs like brentuximab, and others that target B cell markers like CD79 and CD19 (but only have incomprehensible names) that are only available in clinical trials.  There is the emerging technology of "chimeric antigen receptor T-cells" which most of my patients call "gene therapy" and has been the subject of intense media attention recently.  This technology holds out hope that we can cure some patients that we have previously considered incurable.  Finally, there are new genetic tests that can be run on DLBCL that may point toward therapies that are uniquely appropriate for a specific individual based upon their mutation profile.

At least for now, the goal of MOST of these is to slow the lymphoma down and maybe even get to a remission.  While I would love to think that we were aiming for a cure when relapsed DLBCL either can't make it to transplant or transplant would be inappropriate, that is infrequently the case.

Hopefully this gives a reasonable roadmap for patients whose DLBCL.  It is not meant to be exhaustive or substitute for individual discussions with your own doctor.

Thanks for reading.

Diffuse Large B Cell Lymphoma (knowing your ABC's and GCB's)

Growing up, I religiously read the comic strip, “The Far Side.”  In one strip I remember clearly, there was a woman reading her veterinary medicine textbook.  In chapter 9 she came to equine medicine where the remedy for just about anything that bothered a horse was exactly the same.  The captions said, “Like most students, Doreen breezed through equine medicine.”  I’ve posted a link here for a quick laugh.  Sometimes treating patients with diffuse large b cell lymphoma (DLBCL) can feel the same  - R-CHOP for all (here is a description of R-CHOP and my personal approach to DLBCL).  

If you look at the most recent update of the world health organization classification of blood cancers, they identify thirteen different types of “aggressive lymphoma.”  Most patients are familiar with the most common subtype lovingly called DLBCL-NOS (not otherwise specified).  The “plain vanilla” DLBCL proves to be far and away the most common version of the disease.

Despite being lumped together as a single entity, if you pop the hood and look deeper inside DLBCL-NOS, there is a lot of biologic heterogeneity – those differences are starting to look more and more important.  A number of years ago, one of my colleagues (who I still insist is the smartest guy I’ve ever met – Ash Alizadeh at Stanford) took advantage of a brand new technology called “Gene Expression Profiling” to look at a bunch of DLBCL samples and got his findings published in the journal Nature.  Other labs (Lou Staudt at NIH and Margaret Shipp at Dana Farber) had similar findings – it is pretty robust.  This allowed scientists to take cancer samples and test them to see which genes were turned on and turned off (a term we call “expression”) and evaluate tens of thousands of genes at a time.

What they all found was that there were two “main” subtypes of DLBCL-NOS.  Those two subtypes were the “Germinal Center DLBCL” and the “Activated B Cell DLBCL” (GCB and ABC subtypes respectively).  Purists who know the science well could fault me for not being completely precise here, but that will do for now.  When normal B cells undergo proliferation in response to discovering the “germ” they were destined for all their life, they do so in a specialized region of the lymph node called the “germinal center.”  GCB-DLBCL-NOS appears to have similar genes turned on and turned off (ie expressed) whereas ABC-DLBCL-NOS looks like a cell that has left the germinal center in an “activated” state.”

Why does this matter?  It turns out that these biologic differences have significant clinical impact.  If you segregate ABC from GCB DLBCL, the ABC do quite a bit worse than the GCB in terms of overall survival and response to R-CHOP chemotherapy. 

Since there is such a big clinical impact, you would think we would all know if our DLBCL patients were ABC or GCB subtype – but we don’t!  It turns out that gene expression profiling (GEP) is pretty expensive and it has to be done on biopsies handled a certain way that most surgeons / pathologists don’t do.  Instead of GEP testing, pathologists figured out how to make the determination of ABC vs. GCB using tests that are a lot cheaper and easier to use – called “immuno-histo-chemistry” (or IHC).  Any pathologist who looks at cancer specimens knows how to do IHC.  You essentially take a small slice of the tumor / lymph node / marrow / etc., stain it with an antibody of interest, and use a marker on the antibody to help you know if it stuck after you washed the heck out of it.  ABC has different IHC staining than GCB DLBCL when you look at markers like CD10, BCL-6, MUM-1, and so forth – so just about any lab can do this testing – but they don’t always do it!  There are two main reasons why many don’t.  First, the test isn’t nearly as reliable as GEP testing.  In fact, there are several different antibody combinations that can help make the IHC distinction, but get a bunch of pathologists together and they will only agree about 70% of the time when they do the stains themselves.  The second reason is when I come back to the far side comic strip.  At least for now, you pretty much have the same R-CHOP no matter what the test shows – but that is starting to change.

For patients interested in a purely “prognostic” test, I suggest getting this one done.  It distills all of the gene expression profiling down to two genes and can be ordered easily today.

Since fewer than half of ABC DLBCL patients are likely to be cured with their R-CHOP chemotherapy, lots of pharmaceutical companies are interested in building a better version of R-CHOP.  Quite a few drugs have been explored in DLBCL in the last few years that seem to have preferential benefit in the ABC subtype of DLBCL.  Ibrutinib yields a 40% response rate as a single agent in relapsed ABC-DLBCL but only a 5% response rate in GCB subtype.  For Celgene’s lenalidomide, it is more like 50% versus 5%.  Millennium’s bortezomib can be added to R-CHOP and when you look at the patients with ABC vs GCB, they do almost identically suggesting that the drug overcomes the negative impact of the ABC subtype of the disease.  Indeed, adding ibrutinib to R-CHOP gives a 100% response rate in preliminary studies, and adding lenalidomide to R-CHOP makes the ABC look ever so slightly better than the GCB subtype.  Not surprisingly there is intense interest in ongoing phase III studies that restrict enrollment to patients with ABC subtype DLBCL to see if any of these three drugs can be added to standard R-CHOP.

My prediction?  I bet several of these end up crossing the finish line and getting approved by the FDA (disclaimer: I am not currently involved in ANY of these studies and have not seen any preliminary data).  So what happens if two or three such drugs actually get approved – how would a doc and patient choose which combo to take?  Now we go back deeper into the biology.

If we look at gene expression profiling or use immunohistochemistry staining to categorize DLBCL-NOS into ABC or GCB we are really only using surrogates for a more fundamental process – what mutations have occurred at the DNA level.  Several publications have recently come out where the entire genome of DLBCL has been “sequenced” and when you look at the data, you realize there are a handful of mutations that seem to recur.  Those mutations often determine which genes are expressed, and how the cell looks under the microscope when you use IHC.  In essence GEP and IHC are merely proxies for the underlying mutations.

Here is where it gets really interesting and makes a lot of sense.  The ABC subtype of DLBCL appears to have “chronic active signaling” through the B-Cell receptor (BCR).  This has some similarities to what we have seen in CLL through different mechanisms.  If you look at the BCR signaling pathway (think of an electrical circuit), you can create a “short circuit” at any number of steps along the way, yet the result seems to be a light that either won’t turn on or off appropriately.  In this case, that is a protein called NF-kB which regulates the expression of a bunch of important B cell genes.

If that short circuit is really high up in the pathway (CD79 stuck in the “on” position) or low in the pathway (CARD-11 mutation) you get the same activation of NF-kB, but turning it off at different places may make a difference.  BTK is a protein that lies just “downstream” of CD79 in the BCR signaling pathway and lies “upstream” of CARD-11.  It is also the target for ibrutinib.  You can have ABC-DLBCL where there is a mutation in EITHER CD79 or CARD11.  Interestingly, very preliminary work makes it look like ibrutinib works well when there is a CD79 mutation but it isn't clear yet how well it works when  there is a CARD-11 mutation.  This makes a lot of sense.  To get to NF-kB, BCR signaling from abnormal CD79 has to go through BTK but BCR signaling that starts from abnormal CARD-11 does not.  That would perfectly explain why ibrutinib might work in one case but not the other (if larger numbers of patients make that theory hold up).

A similar but different story may be developing for lenalidomide where either MYD88 mutations or others may explain when that drug works or doesn’t.

So my challenge to my pharma colleagues is the following: figure out which mutations confer activity for your drug (as some are trying to do right now) so that the docs know what to do once your drug is approved.  Molecular diagnostic tests are now available that enable you to test for each of these mutations all at once.  This should be in their interest anyway because the FDA loves "companion diagnostics" for selecting individuals for therapy.  I predict that in the future, DLBCL management will go like this:

Patient walks in with new diagnosis of DLBCL

Since therapy is often needed very quickly, the patient will get their first cycle of R-CHOP

While the three weeks between cycles has passes, the patient will have their cancer sent for analysis and they will find out what unique mutations they have

The patient will come back for the second dose of therapy and an appropriate targeted drug will be added based upon the mutation analysis

In some cases no “pathway specific” mutation will be found.  In these cases, there are other drugs working through the system that may be added like the antibody drug conjugates (see here and here).  Pharma companies developing such drugs would be wise to know where their drug works even if it is felt not to be mutation specific so that they can pick up the pieces for the patients who don’t get ibrutinib, lenalidomide, bortezomib or others.

R-CHOP has served us well for quite a few years.  We are spoiled in NHL management that we get to cure a lot of our patients.  It is really fun as a doc to have a patient walk in doing great with their cancer a fading memory.  Unfortunately “a lot”doesn’t feel that great if you are not one of the ones who is cured.  I think we are getting really close to making some important steps forward in the management of DLBCL-NOS and it will be driven by molecular information that leads to targeted therapies that are specific to the patient.

Thanks for reading!

Jeff

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

Follicular Lymphoma Grade and Stage

A while back, one of my readers asked if I would make a post about “grading” in follicular lymphoma.  She has been a great help to me in attracting readers to this blog so I promised her I would write something up.  Unfortunately I think I’ve had a mental cramp on this one for a while – but I am trapped on a seemingly endless flight (Dang Texas is big) so I thought I would give it a try.  The flight doesn’t have internet so this one may be a little brief on the outside references.

Most of you know about “staging.”  In lymphoma, staging is a clinical measurement of how much disease you actually have.  Stage I disease is typically one affected lymph node or a few that are tightly clustered in one place.  Stage II disease is when there are multiple affected lymph nodes in different areas, yet on the same side of the diaphragm (ie all in abdomen/pelvis or all in neck, chest, armpits).  In stage III disease you can have lymph nodes on both sides of the diaphragm.  Stage IV disease is when it either involves the marrow or more than one site outside of the lymph nodes (ie skin, liver, lungs, bone lesions).

I should make a comment here that frequently comes up in my clinic.  Patients often ask me, “what stage am I?”  There is nothing worse than the look you get when you tell someone they have stage IV disease.  We are primed from our knowledge of a lot of cancers that stage IV means you are going to die.  It can sometimes be a challenge to “pick up the pieces” after you tell someone their disease is that far advanced.

Stage IV lymphoma is very different than stage IV lung cancer.  I tell my patients that lymphoma is a cancer of the immune system and that the immune system is pretty much everywhere to begin with (ok – we can make exceptions for both the brain and testicles which are considered immune “privileged”  - draw your own conclusions).

In diseases like lung cancer, if that cancer has spread outside of the lung or adjacent lymph nodes – that becomes an incurable disease and the prognosis is often comparatively short.  Same thing holds true with a bunch of other “solid” tumors for that matter (bladder, kidney, pancreas, colon, stomach, and so forth).  It is certainly true that less lymphoma is better than more lymphoma – but not to the same degree as those other cancers.  Stage IV lymphoma is very common but often still quite manageable (and even curable in DLBCL).   In fact stage III/IV follicular is considerably more common than limited stages of disease – so most of the statistics you hear about survival  are typically for patients with advanced stage disease (which are often way outdated since by their very definition are retrospective and do not necessarily account for improvements in therapy).

OK – moving on – this was supposed to be about grading right?  Grade has absolutely NOTHING to do with stage.  I tell patients, “grade is what it looks like under the microscope – stage is what it looks like on the CT scan.”  Unfortunately, there is a fundamental problem with using appearance under a microscope as an objectivemeasurement – it is difficult to reproduce this well.  Even though there are well established criteria about grading lymphoma – trying to make solid black / white distinctions can be hard when the biology does not conform to the rules.  You can look at different regions of the same node and come to a different answer, or you can even look at the same region and have two different pathologists give you a different answer if they count things a little differently – and that is easy to do!

Grading typically applies to cases of follicular lymphoma.  We assign one of four grades – you would probably guess I, II, IIIa and IIIb right?  The way we distinguish between these are the number and arrangement of “large cells” within a node.  Large cells are typically called “centroblasts” while small cells are called “centrocytes.”  Large cells are thought to be more rapidly proliferating.  Since faster proliferation is bad, the more large cells you have the worse we think it would be.

Ultimately, there is VERY LITTLE difference between the grade I’s and the grade II’s either biologically or clinically.  Even grade IIIa disease is pretty much something we can lump together.  We treat them exactly the same way, they do just as well.  It is pretty much just a pathology distinction without much clinical impact.

Distinguishing between grade IIIa and IIIb though can have clinical implications.  In grade IIIa there are enough centroblasts seen in the lymph node (15  per “high powered field”) to be categorized differently than grade II yet clinically we still treat all these exactly the same.  Grade IIIb on the other hand has “sheets” of centroblasts within the node and really starts to behave more like diffuse large B cell lymphoma (DLBCL).  In the past that often meant the difference between getting R-CVP or R-CHOP (the latter being more intensive and causing hair loss – see my post about it). For a lot of docs though, R-CHOP was historically (and still is in some cases) the choice though even in grade I-IIIa  follicular lymphoma so the distinction didn’t matter quite so much. 

Now it is more significant because in grade I-IIIa utilization of bendamustine-rituxan is extremely common yet R-CHOP would probably still be considered standard for IIIb.  Since BR is both superior and better tolerated than R-CHOP in I-IIIa, I sometimes anguish a little when I see a IIIb come into clinic. I will often call the pathologist to get a better feel as to how “clear” the distinction is to them in the sample.  Alternatively, I may look for other clues about the aggressiveness of the disease.  Does a PET scan show one area to be a lot worse than others to suggest a transformation?  Does the clinical pace or labs suggest higher grade disease? etc.?

There are a few problems with this though.  1) This is an area where pathologist reproducibility is not so great.  This is not to say they are not good pathologists but that there is a lot of judgment involved as well as sampling differences.  2)  It is not clear that appearance is a good surrogate for biology.  We are learning about the remarkable complexity of these cancers and I am not convinced that appearance gives us adequate insight into the molecular mechanisms that are going on.  3) As humans we like to compartmentalize things even if they are really continuous variables.  In other words, if we use the number 50 as a cutoff – are patients with 49 or 51 really all that different from one another?

Clinical studies have tried to get at differences in outcomefor patients with grade IIIb follicular lymphoma but drawn somewhat different conclusions. (another link here and here)

If good researchers come to different conclusions when asking some of the same questions – it is often because the data input is faulty (ie. in a study of 100 patients- 15 are categorized incorrectly and results in a smaller difference than would have occurred if everyone was put in proper group).  Other times we may be falling victim to the belief that appearance is a surrogate for biology AND that the biology is actually different.

One other key point I should make before wrapping up.  Grade IIIb is not the same thing as histologic transformation which is evolution from low grade disease to high grade disease.  We are getting to understand that biology better and histologic transformation is likely worse than grade IIIb on account of a different mutation profile.

For now, grades I-IIIa can be treated with rituxan, R-CVP, R-CHOP, BR, or any of the new research drugs.  See my posts on “my approach to follicular lymphoma part 1 and part2.”  Grade IIIb I will use R-CHOP even though I have all the questions I ask above.

I hope that helps – thanks Anjou!