Off label drug use

How do you get access to a hot new drug if it isn't approved in your condition?  With recent or pending approvals of ibrutinib, idelalisib, lenalidomide, obinutuzumab, etc. lots of people are asking these questions.

In the past, a drug that got approved by the FDA could largely be used by oncologists without much regard to the the specific "labeled indications"  (see ibrutinib / imbruvica here) When a clinical trial is done that leads to the approval of a drug, the FDA evaluates the data and creates a "label."  That label defines what the drug is approved for and that is generally based upon the specifics of the study that led to the approval (ie. the specific population, what other drugs were used, etc).  There is a lot of attention to how broadly or narrowly a label is written because it will have enormous downstream impacts on utilization.

When brentuximab was approved in Hodgkin's lymphoma, it was originally approved for patients with relapse following stem cell transplant, or for patients ineligible for transplant who had received two prior regimens.  Some were hoping the label would be more inclusive (ie to get patients to transplant, or in first relapse etc).  That is why the stock initially went down substantially immediately after approval. Since it was a more narrow label doc's couldn't go prescribe it as frequently as some had hoped.

Many of the same questions surround ibrutinib.  It was given "breakthrough designation" for patients with relapsed CLL that has the 17P deletion.  Recall that 17P is one marker for high risk CLL among several others that determine prognosis.  If I read the press releases correctly though, pharmacyclics submitted for approval in patients with relapsed CLL (irrespective of the 17P deletion).  That sets up a potential scenario where the specifics of the label can make a huge difference in the initial approval in CLL.  In relapsed CLL patients with 17P represent only about 20-30% of all patients.  So if you don't have that marker will you be able to get the drug?  What if you have a P53 mutation without the deletion?  That is essentially the same population?  How will insurance make that decision?  If the drug is approved for relapsed disease only, what would stop a patient from taking a single dose of rituximab and then saying their disease is "previously treated?"

So who governs what can or can't be prescribed?  That is complicated.  For patients with medicare, it is hard to prescribe any of the "new" medications "off label."  This is because medicare won't pay for it.  For some of the older drugs though, they really got established into disease management before they became super expensive.  If a drug gets "NCCN compendia listing" (which is an association of leading academic medical centers who agree on standards of care) it often gets covered by medicare.  Nowadays it is pretty hard to get "compendia" listed unless a specific trial proves that a drug has a role in a very specific situation.

It is possible to prescribe a drug and administer it, but if it goes for ten thousand dollars per dose and medicare won't reimburse you for it, you can put yourself into enormous financial pain very quickly as an oncologist by getting too adventurous.

For patients with private insurance, it can be a lot more difficult to predict.  If ibrutinuib or lenalidomied are currently approved for mantle cell lymphoma, what would stop you from prescribing them in CLL? Since the drugs can cost 10K/month, getting insurance to pay for it is the biggest issue.  These drugs have been clearly well studied in these diseases, it is not like a doc would just be "flying by the seat of their pants" to recommend such a drug.  The reality is that some insurance will cover it and some won't.  In the case of ibrutinib, it will likely be approved in CLL in a few months so it may not be as much of an issue, but for a patient who needs therapy for CLL NOW and wants ibrutinib it all comes down to whether insurance will pay for it or not.

Since the doses are a little different between the two diseases, it shouldn't be a surprise that insurance could figure it is being given "off label."  When you submit a "prior authorization" to insurance for a drug, they also ask for a diagnosis code (ICD-9) that is specific to the disease - i.e. CLL vs MCL vs other.  If the code and the drug don't match, that is another red flag.

Does that mean it can't be done?  I've had success giving patients unusual drugs off label where it was clear to the patient, insurance, and everyone else that we were off label.  In some cases there was something uniquely compelling such as a specific mutation that matched a specific drug in a patient who had received all the available therapies already.  In short - there really are not rules - just financial realities.  In the UK, Europe, and Canada, it is a lot more strict and "off label" use is a lot less frequent. I guess our reputation as cowboys in the US has some truth.

For patients who are determined, a careful, thoughtful letter to the insurance company by the patient or the doctor citing relevant medical literature can sometimes help.  I would suggest strongly that a respectful dialogue goes a lot farther than yelling and screaming in such a situation.

With a bunch of new drugs coming, the landscape of CLL and NHL are going to change dramatically. It will move fits and spurts.  With all the dramatic changes coming in health care (that I have written and tweeted about quite a bit)  it is really hard to predict how it is going to play out.

Thanks for reading

ASH 2013 - my abstracts

ASH abstracts are out.  This has been a productive year.  I had a few more that we just not quite ready when the ASH deadline hit - but I guess that means ASCO will also be pretty busy.  The following are the presentations I will be a part of this year.  Many of these are familiar from prior blog posts.

Should be pretty easy to pick out two themes.  The B cell receptor signaling pathway involves a sequence of enzymes that start with Syk (fostamatanib, GS-9973), goes to BTK (ibrutinib and CC-292), then on to PI3K (idelalisib).  Antibody drug conjugates are another favorite topic of mine.  Brentuximab leads the way in several diseases but others are coming on strong.

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib and Rituximab for Previously Treated Patients with Chronic Lymphocytic Leukemia (CLL)

Clinical Activity Of Idelalisib (GS-1101), a Selective Inhibitor Of PI3Kδ, In Phase 1 and 2 Trials In Chronic Lymphocytic Leukemia (CLL): Effect Of Del(17p)/TP53 Mutation, Del(11q), IGHV Mutation, and NOTCH1 Mutation

Phase 1 Study Of Single Agent CC-292, a Highly Selective Bruton’s Tyrosine Kinase (BTK) Inhibitor, In Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

The Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) Monotherapy Demonstrates Long-Term Safety and Durability Of Response In Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) Patients In An Open-Label Extension Study

A Phase 1 Study Of The Selective PI3Kδ Inhibitor Idelalisib (GS-1101) In Combination With Therapeutic Anti-CD20 Antibodies (Rituximab or Ofatumumab) In Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia

Chemo-Immunotherapy Combination Of Idelalisib With Bendamustine/Rituximab Or Chlorambucil/Rituximab In Patients With Relapsed/Refractory CLL Demonstrates Efficacy and Tolerability

Idelalisib, a Selective Inhibitor Of PI3Kδ, In Combination With Bendamustine, Fludarabine Or Chlorambucil In Patients With Relapsed Or Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)

Phase 2 Trial Of GS-9973, a Selective Syk Inhibitor, In Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma (NHL)

A Phase 2 Study Of Brentuximab Vedotin In Patients With Relapsed Or Refractory CD30-Positive Non-Hodgkin Lymphomas:  Interim Results In Patients With DLBCL and Other B-Cell Lymphomas

A Phase 2 Study Of Single-Agent Brentuximab Vedotin For Front-Line Therapy Of Hodgkin Lymphoma In Patients Age 60 Years and Above:  Interim Results

Ibrutinib gets first approval in Mantle Cell Lymphoma

Not sure if you caught the news (see NY Times) but the FDA has now approved ibrutinib (now called Imbruvica) for treatment of patients with mantle cell lymphoma (see my post on the different types of NHL). 

ASCO has put out a broadcast so that you can see the data here.

The label is fairly broad (approved for patients who have had one prior therapy).  That is significant because historically drugs that have been approved on the basis of single arm phase II studies (read NEJM article here) have required patients to have had exposure to all approved drugs in a particular disease.  In mantle cell lymphoma, that would include bortezomib which does not have a huge role in the management of the disease.  Keep in mind that lenalidomide was also recently approved in this disease. You can tell by stock price that the analysts think this is a good result for the company.

This is great news for MCL patients as it will give another treatment option.  Furthermore, once approved it will allow for a lot more research to begin taking place.  Not sure how much off label use will be allowed (will vary from insurance to insurance), but certainly hoping that the CLL indication comes soon. 

FCR versus BR in frontline CLL

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

Here is a link to the data

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

Why the balance?

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

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

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

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

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

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

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

Thanks for reading

More on Gazyva (Obinutuzumab)

Genentech / Roche put out a press release this morning about the German CLL11 study that we have talked about several times previously.  American Society of Hematology meets in December and the abstracts were just released - hence the multiple press releases you will see in the news.

The drug was approved last week for the front line treatment of "typical patients" with CLL (they tended to be older and sicker than the FCR crowd).  Our center has had the opportunity to study the drug extensively and in the surrounding news coverage, one of my patients was featured in local news.  I think it is a nice story about a person taking the drug.  I encourage you to watch it (note this was different study design than CLL11, there was no chlorambucil in this study).

The reason for the press release today is the big news that we had been expecting / waiting for to show that GA-101 (obinutuzumab, gazyva) looks like it did quite a bit better than rituximab.  If you recall, at ASCO, they did a presentation where they compared chlorambucil (C) alone to C-Rituximab and a second comparison of C alone to C-Obinutuzumab.  They did not release the comparison that everyone wanted to see which was the C-Rituximab versus C-Obinutuzumab.  That is what is in the press release and will be presented in the plenary session at ASH in December.

The "progression free survival"  is actually two separate criteria: 1) alive AND 2) no relapse of CLL.  In the C-R arm the rate was 15 months and in the C-G arm it was 26 months - a full year better.  The rest of the data will need to wait for the presentation - can't wait to see it.

Thanks for reading

11q deletion CLL

Most patients who make the effort to learn about FISH in CLL know that 17P is bad and 13Q is generally favorable.  Trisomy 12 segregates based upon Notch mutations (if you can find a way to test for it) .  Somewhere between the badness of 17P and the middle of the rode trisomy 12 lies 11Q.

CLL with 11Q deletion has a unique personality.  It is notorious for having disproportionately bulky lymph nodes compared to the elevation of white blood cells (though WBC elevations are common).  Men with 11Q are considerably more common than women, and patients are often younger than the typical 72 year old average.  Furthermore the substantial majority also have unmutated B-cell receptors (unfavorable).  Patients often have need for initial therapy more quickly than others following diagnosis and patients with 11Q have shorter survival than many others.  This is in part because 11Q is often thought of as a “chemotherapy resistance” marker and I wanted to go into a deeper biology of this marker as I have for 13Q, trisomy 12, and 17P.

Once again, recent biologic insight has dramatically reshaped our thinking about 11Q.  We have previously addressed “clonal evolution” where CLL is a mixture of different “subclones” that jockey for dominance.  In the past it was observed that patients with greater than 25% of cells on FISH had worse prognosis than patients with less.  In light of clonal evolution, I tend to just think it is a continuous spectrum and if you have an 11Q clone it is likely to become dominant over time in most cases.  At any given time point, the less you have the better.  Like all other high risk genomic alterations, 11q deletion increases over time (10-15% at initial diagnosis but as high as 30% in relapsed / refractory).

Classically, 11Q deletion was thought to be all about a single protein called ATM (for ataxia telangiectasia mutated – the gene that causes a rare genetic syndrome Ataxia Telangectasia).  The gene for ATM is truly massive.  The DNA that encodes the gene (like most all genes) is broken up into a bunch of smaller pieces (exons) that all get glued together into one sequence (mRNA) before the cell can use the template to synthesize the protein.  The protein is very large and has quite a few different functions.  Consequently older techniques of measuring mutations in DNA (sequencing) couldn’t really address whether an individual patient had a mutation in the gene or not.  Furthermore, we didn’t really know the functional significance of many of the mutations because they were scattered throughout the entire gene.

Newer sequencing technologies allow us to measure with considerable precision BOTH the mutations AND the fraction of cells that have them.  It should therefore not come as a surprise that we have found an important number of cases where ATM can be mutated whether there is an 11Q deletion or not.  It is very similar to the P53 story on 17P.  You can therefore have deletion with or without mutation and vice versa.  It appears that having BOTH deletion of ATM on one copy of the chromosome and mutation on the other copy of the chromosome is worse than only having the deletion.

Whether it is deleted or mutated or both (you do have two copies of the gene), ATM plays an important role in detecting DNA damage, passing that information along to P53, and triggering an arrest in cell division and cell death.  Without ATM in place, you don't have the same response to DNA damage.  Drugs like fludarabine, cyclophosphamide, bendamustine, chlorambucil all require an intact DNA damage response for their efficacy. 

While that may seem complicated – it gets a lot worse.  I wrote quite a bit about the deletion size in cases of 13Q deletion where there are type I, type IIA, and type IIB chromosome changes that may have different prognostic significance.  Not all losses of DNA are equal to one another.  Bigger deletion sizes may include other important genes.  Indeed, the far end of the 11Q deletion variably affects a protein I’ve written about previously that is extremely important – BIRC3.  It has been shown recently that some 11Q’s have loss of BIRC3 and some don’t.  While we don’t directly know how important that is just yet, BIRC3 is a big deal as having a mutation in that protein is about as bad as 17P.  I think we will be hearing more and more about BIRC3 in the coming years as we look at it more frequently.  Finally, there seems to be an association between mutations in the protein called SF3B1 and cases with 11Q.  SF3B1 is not in the region of the deletion - BUT - there seems to be a relationship between this mutation and 11Q (sort of like NOTCH and trisomy 12).  SF3B1 is a mutation that confers resistance to fludarabine and possibly other chemotherapies.  Why this associates with 11Q really isn't known just yet but it is an important observation.  Patients with SF3B1 mutations often need therapy earlier on and don't do as well in the long term.

Wikipedia has a short description of BIRC3 here.  This pathway is also quite important as it governs the "execution pathway."  Once a cell has made the decision to die, it uses a series of enzymes called caspases.  BIRC3 is involved in governing that pathway.  BIRC3 abnormalities appear to be particularly bad thing to get.  Some data sets make it look just about as bad as having 17P deletion.  I think we are only at the start of understanding the interaction between ATM and BIRC3 in terms of deletion size, inclusiveness, exclusiveness etc.

Terry Hamblin did a very good job explaining the role of alkylating agents in CLL with del 11q, you should definitely see his discussion of the topic - link here.  In short, if you are going to give fludarabine based regimen to a CLL patient with 11q minus, many experts think you should include cyclophosphamide (ie. FCR more than FR) if the patient can tolerate it.  Some have even gone farther and asked if you need the "C" in FCR if you don't have an 11q deletion.  Most of this was based upon data generated when fludarabine was compared to fludarabine / cyclophosphamide (and rituximab wasn't in the mix).  Newer publications have suggested that the combination of FCR overcomes the negative prognostic implications of del(11q).  They definitely respond well to the regimen, but earlier relapse remains an issue.

Some are anticipating the results of the big German study comparing FCR to BR in the frontline setting.  These results may come as early as this December at ASH.  I am most interested in the subgroup of patients with 11q deletion in this study because of the question marks about alkylating drugs (chlorambucil, cyclophosphamide, bendamustine) in this patient group.

New drugs like ibrutinib and idelalisib do not have a long track record in subgroups like 11Q.  In our New England Journal of Medicine article, we saw that patients with 11Q OR 17P didn't do as well as patients without either abnormality.  The still did very well on this drug - but I expect that 11Q will remain problematic under most circumstances since it is a marker of genomic instability which is NEVER a good thing in cancer.  My guess is that earlier utilization of these targeted agents in smart combinations with other drugs may be best strategy (I've written about that here).

Anyhow, that is probably enough for now.
Thanks for reading.

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

Gazyva (obinutuzumab) approved

It is really satisfying to work on a drug before it gets approved.  I have had the opportunity to treat quite a few patients with both DLBCL and CLL with a drug that was approved earlier today called Gazyva (AKA: obinutuzumab or even GA-101).  Some people just call it "G."

I was aware this day was coming for a little while as Genentech did a video series on several of my patients who had been treated with the drug so that they could use the video in news / media once the drug was approved.

Drug companies have to be EXTREMELY CAREFUL what they say publicly about their drug.  Virtually every word they put out in advertisements gets carefully reviewed by the "commercial team" because if they make claims that are "off label" they can get into pretty deep trouble: see here.

I do not work for Genentech.  I have not received any direct payment from them (they do provide research funding to my organization - US Oncology for studies we have performed).  I have declined offers to be on a "speakers board" where I would receive compensation for speaking about their drug.  In short, I am not bound by the same restrictions they are - so I thought I might share my thoughts.

I really think that this drug is a big deal in CLL - and they can't say it.  In NHL the answer is still up in the air.

"Minimal residual disease" is a term we apply to a sensitive type of test (flow cytometry) where we can look for very small amounts of CLL in either the blood or the marrow.  Patients can be categorized as MRD negative, MRD positive, or MRD intermediate.  Not surprisingly, the less CLL you find, the longer the response lasts.  I desperately need to do another post about MRD because I think it is how we are going to be comparing the efficacy of new drugs in the future.

If you look at data from the german CLL8 study in which FC was compared to FCR, the rate of achieving minimal residual disease negativity in the FCR arm was about 50%.  If you look at the patients in the CLL11 study (that served as the basis for approval for this drug) the rate of MRD negativity in the GA101 / chlorambucil arm was about 30%.  Since the MRD negativity to chlorambucil alone arm was a big fat zero, you can attribute most of the MRD activity to the GA-101.

What is remarkable to me is that you can get rates of MRD negativity of 30% with an antibody.  I can tell you that ofatumumab, rituximab, and alemtuzumab can't touch that.  Indeed, MRD negativity to the rituximab plus chlorambucil arm was only 8%.  The FDA granted approval on the basis of the improvement of GA-101 plus chlorambucil over chlorambucil alone.  There is no mention in the approval of the difference between the GA-101 plus chlorambucil versus the rituximab plus chlorambucil.  Indeed, if you look at the graphs of how patients do, it is pretty apparent that GA-101 (obinutuzumab) is better than the rituximab arm - but since that is not what the data that supported approval, they cannot make that statement.

Rituximab is pretty much the only drug so far in CLL to improve overall survival.  I am convinced that obinutuzumab is a much better drug in this disease.  Median progression free survival for R-Chlorambucil was 15 months while it was 23 months for G-Chlorambucil.   I have written a prior post about what makes GA-101 different.  Until the FDA is able to review that arm of the study (which simply takes longer to evaluate because the data isn't yet "mature") - Genentech can't say that.

So how will the drug be used?  Insurance will be the police making sure it is used according to the label.  Every insurance company will have its own policies so some may allow off label use, some won't.  The drug is approved in combination with chlorambucil for front line therapy of patients with CLL.  Genentech is making much use of the word, "typical patients."  That is because the average age of the patients in the study was 73 years old.  Since that fits the exact age for average age for first therapy in CLL they like the word "typical."  Others have used the term "elderly."  I guess I sort of agree with their word.  Keep in mind the average age in the FCR front line study was 62 years old.  Those 11 years are enormously important.

Chlorambucil is hardly ever used in North America (although common in much of Europe and Australia).  In the US, I am guessing that many patients will use the drug alone (without chlorambucil). Chlorambucil really has a reputation that is pretty unfair.  It is a good drug, but there are many that are better.  In the right patient though, chlorambucil can be really helpful.  There have been studies that have combined GA-101 with bendamustine or even FC.  That data has not really seen the light of day so I would be nervous to use it in combination with those drugs just yet.

The main downside to GA-101 is the infusion reactions.  I have compared rituxan to rolling thunder and GA-101 to lightning.  On the first dose of either drug it is common in CLL for a patient to have either shortness of breath, low blood pressure, hives, etc.  With rituximab, it seems like those can come and go.  Every time you turn up the rate of the infusion the symptoms can start again.  You resolve the problem by slowing down, giving more tylenol, benadryl, steroids and starting again.  It can feel like the rolling thunder that goes on for minutes in a good east coast storm.  With gazyva the reactions happen very early in the infusion and feel a little more severe.  Once they are done though it seems they really don't come back - more like lightning.  With either drug it is considerably less frequent to experience these reactions on the second or subsequent dose.  My fantastic infusion nurses seemed to figure out that if you stop the infusion at the first sign of trouble, the reactions were very manageable in the patients we treated.

What I found shocking working with the drug was that when the infusion reactions had settled down, if you rechecked the blood counts they had almost normalized - even just a few milligrams into therapy and after only thirty minutes.  My research nurses and lab manager asked me several times, "what did you do to that patient?"  It defied our experience to see blood counts change so quickly.

I am pleased to see this drug get approved.  It was always a dark horse in the race.  Everyone has been focused on ibrutinib and idelalisib but I had my bets placed on this drug crossing the finish line first.  I think it is a significant new option for docs who treat the disease - but more importantly, combining it with other new drugs will give us the option to achieve very successful results without chemotherapy.  Keep in mind that Genentech is co-developing ABT-199 (GDC-0199) with Abvie.  That will be their obvious drug to combine it with.  Now that obinutuzumab has been approved though, any company can begin to combine their drugs with it.  Pharmacyclics, Gilead, and Jannsen would be smart to start combining their BCR signal inhibitors with obinutuzumab.  I bet MRD rates will be VERY impressive with such combinations!

Thanks for reading.