Rituximab monotherapy in CLL

I expect this blog post is going to ruffle some feathers. I can’t wait to see the responses in CLL forum, ACOR and elsewhere.

Patterns of care databases report that during the course of CLL approximately one third of patients will receive mono-therapy with rituximab (ie. rituximab with NO OTHER CHEMOTHERAPY). In fact, it is one of the most commonly utilized therapies in the management of CLL but should almost completely disappear in light of new clinical trial data. Based upon information published within the last 6 months, I think any treatment recommendation for single agent rituximab should he held to some additional scrutiny.

I will admit that I have given this therapy a limited number of times in CLL/SLL before under circumstances where I thought it might be appropriate. In CLL/SLL I think rituximab monotherapy is mostly outdated as of late 2014. Newer drugs such as obinutuzumab and Ibrutinib or new combinations such as idelalisib with rituximab have taken the place of rituximab monotherapy and I have changed my practice patterns as a result.

I recently blogged about rituximab monotherapy in follicular lymphoma and highlighted several key papers published that show how well this immunotherapy drug works. I also blogged about how the addition of lenalidomide may alter the landscape of front line treatment in follicular / indolent lymphoma. Indeed, rituximab monotherapy in indolent NHL (follicular, marginal zone) is a good treatment and definitely appropriate in many circumstances - particularly low tumor burden disease. But what is true for some indolent lymphoma isn’t necessarily true for ALL indolent b-cell disorders.

Small lymphocytic lymphoma and chronic lymphocytic leukemia are often considered two different manifestations of the same disease. Indeed, they are often referred together as CLL/SLL and lumped in with the rest of the indolent lymphomas. But different lymphomas have different behaviors and the response to rituximab is one key difference. Unfortunately, many doctors don’t pay too close attention to this distinction.

Rituximab is often a very easy drug to administer (some uncommon exceptions apply). In most indolent lymphomas and even CLL, you can see things get better and everyone seems happy.  Both doctors and patients can be lulled into a sense that they are getting good therapy when they see things going the right direction – but good can sometimes be the enemy of better and may not be best in long term. 

When rituximab first came out as a new drug it was noted that it had fairly modest activity in the management of chronic lymphocytic leukemia. Response rates were lower than in follicular lymphoma and didn’t last as long. Two key papers were published in the Journal of Clinical Oncology in 2001 authored by John Byrd (linked here) and Susan O’Brien (linked here). Both of them looked at ways to increase the dose of rituximab in order to get a better response in patients with relapsed disease. Dr. Byrd's paper looked at more frequent dosing and Dr O’Brien’s paper looked at giving mega-doses. Despite these efforts the overall response rates were between 35-45% and generally lasted 8-10 months.
 
Two key caveats though should dampen even that modest efficacy. The first is that this was in a population that had largely not been exposed to rituximab previously. Rituximab works better in patients who have never received it before. Nowadays virtually all patients get rituximab added to their first line therapy. When their disease relapses, a sizable population is getting rituximab mono-therapy and it is less likely to work when used a second time. The second caveat is that in 2001 we had different criteria for response assessments and CT scans were not used the same way they are today. Since lots of patients have enlarged lymph nodes hanging out in their chest or abdomen that cannot be detected by physical exam, looking more closely with CT scan would influence the determination of response and progression.

To get a good estimation of how well rituximab or even ofatumumab actually works, I would suggest looking at the control arm of the recently reported studies that led to the approval of idelalisib and Ibrutinib (linked here and here respectively). In these studies patients were randomly assigned to one of the “tried and true” or one of the new drugs but looked at rituxan exposed patients and used CT scans to determine progression. In the rituximab alone arm of the idelalisib study, the lymph node response rate was only 6% and the median progression free survival was under six months. Those response rates are really lousy. In the ofatumumab alone arm of the ibrutinib study, patients didn’t fare much better.

CLL researchers look at the patterns of care data and look at the utilization of rituximab monotherapy with a measure of disdain. While in the past I might have argued back that CLL patients treated in academic centers are fundamentally different from those seen in community practice (an assertion which has good data to support). Indeed, community patients are on average older, have more medical issues, and less good baseline organ function, and several other key differences compared to patients seen in academic medical centers. In the past, I think you could have used that logic to support some utilization of rituximab monotherapy but new data sets strip that away.

So what are the key new data sets?

In previously untreated CLL, obinutuzumab is better than rituximab. These are both CD20 antibodies but obinutuzumab has a number of key modifications that make it more effective than rituximab. In a paper published late last year (linked here), the German group performed a three arm study comparing chlorambucil to chlorambucil in combination with either rituximab OR obinutuzumab. From progression free survival perspective these came in at 11, 16, and 26 months respectively with obinutuzumab the clear winner. If you only compared the chlorambucil arm to the obinutuzumab arm, you even saw an overall survival benefit (second paper to ever show this in CLL). I have heard some people argue that the better performance of obinutuzumab was just based on differences in dosing in the study.  I believe that is an argument made by people who are unfamiliar with obinutuzumab (gazyva).  Clinically, it is a very different drug and the differences in dosing are pretty minimal.

This study was in CLL patients that are more typical for the disease (average age 71). Of course chlorambucil is somewhat of a pariah in the US and many have asked whether it is even a necessary part of the regimen. I was recently at the International Myeloma, Lymphoma, and Leukemia conference in NY where this topic was the subject of a one hour debate (hot Friday nights in the CLL research world). Hard to debate the topic given the lack of published data in this space but our group led a large study of obinutuzumab monotherapy that was presented at ASCO (link here) and will hopefully be published soon. My take on the data: you get a little more bang for the buck when you add the chlorambucil but not clear it is worth the cost, particularly with the agents available now in the relapsed setting.

Two years of average benefit in this disease can be meaningful. It will even be more meaningful if we can apply molecular data to pull out the patients less likely to benefit as well. There is new data from two studies that suggest the presence of NOTCH1 mutations makes CD20 antibody therapy considerably less effective (FC vs FCR and Chlorambucil vs chlorambucil-ofatumumab). Not sure if it applies yet to obinutuzumab yet, but hopefully that data will come out soon. You can test for NOTCH mutations here.

The second key data set (linked here) led to the approval of idelalisib. In this study, patients received either rituximab alone or in combination with idelalisib – a twice daily, non-chemotherapy pill. The difference was striking. Instead of a nodal response rate of 4% it was 96% and the difference in progression free survival was improved by 82%. In fact the difference was so striking the study had to be terminated for ethical reasons because the difference in overall survival started becoming too obvious to ignore (which we were not expecting to be different for technical reasons attributable to cross-over study design). This was the third study ever reported to show that there could be a survival difference in CLL with a new regimen.

I fundamentally believe that there is a significantly sized population of CLL patients who are not appropriate for an aggressive chemotherapy regimen. Let’s face it, the average age at first treatment in CLL is between 71-74 years old. Many are much older. Tack on heart and lung disease or multiple other medications, arthritis, etc which is entirely common in the population and things like FCR are absolutely prohibitive and even bendamustine-rituximab can be a stretch. If a CLL patient TODAY received the recommendation for rituximab therapy alone, I think it would be hard to justify why idelalisib isn’t included (note, I do not put rituximab or ofatumumab in combination with ibrutinib outside of a clinical trial as there is some suggestion that the ibrutinib may make the antibody work less well).

The third data set (linked here) compared Ibrutinib pills to ofatumumab infusions. Here too, the differences were so striking the study had to be terminated before it was planned to do so. In clinical research you set out to conduct studies when there is a sense of “equipoise.” That means there is an honest uncertainty about the difference between two therapies that you need to prove. The difference between ofatumumab and Ibrutinib in this particular study shatters the possibility of equipoise – the differences are too overwhelming.  Response rates, progression free survival, and overall survival for patients treated with ibrutinib absolutely trounced ofatumumab.

So between these three papers the justification for rituximab monotherapy in either front line or relapsed CLL disappears. In front line, obinutuzumab is better than rituximab and in relapsed disease either adding idelalisib or swapping the two for Ibrutinib improve outcomes enough to fundamentally change the paradigm.

The remaining setting where CD20 antibody therapy such as rituximab or ofatumumab is used in CLL is as a “maintenance therapy” following some other chemotherapy. There have been several recent updates in this space and I think you could make a rational argument in support of maintenance though I’m not sure this is widely adopted in CLL treatment. I have provided a few links (here and here) but will leave this discussion for another time.

To summarize:

In previously untreated CLL, I think obinutuzumab has demonstrated sufficient clinical superiority over rituximab (either monotherapy or in combination with chlorambucil) to justify the swap in most cases - there is some debate about this point but I think the argument is settled.  To date, there is not enough published data to routinely combine obinutuzumab with drugs like bendamustine or fludarabine outside of a clinical trial.  

In patients with relapsed CLL, adding idelalisib to rituximab makes it work a whole lot better and Ibrutinib monotherapy trounces ofatumumab. Neither rituximab nor ofatumumab look nearly as good as single agents as we had believed in the past.

I anticipate the next several years of research will be about swapping out the various parts and putting them together again. Newer antibodies will be combined with newer pills and newer pills will be used earlier and earlier in the disease. It is a new era and we are quite fortunate to be in a time period where many of the “rules” are being re-written. Patients will live longer than our standard “prognosis” dictums and maybe we will even begin see a disease once considered incurable to be curable. Throw in BCL-2 inhibitors, CAR-T cells, bi-specific antibodies, and immune checkpoint inhibitors and I hope all patients will look to join in research studies so we can move the needle more quickly.

Thanks for reading

Predicting outcome to therapy

There is an interesting article out today via pubmed that talks about the ability to predict response to chemotherapy in CLL (summary editorial here, actual article here).

As I've been talking about quite a bit, it involves knowing the detailed molecular genetics associated with an individual patient which you can now test for.

I wanted to briefly point out the difference between "prognostic" and "predictive" biomarkers.  First of all, a biomarker is any sort of test such as a blood test, type of scan, etc that correlates with a biologic behavior.  Ideally those biomarkers can help influence treatment decisions to make more personalized treatment decisions.

"Prognostic biomarkers" give a general sense of how a patient is likely going to do with their disease.  In CLL, you might look at things like ZAP-70 or CD38 to estimate how a patients disease is going to behave over time.  You might say that they are "high risk patients" or "low risk patients" for progression / survival etc. but it doesn't necessarily tell you if a specific therapy is going to be useful.

"Predictive biomarkers" on the other hand help with specific therapeutic decisions.  They can be either positive or negative predictors.  Patients with 17P deletion for instance do not experience durable benefit from FCR therapy so in essence it "predicts" an inadequate response to this treatment.  Patients with TP53 or BIRC3 mutations have similar negative outcomes therefore these are considered "negative predictive biomarkers."

On the other hand, some biomarkers may be "positive predictive biomarkers."  I am VERY interested to find out if CLL patients with NOTCH1 mutations derive unique benefit from new research medications that target that mutation specifically.  In other cancers like melanoma or lung cancer, the presence of BRAF or EGFR mutations are required before you can even use certain meds that have very high levels of activity in those specific settings but are useless or even harmful if a patient lacks the mutation.

This particular CLL paper looks at the German CLL8 study which compared FC to FCR and was the first paper to establish a survival benefit in CLL.  It offers a wealth of new insight into the newer prognostic and predictive biomarkers that have emerged in CLL.  We find out that patients with SF3B1 mutations respond well, but experience more rapid relapse.  Patients with NOTCH1 mutations don't derive benefit from the addition of rituximab to FC.  Patients with 17P deletion / TP53 mutation and IgVH unmutated CLL have shorter survival following FCR therapy compared to patients lacking these abnormalities.

Both the technical article and the associated editorial are worth the read.

Thanks

CLL Prognosis Markers Defined

One of the "legnedary" papers in CLL literature is the Dohner paper in New England Journal of Medicine from 2000.  It is the landmark paper that taught us about 13q, 11q, 17p, trisomy 12, and normal cytogenetic CLL.  The FISH technology it employed was developed in the early 1980's.  For the last 13 years knowing the "FISH" status helped with prognosis and treatment selection.  We are now on the eve of a major change of how we think about molecular markers in CLL.  These markers will help us pick treatments that are best for a patient, monitor dangerous subclones, and give a much more clear picture of prognosis when the disease is diagnosed and at each relapse. 

The human genome project took 13 years and 6 billion dollars to “sequence” the genomes of four individuals.  DNA is the “building plans” for just about every important task a cell has to do.  Even though it is given this amazing task it does so with only four different building blocks called “bases.”  There are two purines: guanine (G), adenine (A) and two pyrimidines: thymidine (T) and cytosine (C).  The complexity comes by putting these together in very long sequences that make them unique.  Add some extra bells and whistles and you have a “gene.”  Actually determining the sequence (ie. g-a-a-t-c-c-a-a-c-a-t-g-c and so forth) or order of a particular segment of DNA is called sequencing.

What is remarkable is that the same amount of work that went into the human genome project can now be done in a matter of days to weeks with considerably higher resolution for several thousand dollars.  The cost and efficiency of sequencing is dropping faster than microchips are getting faster.  We are getting very close to being about to sequence an entire genome in only a day for a thousand dollars.

With that diagnostic power comes an incredible ability to probe the very fundamental causes of a particular cancer.  CLL has been a beneficiary of this effort and we now have a very nice short list of the most common mutations found in CLL and several groups have done a great job figuring out the clinical significance of each of them.  Since most of these are likely to be new terms, I thought a brief write up on what these mutations do and what they mean would be great.  I think we are very close to incorporating these markers into our routine work up of a new CLL patient.

Quick note about biology: genes are found in DNA and DNA pretty much hangs out in the nucleus of a cell.  They serve as a template for making RNA.  Once a gene gets “transcribed” from a region of DNA into a much shorter strand of RNA (often times one RNA molecule per gene), it goes out into the main part of the cell called the “cytoplasm” where the RNA gets “translated” into a protein.  Proteins are the tools that do most of the tasks in the cell.   When there is a mutation in DNA, it gets copied into the RNA (which is a lot like DNA but gets out of the nucleus), and leads to the synthesis of an altered / mutated protein.  Sometimes we speak of mutations as though they occur in a protein but really it is in the DNA.  Just in case I am sloppy in my descriptions, I wanted to clarify the biology.

NOTCH1

NOTCH1 is the most interesting of the new markers to me.  It is highly associated with CLL cases that have trisomy 12 as the chromosome change and especially those cases that have an “unmutated” B cell receptor.  NOTCH1 has been a well-known protein because it is extremely important in childhood acute lymphoblastic leukemia where it is present in almost half of all cases.  Over the past few years, there have been a number of efforts to find drugs for mutated NOTCH.  So far I wouldn’t consider those efforts successful, but I am really hopeful about a new class of drugs just entering the clinic now.

NOTCH hangs out in the plasma membrane which keeps the inside of cells in and the outside of the cells out.   NOTCH is like a light switch stuck in the off position waiting to be turned on by another cell.   When that other cell comes by and “flips the switch” a piece of NOTCH gets cut free from its membrane anchor so that it can float away from the membrane.  NOTCH then travels to the nucleus where it interacts with the DNA and makes a bunch of other genes get turned on.  Those genes get copied (transcribed) into RNA and then proteins are synthesized (translated) to do their tasks.  For this reason NOTCH is called a “transcription factor.”  Once it has the right cue, it turns on the transcription of a bunch of genes and therefore determines a whole bunch of important functions.

The genes turned on by NOTCH are really important.  One critically important NOTCH regulated gene that helps cause Richter’s syndrome is MYC.  That is a protein that is a really bad actor in a bunch of different types of lymphoma and leukemia. 

Once NOTCH has done its job and turned on / off a bunch of other genes it gets marked for its own destruction.  The cell wouldn’t want to leave that signal on forever so it needs to turn it off.  Sure enough there is an entire system in place to make sure NOTCH gets shut down after it has done its task.  The particular mutation in this case makes it harder for the cell to turn off NOTCH so it ends up being a signal that won’t stop – sort of like a car where the brake pedal isn’t actually attached to the brakes.  Press all you want and the car won’t stop.

Clinically, the most important thing about NOTCH mutations is that they pretty much split the trisomy 12 patients into two groups, the good ones and the bad ones.  The good ones who lack a NOTCH mutation end up behaving as though they have normal cytogenetics (chromosomes).  The bad ones with a NOTCH mutation are now considered high risk.  They undergo transformation to Richter’s syndrome a lot more frequently and survival is shortened.  See my other post on “new risk groups.”

FBXW7

If NOTCH is important you were probably all expecting that this protein should be on the list too (well ok, maybe just some of you).  Remember all that business about turning off NOTCH?  FBXW7 is the protein that does it.  Take the same car analogy – now just throw out the brake pedal altogether. 

FBXW7 has not been evaluated as closely in terms of clinical significance so I can’t really tell you what it means to have a mutation here – but safe money would bet that will be a lot like a NOTCH mutation.

P53

I have written about P53 before.  It is the protein encoded by the TP53 gene which lives on the short arm of chromosome 17 (yes – that would be 17p).  I would encourage the interested reader to read my post about 17p deletion as well as my post about new risk groups in CLL because it really goes into deep detail about this protein.

Turns out that P53 can be mutated even when 17p is normal and they are just as bad.  The problem is that right now we don’t test for P53 mutations.  Fortunately most of the time you have a mutation in P53 you also have a deletion of 17p on the other chromosome (remember – we have a pair of each chromosomes) but that relationship isn’t air tight.  You can have mutation without deletion, deletion without mutation, deletion with mutation, or normal/normal.  The more 17p dysfunction the worse off you are.  In other words, having one good copy is better than none.  It has been a while since I have seen the number so I might be off a little bit, but something like 20% of cases with P53 mutation do not have 17P deletion so you might have a high risk marker and have no idea based on current testing.

The quick explanation of why this marker is SO IMPORTANT is that it is the protein that pretty much tells the cancer cell to die in response to damaged DNA.  Since drugs like fludarabine, bendamustine, chlorambucil, cyclophosphamide and so forth attack DNA – you need a functional P53 for the chemotherapy to work.

Patients with P53 mutations are considered “ultra-high risk” – it would be nice if we routinely tested for this – but we don’t!

ATM

ATM is to 11q as P53 is to 17p (are you following me?)  ATM lives on the long arm of chromosome 11 (long arms are designated “Q”).  When patients have deletion of chromosome 11q it is a pretty big chunk of DNA that goes missing and includes a handful of genes but ATM is one of the ones that almost always goes missing.

Like P53/17P above, you can have mutation of ATM with or without deletion of the other chromosome.  While a high frequency of 17P deleted cases (70-80%) ALSO have P53 mutation, only about 30% of 11q deleted cases of ATM mutation.  On the other hand, mutations of ATM without deletion of 11q can happen too and once again although it isn’t too common.

Like P53, ATM is important for sensing DNA damage.  If you recall DNA is what we call “double stranded.”  It is like a set of train tracks that gently twist around each other.  When DNA gets damaged it can result in a single or a double stranded break.  ATM is one of the sensors of this broken DNA and it sounds the alarm to stop cell division and also activates our friend P53.

In some studies we’ve seen that having both 11q deletion and ATM mutation is worse than just having one or the other.  Once again, current testing does not look for this.  ATM is an ENORMOUS protein.  It is hard to measure all the possible alterations but new technology is making it a lot easier.

I’ve written previously about clonal evolution both here and here.  It might not be immediately obvious if you haven’t thought about it before but I think it is fairly intuitive that when you use DNA damaging chemotherapy, the cells that survive are the ones that have higher frequency of alterations in 11q/ATM or 17p/P53.  It is sort of like taking a short course of antibiotics for a sore throat and finding that those same antibiotics don’t work well the next time around.  We therefore see a lot more alterations in 11q/17p in patients with relapsed disease than we do in newly diagnosed patients.  This is why it is so imperative to repeat molecular testing before each new line of therapy.

Clinically we think it isn’t enough to give fludarabine / rituxan for patients with 11q.  There is some data to suggest that they do better with cyclophosphamide and fludarabine than just fludarabine alone.  Add in the rituxan (ie. FCR described here) and you overcome some of the negative prognosis associated with 11q.

BIRC3

BIRC3 is another new marker of considerable importance and guess where it lives in the genome?  It lives at the far end of the same 11q deletion that knocks out ATM.  Interesting not all 11q deletions are created equal.  Most include BIRC3 but not all do – so it is possible to have an 11q deletion and have either normal or deleted BIRC3 depending on the size of the deletion.  Sadly FISH doesn’t tell us which is which because BIRC3 is a bad thing to go wrong.

Since BIRC3 is one of the newest abnormalities, we know less about how it interacts with all the permutations of 11q / ATM etc.  For now I think we can just summarize that having a mutated BIRC3 puts you in a high risk category even if everything else appears normal or favorable such as 13q deleted.

BIRC3 is a protein from a family known as IAP or “inhibitor of apoptosis.”  BIRC3 therefore helps regulate cell death and influences another very important protein known as NF-kB.  BIRC3 is another way cells can become resistant to fludarabine.

SF3B1

This is a new marker that burst onto the scene just about two years ago.  Right now, we do not routinely test for it (catch a theme here?). 

When you make an RNA copy of DNA it often consists of long segments of RNA called “introns” that need to be cut out of the final RNA strand (I remember it by saying “introns interrupt”).  Once all the introns have been removed you are left with the “exons.”  When all the exons are lined up end to end it can be copied (translated) into a protein.  We used to think this was just a bunch of cellular waste from millennia of evolution, but now we know that these introns have a bunch of important functions.

SF3B1 has the task of cutting out all those introns and creating the uninterrupted sequence of exons.  Right now, I don’t think we totally understand what happens at a cellular level when SF3B1 is mutated but we do understand some of the clinical implications.   Patients with SF3B1 mutations are resistant to fludarabine.  The other thing about SF3B1 mutations is that it makes you “high risk.”  It isn’t as bad as 17P deletion or P53 mutation but you are still worse off with it than you are without it.

SF3B1 can be sneaky, it can hide in the background of cases with normal chromosomes or even in the 13q deletions where you might otherwise expect a patient to do fairly well. There are now several markers for fludarabine resistance and including P53, BIRC3, and SF3B1. In my mind it would be pretty helpful to know a patient’s markers when they are first diagnosed or when you are picking out a treatment. 

There are several other important new molecules such as XPO1, MYD88, etc.  I have not really seen good data yet that indicates that they influence treatment choice or prognosis.  I wouldn’t be surprised if we learn more about them in the next 1-2 years.

It is an alphabet soup out there but right now these markers are not readily available.  I anticipate we might have a test for them soon and it will be helpful but unfortunately it will add a whole new dimension to the way so many patients worry about their future.  In the future people will now no longer say, “phew, I am a 13q, BCR mutated CLL.”  Instead they may say, “I am 13q deleted, BCR mutated, P53/BIR3 normal, SF3B1 6% subclone mutated.”  It is going to get very complicated very soon!

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