Lenalidomide and Rituximab in Lymphoma

In a recent post I outlined some of the important historical milestones of how we arrived at current standards of care in lymphoma.  I ended my list with the advent of “immunotherapy.”  Last week there was a paper published (link to article here) that helps lay the groundwork for a paradigm change in indolent (slow/follicular) lymphoma – and I want to highlight it here.

I think patients are instinctively drawn to the idea of immunotherapy when they understand it.  Most clinicians use the term to describe some intervention that helps shape the immune system to fight off a cancer rather than traditional chemotherapy.  Just about every patient I meet asks me if there are some nutritional supplements that can “boost the immune system.”  While maintaining healthy Vitamin D levels is a good candidate some of the new treatments that are being developed are pretty fantastic.

At the most simple level, rituximab is an example of immunotherapy.  I have blogged about CD20 antibodies previously.  You naturally make antibodies to fight off bacteria and viruses.  Rituximab is merely an antibody that we give to you that fights off lymphoma and CLL.  When you give the medicine, it binds to the outside of cancer cells and alerts the remainder of the immune system to eliminate the cancer cells – no chemo involved.

For the last 15 years we have shown in study after study after study that adding rituximab to just about any other sort of chemotherapy makes that chemotherapy work better.  I have also recently blogged about giving rituximab by itself (link here).

There have also been a lot of other studies that have tried to make better versions of rituximab.  We now have FDA approval ofatumumab and obinutuzumab which are all “CD20 antibodies.”  In the case of obinutuzumab it has been shown to definitively work better than rituximab in chronic lymphocytic leukemia.  There is also a huge list of CD20 antibodies that are lingering in development or have been killed off all together because they weren’t any better.

A different approach might be to ask if adding a second drug can make rituximab work better.  One interesting theme that has evolved in research is the concept of “T cell pseudo-exhaustion.” Lymphocytes primarily come in three flavors (T cells, B cells, and NK cells).  Rituximab works in part by recruiting the T/NK cells to kill the B cells.  But B cells are crafty – they are able to use cell surface receptors and micro-hormones to lull the T/NK cells to sleep – aka – pseudo-exhaustion.  It is as if the T/NK cells identify a problem, but they have  a post thanksgiving turkey coma and can’t do anything about the problem.  We call it “pseudo” though because it is entirely a reversible biochemical process.  Give those T/NK cells a jolt of biochemical “coffee” and now they can wake back up.

It has now been well shown in multiple laboratory studies that lenalidomide can reverse T/NK cell pseudoexhaustion.  Lenalidomide is a pill that is FDA approved for treatment of multiple myeloma , another blood disorder called MDS, and even mantle cell lymphoma but a handful of studies have shown it has substantial activity in both follicular lymphoma and DLBCL.  More impressively when you give those T/NK cells a medicinal jolt and then the rituximab helps tell them where to go, the results are pretty spectacular.

The article I referred to at the start of this is (linked here).  It reports the activity of lenalidomide (revlimid) in combination with rituximab for previously untreated indolent NHL.  Here is the punch line, it works extremely well.

When you use rituximab with chemotherapy for untreated follicular lymphoma (like R-CHOP or R-Bendamustine), the overall response rate is a health 90+% and the rate of “complete response” is about 35%.  Somewhere between 50-60% of patients have their disease still in remission at the 3 year mark (link to key article here).

When you use rituximab in combination with lenalidomide toe overall response rate is also a healthy 90+% but the rates of complete response are an astounding 87% in follicular lymphoma.  Furthermore the rates of three year remission are closer to 80%.  If you look at rates of PET negative scans at end of treatment (an important prognostic marker) it is virtually everyone and looking at markers like “complete molecular response” they are extremely high.

All without chemotherapy! 

A few caveats to note.  This study was a “single institution study” from the MD Anderson.  In multiple prior studies things that came out of MD Anderson didn’t pan out when tested in more diverse treatment settings (selection bias, patient comorbidity, etc.).  That said, this looks like it could herald a paradigm change in low grade lymphoma.

So what does it take to change the status quo?  For starters, insurance typically wouldn’t cover lenalidomide in this setting because it is not yet approved for frontline treatment.  Some patients may be able to get it paid for but it is extremely expensive so without coverage few will probably take it.  Fortunately a prospective randomized multicenter phase III study that compares lenalidomide and rituximab to either R-CHOP / R-Bendamustine (link here) has nearly completed accrual and if the results from that study hold up, the drug will likely be approved in this setting and insurance will have to cover it.  If that happens, I think you will see a large change in practice patterns as patients ask / push for non-chemo treatments that may be better than chemo treatments.

In the meantime, there are still studies patients can join.  In PREVIOUSLY TREATED lymphoma (including follicular, marginal zone, mantle cell) there is a study going on where EVERYONE gets the combination of these two drugs and then there is a randomization for the duration of lenalidomide treatment (link here).

There are also a handful of other studies using lenalidomide in lymphoma in a variety of combinations (see clinical trials webpage linked here)

When you can get the immune system to do its job, it can be a fabulous thing.

Thanks for reading

Immunotherapy for Indolent (low grade) Lymphoma

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Thanks for reading

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

Treatment patterns in indolent nhl from Jeff Sharman

Rituximab monotherapy in follicular lymphoma

When patients are diagnosed with follicular lymphoma, the treating doc often uses the “eye ball” test on the CT scans, blood work, and physical exam to figure out whether or not a patient has “a lot” or “a little” follicular lymphoma.

While the “eyeball test” is an approximation that requires individual physician judgment (ie. subject to considerable error), such measurements have been codified by what we call the “GELF criteria” which is a French acronym for “groupe d’Etude des lymphomes folliculaires” (ie. French study group of follicular lymphoma).

You are considered “low tumor burden” provided you lack any node > 7cm, have less than three nodes areas > 3cm each, no B symptoms (night sweats, fever, weight loss), spleen below the belly button, circulating follicular lymphoma, or bone marrow dysfunction from involvement (and a few others).

The distinction between “low tumor burden” and “high tumor burden” is relevant because clinical trials often distinguish between such patients in terms of the appropriateness of certain therapies (see: how I treat follicular lymphoma part 1 and part 2).  Patients with “low tumor burden” follicular lymphoma have been studied in studies such as “rituximab vs watch and wait” or the Resort trial (how much rituxan alone do you need), or even the SAKK study (some rituxan vs some plus more rituxan) whereas patients with high tumor burden are more likely to be studied in chemotherapy type studies such as bendamustine-rituximab vs R-CHOP type studies or perhaps other new study designs.

I wanted to focus on the “low tumor burden” population because I was preparing a talk and thought there were a number of important statistics that such patients should be aware of.  I want to simply list them here for your consideration.  They are drawn from three main studies linked here:

Rituximab vs Watch and Wait

Resort Trial (Induction and Maintenance vs Induction and Retreatment when needed)

SAKK Trial (Four doses in one month vs eight doses in nine months)

From the study of “rituximab vs watch and wait”

Approximately 20% of patients with asymptomatic advanced stage disease can be followed for over 10 years without requiring treatment

Thus far NO study has shown that starting treatment EARLIER (ie immediately at diagnosis vs when needed) improves overall survival (very few studies have ever tried to prove this point

Patients who undergo watchful waiting may experience spontaneous regression in 12% of patients by two year mark evenly split between ones that completely disappear from CT scans and ones that partially disappear (in no case do we think the body has “cured” it, we just can’t detect it on scan

40% of patients with low tumor burden follicular lymphoma on watchful waiting will have growth of their lymphoma by two year mark.

Between 80-90% of patients with low tumor burden follicular lymphoma who receive rituximab will experience a response when evaluated several months post treatment

Between 10-30% of patients suitable for watch and wait yet receive rituximab will experience progression within 24 months (partially depends on how much rituximab is given)

Despite responses seen following rituximab, after following patients on average four years after randomization there is no apparent difference in overall survival or rates of histologic transformation between patients assigned to watch and wait versus rituximab (perhaps will change when data more mature?)

The average time a between diagnosis and disease progression when following watch and wait is approximately two years.

The patients who have most emotionally stable reaction to their lymphoma are patients who start rituximab and then continue on maintenance compared to those who take four doses and stop or those on watch and wait.

From the RESORT study (Rituxan followed by rituxan maintenance versus four doses or rituxan and rituxan re-use when needed)

In the average patient with low tumor burden indolent lymphoma who starts rituximab (whether with maintenance or reuse) it will work for about four years before something new is needed.

Patients who stay on maintenance rituxan are less likely to have disease progression, but those patients who “reuse” rituxan are often able to keep the disease under control for about same amount of time and use less rituxan (about 75% less rituxan)

From the SAKK study (which compared four doses of rituximab over one month versus eight doses over nine months in both previously treated and untreated follicular lymphoma)

If you don’t respond initially to rituxan, continuing it for four more doses doesn’t help

In previously untreated follicular lymphoma patients who respond to rituxan and get total of eight doses, almost half have not experienced any progression by 8 years compared to about a quarter of patients who only get four doses

There is a trend that does not reach the level of “statistical proof” that any patient with follicular lymphoma who gets eight doses compared to four might have better overall survival.  Caution here – not clear if this is real or statistical chance just making it look better

Long story short, you can slice and dice this info to do just about anything you want it to mean.  In my own practice, I generally start with rituximab once per week for four weeks then give one dose every other month for four more doses if I am starting rituximab alone in previously untreated patients.  I would not strenuously argue with others if they did it differently.  Here are a few key slides that come from the representative papers as well as a beautiful view of Mt. Washington in the Cascades east of Eugene

Rituximab Therapy in Follicular Lymphoma from Jeff Sharman

Watch and Wait (AKA: Watch and Freak Out)

Nothing can make a patients head spin faster than the two juxtaposed statements, “you have cancer” and “we’re not going to treat it right now.”

Huh?

“Watch and wait” has been a mantra for patients with asymptomatic CLL and indolent lymphoma for quite a few years and sometimes no explanation is enough to comfort a patient who is understandably worried about their new diagnosis (see: when to treat CLL, choosing first treatment in CLL, and how I treat follicular lymphoma part 1).  Quite a few people have dubbed this “watch and worry” instead of watch and wait.  There is an avalanche of messaging out there about early detection and early treatment saving lives in so many cancers that watch and wait can sound more like medical quackery than good science.  For some patients, taking a nutritional supplement and avoiding chemotherapy is an easy sell – but for others, the thought of living with untreated cancer is too much.The short answer is that CLL and low grade (indolent lymphoma) are different than a lot of solid tumors – but this blog is about the long answers – so here goes.

Historically, the argument in favor of watch and wait was that our treatments did not impact overall survival – so why take chemotherapy unless you needed to get rid of some bothersome symptom.  We would argue that chemotherapy was a steep price to pay if it didn’t do you any good in the long run (see risk stratification in CLL).  Admittedly, those conclusions were based on studies from the 80’s and 90’s that used fairly ineffective treatments or drug combinations with moderate to significant side effects of their own. 

But science continuously evolves.  Several recent studies have shown that IF you are going to treat CLL, certain treatments may improve survival compared to others (FCR better than FC, Fludarabine better than chlorambucil).  While this later observation does not indicate that treatment is better than NO treatment, now that we know we can improve survival with some of our treatments those old assumptions need to be retested.

In follicular lymphoma (which is a model for many of theindolent diseases), an ongoing study already presented at ASH compared rituxan to observation.  Not surprisingly that has shown that patients who get rituxan are generally able to wait longer until their next treatment compared to the folks who were randomized to observation – not necessarily an earth shattering observation.  Whether this approach influences how long patients actually survive remains to be seen as that will take quite a few years for the study to collect data.  While the data from that study continues to evolve, others have pointed to the SAAK study in which eight doses of rituxan were given over nine months (weekly x4 then every other month x4) and note that nearly 40% of patients have not required any more treatment over the next ten years.  It is possible that early intervention may be better, but we really still do not know.  I suspect the data will look different from those old studies now that we are using drugs like rituxan that are both effective and well tolerated – but whether that means you live longer has yet to be seen.

In CLL however, single agent rituxan doesn’t pack the same punch as it does in follicular lymphoma.  There is less of the CD20 target on the surface of CLL cells than there is in follicular lymphoma.  Furthermore, CLL has some tricky ways of lulling T cells to sleep (anergic).  Interestingly revlimid may help wake those T cells up (not FDA approved for this indication and should be done very carefully as there have been reports of tumor lysis syndrome).

Along comes a new paper though that I think has profound implications on how we thing about managing ANY of our patients with ANY lymphoid cancer.  I’ve written several times on clonal evolution (here and here) because I think CLL highlights this principle better than just about any other cancer and may actually have lessons for metastatic breast cancer or other solid tumors.  I realize that I’ve probably been trying to write about watch and wait in these posts but never really put it into the right context – so here goes.

Consider the following hypothetical experiment.  You are welcome to try this at home though I would not recommend it.  Plant a lawn but make sure you have a few weed seeds included in the mixture.  Let that lawn grow but resist the temptation to pick the dandelions.  Once you have a nice back yard scattered with a few weeds here and there go down to Home Depot.  Pick up a big bottle of round-up and spray your entire back yard.  Make sure the entire lawn is covered well enough so that you will have a completely brown mess in two weeks.  Now wait……

Ok, so you have waited twelve months without doing anything to the brown mess.  Go out back again and tell me what is growing.  Is it a lush green yard with a few scattered weeds or is it a mess of ugly weeds.  Chances are, you will have a bunch of mutant dandelions that have totally taken the place over.

In SOME cases – that example MAY illustrate the effect of chemotherapy on CLL on the “clonal architecture” surviving cells.  In evolutionary biology terms, we may refer to effective chemotherapy as a “mass extinction event” – think asteroids and dinosaurs.  Any time you have a mass extinction event in a biologic system you may see “survival of the fittest” play out right in front of your eyes.  In our example above, the reason the dandelions didn’t run amok before the round-up was that there was a lot of grass competing for the soil, water, etc.  You could say that the grass was the dominant (incumbent) clone holding the dandelions back.  Once you cleared out the grass though, the weeds had plenty of room to take over (boy with weed and grass both in this post – really curious to see what sort of google searches land on this page).

In this prior post, I highlighted a paper that followed a single individual at several time points and showed how there were three separate subclones at the time of diagnosis.  Before FCR chemotherapy there was a small subclone (1% of total cells) with a bad mutation.  After chemotherapy, that clone which was the “fittest” took off and became the dominant clone and ended up being the one that caused the patient to pass away.  This example has been replicated in a few other papers too so I think it has some validity to it.

Now – it is really important to stress the things we DO NOT KNOW.  If we go back to our analogy of the backyard, would we expect the dandelions to take over if we used napalm instead of round-up?  What if we just turned on the hose and let it flood the backyard for a month – would that select for the dandelions?  Or is it possible that may cause the crabgrass to run wild.  Perhaps we could just put a bunch of biblically hungry locusts in the back yard.  After they ate everything in sight – maybe it would be the grass that came back instead of the dandelions or the crabgrass.  In other words – does the nature of mass extinction event select for different types of “fittest” to come back?  Maybe the extinction has no bearing on what comes back in some cases.  Put into chemotherapy terms – does bendamustine have different outcomes for clonal selection than fludarabine?  Is rituxan different than chemotherapy?  Do the new drugs like ibrutinib and idelalisib have any effect on clonal selection?  We DON’T KNOW the answer to that question BUT we do know that treatment DOES exert a selection pressure on cancer cells and gives me an argument to consider “watch and wait” that I believe is more sophisticated than just saying, “our treatments don’t keep you alive longer.”

I often tell patients, “bad” may be a good enemy of “worse.”  Yes, having indolent lymphoma or CLL may be a bummer, but it may be better than having a super mutant, chemotherapy resistant, transformed beast come back at you.  I have often been puzzled by studies that show a dramatic improvement in “progression free survival” that have zero impact on “overall survival.”  In other words, treatment “x” does a better job keeping your disease away than treatment “y” but ultimately you both pass away at the same time – huh?  Maybe the better treatment is beating the disease back further – but also selecting for a more resistant set of cells to come back when it does come back.

In the paper I referenced above that shows how “clonal architecture” can change over time, one of the most interesting findings to me was that the presence of a “subclonal driver mutation” generally predicted for a shorter remission duration and the emergence of resistance.  “Subclonal driver mutations” are a lot of the bad markers we’ve been describing in other posts such as BIRC3, NOTCH, SF3B1,P53 etc. but that these mutations are in a very small population of the cells.  In other words, you may only have 3% of your cells that are really smart (ie P53 mutated) and 97% of your cells that are generally dumb (del 13q), but that 3% of cells are the dandelions.  Your chemo may make your numbers look a whole lot better and even make you feel better, but now you’ve traded the devil you know for the devil you don’t know – and that second devil might be really nasty.

Newer sequencing technologies are about to enter the clinic and help us find these “subclonal driver mutations” with vastly better skill (though there will still be limitations on how well we can look).  I HYPOTHESIZE (though this is absolutely conjecture and should not be taken as settled science) that in 5-10 years knowing the full clonal architecture will influence our recommendations surrounding watch and wait.

With all this in mind, I think it is easy to take the "watch and wait" strategy too far.  Some folks will do anything possible to avoid treatment and get themselves into a deeper hole than they need to.  Sometimes with a slow disease, it can feel like you can just wait it out a "little bit longer."  For low grade lymphoma there are criteria for treatment.  In CLL, I've written about "when to treat" which is my summary of the IWCLL guidelines.  The caution here is that you can get yourself a lot sicker than you need too if you hold things off for too long.  I would wager that it is even quite possible to feel a lot sicker from the disease than from some of the treatments available.  I've seen quite a few patients literally feel A WHOLE LOT BETTER after starting treatment that they had delayed longer than they should have.

So a few key take home points

1)      Watch and wait was historically based on ineffectiveness of therapy

2)      Newer treatments have led scientists to revisit #1 but the answers are not in yet

3)      One risk of treatment is the emergence of resistance but not all patients experience this

4)      We may be able to begin measuring a patients risk for resistance based upon “subclonal driver mutations” soon

5)      To date, we do not have much insight into what sorts of therapies influence emergence of resistance

6)      Watch and wait is not crazy in appropriate patients – there may have been benefit to it for a long time that we are only just now starting to figure out.

7)    Patients should not wait too long otherwise they just feel lousy when they could have been feeling better with treatment.

Thanks for reading

Follicular Lymphoma Grade and Stage

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

I hope that helps – thanks Anjou!

Richter's Syndrome / Histologic Transformation

Patients with CLL or indolent NHL occasionally experience a significant clinical change in their disease where it becomes a lot more aggressive.  When this happens, the formerly "slow growing" cancer becomes a lot more nasty and in many cases the prognosis gets a lot worse.  In a number of publications, NHL, CLL) the average survival when this happens is about a year.  A number of those are older articles (retrospective / in pre-rituximab era) which may have been confounded by patient selection bias.  My own impression is that many patients do quite a bit better but that is at least what the literature reports.

In CLL/SLL this is called "Richter's Transformation (RT)" while in the indolent NHL's this is called, "Histologic Transformation (HT)."  Sometimes docs jumble these terms and call it "Richter's Syndrome" or "transformation" regardless of which disease it started out as.  There is a different discussion about what we call Grade 3 follicular lymphoma.  Sometimes these can be confused by the patient.  I will save the discussion of Grade 3 until an upcoming post.  In follicular lymphoma HT occurs at a rate of about 3%/year.  While that is a pretty small number, it is cumulative so by 10 years it may be as high as 30%. In CLL the rate appears to be a fair bit lower so that the cumulative risk is only about 10-15%.

The best clue that a patient has undergone RT/HT is when the disease acquires a bad attitude.  Instead of just involving blood and lymph nodes, you see it in new places like liver, lung, intestine, bone nodules, sometimes even brain.  Patients might experience increasing fevers, night sweats, weight loss.  Laboratory changes are notable for a significant rise in a blood marker known as LDH (we are not talking about subtle changes, but 2-4x higher).  If you get a PET scan (which measures metabolic activity of tissues), you might get one spot which is disproportionately "hot."

Traditional risk factors for developing this in CLL include an increasing number of prior therapies, CLL diagnosis at a younger age (longer exposure to risk), and more advanced disease.  A number of newer studies show that pre-existing NOTCH mutations, "stereotyped B-cell receptors (a topic for a future post)," 17p deletions etc. also increase the risk.  In indolent NHL, risk factors include the diagnosis of grade III follicular NHL, advanced disease, high flipi scores, and several lab variables (LDH, B2 microglobulin).

Under the microscope, the new disease most commonly resembles the "intermediate grade" Diffuse Large B Cell Lymphoma.  Less commonly it can look like Hodgkin's Disease, and extremely rarely it may look like Burkitt's or Lymphoblastic Lymphoma.  In any case, it goes from "indolent" to aggressive, or even the highly aggressive.

Because it is so easy to get samples of cancer cells from patients with CLL (blood draw), we know a lot more about transformation in CLL than we do in low grade lymphoma.  It is probably worth while therefore writing about what occurs in CLL and then highlighting the differences that we know about in NHL.

In CLL there are two main and one uncommon way of experiencing RT.  The most common way (80%)  is for the dominant CLL clone to acquire more and more genomic mutations over time.  Typically these involve several important genes including p53, Myc, and NOTCH.  The second most common way (20%) is for a patient with CLL to "spontaneously" develop an entirely new diffuse large B cell lymphoma that is clonally unrelated to the original CLL. You might think no patient should ever have such bad luck, but in a prior post about 13q, I detailed how some genomic deletions can predisopose to lymphoid malignancies.  Some patients who develop CLL may in fact be predisoposed to the spontaneous development of DLBCL.

The difference is significant.  In the first case, you have a highly resistant clone - often with a p53 mutation - giving rise to an aggressive lymphoid malignancy.  When p53 mutations are present, chemotherapy often does not work well.  Just like every other cancer we have ever studied, p53 is a BAD THING to have mutated in DLBCL.  Conversely, when DLBCL develops spontaneously, it is often a curable cancer.  This plays out with regard to prognosis of the transformation.  In the former, survival averages about a year, whereas in the latter a good number of patients are cured.  Once again, I would point out that it is frustrating that we have no way to tell which one a patient has with testing that we would consider readily available.  In indolent lymphoma, it seems far more likely that the new DLBCL is clonally related and p53 mutations are as high as 80%!

Treatment often consists of R-CHOP chemotherapy regardless of which sort of RT you have.  While this is typically a well tolerated treatment, it is harder on the patient if they have already been exposed to a bunch of chemotherapy previously.  You only get to beat up the bone marrow so many times (chemo) before it starts telling you it can't accept more flogging.  It is not uncommon to run into dose delays, or reduced dosing, etc.  Add this to more resistant disease and you can probably figure why it is less effective.  Furthermore, a lot of patients with follicular lymphoma have been previously treated with the "H" in R-CHOP and you can only give so many doses of that drug before the heart starts to complain.  Since treatment is less effective, some patients will be treated with an "auto" stem cell transplant but a lot depends on how robust the patient is at that point and how well they responded to therapy.

In the future, I think this may be one situation where the "engineered T cells" could become an important therapy.  NOTCH antibodies have recently entered clinical trials and might be appealing.  We have used brentuximab vedotin in one clinical trial and been pleased with the results for some of our patients.  Hopefully these newer approaches will give a more favorable outlook to patients with RS/HT sometime soon.

Here is a video I did with Brian Koffman describing it all:  Richters Transformation

The Slow (Indolent) Lymphomas

In my prior post "Understanding The Different Types of Lymphoma" I spent a bit of time explaining how there were three main categories of B cell NHL; slow, medium, fast.  I encourage readers of this post to review the prior post if coming to this for the first time.

The slow lymphomas probably have the greatest number patients falling into different disease categories.  I've had a lot of traffic on my website for the intro post so I thought it was time to go deeper into detail for some of the "indolent - aka: slow" lymphomas.

For now, I am going to restrict the discussion to the B cell cancers.  Many of the T cell disorders that affect the skin are also considered "indolent" but they are really an entirely different discussion probably best saved for later.


Follicular lymphoma 
(read this even if it isn't the type you have)

The most common indolent lymphoma is follicular lymphoma.  In fact, this is the second most common type of NHL.  In a number of important ways, you can generalize from follicular lymphoma to many of the other indolent subtypes of lymphoma.  I've got a few blog posts that outline what I think is the current approach I use to treat the  disease (low risk & high risk).

Follicular lymphoma comes in many shapes and sizes - there is considerable diversity in terms of patient presentation.  It can range from an asymptomatic enlarged lymph node that does not require any treatment - all the way to life threatening cause of marrow or organ dysfunction.  I have a number of patients in my clinic who have carried the diagnosis for many years never requiring any therapy.  In fact, I have one patient originally diagnosed in the 1950's still chugging away - pretty remarkable.

Pathologists determine the diagnosis of follicular lymphoma in several ways.  In fact, if you simply hold a microscope slide of a lymph node up to the light, you can often have a pretty good idea that you are dealing with follicular lymphoma.  They look for a particular growth pattern (nodular), cell size (mostly small), and can use a handful of special stains (CD10, 19, 20 positive, CD5, 23 negative) or DNA probes (translocation of chromosomes 14:18) to verify the diagnosis.

The name "follicular" comes from the "cell of origin."  When a b cell runs into the bacteria or virus it was born to fight it goes into the "follicle" of the lymph node.  There it undergoes a number of changes to make it a better infection fighter and spits out a bunch of copies of itself.  It is a genomically unstable time in the life of a b cell (see my post: why did I get lymphoma) and can give rise to a lymphoma.  When lymphoma starts here it is typically either a follicular lymphoma or a diffuse large b cell lymphoma.

When I consider a new patient with follicular lymphoma, there are several key features I want to know about before making my management decisions:  1)  What stage is the patient?  2) How much disease do they have? 3) How aggressive does it look?  Though you might think these three characteristics are all the same, I actually think they are quite different.

Stage is fairly straight forward in NHL terms but often misunderstood by a patient who is already shellshocked by the diagnosis.  It is quite common for follicular lymphoma to be stage 4 at diagnosis but that is very different than a lung cancer that is stage 4.  Since lymphoma is a cancer of the immune system, it is pretty much everywhere to begin with.  In contrast, a lung cancer that has spread beyond the confines of the lung and lymph nodes has "metastasized."  We don't think of lymphoma as undergoing "metastasis."  While stage 4 follicular lymphoma is typically worse than stage 2 follicular lymphoma, I would still take it over stage 4 lung cancer any day.  Stage 1 is a single lymph node, stage 2 is lymph nodes confined to one side of the diaphragm, stage 3 is  lymph nodes on both sides of the diaphragm and stage 4 involves the marrow.

Embedded within "stage" though is a consideration of how much disease a patient has.  If a patient has an 18cm lymph node in their abdomen and nothing in their marrow - I still worry more about that patient than the one with a handful of 2-3 cm nodes in the chest and abdomen and a little bit in the marrow.  We refer to this as tumor "bulk."  It is often a subjective evaluation but one that is important.  If there is a single disproportionately large node we begin to worry about transformation.  Sometimes a PET scan or additional biopsy is necessary.

Aggressiveness is another qualitative / semi-quantitative evaluation.  Pathologists will assign a "grade" to the lymphoma that is either 1, 2, 3a, or 3b.  This is a measure of how many "large cells" are visible.  Large cells are bad as they tend to be more proliferative.  The lower the grade the better.  Unfortunately there is a lot of variability between pathologists when they try to sort out the 3a/3b's.  We are taught to think of the 3b's as the same thing as diffuse large B cell lymphoma.  Pathologists can also use a marker known as Ki-67 that indicates how many cells are in the cell division process.  Once again, the lower the better.

There is a score that does a pretty good job integrating a lot of this known as the FLIPI score.  It looks at patient age, stage, number of nodal sites, marrow function (hemoglobin), and a blood test known as LDH.  The higher the worse.  FLIPI is helpful for allowing us to evaluate results across trials and getting a sense of an individual patient but I still take the other measures as important as well.

Anyhow, that is the basics of follicular lymphoma.  See my other posts for treatment etc.

Marginal Zone Lymphoma

Marginal zone lymphoma is a lot like follicular lymphoma in terms of how it shows up, behaves clinically, gets treated, etc.  There are a few key differences though that are worth pointing out.

The first difference is seen by the pathologist.  It arises from a different part of the lymph node architecture (any guesses - yes - the marginal zone - which surrounds the normal follicle areas).  They often do the same panel of stains on the sample but in contrast to follicular lymphoma, it is negative for CD5, 10, 23, and positive for CD19, 20.  They don't necessarily look for the translocations common to other lymphomas like 14;18 in follicular or 11;14 in mantle cell - largely because they are not there.

Marginal zone lymphoma comes in three main varieties, nodal, primary splenic, and extranodal mucosal associated lymphoid tissue (Aka MALT).  The nodal variety may as well be follicular lymphoma in terms of treatment, prognosis, etc.  Some of these can make really highlight how slow these lymphomas can be.

Primary splenic marginal zone lymphoma is a little interesting.  It can be closely related to hepatitis C.  In fact, treating hepatitis C in these patients can even lead to remissions of the lymphoma.  Hep C probably gives some growth signals to B cells - so if you get rid of the hep C the lymphoma can go away.  It is certainly worth an attempt at Hep C treatment and it should be noted that Hep C treatment is getting a lot more effective.  This disease is often also often confused with CLL to a doc unfamiliar with lymphoid cancers.  Sometimes you see an elevated lymphocyte count in the peripheral blood, the flow cytometry shows a b-cell cancer, and the doc misunderstands this to be CLL.  In the past this might not have been too big of a deal but now that there are some extremely effective CLL drugs, getting the diagnosis right might be more important.

Finally the extra-nodal varieties that are associated with mucosal tissues (the lining of the stomach, tear glands, etc) can be interesting because of their associations with paticular infections.  The stomach version can be associated with the same H. Pylori bacteria that causes ulcers.  Treating the bacteria is often effective at getting rid of the lymphoma.  The eye version can be associated with a chlamydia infection (no not the sexual transmitted disease).  Here too, treating the infection can cause remission of the lymphoma.


Small Lymphocytic Lymphoma

Small lymphocytic lymphoma (SLL) is essentially chronic lymphocytic leukemia (CLL) except it affects the nodes more than the blood and marrow.  The two disases are so similar we often refer to them together as CLL/SLL.  We arbitrarily define CLL as cases with lymphocyte count greater than 5000.  In virtually all other ways the two disease are the same.

The pathologist will often look at a node and call it SLL/CLL when it stains positive for CD5, CD23, and CD19.  The B cell receptor is characteristicly "dim" so any BCR markers such as kappa, or lambda or CD20 are present at lower levels than other B cell cancers.  Translocations are not common.  Unfortunately the same FISH tests that are so vital in CLL are often not obtained in SLL.

Staging can sometimes seem "unfair" to the patient because of how arbitrarily the distinction between the two diseases (CLL vs SLL) are defined.  In SLL, staging is done in the same way as follicular lymphoma above.  In CLL staging is different though.  Stage 0 is elevated WBC, Stage 1 has WBC and enlarged nodes, Stage 2 has the above and an enlarged spleen, Stage 3 has low red blood cells and stage 4 has low platelets.  Therefore a SLL patient who has a few nodes and some marrow involvement but a lymphocyte count of 4900 is stage 4 SLL, but if they had a count of 5100, their CLL would be stage 1.  It is arbitrary and unfair because they are really the same biologically and calling it stage 1 or 4 sounds a lot worse than it really is.

The other thing about SLL that is important and sometimes overlooked is that it should be approached in the way one things about CLL instead of follicular lymphoma.  A lot of docs will give lymphoma regimens for SLL when it probably makes more sense to use CLL regimens.  I would tend to favor fludarabine based treatment instead of things like R-CVP.  It is also important because the new drugs like CAL-101 and ibrutinib are quite active in SLL and should be considered.

Mantle Cell lymphoma

It isn't totally clear if mantle cell lymphoma belongs in a discussion of the "slow lymphomas."  Mantle cell can take on the "incurable" clinical features of follicular lymphoma while sometimes having the growth rates of the more aggressive diffuse large B cell lymphoma.  It gets the worst of both.

Our knowledge of Mantle cell lymphoma is clouded by the fact that we didn't even recognize this as a discrete type of lymphoma until the mid to late 1990's.  Some of the early reports may have been biased by more aggressive cases.  More recently, we've come to identify that some mantle cell really can indeed behave slowly.

The lymphoma gets started from yet another part of the lymph node - the mantle zone.  It stains positive for CD5 but negative for CD23 in distinction to CLL/SLL.  Mantle cell does have a characteristic translocation between 11:14 resulting in too much "cyclin D-1"  Sometimes this test helps a pathologist determine whether it is CLL or mantle cell.  In B cell biology mantle cells arise from B-1 b cells which are similar to CLL.  It is therefore interesting to me that the research drugs ibrutinib and ABT-199 look very exciting in this disease since they are also so impressive in CLL. 

Mantle cell has another few curiosities.  It loves the colon.  In order to fully stage a patient, it is sometimes necessary to do a colonoscopy and get "blind biopsies."  GI docs are often unaware of this so sometimes it requires some physician education.  Not every patient needs a colonoscpy but it is common in clinical trials or chasing down symptoms.

Treatment of mantle cell lymphoma is all over the map.  It can range from transplant to observation.  I should probably just save that for another post.  Instead of using the FLIPI from follicular lymphoma, we use the MIPI (mantle cell international prognostic index).  It uses age, functional status, WBC count, and LDH.  The original paper did not use the proliferation rate called the Ki-67 but this is very important (<10%, 10-30%, >30%) and separates prognosis quite well.


Waldenstrom's (lymphoplasmacytic lymphoma).

Waldenstrom's is named after the Sweedish hematologist who characterized the disorder.  It is often a marrow only disease that arises from a b-cell en-route to becoming a plasma cell (the type of B cell that gives rise to multiple myeloma).  It can involve lymph nodes however so that should not give rise to diagnostic confusion.

One unique feature to this disease is that it secretes an antibody into the circulation that can cause a variety of problems.  The particular form of the antibody (IgM) is a big / bulky molecule.  If the concentration gets too high it can make the blood become too viscous (think olive oil in the refrigerator).  In fact "hyper-viscocity syndrome" can be a life threatening situation that requires emergent "plasmapheresis" which is a lot like dialysis.

One odd consequence of using rituxan in this disease is that it sometimes leads to a sudden rise in the antibody levels.  To the unsuspecting doc, this can be confused for progression.  If patients start with a high level of protein, this spike can be dangerous and should be monitored.

The protein can cause other problems as well.  Neuropathy is not uncommon and sometimes pushes a patient toward therapy they might have otherwise been able to hold off on.

Steve Treon M.D. is the guru of this disease and practices in Boston.  In addition to being extremely helpful to patients and other docs managing these patients, he has done a fantastic job organizing a number of academic centers into a combined research effort.  Since the disease is uncommon, it would never get much research attention if it were not for the combined effort of some of the major centers. 

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.”