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

Molecular Prognosis in DLBCL

There is a new test for patients with diffuse large B cell lymphoma (DLBCL) that has the potential to alter the way we manage the disease.  R-CHOP is very good treatment for approximately 2/3 of patients with DLBCL who are cured - but that still leaves quite a bit of room for improvement.  What we really need is a way to identify the patients who are high risk right from the outset.  That will enable us to concentrate our efforts to improve R-CHOP in the high risk group - and perhaps even consider ways to make therapy less intense for the low risk patients (in clinical trials only for now).

As you probably know from my prior posts - there are a bunch of different types of lymphoma.  My post about telling them all apart has been the most frequently visited page on my blog.

What makes lymphoma interesting to manage is that a two cases of a specific disease like DLBCL that may look identical under the microscope can be very different biologically.  Those differences may have consequences for treatment, prognosis, etc.  We are now in an era where we can begin to measure those biologic differences and figure out what to do about it.

In the past DLBCL was DLBCL was DLBCL.  If you looked into the microscope and saw larger cells (centroblasts) and they infiltrated the lymph node in a "diffuse" pattern and applied a few extremely simple tests to prove it was of B cell origin - the diagnosis was DLBCL.  We really didn't understand that cases had fundamental biologic differences and they were pretty much treated all the same.  You gave them all CHOP (rituxan wasn't around yet) and about half of patients did well and half didn't.

Understandably docs and patients want to be able to predict how an individual patient will do right from the outset.  Researchers looked at large data sets and realized several "clinical variables" (i.e. easy lab tests or patient characteristics) could segregate patients into risk categories.  By looking at a patients age, stage, ldh (blood test), patient functional status (ECOG score), and the number of places where the lymphoma affected the body outside of the lymph nodes - you could calculate a score called the international prognostic index (IPI).  After rituxan improved things - the IPI was revised - giving the R-IPI which can be calculated online.

IPI and the R-IPI were good for their day, but in 2000 a new technology called "Gene expression profiling" was applied to a large group of DLBCL samples.  A buddy of mine from Stanford named Ash Alizadeh (the smartest I've ever known) published a paper in the journal Nature that helped identify two subgroups of DLBCL called "germinal center DLBCL" (GCB) or "activated B cell DLBCL" (ABC).

This technology measures a differential quantities of a specific type of RNA called mRNA.  mRNA is called "messenger" RNA because it is synthesized in the nucleus of the cell by being copied off the DNA template.  It then goes to the cytoplasm where it serves as a "messenger"for the protein synthesis machinery.  Different types of lymphoma need to make different proteins.  By measuring the mRNA you can tell these lymphomas apart.

One of the cool aspects of this technology is that you can simultaneously measure THOUSANDS of mRNA's at once.  You can let the data sort itself out into patterns (unsupervised analysis) or you can ask questions of the data (supervised analysis).  One thing to shake out of letting the patterns sort themselves out was that there are two main types of DLBCL - the Activated B Cell (ABC) and the Germinal Center B Cell (GCB) subtypes.  Understanding that there are two main types of DLBCL has been a big advancement in the disease.  We are now learning that underneath this differential expression are unique mutations that probably cause the diseases in the first place.

The main categories of DLBCL to emerge from this was the Germinal Center B Cell  / Activated B cell subtypes.  The GCB subtype do a lot better than the ABC subtype.  Since those patients with ABC generally do not do as well, there have already been a number of clinical trials focusing on that subgroup specifically (such as the addition of velcade to R-CHOP for this group).

The were two big headaches with this technology that prevented it from becoming a standard test.  The first is that it has required a chunk of tissue that was taken directly from the patient and put into the freezer instead of being immersed in paraffin which is the standard in most pathology labs.  The only "frozen" samples were pretty much the domain of major research centers (these specialized freezers are expensive).  That meant that the vast majority of patients who had a biopsy to get the diagnosis might have to have a second biopsy if you wanted to get the expression profile.  The second problem is that the "chips" that enabled you to measure thousands of genes at once were expensive.  Those barriers essentially kept this knowledge out of routine practice.

There have been a number of efforts to substitute a commonly used technology called "immunohistochemistry" which is pretty inexpensive and readily available.  Unfortunately several groups have developed different testing criteria, it can be hard at times to get labs to agree on the results etc.  Even with these limitations though, more and more people are getting this testing done as part of their work-up.

In an effort to make the expression profiling technology more applicable to clinical samples, the Ron Levy laboratory (where I proved I have no business working in the laboratory) went back to the ABC / GCB expression profiling data sets and asked the question - which markers best predicted prognosis - both good and bad (supervised analysis).  They pulled out six genes that helped determine which patients had high or low risk.

Unfortunately these samples came from the pre-rituxan era and it was unclear if the gene would hold their value in the rituxan era.  Researchers then went and rounded up a bunch of clinical samples from patients treated with either CHOP or R-CHOP.  They found that a few of the markers were not as good but two main markers stood out in their ability to predict outcome - those were LMO2 (which helped segregate GCB/ABC pretty well and TNFRSF9 (aka CD137 or 4-1BB) which served as a marker of the surrounding immune system.  By focusing on just two markers - you could run the test without using an entire gene expression chip (making it a lot less expensive).  Furthermore, they were able to use a newer technology to extract the mRNA from samples embedded in paraffin.  This allowed access to the test for routine clinical samples.  The results come from a mathematical formula that converts expression into a score and spits out high / intermediate / low risk.

Finally - a test that can be run on routine clinical samples, that is relatively easy, and reflects tumor biology instead of just clinical variables.  The next question was what happens to IPI.  Fortunately the results enhanced each other instead of just replicating one another.  They found that you could combine the IPI and the biologic score to further refine the prediction model.

So where does this go from here?

Right now, a lot of frontline DLBCL studies require certain IPI in order to enroll (commonly an IPI score of 3 or higher)  I think this test could be integrated into clinical trials to enlarge the population of eligible patients.  It is also useful for the newly diagnosed patients who wants to understand their prognosis better.  Right now, outside of a clinical trial, I am not totally sure what to do for the patient who has a high score.  Do I give them R-CHOP or do I try to intensify their therapy.  At this point, I am unclear what alternative therapy to choose - perhaps R-EPOCH?

Anyhow, I think this is a step forward in DLBCL.  Hopefully we will see more data sets that validate the test.  It can be ordered today.  I am optimistic that this will take a lot of science developed over the last 13 years and adjust our management of DLBCL - particularly for that group that isn't cured with R-CHOP.

Thanks for reading.









(Disclosure- I worked in Ron Levy's lab and I personally know Izidore Lossos - I think they are great researchers so I tend to believe their conclusions - I have no financial relationship pertaining to this test to disclose)

What is Tumor Lysis Syndrome (TLS)?

Tumor Lysis Syndrome (TLS) is the term applied to the death of cancer cells at a rate that exceeds the body's abilities to deal with the consequences.  While we normally think of a "tumor" as a solid mass, this syndrome is probably more common in the lymphomas and leukemias then it is in cancers of the lung, breast, colon, and prostate.

While we might think that killing cancer cells is a good thing - killing too many at once can be a disaster.  In general this is a sufficiently uncommon problem that most patients do not need to worry about it - but for patients receiving treatment for any lymphoma or leukemia it is reasonable to ask your doctor if it is much of a concern and what to watch for.  I find that most patients are pretty unfamiliar with TLS so I though a brief description might be useful for patients who want to understand more.

In human physiology, cells have an extremely important boundary called the "plasma membrane."  It essentially is the zip-lock bag that keeps the insides in and the outsides out.  It is pretty remarkable because the insides of cells are a lot different in composition than the environment outside of the cells.  Cells spend a lot of energy keeping things that way.

If you consider something simple like potassium - there is a lot of it inside of cells and very little outside of cells.  Sodium is the exact opposite - lots on the outside and not much inside.  This separation of ions is important because it serves as the basis of a lot of electrical impulses in a wide variety of cells.

Under appropriate stimuli, you get a sudden reversal of these ion distributions.  Sodium flows in through specific protein channels and potassium can flow out just as quickly (so that we don't spark).  This creates an electrical current that can serve a ton of important physiologic needs.  In nerve tissues, it is what helps send nerve impulses all the way from your toe to your brain.  In cardiac muscle, it is what helps coordinate your heart beat.  In B-cells it helps the b-cell identify that the b cell receptor just found the virus it was supposed to fight off.

Just like all aspects of human physiology, things can go wrong.  Push yourself too hard in a sporting event and you overwhelm your skeletal muscles ability to keep things in balance - you get a cramp.  In cancer medicine, we occasionally encounter "tumor lysis syndrome" where we kill off a bunch of cancer cells all at once - and the insides of the cells ends up outside the cells causing a variety of problems.  Do this slowly enough and the kidneys and the liver clean up the mess.  Do it too quickly and those organs can't keep up.

Since we already talked about sodium and potassium we might as well start there.  When too many cancer cells die at once (and the inside / outside barrier breaks down), you can sometimes see sudden dangerous elevations of potassium.  While potassium is normally a good thing too much potassium is very dangerous.  As I mentioned above, potassium balance helps your heart beat right.  While the body is pretty good at adjusting to slow changes, if you suddenly raise your potassium it causes the electrical impulses of the heart to become ineffective and in extreme cases can cause it to stop.  Fortunately we can often bring it back down by giving lots of IV fluids, diuretics, insulin, sugar, and even something that helps you poop it out.  Administering calcium can help reset the balance as well.  Sometimes people even need temporary dialysis to get rid of the extra potassium.

Potassium isn't the only problem though.  All that cellular DNA has to go somewhere.  It gets broken down into a compound known as uric acid.  Folks with gout probably know a little about uric acid because it can sometimes form crystals in joints like the big toe or the knee which can be extremely painful.  In tumor lysis syndrome, sometimes those crystals form in the kidney and can cause significant organ dysfunction.

Once again, there are lots of things we can do to prevent this like IV fluids (to flush the through), change the pH of the urine so that it is harder for crystals to form, administer a medication (allopurinol) that prevents the formation of uric acid, or even a super expensive medication known as rasburicase which can break it down into smaller molecules super fast.

Phosphorus can also cause problems as it oozes out of dying cells.  Phosphorus likes to bind onto calcium and make calcium-phosphate.  In bad tumor lysis syndrome that can cause your calcium to start to fall (another problem with muscle tissue), or it can even form crystals in blood vessels and block blood flow to the skin.  That would typically be in a pretty extreme case of tumor lysis.

So while killing cancer cells is a good thing - you don't want to kill them all too fast.

Tumor lysis syndrome is most common in the really fast growing blood cancers like acute leukemia (not chronic) or the intermediate / high grade lymphomas like DLBCL or Burkitts.  See my post on the difference between these.  Sometimes these cancers grow so fast that you see an "intrinsic" tumor lysis syndrome even without any sort of treatment.  The cells are proliferating so quickly that the ones dying around the edges can cause all of the problems above.

It is pretty uncommon in the slow growing lymphomas and infrequent in CLL though more of a problem with some of the very effective treatments we have now (including FCR and some research drugs).

As in most things medical we need to be able to quantify TLS.  Therefore there are two categories of TLS - laboratory TLS and clinical TLS.  In the former, there may just be some mild asymptomatic laboratory changes.  In clinical TLS you have laboratory TLS and either kidney dysfunction, heart arrhythmias, or seizures.  Clinical TLS is graded on a scale from 0-5 with 0 being mild kidney abnormality and 5 being fatal.

In 8 years of practicing oncology I cannot recall a patient who either had a seizure or died from TLS (read: uncommon), though I have certainly seen bad electrolyte changes, renal function shutting down (though it typically comes back), and cardiac rhythm abnormalities.  That said, I am aware of a number of my colleagues who have taken care of a case that got that bad.

Anyhow - I am struggling with how to end this post.  I do not want to alarm patients unnecessarily, but I was thinking about tumor lysis syndrome and figured a good number of patients may not be aware of what it is.  This is meant more for education than any specific warning.  Hopefully I have not added to the anxieties of having one of these diseases.

Once again - thanks for reading!

p53 matters in DLBCL too.

I've written about 17p deletion in CLL previously.  You may recall that this is the chromosomal home of TP53 - the gene which encodes the p53 protein- one of the most important determinants of chemotherapy success.  P53 is mutated with lower frequency in many of the lymphoid cancers than it is in solid tumors (such as pancreatic, esophageal, etc) which may partially explain the success we enjoy in treating diseases like DLBCL.

A recent paper has evaluated the impact of p53 mutations on survival of patients with DLBCL treated with R-CHOP chemotherapy.  They found a mutation in about 1/5 patients.  It was important!  Those without a mutation survived about twice as long as those in whom it was not mutated.

I've attached a link to an editorial / summary I wrote on behalf of Clinical Oncology News for the interested reader:  p53 Is a biomarker in patients with DLBCL on R-CHOP.  Below is a copy of the text.  It is written for an audience of oncologists so the writing might be a little more technical than what I usually put here in the blog.  Hopefully it is still worth the read.


Personalized medicine is the goal of detecting unique characteristics of an individual’s cancer and appropriately modifying therapeutic interventions to maximize efficacy and minimize side effects. A growing number of molecular diagnostics offer multiplex analysis of many oncologic targets bundled within one commercial assay. With the explosive progress in genome sequencing technology, a thorough understanding of molecular biomarkers is imperative if the goal of personalized medicine is to be reached.

p53 is one of the most important molecular markers in cancer. Known as the “guardian of the genome,” p53 determines cell fate in response to a variety of cellular stresses by regulating transcription of important proteins resulting in cell cycle arrest or activation of pro-apoptotic machinery. Loss of p53 activity is therefore a common mechanism by which cancer cells avoid cell death in response to chemotherapy.

The article by Xu-Monette et al highlights the importance and complexity of p53 analysis in patients with DLBCL. Despite histopathologic similarities, patients with DLBCL can be clustered into distinct subgroups based on gene expression profiling. Beyond RNA expression differences, DNA mutational analysis adds further insight into the prognosis of these patients.

This study evaluates a large multi-institutional cohort of patients with de novo DLBCL (excluding patients with transformed disease), treated in uniform manner according to p53 status, using a variety of molecular techniques including sequencing, expression profiling, fluorescence in situ hybridization and immunohistochemistry.

p53 mutation is shown to be an adverse molecular finding in the 21.9% of patients with abnormalities. Overall survival in patients with wild-type p53 was nearly twice as great as it was for those patients with mutated p53, with similar effect on PFS. This effect was independent of germinal center (GC) or activated B-cell subtype, which differs from the prior analysis of DLBCL patients treated with CHOP alone (pre-rituximab) where the effect was limited to patients with GC subtype DLBCL. This highlights the importance of re-evaluation of prognostic markers as standards of care change.

One concern is the incredible complexity of p53 alterations. This study highlights the multitude of ways p53 can be altered in gene sequencing. Although there are hotspots for recurring abnormalities, not all mutations are created equally. Some mutations may not affect amino acid sequence, whereas others cause an amino acid substitution or premature termination of the coding sequence.

It is tempting to consider p53 changes in a binary “yes/no” manner but that probably oversimplifies the biology. As personalized diagnostics emerge, the interpretation of such abnormalities may be as important as the detection of the change in the first place.

Identification of a high-risk cohort may enable therapeutic intensification, but such trials are difficult to design and execute. As the molecular taxonomy of cancer advances more quickly than our ability to know what to do with the data, clinical research remains a vital link in advancing the care of these patients.

How did I get lymphoma / How did I get CLL?

I am sure there is a profound philosophical lesson to be learned about why this question comes up so frequently in clinic.  Being on the receiving end of bad luck doesn’t make sense to a lot of people.  Maybe others are thinking of missed prevention opportunities, prior bad behavior, or risks to loved ones.  Understanding “why me?” is important and I wish we had a better answer.  I suspect most patients instinctively know that despite our white coats and walls of framed diplomas, we really don’t know – medical science does not have a good answer. 

Despite the absence of a universal answer for all patients, we do know enough about lymphocyte biology to make some educated inferences.  More often than not, I feel compelled to ask the question, “why not me?”   

I am constantly in awe of the unbelievable sophistication of the human body.  Our genome contains six billion base pairs encompassing over thirty thousand genes across forty six chromosomes – in every cell.  If you were to line them up end to end, they would stretch several feet long yet they get packaged into a tiny nucleus.  Somehow those six billion base pairs need to be faithfully copied with no errors every time a cell divides.  For a B cell this may be thousands of replications. 

I saw one paper that estimated that human bone marrow stem cells acquire about ten mutations per decade of life.  That is an such an amazingly low error rate that it should affirm your faith in evolution or God depending on your leaning.  The fact that life can persist at all is more remarkable to me than the observation that it can break down from time to time.

B lymphocytes however have a number of molecular behaviors that increase the risk of genomic malfunction.  B lymphocytes make antibodies (aka B cell receptor / BCR).  You make antibodies to fight of bacteria, viruses, and all manner of germs.  The mechanism that gives us unlimited antibody diversity involves very deliberate damage to DNA – sometimes with cancerous consequences. 

Despite having six billion base pairs, that is not nearly enough to “hardwire” every antibody we may ever need into our genome.  Instead, our antibodies are built in a more modular way.  We have five types of heavy chains, two types of light chains and every antibody pick one of each.  Furthermore, each heavy or light chain has a number of choices for the “variable” region that gets attached to the “D” and “J” regions to create the “VDJ” re-arrangement.  At this point, I’ve already lost track of how many possible combinations there are.  When it comes to antibody creation, it is like a huge game of Mr. Potato Head.

Each time your B cell takes one “v” region and attaches it to a “d” and then a “j” region, it has to deliberately break the DNA and have it come back together in a different place.  That is biologically like trying to jump out of an airplane and land in your swimming pool.  Unfortunately that process is sloppy at times – perhaps more amazing is that it ever works at all.  Many lymphomas are recognized for having pieces of chromosomes come together wrong called translocations (such as t 4:14, t11:14, or t14:18).  If you notice that chromosome 14 seems to keep showing up, that is because it is the chromosome where most parts of the b cell receptor heavy chain are encoded.  Sometimes that break and re-attach process comes down in the wrong place near important proteins like Myc, Cyclin D-1, and BCL-2 that cause these cells to take on cancerous behavior (Burikitt’s, Mantle Cell, Follicular respectively).

Even though that process should give us hundreds of antibodies, we need other processes to create antibody diversity enough for life on planet earth.  Not surprisingly, there is another diversity mechanism that can run amuck known as “somatichypermutation.”  This process takes a perfectly well constructed antibody and starts adding in random mutations.  This is key to helping us generate the virtually unlimited number of antibodies necessary.  Unfortunately we can find evidence that these deliberate mutations are not always confined to the “variable” regions of antibodies.  In fact we can find them sprinkled throughout the genome and sometimes they turn on key proteins like BCL-6, CD79, A20, etc.  In CLL we even look for evidence of this process to classify our patients as “mutated” or “unmutated” as it confers a different prognosis between the two.

If you took those two processes alone I think it would probably be enough to explain a lot of cases of lymphoma – but wait there is more.

Abnormal b-cell receptor (BCR) activation appears to be an enormously important event that plays out across many b cell malignancies and possibly explains the fantastic clinical activity of drugs like ibrutinib, CAL-101 (GS-1101) and the like.  Different lymphoid cancers get there by different ways.  Diffuse large B cell lymphoma occasionally has a mutation in CD79 that locks the BCR into an active state.  Other DLBCL’s have mutations in CARD-11 which is farther downstream in the signaling pathway, but activates a key inflammatory complex called Nf-kB.  Some cases of CLL may have abnormalities in their “variable” region that trick the cell intothinking it has identified the germ it is supposed to destroy and thereforesends off growth signals to the cell.  In follicular lymphoma antibodies may recognize abnormal sugar molecules on each other and get turned on etc.  Marginal zone lymphoma sometimes regresses when you treat the stomach or viral infection it is trying to fight off.  In Hodgkin’s lymphoma, a viral protein encoded by Epstein-Barr virus (LMP-2) can actually mimic the BCR.  That observation was whatled me to hypothesize that inhibiting BCR might be a good idea – way back in2006 before many others had ever thought of the idea.

The theme is that something turns on the BCR in many of these diseases and that gives off growth signals that can lead to cancer.  It also explains why some of our most exciting research drugs are ones that turn off that signal.

None of this explains though why some of these things run in families.  Occasionally you will find a single family with five cases of CLL.  The odds of that happening by chance are a lot worse than your chance of winning the powerball jackpot with one ticket. 

One of my favorite researchers / colleagues Dr. JenniferBrown at Dana Farber in Boston is studying this with some of the most powerful technology available.  She has identified several families where a shared genetic abnormality explains the occurrence of lymphoid cancer in each of the family members.  One interesting example is the loss of a gene called DLEU7 (deleted in leukemia #7).  I find this fascinating because that is buried in the middle of chromosome 13q – the most common geneticabnormality in spontaneous CLL.  It really points to an area of significant biology for future therapeutic intervention.  If you introduce the 13q abnormality into lab mice you will find that they get a variety of lymphomas and CLL.

Finally, there are environmental considerations such as being a meat packer, exposure to pesticides, exposure to certain viruses, etc.  This is where science gets a little hard to pin down as it is subject to a lot of forms of bias.

So doc – why did I get my cancer?  If “all of the above” was a test choice – that would be my answer.  Genomic instability of lymphocytes, a rogue B cell receptor, bad genes, something you were exposed to…

As genomic sequencing gets cheap enough to become a routine clinical test, we may be able to profile an individual cancer for the various hallmarks above and give a more precise answer – but for now, I still have to shrug my shoulders and admit that, “I don’t know.”

How I treat Diffuse Large B Cell Lymphoma (DLBCL)

In contrast to the debate about how to select initial treatment for patients with follicular lymphoma, treatment in DLBCL is considerably more straight forward.  These two lymphomas represent the most commonly diagnosed subtypes of NHL.  For further questions about thedifferent types of NHL link here.

Most patients with DLBCL are going to be treated with R-CHOP.  I have a lengthy post about this regimen that describes the regimen in detail for the interested reader.  There are a number of considerations that may individualize therapy for some patients so it is not just a blanket – one size fits all.

When R-CHOP is the selected regimen, several important questions need to be asked.  The first question is “how many cycles.”  In most patients the answer will be six.  I normally repeat CT scans after cycles two, four, and six.  If the patient still has measurable disease and it continues to shrink between cycles four and six – I will occasionally go to eight cycles – but that is definitely the minority of patients.  You cannot continue R-CHOP indefinitely because the “H” which stands for “hydroxydoxorubicin” aka “Adriamycin” can be hard on the heart and you can only give so many doses before running into long term cardiac issues.

For the less common patient who shows up with “limited stage” (ie. Stage I or stage II disease mostly in one spot), you can consider a shorter duration of R-CHOP when combined with radiation.  Usually 3 cycles followed by radiation is enough.  Sometimes that is more difficult when the site of disease is less agreeable to radiation such as in the colon.

I will also use radiation in patients who present with stage III, or IV disease provided there was one spot that was particularly bulky at the start (>10cm) but this is a little more controversial.  This tends to reduce the likelihood that disease will relapse at the same site of disease, but does not necessarily prevent distant spread of the lymphoma.

The next question is whether a patient is at risk for their lymphoma coming back in their brain.  Since chemotherapy does not get into the brain very well, it is a site of relapse in a minority of high risk patients.  This includes patients whose initial disease started in the testicle, the nasal sinuses, or someone who has a lot of disease outside of their lymph nodes (what we call extra-nodal disease).  For those patients with high risk of CNS relapse, we have the option of administering a shot of a drug called methotrexate by way of a lumbar puncture.  When done by our radiology colleagues using fluoroscopy, this doesn’t typically bother a patient too much. 

The problem with methotrexate is that we really don’t have a lot of confidence that it works particularly well.  It is one of those things we do by convention when what is really needed is a change of convention.  Some docs will actually give a much higher dose of methotrexate into a vein.  The dose in this situation typically requires the patient be admitted to the hospital for a few days.  This may be a more effective strategy, but obviously a lot more difficult to perform.

There are circumstances where R-CHOP may not be a good idea for a patient.  In patients with prior exposure to Adriamycin (perhaps for a breast cancer many years ago), or who are starting with a bad heart to begin with, you may need to substitute the Adriamycin for something more “heart friendly.”  Sometimes these substitutions are done for patients that you think might be a little too old or fragile to handle R-CHOP.   I did recently treat a 92 year old with DLBCL giving him six cycles of R-CHOP.  Granted, he was still out there chopping wood – but another example of where age does not equal limitation.  He is two years out from therapy now and just celebrated his 70^th anniversary – way cool!

There are a number of ways to do swap things around.  I know some docs who use a different formulation of Adriamycin known as “Doxil” which is more heart friendly.  Others have used a drug with a lot of similarities to Adriamycin known as mitoxantrone.  Unfortunately, this substitution reduces efficacy and it isn’t totally clear that it protects the heart all that much.  I have periodically used a substitute for Adriamycin known as etoposide.  The published study for this is pretty old and I cannot be certain it is a great substitute.  I try to use R-CHOP as much as I can, but sometimes you just have to avoid the Adriamycin.

Another key group of patients for whom I choose a different path are the patients with “double hit” lymphoma.  I need to explain some biology here.  There are common DNA abnormalities in DLBCL.  The most common is where a gene known as BCL-6 gets abnormally activated by getting the chromosomes rearranged, resulting in excessive protein.  This can happen with other genes including BCL-2 or Myc.  When a lymphoma has two of these (most commonly Myc and one of the others), we think these patients do not do as well as our more common “single hit” DLBCL.  Most scientists agree this group is considered “higher risk” but what to do about it is less agreed upon and subject of practice patterns not necessarily scientifically proven to be any better.

When Myc in locked on, the cells cannot stop dividing.  We see exceptionally highly proliferative tumors in this setting.  We can measure a “Ki67” which is just a marker for dividing cells.  While normal DLBCL might be anywhere from 40-80% of cells staining positive, Myc affected cells are almost always > 90%.  Myc is also a hallmark of a particularly aggressive version of lymphoma known as Burkitt’s lymphoma.  Unfortunately, if you show microscopic slides of very aggressive lymphomas to a bunch of pathologists, you will find a surprising degree of disagreement as to whether a lymphoma is Burkitt’s or DLBCL.  In fact there is even a new category known as “Aggressive B Cell lymphoma with features indeterminant between Burkitt’s and DLBCL.”  The main point for me, is that we sometimes under-diagnose either double hit lymphoma or it’s close cousin Burkitt’s and instead call it DLBCL.

Clinical science gets a little thin here so please do not take the following as the only acceptable strategy.  For those patients with highly proliferative tumors, I will use a regimen that has been studied in both DLBCL as well as Burkitt’s.  The regimen is known as “R-EPOCH”  A lot of the letters (as well as the drugs) are actually the same.  In fact, there is only one new drug – etoposide.  The main difference is that all the drugs are infused over four days through a pump followed by some injections on day five.  This is different than R-CHOP which is commonly given over just one day.

Since the regimen is good in Burkitt’s as well as DLBCL, I use it when there is gray area with the diagnosis.  I cannot say that this is definitively the right thing to do but I know a number of academic physicians who do the same.  There is a large research study currently comparing R-EPOCH to R-CHOP but it is accruing slowly and I don’t know if it will ever give us the answer as to which regimen is the best. 

R-EPOCH is also my preferred regimen for those patients with HIV who have been diagnosed with DLBCL.  This is a unique subpopulation that used to be a lot more common than it is today.  There have been a number of studies using this regimen in this setting.

Hopefully that should cover a number of questions about how to select a front line regimen in DLBCL.  It is not meant to be a replacement for your own doctors advice but hopefully give you confidence that your doc is on the right track.  I hope I’ve highlighted where things are pretty clear and where they are controversial so that any differences in strategy might be explainable.

Thanks for reading!

Jeff

What is R-CHOP?

R-CHOP is one of the most commonly used regimens out there for lymphoma.  I wanted to briefly write about what the different ingredients are - how they work - what patients experience - etc.  R-CHOP actually is a cocktail of 5 different drugs.  Each letter represents one of the drugs.  Here goes...

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.

H=Hydroxyrubicin (which we call Adriamycin).  Some call this drug "Big Red" as it has a pinkish / red color and can make your urine discolored for 24-48 hours.  When you talk about R-CVP the only difference is that this drug is missing.  Hydroxyrubicin "intercalates" or "slips between" the base pairs of DNA.  DNA is a coiled structure.  In order to copy it, you need to unzip the two strands.  This creates a lot of "torque" or "strain" that needs to be released.   It is like a hair dryer cord that gets turned around and bound up in knots.  To relieve the strain there are enzymes called "topoisomerases" which nick the DNA so it can spin around and release the tension and then get re-attached.  Adriamycin prevents that and results in "double stranded DNA breaks."  These are harder for the cancer cell to repair than single stranded breaks.  The side effect profile is notable for hair loss and low blood counts.  The fear of adriamycin is that it can weaken the heart muscle.  You can usually get away with 6-8 doses of the drug, but after that point the risk of heart damage really goes up.  In uncommon situations, it can cause some permanent injury to your bone marrow stem cells and in extremely rare circumstances even cause a second cancer.... aargh!

O=Oncovin (which we call vincristine).  Vincristine is what we call a "microtubule inhibitor."  Other microtuble drugs include vinblastine, taxol, taxotere, eribulin, etc.  Microtubules are like the cellular "skeleton."  It helps hold all the pieces of the cell where they want to be.  When cells need to separate their chromosomes into daughter cells they use microtubules to help pull them apart to the opposite sides of the cell.  They chew up one end and add pieces to the other which creates a sense of "movement."  Vincristine freezes that process and cells don't like that.  If they stay frozen too long they trigger cell death.  It causes some numbness in finger tips and toes and possibly constipation.

P=Prednisone (yes the good old fashioned steroid).  You are probably familiar with prednisone for things like rashes or arthritis etc.  We use it to lower the immune system.  Lymphoma is simply a cancer of the immune system.  I have had occasion to "cool off" a patient while trying to collect additional tests.  I can sometimes give them a slug of steroids while I am waiting and see their lymph nodes shrink.

Sometimes when we tell patients about potential side effects, I get the impression the cure sounds a lot worse than the disease.  Doc's probably practice defensive medicine more than we realize.  If we tell you everything that can go wrong, then we feel we are less likely to get sued if something bad happens.  Unfortunately you see some patients go through the side effect list and freak out - understandably.

I often say that chemotherapy is a lot like a "stereo dial."  We can turn it up to 10 (unbearable) or down to 1 (was that chemo you just gave me?).  R-CHOP is somewhere between a 4-6.  Nausea isn't often much of an issue.  Fatigue is considerable.  Many people can work while getting chemo, but some folks are better off taking the time off of work (if they can).  Somehow the hair loss makes you feel like a cancer patient.  After you have had one dose of chemo (a cycle is every three weeks you get one dose) I tell patients that they have seen 80% of the side effects.  Yes there is some degree to which things are cumulative, but for the most part you have seen the side effects.

Hopefully that helps.  In another post, I will talk about how I approach DLBCL and when I choose alternatives.