Tuesday, September 25, 2012

CLL treatment - avoiding chemotherapy

Managing Untreated CLL - When the patient does not want chemotherapy.
(frontline ibrutinib pt here)
(frontline GA-101 pt here or here)
Who wants chemotherapy? Well, virtually nobody would ever sign up for a dose just for the fun of it.  Yet for quite a few years, nothing has come close to the disease control offered by chemotherapy for patients with CLL.  While six months of FCR/FR may be one of life’s less pleasant experiences (see my FCR post here), durable disease control is something many would want.  Furthermore, in favorable risk CLL, there are some patients that remain without detectable disease for over 10 years.  Some thought leaders are even starting to wonder if a small proportion of CLL patients have been cured by aggressive therapy.  Fortunately the standard paradigm is beginning to change.

I did my residency at Harvard, my fellowship at Stanford, and now I practice in Oregon.  Furthermore, my research efforts have me continually in contact with the well-known investigators from Texas, Ohio, New York and beyond.   I am amazed by the geographic variation in both physician and patient attitudes toward treatment options.  While generalizations always have limitations, I’ve seen Northeastern / Southern patients enter chemotherapy more willingly than my Stanford / Oregon patients who want just about anything other than chemotherapy.  In fact, the “anti-chemotherapy” attitude is so strong in my area I’ve seen numerous patients willing to turn down potentially lifesaving therapies to pursue “alternative care” over my strenuous objections in some cases.

At this point, chemo-immunotherapy rules the day but a handful of other investigators are eagerly trying to advance the idea of avoiding chemotherapy in CLL.  Please read the following with considerable skepticism as any deviation from “standard of care” should prove itself before it is offered widely.  While different aspects of the science are generally agreed upon, putting it into one entire narrative needs to be directly tested to determine if it is true.  I strongly vote for clinical trials in this setting as it is the only way we are really going to make progress against the disease!  Fortunately, there is an explosion of trials attempting to go after this exact question.

Modern day chemo-immunotherapy regimens (FCR, FR, BR, R-CVP, R-CHOP) are what we call “geno-toxic.”  The best example I can think that illustrates this is a study that came out of the Human Cancer Genome Project looking at brain tumors.  In this project, they took samples of patients brain tumors and carefully examined the DNA  in just about every technical way they could.  In a few cases, they had samples from patients both before and after a treatment called temodar (similar to the “C” in FCR/R-CVP/R-CHOP or the “B” in BR).  What they found was unsettling to me.  After treatment, tumors contained more than 5x the number of mutations than were present before therapy started.

This should actually not be surprising.  “Alkalator” therapy works by binding to DNA and triggering DNA damage.  It really shouldn’t be a surprise if we find that our treatment overwhelms the normal DNA repair machinery and leaves cancer cells with more mutations than before.  Fludarabine also causes DNA damage but through a different mechanism.  While the old adage, “Chemotherapy is more damaging to rapidly dividing cells than stationary ones” has truth, I worry that this sort of approach is like hitting a wasp nest with a baseball bat and killing half the wasps.  While that could definitely be considered progress, you put yourself in danger if you’re not prepared for a bunch of angry wasps.

In just about every type of cancer that has been looked at with the full power of modern sequencing technology, there are some alterations in the cancer cells DNA repair machinery.  Whether that is BRCA in breast cancer, microsatellite instability in colon cancer, ATM deficiencies like those found in 11q minus CLL, or the old enemy p53 (located on 17p in CLL) that is one of the most commonly mutated proteins in all of cancer.  That means that cancer cells are not fixing their DNA as well as normal cells (which is probably how they became cancerous in the first place). 

Therefore, we are causing genomic disruption in a genomically unstable environment.  This is likely one of the reasons our CLL patients with 11q/17p alterations do not experience the same magnitude of benefit from FCR (ok, 11q respond about as well, but durations don’t last as long).  Furthermore, 1/5 patients treated with for CLL will relapse with one of these high risk markers.  If you utilize ultra-sensitive tests you find that those high risk cells were probably there from the beginning at a very low level, but now they are the ones that take over as the more “benign” cells have been killed off (sort of like the angry wasps from the nest you smacked above).

So what are the alternatives?

In patients who walk in the door with CLL that contains a high proportion of 17p deletion at baseline, many English or European docs would utilize therapy that relies less upon DNA damage and more upon immune strategies or other mechanisms of cell killing.  High dose steroids and Campath has become the standard for many such patients.  Interestingly that has not seemed caught on as much in the US.  To extend this further, patients with molecular high risk disease are often offered stem cell transplants (the mother of all immune-therapies) provided they are have adequate disease control, are young enough, fit enough, etc.

Other therapies that exert their effectiveness through “non-genotoxic” mechanisms include rituxan, ofatumumab, and revlimid.  The first two are antibodies against the cancer cells.  Unfortunately, they have their own weaknesses and come nowhere close to matching the effectiveness of FCR, BR, etc. 

Revlimid is an interesting molecule and must be carefully considered.  It is known as an “immunomodulator” or IMID.  Revlimid has a very peculiar activity in CLL that is far from predictable.  It is not uncommon to get a “tumor flare” reaction as healthy lymphocytes come flooding into lymph nodes.  It can be moderately painful and even require some pain medications.  More worrisome however is the occasional patient who experiences “tumor lysis syndrome” in which all the cells die off at once which can cause serious damage to the kidneys or worse.  This appears to be loosely related to dose so it is important to start at a low dose and work your way up slowly.  This treatment is NOT approved in CLL and access to the drug can be very difficult – though studies are currently ongoing seeking to gain approval in this disease.   Some docs who treat a lot of CLL are comfortable using this drug in this disease but many are not.

“Enhancing immunity” is the goal of several new approaches to cancer.  T-Cells can be engineered to fight of cancerous B cells.  This exciting new technology remains a number of years away and will likely be reserved for patients with refractory disease long before it is given to patients in front line.  In solid tumors, new approaches to modify the immune system are definitely turning heads.  Anti-CTLA-4 antibodies or PDL-1 antibodies are able to “turn on” parts of the immune system that the cancer has “turned off.”  In melanoma this has led to the approval of ipilumimab.  Other antibodies are demonstrating efficacy where very little progress has been made in years.  There has only been very limited evaluation of the effects of these treatments in NHL/CLL.

Many of the “novel agents” in CLL would be considered “non-genotoxic” and seek to exploit either enhanced immune mediated / antibody based cell killing or target key aspects of the cancer cells survival.  Preliminary reports indicate patients with 11q/17p abnormalities respond to a number of these agents.  These molecules are currently the subject of numerous ongoing studies.

My hope is that we will be able to utilize therapies in CLL/NHL that do not damage DNA in order to kill off the cancer cells.  With a host of therapies working their way through the system, the trick will be to figure out how to combine different treatments to maximize response and minimize side effects (and protect DNA).  We currently have the drugs in trials today that could make this a possible reality very soon.

With the average age of 71 at diagnosis for CLL, imagine if we could delay chemotherapy for 5-10 years with effective “targeted” or “immune” therapies.  We might find that some patients would never even need chemotherapy.  Honestly, I don’t think that is too far off.  This approach will need to be intensively studied in the context of clinical trials.  When you consider that major research groups are going to begin front line studies in which FCR is directly compared to non-genotoxic  targeted therapies – we may be only a few years away.

Thursday, September 20, 2012

How drugs are made / why it takes so long?

Motivated patients can often get the scoop on an exciting drug very early in a drugs lifecycle.  Occasionally, a drug is obviously effective in early testing yet it can be 5-6 years before the therapy is available to the general public.  I’ve seen patients post their results to the web and entire groups of patients may know about the success or failure of a drug even before the company conducting the study is aware.  When someone is running out of good options the delay between drug creation and drug marketing can feel like an eternity.

So why does it take so long?  It is probably not what you think (in fact the FDA may be one of the faster elements of the process).  Once a molecule is patented, the clock is ticking on how long a company can make a profit on a drug.  Furthermore, companies have a daily “burn rate” which is the cost of keeping their company going.  Conducting scientific experiments is extremely expensive.  Without a product on the market, a small biotech company can get very anxious to move the process as quickly as possible – but data takes time to create.  For bigger companies the daily cost of operations is truly enormous.  They may have more flexibility than a smaller company but bad management, failed late stage studies, and thin pipelines has doomed even some of the biggest companies.

A drug is typically born when a lab scientist working at a pharma or biotech company designs some sort of experiment then screens a range of compounds to see if they can change the result of the experiment in some desired way.  This process isn’t really a discrete step in the process.   There may be a lot of back and forth with compounds that are selected, refined, modified, thrown out, started over, discarded again, re-modified, etc.  Depending on the complexity of the experiment (assay) or number of experiments this can take many months to even years.  Larger companies have introduced automation to the process and “compound libraries” which may literally have tens of thousands of potential drug molecules can be screened very quickly.

Once a compound is identified that accomplishes some biochemical task, it is carefully analyzed to determine if it has pharmacologic properties that make it likely to be a decent drug.   Medicinal chemists may then make any number of modifications to the original molecule to “optimize” it for drug delivery.    Not every drug does a good job dissolving where it is supposed to dissolve, get absorbed where it is supposed to be absorbed, last long in the blood, etc.  Depending on how the process goes, that may punt it back to the prior step a few times.

Once a drug is selected and optimized there may still be a year or more of work to do before it can ever get close to a human study.  It has to be run through a ton of safety screening studies – does this affect cardiac conduction, mutate DNA, alter effects of metabolism in the liver of other drugs etc.  Only after all that is done, a company has to do animal studies mandated by the FDA.  Usually this includes both 28 day safety and longer in rats and two mammal species like mice, dogs, or monkeys. There are a lot of regulations about this sort of testing so it cannot be casually done. Because this step can be so expensive, smaller companies may spend a lot of time on prior steps to make sure the molecule is exactly what they want before doing these sorts of studies.

Once all that is done, the company can go to the FDA and register for an “investigational new drug.”  Once an IND is granted it allows them to conduct the first human experiment so there is a lot of data review at this point.

Companies may have a lot of talent in house to do a lot of things, but most companies do not have “thought leader” level expertise in any particular disease.  At this point there may be a lot of discussions with academic opinion experts, meetings called “scientific advisory boards” to help educate the company about specifics of trial design, disease features, etc. 

I do need to editorialize here for a moment.  In the past, there have been abuses between pharma and physicians.  Docs were given expense paid trips to attend “advisory boards” which were thinly veiled commercials for products.  These were excessive and wrong.  I am glad they are gone.  New policies make it required to disclose all payments from pharma to physicians.   Unfortunately one bystander effect of the regulations and policies has been to stifle the critical communication that needs to be exchanged at this step of drug development.  An increasing number of high level thought leaders are no longer sharing their expertise in these environments for concern of being mischaracterized as “in the pocket” of pharma for receiving a payment that often does not even cover the expense of being out of clinic.  Oh well, such is the cost of our good intentions – back to drug development.

The first step in clinical development is typically a phase I study.  In this sort of study, small groups of patients are given the therapy for a duration of time and closely followed for safety.  If they do well, another group is given the treatment at a higher dose and so forth.  An individual cohort may take a few weeks to a few months to fill with patients.  Often patients are followed for a month.  Following each dose period, there is typically a conference call to address safety.  “Herding cats” hardly does justice to the attempt to get 6-8 research physicians onto a single conference call.  Therefore a single dose cohort often takes between 6-8 weeks in ideal circumstances.   

The purpose of phase I studies is to define “maximum tolerated dose.”  Fortunately / unfortunately many of the new precision drugs have far less side effects.  As a result you can find yourself testing doses far higher than you actually need.  There is always a lot of hand wringing about defining the “RP2D” aka: recommended phase two dose.  I treated the very first two CLL patients in the world with ibutinib.  It was clear within 24 hours that we had something very unique.  Lymph nodes were smaller, WBC shot up, patients felt good, etc.  That was back in 2009 (If I recall correctly).  We are still a ways off from FDA approval despite the clamoring of many patients to get access to the drug.

Once RP2D is established, companies start phase II testing.  Perhaps they got some hints from phase I about certain types of patients they want to evaluate.  Between settling on study design, site selection, IRB approval, contract approval, etc it may take over a year to launch a phase II study and get “FPI” aka: first patient in.  The major academic universities and cooperative research groups recently launched a major initiative to ensure they could meet the one year deadline – pretty sad as far as I am concerned.  My group targets 6 months for phase II/III testing and 3 for phase I studies.  In most cases that trounces the competition.

Patient accrual to studies is often painfully slow.  Often a site commits to 0.3 patients per month in lymphoid studies (4 patients in a year) because a specific population is desired.  Imagine how many sites are required then to execute a 60-120 patient study in a timely manner. 

You also have to think about the purpose of phase II testing which is really about exploration of efficacy.  At the end of a phase II study, you want to have the data you need to design the right phase III study which is typically the basis for drug approval (for many drugs in fact – two positive phase III studies are required).  You typically want to identify the best patient subgroup (prior therapy, molecular details, medical comorbidities etc.).  Not only do you need mature data, you need to make sure the data is clean (there is an entire industry called CRO / contract research organization to assist pharma companies ensure that their data is accurate) and then analyze it.  You may need 2-3 years from phase II FPI to have a good grasp of your drug.  Remember – response rate is the fastest variable to measure, but rarely indicative of true activity of a drug.  Instead, you often need PFS (progression free survival).

During phase II testing, the clamor for a new drug can begin to get very strong.  Often several phase II studies are ongoing at same time and several hundred patients have had access to the drug.  Data has been presented at major conferences and “the word is out.”  RARELY- FDA may approve a drug on the basis of very compelling phase II data.  By FDA standards, approval from phase II requires that a patient have received ALL PRIOR APPROVED THERAPIES for an indication and need new treatment (ie. unmet medical need).  Don’t expect too much logic here – sometimes things just don’t make sense.  Why would ofatumumab not be approved in bulky CLL (where campath does not work) unless patient had prior campath….

Trying to get approval out of phase II is a very valuable shortcut for pharma but becoming very difficult in CLL/NHL. This is where “companion diagnostics” are becoming increasingly valuable.  If you have a test that predicts exactly which patients are likely to respond and which are not – FDA may allow faster passage (eg. Xalkori in lung cancer).

Often small biotechs with successful drugs are swiped up by larger pharma when a drug appears promising.  Just count on a 6 month productivity wipe-out as the two companies merge and figure out who makes what decisions.

Finally, 2-5 years after a drug entered human testing you are probably ready for phase III testing.  Bring all the same baggage from before (thought leaders / protocol design, study start up times, etc.)  Now set out to prove that your treatment helps people live longer than prior therapies.  In CLL where front line therapy may be associated with remissions that may last 6 years or longer – not to mention salvage treatment!  Aargh.  How are you ever supposed to get a drug approved.

Fortunately there is such a thing as “surrogate end points.”  These are clinical variables that the FDA may accept instead of overall survival in studies with such long natural histories.  The slope is ALWAYS slippery here.  Ideally you meet with the FDA beforehand and work out a “SPA” or special protocol assessment.  This essentially is a promise that if you meet a certain endpoint, you can get your drug approved.  Sometimes there can be some “gray territory” between what is a promised endpoint and what is a suggestion.  Quite a few times a company has crossed the finish line and found out that the finish line actually moved….

Phase III testing is a gamblers paradise.  There are so many ways a trial can fail that it is amazing anything succeeds.  Credit belongs to the determination of many individuals who make the science happen.  With single studies often costing tens of millions of dollars to execute – this gets to be really high stakes.

Keep in mind patients are often appropriately  clamoring for “compassionate use” at this point - yet every patient who gets the drug outside of a study could very well be one patient that might have been accrued to the study if they were able to make it to a study center.

Finally after one (or ideally two) successful phase III studies (by which time, estimates are that that a company may have spent $800 million dollars on a drug) you can take your drug to the FDA.  You package up all of your data and file an NDA (new drug application).  FDA appropriately scrutinizes this data extremely closely.  Sometimes individual patients are thrown out (despite the cost of 20k it took to get their data).   FDA is usually able to turn around a decision in 6 months.

Once approval is granted – you have a drug you can sell.  Cost is another conversation all together and I cannot possibly touch that in this post (fingers cramping already).  As you can see – this is a very slow science.  For patients facing a fatal disease it can feel unfair.  I’ve had drugs in my pharmacy that might be significantly life prolonging for a patient who is dying, but cannot give it to them because they are ineligible for the study.   It is hard on me too – but one of those no-no’s you would NEVER do as a research doc as you would be swiftly banned from research if you were to do so.

Emotions run high in the process.  Most of the people I know in research truly want to do it for the benefit of the patients.  I often hear comments about sinister influences on the process but I think most of the time those are more based on ignorance than reality.  Of course companies wish to have a profit at the end of all this.  Who can blame them?  Would you give away hundreds of millions of dollars purely out of altruism?  Perhaps some would, but it wouldn’t look like the research pipeline we have today.

I believe chemotherapy will be obsolete for most patients with CLL within 5-10 years.  After that, I think only a small minority of patients with the disease will die from it.  For NHL, the biology is a little more complicated.  Thus far the targeted treatments have not been as robust, but there are still significant advances being made today.  I hope everyone can take a deep breath and find their way to a center that offers research.  It will speed things up for all of us!

Sunday, September 16, 2012

Genetically Modified T-Cells for CLL (and evetually NHL)

(Sept update of prior post after I heard Carl June present at German CLL conference last weekend)

Last summer there was quite a splash when researchers at University of Pennsylvania used genetically manipulated T-Cells to fight off CLL.  The studies were simultaneously published here in New England Journal of Medicine and here in Science.  This past weekend, I had the opportunity to hear Carl June update us on the progress of this technology so I wanted to update this post in light of what I learned.

Looks like Novartis is going to purchase the technology and in my mind that is the best possible outcome for making this move more quickly.  While I love the science done in academic settings - those settings are not designed to bring these breakthroughs to patients on a broad scale.  I know many of the folks at Novartis and they are very good at advancing technology quickly.

I've had a lot of patients ask me about these studies so I thought it might be interesting to describe the technology at play.

The "brains" of the immune system is probably the T-Cells with the B-Cells being second in command.  T-Cells help coordinate many aspects of immunity and heavily rely upon their "T-Cell Receptor" (TCR) which is unique to each individual T-Cell to figure out when to engage a target or not.  B-Cells also have a "B-Cell Receptor" aka. antibody / (BCR).

We've gotten pretty good making artificial antibodies and they are a good therapy (rituxan, GA-101, herceptin, ofatumumab, etc).  So far we have no idea how to make a good T-Cell Receptor.  Much to my surprise though, you can take the part of the BCR that hangs out outside of a cell and the part of the TCR - stick them together as a "fusion gene,"  and the thing works as a "chimeric receptor" (I forget the greek story of the half lion, half human - called a chimera - I may also have my story completely wrong but the idea is the same).

Now you can make your artificial B cell receptor - plug it onto a T-Cell receptor and make T-Cells do things you want them to do - like get rid of cancerous B cells (aka CLL/NHL).  There were a number of other key features (costimulatory molecules, lymphoid depletion, etc) but for now it is reasonable to focus on the main technology.

Viola - it works!  The have now treated about 11 patients at Penn.  Most were CLL but a few were Acute Leukemia.  If it works in ALL, that is very interesting.  That disease is extremely aggressive and new therapies are needed there even more than CLL.

But there are potentially problems.
1)  To get this new T-Cell chimeric receptor into the T-Cell, you need to infect the cell with a virus that has some resemblance to HIV.  It is heavily modified, but you can get the picture, there is need for caution.

2) So far, many of the patients who respond favorably to the therapy undergo a very medically frightening reaction when the T cells attack the B cells.  In some cases it has been life threatening and required ICU level support.  As if that is not bad enough, you cannot predict when this will happen.  In some patients it happens a few days later, in others, it may be 3-4 weeks later.

3)  The manufacturing of the genetic modified T cells may be finicky and it is possibly the reason this does not work in all patients - when they try to achieve scale to make this work for lots of patients, this may be a big problem.

4)  If this works, it permanently depletes all health and cancerous B cells.  So much for B cell immunity.  Furthermore, it looks like plasma cells (the professional antibody producing cells) also slowly disappear.  Therefore you may need monthly IVIG shots for the rest of your life.

5)  What happens if the T-Cells and B-Cells fight to a draw?  Do the T-Cells keep proliferating?  What happens then?  Right now there is no "off switch."  You might be able to program in a "suicide gene" but that was not a part of this treatment.  Talking with some folks at the conference, it sounds like that may be a future consideration with these treatments.

6)  Gene therapy periodically causes a whole different kind of cancer - a really nasty one.  Hard to exchange a slow disease for a chance of a  fast one unless that slow one has ran out of other good options.  They are using a "lentivirus" platform instead of a "retrovirus" platform.  They feel this minimizes this problem but I'm not convinced.  Either way, the FDA requires that patients get observed for 15 years since that is the standard for "gene therapy" studies.

7)  Timing - this is not likely to be available for another 5-10 years at best.  In the meantime, new CLL drugs like ABT-199, ibrutinib, CAL-101, GA-101 and so forth are making CLL such a different disease that it may render this approach less interesting.  It could still be extremely valuable in NHL where we need more breakthroughs.

So who will this be appropriate for?

In CLL, I would send someone for this if they required a stem cell transplant.  This may be quite a bit better than getting someone else immune system as it will get rid of the graft vs host disease.  This may be great therapy for the patient with NHL - particularly DLBCL that has relapsed.  Furthermore, it may make some older patients eligible for immune intervention who may otherwise be ineligible for a transplant.  I would NOT think this is a good front line therapy for anyone - not any time soon at least.

Many of these limitations may have answers and I am excited that a company is willing to invest in the idea - it often moves ideas a lot faster than the grant cycles of the universities.  Hopefully this goes someplace exciting but for now it is still a ways off for mainstream CLL treatment.  Huge gratitude to the brave patients who are the first ones on this experimental therapy - they may be paving the way for many others.  Will keep you posted as I hear more....

Friday, September 14, 2012

What is FCR?

FCR is a combination of three drugs that are each active in CLL – fludarabine, cyclophosphamide and rituximab.  Although the regimen has been used in mantle cell lymphoma and other NHL’s it is primarily a regimen used in chronic lymphocytic leukemia.  If there is such thing as a “standard regimen” in CLL, FCR is probably it.  For a regimen considered to be a “standard” there is a lot of emotional debate among academic physicians about how broadly to utilize this regimen.

I had the privilege of presenting the initial “patterns of care” data set at American Society of Hematology 2011 Annual Conference.  Put together by many of the leading minds in CLL research, this study attempts to determine just how American patients with CLL are treated in the “real world” (ie. 90% community practice, 10% academic).  The findings were surprising.  I invite you to review the 2011 data set linked here and draw your own conclusions.  In short, many US physicians hesitate to use FCR - even in the populations where clinical trial evidence suggests it has most impressive activity.   

Several years ago at a major scientific meeting one of the most important characters in CLL research was asked to give his three favorite CLL regimens.  His answer was, “FCR, FCR, FCR.”  Just a few years later though, we are hearing of the exciting new therapies including ibrutinib, CAL-101, ABT-199, new antibodies etc.  It was therefore profound to hear the "father" of the regimen state recently, “We are going to get rid of FCR.”  While I am optimistic about the future, we live in the present.  FCR is a very effective regimen and for all its flaws - it provides some of the most durable remissions we can obtain in this disease and in some cases people have even questioned if a minority of patients might be cured.

Much credit belongs to the MD Anderson team for developing and advancing FCR.  Many of the regimens created at MDA regimens follow a theme – “if a drug works, put it together with any other drug that works and pack as much punch into a single regimen as you can.”  FCR is pretty close to the maximum amount of chemotherapy you can put into a single regimen.

It is important to note however that the average patient who travels to MD Anderson is not the same as the average patient seen in most community practices.  If you have the means, resources, insight, and physical ability to travel to Houston you are not the “typical” patient with CLL seen in the community.  Consequently, what can be done well there does not always reflect what can be done elsewhere (ie. the input influences the output). 

None the less, the German CLL research group in the CLL8 study compared FC to FCR and published one of the first studies that showed an improvement in overall survival in CLL based upon front line therapy choice in a disease that can often last many years.  Multiple other research consortiums use FCR as the standard from which to try to build, modify or compare.  With so many votes of confidence from so many smart CLL docs, the discussion about what regimen to use should often include FCR even if the unique clinical circumstances result in a different final answer.

I thought I would start by giving a brief description of each of the drugs.  For purpose of this post, I will go in reverse order because I need to spend the most time talking about fludarabine.  So I will describe RCF….

R=Rituxan. Rituxan is an antibody. You make antibodies to fight colds, flu, e.coli, etc. Instead of a naturally occurring antibody, this one is "engineered" to bind to the outside of a lymphoma/leukemia cell and alert the immune system to go after it. See my other post "Building a better CD20 antibody." People can often have "infusion reactions" with the first dose (chills, shaking, shortness of breath, rash, etc). If you actually measure "b-cells" in the blood while administering the antibody, you can see them disappear from the blood during the infusion. As those b-cells go away they release little hormones that cause the symptoms. Often the symptoms do not recur with subsequent doses as the B cells are gone. Overall, most people tolerate the drug extremely well and are not even aware they are getting a very effective anti-cancer treatment. Those patients with side effects can often be managed by extra tylenol, benadryl, steroids, etc.

C=Cyclophosphamide. This is an old school chemotherapy that has been around for quite a few years. It binds to DNA in the nucleus of the cancer cell and prevents effective replication of the cells genome. Those cells that divide more rapidly are more sensitive to the treatment. Therefore cancer cells and normal bone marrow are most affected. It lowers healthy blood cells as well as bad ones. Fortunately the good guys recover more quickly. It can also cause nausea but our nausea medications are so good, that is rarely a problem. There can be bleeding in the bladder but I have given a ton of cytoxan and I've never seen it as a problem.

Fludarabine is what is known as an “anti-metabolite.”   It earns this name by functioning as a “purine analog.” In order to explain this I have to make a quick diversion to basic cellular biology -  I promise to be brief. 

Recall, DNA is the basic “master plan” for all the genetic material a cell needs for daily living as well as replication.  It contains all the “codes” to lead to the production of all the proteins the body needs.  Proteins are the actual engines, enzymes, building blocks, etc. that do the work in the cell.  Between DNA and proteins is a molecule fairly similar to DNA called RNA.  RNA is the intermediate step between DNA and proteins.  Most of the work of protein building happens in a part of the cell known as the cytoplasm whereas the DNA stays hunkered down in the nucleus.  RNA is the “messenger” that takes the protein building instructions from the nuclear DNA to the protein assembly lines in the cytoplasm.  Both DNA and RNA are made up of a series of 4 basic building blocks.  These are two types of purines and two types of pyrimidines.

Fludarabine is just a modified version of one of the purines you already use billions of times every day.  It is similar enough to the “A” molecule in DNA and RNA that the cell can’t totally tell the difference.  Therefore, as your cells happily go along the way making or fixing DNA or sending RNA out to the cytoplasm, they can mistake a fludarabine molecule for an “A” molecule.  The “chemotherapy twist” here is that the modifications of fludarabine cause the DNA or RNA molecule to be synthesized wrong (premature chain termination, mis-matches, etc) and fall apart.

If there is one thing most cells are good at, it is making sure their DNA is just right.  We spend a ton of energy making sure we don’t have mutations in the basic blueprint of our cellular DNA.  All sorts of very important molecules such as p53, ATM, BRCA-1, PARP, etc  are there just to make sure our DNA maintains structural integrity.  If those proteins get wind that the DNA has been mutated, they try to fix the error.  If the error can’t be fixed, the cell is programed to die.

That is the basis for fludarabine activity – mess up the DNA/RNA and count on the cell to take itself out of the picture.  For a variety of reasons, your cancer cells are more sensitive than your normal cells. 

Put all these together and you have FCR!  The combo is very effective.  In studies, the median (50% do better, 50% do worse) time previously untreated patients both remain alive and without disease progression (Progression Free Survival aka PFS) is about 5-6 years!  At 10 years, 1/3 of patients still have not relapsed.  Not bad.  If you could opt for 4-6 months of therapy and not have to deal with the disease for another 10 years, I think most people would think that is a good wager (even if only 1/3 get that sort of benefit).  Current guidelines suggest that if your initial remission duration lasts greater than two years, you use the same regimen again when the disease comes back.

For most patients FCR is a moderate hassle (3 days of treatment every 28 days for 4-6 months) but the average person doesn’t feel too sick.  With FCR, you keep your hair, nausea isn’t often that big of a deal, fatigue is fairly common but not overwhelming. 

There are problems however.  T-cells are also pretty sensitive to fludarabine.  Since they are the “brains” of the immune system, FCR can really lower the immune system.  I often give patients preventative antibiotics against both the chicken pox virus (which causes shingles in adults) and an odd lung infection known as PCP which is otherwise only seen in patients with very low immune function (such as HIV).  You also have to watch out for reactivation of a virus most of us carry but rarely notice called CMV.  It can cause a whole host of strange problems.

Another issue is definitely age.  FCR gets harder to tolerate the older you are.  In the MD Anderson studies, the average age was in early to mid 60’s whereas in typical practice most patients are in their 70’s.  Those several years can make a huge difference.

Kidney function declines as a function of age.  Fludarabine gets removed by the body through the kidneys.  The same dose given to a young patient has a very different effect than it would on a patient in their late 70’s.  When given as a single agent, beyond age 70, it isn’t really clear that fludarabine works as well as old fashioned chlorambucil (a commonly utilized standard in Europe that is neglected in North America)  – at least in part because the side effects are worse.  Occasionally you see someone get really wiped out bone marrow from fludarabine based therapy.  Often it is only in retrospect that you identify that their kidney function was getting a little borderline. 

Long term, there is concern about the effect on the bone marrow.   After several cycles of fludarabine based treatment, it is not uncommon to see it take longer and longer for the marrow to recover to full strength.  Furthermore at its extreme, FCR can give rise to another big marrow problem called MDS which can even become a much more aggressive version of leukemia.  There is even a significant proportion of patients who pass away while in remission from their CLL from a second cancer.  It is not clear if this is related to FCR but it is definitely worrisome.

Those are the clinical concerns – then there are the biologic concerns.

I mentioned above that there are a lot of proteins responsible for making sure DNA is intact.  Two are of particular relevance for patients with CLL.  P53 is called the “guardian of the genome” and it is thought to be the main problem when somebody has 17p deletion because that is where p53 lives in the genome.  The other is the ATM protein which lives on chromosome 11q.  The ATM protein on 11q is responsible for fixing double stranded DNA breaks.  These two familiar proteins are often missing in patients with relapsed or refractory disease.  If someone has a FISH result that shows they have most of their cells lacking a copy of 17p they get very short durations of benefit from FCR compared to patients lacking the abnormality.  Although the published response rates to FCR exceed 90%, I had a memorable patient with 100% 17p deleted stage 4 disease not even budge in response to FCR. 

Recent technologies have made significant advances in our ability to detect if someone carries cells with p53 abnormalities.  I have written in other posts about clonalevolution in CLL.  It turns out that if you look hard enough 1/5 patients may have cells with a p53 abnormality at diagnosis even if it does not show up on their FISH panel.  It may be that only one out of several thousand cells actually has the abnormality – but it is there early on.

Now treat that patient with FCR and get rid of all the sensitive cells and you may find that what you have left are the ones that are resistant.  Even if you have a “complete response” that does not mean you may not have some resistant cells lurking – we just don’t see them very well with conventional testing.  When that patient’s disease comes back, it may be that the “resistant clone” has become the dominant.  Therefore, they may not have been 17p at diagnosis but they are at relapse.  

While 17p disease at relapse is still not the majority of patients, it is a disproportionate amount of the patients who we really struggle to get back under control and may be well served with a transplant or one of the novel agents that seem to be less influenced by 17p.

There are some very passionate feelings out there among thought leaders about the role of FCR and I need to tread carefully here.  FCR is a VERY EFFECTIVE regimen that most younger patients tolerate very well.  In a younger, good performance status patient lacking 17p at diagnosis, I think it is felt to be the treatment of choice.  In patients > age 65 I might consider alternatives unless they are very fit with good kidney function.   With newer drugs that “king of the hill” status is eroding but things never move as fast in science as our patients want.  Investigators are hoping to “replace” FCR but we have a ways to go before we are there.

We are very fortunate to have a bunch of tools in our tool shed when it comes to CLL.  The newer agents really look to be like a dramatic step forward in terms of both efficacy and tolerability.  I am optimistic that CLL treatment is going to move away from drugs that damage DNA as a basis for efficacy very soon.  We do not know what we will find in terms of resistance to the newer agents but I anticipate we will see less 17p/11q upon relapse.   Since so many new drugs are winding their way through the system, I don’t think we are too far from providing targeted treatments that may allow some patients to never get traditional chemotherapy.

That’s all for now.  There is a lot more I should probably write about the topic but perhaps it will serve as a motivation for more posts on the topic soon.  Perhaps next I will write about the patterns of care I mentioned above….

Here is video link for Michael Keating perspective on the topic.

Tuesday, September 11, 2012

How to read a flow cytometry or FISH report

This is a "webinar" presentation I gave to a number of research nurses on how to interpret clinical reports for flow cytometry, FISH, and cytogenetics and enter the test results into research "report forms."  These reports can be VERY confusing unless you are familiar looking at them and I often find docs often miss many of the subtle findings that can be buried in the fine print - so my presentation is really about the fundamentals.  If you are a patient confused by these reports, hopefully this may be useful to you. 

Although I touch on the prognostic information contained in these reports, it is primarily about how to understand the actual test results.  It is directed to an audience involved in a CLL research study but the nature of the material makes it useful for patients with NHL as well.

I would recommend skipping the first 3 minutes as webinars are a little clumsy and this one is no different.  I give some useless background info before launching into how to read CD19 / CD5 coexpression, trisomy 12 and so forth.