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.
Monday, December 31, 2012
Friday, December 28, 2012
CLL Prognosis
Many CLL patients identify themselves by their prognostic markers when writing in social media outlets. "Diagnosis age 63, unmutated, trisomy 12, treated FCR age 67, still in remission 2 years later" is the sort of "tag line" I've seen people write. For individuals who visit social sites frequently it is a way to tell your story in a few words. For individuals who are new to CLL, it can all seem very confusing. Well it is about to get a whole lot more complicated for everyone very soon.
A lot of what follows is very technical but I wanted to get it all written in one place. I hope patients actually read and re-read this material several times. For people who are prone to sleeping every time they read one of my posts, here are two videos I did with Brian Koffman in Sept 2013 that goes over the same material in video format:
Part 1: New Prognostic Markers
Part 2: Another on New Prognostic Markers
I've been wanting to write this post for a while but a recent paper has really brought this to the forefront of management of our CLL patients. Unfortunately the names are strange and I worry this post may fall toward the technical side - sorry. I will create a separate post that specifically defines many of these terms.
Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia
For people who have read all my posts on FISH testing, you are probably aware that it is an antiquated technology that has served us well for 20 years but needs desperately to be replaced. Sequencing technology has advanced incredibly quickly and is now poised to refine our understanding of CLL risk groups with new molecular detail.
While most patients are aware of the incredible advances in CLL therapies (ibrutinib, CAL-101, GA-101, ABT-199), fewer are aware of the really important advances in molecular markers that have been recently discovered. Once these are rolled out to the general public we will be able to understand with much more precision how a patients disease will behave. Pretty soon, folks will not only be talking about 13q, 17p without also talking about BIRC3, SF3B1, and NOTCH.
In the last 24 months, genomic sequencing has been applied to cases of CLL with pretty remarkable results (see New England Journal of Medicine article or Journal of Experimental Medicine article)
Several key findings have emerged from these data sets.
1) CLL has a relatively simple genome. While some "smart cancers" (cancers that quickly gain resistance to our treatments and are far more aggressive) like small cell lung cancer may have 50,000 mutations per tumor, CLL (a comparatively dumb cancer - which is typically slow, responds well to most treatments, does not gain resistance all that fast) may have fewer than 100 mutations per case and only a small fraction of those (around 10-20) affect important proteins (the enzymes that make all things happen inside a cell).
2) Certain mutations seem to be observed fairly commonly in CLL and have some defined prognostic or predictive value. For instance BIRC3 turns out to be a really bad thing to have - it is the new 17p. NOTCH probably is one way to get to Richter's and helps sort out the trisomy 12 cases, SF3B1 makes you resistant to fludarabine chemotherapy.
3) Certain mutations are seen early in the disease, while others seem to accumulate with time. Furthermore, some of the ones present later on are actually present early but only emerge through "clonal selection."
4) Some cases of "familial CLL" (ie those cases that run in families) have an unifying genomic explanation that point toward things we already knew were important.
With all of this new information, it was only a matter of time before someone took on the herculean effort to figure out which of these were most important and what they all mean when you analyze them simultaneously in a large group of patients (1300 of them to make this model).
The old risk groups were:
High risk: 17p changes (home of the p53 protein)
Intermediate risk: 11q changes
Low risk; normal cytogenetics & trisomy 12
Very Low Risk: Isolated 13q changes
Unfortunately, there is a lot of biologic diversity that FISH testing misses since it only looks at large chunks of missing or added DNA. Using sequencing technology (think microscope compared to telescope) as an adjunct to FISH we can now help sort all of these out.
The new risk groups
Very high risk: 17p deletions, p53 mutations, or BIRC3 mutations (10 year survival 29%)
High risk: 11q deletions, SF3B1 mutations, NOTCH mutations (10 year survival 37%)
Low Risk: Normal cytogenetics, trisomy 12 (without NOTCH mutations) (10 year survival 57%)
Very low risk: Isolated 13q deletions (10 year survival same as age matched controls).
There are some really interesting observations contained within this.
1) It is not a surprise that 17p deletion and p53 mutation are both really bad - we've known that for a long time. They commonly run together (ie. most 17p deletions also have p53 mutations - but not all cases).
2) BIRC3 is a new kid on the block. It has only been recognized for about 18 months. Turns out it is really bad to have. It confers chemotherapy resistance and is often very discrete from p53 alterations (i.e., if you have one, your probably don't have the other). We've known for a while that p53 doesn't explain all cases of chemotherapy resistance - BIRC3 explains a lot of them.
3) We have known for a while that 11q deletions often associate with bulky lymph nodes, unmutated B-cell receptors, faster growth kinetics, requirement for alkylating drugs (cytoxan, bendamustine). It has often been considered a poor risk feature. SF3B1 and NOTCH are totally new though and we didn't know where these fit in terms of hierarchy. Turns out, they are about equal.
4) Last year the relationship between NOTCH and trisomy 12 was identified. About half of trisomy 12 cases carry a NOTCH mutation - particularly those with unmutated BCR (ie. cases with unmutated BCR and trisomy 12 have high frequency of NOTCH mutations - sorry if this gets confusing). We have been aware that trisomy 12 was a bit of a wild card - some did fine, some did poorly. Turns out that NOTCH mutations can sort the two apart. Those with mutations do worse, those without mutations are now considered "low risk." I am very eager to learn if the new NOTCH antibodies turn into personalized medicines for patients with the NOTCH (or even FBXW7 changes).
5) Our good old friend 13q is still "good risk." The surprise here is that 25% of 13q cases get put into higher risk categories when you do the mutation analysis. They might have an SF3B1 mutation or BIRC3 mutation you would have otherwise never known about. By carving out the bad players, it makes the good group even better. "Matching age controls" does have some limitations because the model is built upon typical CLL cases. There are probably not sufficient number of 42 year olds with 13q in the model to say that they necessarily match their peers.
6) This model holds true no matter when you evaluate a patient. In other words, if clonal evolution occurs and you go from very low risk to high risk by molecular definition - your clinical outcome changes too.
There are some important questions in all of this.
1) The most obvious is - how do I know what I am? Right now - you can't easily tell. There really are not commercial tests to sort this out - I'm trying to make one but seem to running into more walls than doors. If anyone out there wants to finance this idea, let me know!
2) What defines "positive" for mutation? For 17p by FISH we do not define a patient as positive until 20% of their cells are positive. With ultrasensitive testing you may find 0.07% of cells have a BIRC3 mutation. That patient isn't "positive" but I would be very concerned that clone may evolve in the future. Do you therefore do anything different when you choose to treat them?
3) This analysis may miss some of the subtlety of different FISH abnormalities. We already know there are type I and type II deletions on chromosome 13 with different prognostic value. We also know that the overall percent of cells with 11q or 13q makes a difference. This model does not capture that degree of subtlety.
4) Mutated vs unmutated is not included necessarily in this model - I would like to know if it "sub-stratifies" amongst the various different risk groups (although it is more common to see unmutated with 17p and 11q than the 13q cases so perhaps the model was just not big enough to take it all into account)
5) How do these markers hold up in the face of the new drugs. ABT-199, ibrutinib, CAL-101, GA-101 are so remarkable. Will traditional markers hold up in the "new era?" It is important to note that this model is based upon cases that have already been followed for quite a few years. Some didn't get rituxan with their first line of therapy. Presumably none were able to take advantage (since it is an Italian study) of the new drugs. By definition, this is a backwards looking model and does not capture what I see as a very optimistic future. For example, 29% 10 year survival for poor risk does not reflect the impressive durable control obtained in front line 17p patients treated with ibrutinib.
Though there are questions, the authors of this paper are to be thanked profusely for their remarkable effort to create a single predictive model of this magnitude. I would imagine that there were thousands of hours put into creating and analyzing the data. This paper will serve as a landmark for quite a few years and will help guide countless numbers of patients.
A lot of what follows is very technical but I wanted to get it all written in one place. I hope patients actually read and re-read this material several times. For people who are prone to sleeping every time they read one of my posts, here are two videos I did with Brian Koffman in Sept 2013 that goes over the same material in video format:
Part 1: New Prognostic Markers
Part 2: Another on New Prognostic Markers
I've been wanting to write this post for a while but a recent paper has really brought this to the forefront of management of our CLL patients. Unfortunately the names are strange and I worry this post may fall toward the technical side - sorry. I will create a separate post that specifically defines many of these terms.
Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia
For people who have read all my posts on FISH testing, you are probably aware that it is an antiquated technology that has served us well for 20 years but needs desperately to be replaced. Sequencing technology has advanced incredibly quickly and is now poised to refine our understanding of CLL risk groups with new molecular detail.
While most patients are aware of the incredible advances in CLL therapies (ibrutinib, CAL-101, GA-101, ABT-199), fewer are aware of the really important advances in molecular markers that have been recently discovered. Once these are rolled out to the general public we will be able to understand with much more precision how a patients disease will behave. Pretty soon, folks will not only be talking about 13q, 17p without also talking about BIRC3, SF3B1, and NOTCH.
In the last 24 months, genomic sequencing has been applied to cases of CLL with pretty remarkable results (see New England Journal of Medicine article or Journal of Experimental Medicine article)
Several key findings have emerged from these data sets.
1) CLL has a relatively simple genome. While some "smart cancers" (cancers that quickly gain resistance to our treatments and are far more aggressive) like small cell lung cancer may have 50,000 mutations per tumor, CLL (a comparatively dumb cancer - which is typically slow, responds well to most treatments, does not gain resistance all that fast) may have fewer than 100 mutations per case and only a small fraction of those (around 10-20) affect important proteins (the enzymes that make all things happen inside a cell).
2) Certain mutations seem to be observed fairly commonly in CLL and have some defined prognostic or predictive value. For instance BIRC3 turns out to be a really bad thing to have - it is the new 17p. NOTCH probably is one way to get to Richter's and helps sort out the trisomy 12 cases, SF3B1 makes you resistant to fludarabine chemotherapy.
3) Certain mutations are seen early in the disease, while others seem to accumulate with time. Furthermore, some of the ones present later on are actually present early but only emerge through "clonal selection."
4) Some cases of "familial CLL" (ie those cases that run in families) have an unifying genomic explanation that point toward things we already knew were important.
With all of this new information, it was only a matter of time before someone took on the herculean effort to figure out which of these were most important and what they all mean when you analyze them simultaneously in a large group of patients (1300 of them to make this model).
The old risk groups were:
High risk: 17p changes (home of the p53 protein)
Intermediate risk: 11q changes
Low risk; normal cytogenetics & trisomy 12
Very Low Risk: Isolated 13q changes
Unfortunately, there is a lot of biologic diversity that FISH testing misses since it only looks at large chunks of missing or added DNA. Using sequencing technology (think microscope compared to telescope) as an adjunct to FISH we can now help sort all of these out.
The new risk groups
Very high risk: 17p deletions, p53 mutations, or BIRC3 mutations (10 year survival 29%)
High risk: 11q deletions, SF3B1 mutations, NOTCH mutations (10 year survival 37%)
Low Risk: Normal cytogenetics, trisomy 12 (without NOTCH mutations) (10 year survival 57%)
Very low risk: Isolated 13q deletions (10 year survival same as age matched controls).
There are some really interesting observations contained within this.
1) It is not a surprise that 17p deletion and p53 mutation are both really bad - we've known that for a long time. They commonly run together (ie. most 17p deletions also have p53 mutations - but not all cases).
2) BIRC3 is a new kid on the block. It has only been recognized for about 18 months. Turns out it is really bad to have. It confers chemotherapy resistance and is often very discrete from p53 alterations (i.e., if you have one, your probably don't have the other). We've known for a while that p53 doesn't explain all cases of chemotherapy resistance - BIRC3 explains a lot of them.
3) We have known for a while that 11q deletions often associate with bulky lymph nodes, unmutated B-cell receptors, faster growth kinetics, requirement for alkylating drugs (cytoxan, bendamustine). It has often been considered a poor risk feature. SF3B1 and NOTCH are totally new though and we didn't know where these fit in terms of hierarchy. Turns out, they are about equal.
4) Last year the relationship between NOTCH and trisomy 12 was identified. About half of trisomy 12 cases carry a NOTCH mutation - particularly those with unmutated BCR (ie. cases with unmutated BCR and trisomy 12 have high frequency of NOTCH mutations - sorry if this gets confusing). We have been aware that trisomy 12 was a bit of a wild card - some did fine, some did poorly. Turns out that NOTCH mutations can sort the two apart. Those with mutations do worse, those without mutations are now considered "low risk." I am very eager to learn if the new NOTCH antibodies turn into personalized medicines for patients with the NOTCH (or even FBXW7 changes).
5) Our good old friend 13q is still "good risk." The surprise here is that 25% of 13q cases get put into higher risk categories when you do the mutation analysis. They might have an SF3B1 mutation or BIRC3 mutation you would have otherwise never known about. By carving out the bad players, it makes the good group even better. "Matching age controls" does have some limitations because the model is built upon typical CLL cases. There are probably not sufficient number of 42 year olds with 13q in the model to say that they necessarily match their peers.
6) This model holds true no matter when you evaluate a patient. In other words, if clonal evolution occurs and you go from very low risk to high risk by molecular definition - your clinical outcome changes too.
There are some important questions in all of this.
1) The most obvious is - how do I know what I am? Right now - you can't easily tell. There really are not commercial tests to sort this out - I'm trying to make one but seem to running into more walls than doors. If anyone out there wants to finance this idea, let me know!
2) What defines "positive" for mutation? For 17p by FISH we do not define a patient as positive until 20% of their cells are positive. With ultrasensitive testing you may find 0.07% of cells have a BIRC3 mutation. That patient isn't "positive" but I would be very concerned that clone may evolve in the future. Do you therefore do anything different when you choose to treat them?
3) This analysis may miss some of the subtlety of different FISH abnormalities. We already know there are type I and type II deletions on chromosome 13 with different prognostic value. We also know that the overall percent of cells with 11q or 13q makes a difference. This model does not capture that degree of subtlety.
4) Mutated vs unmutated is not included necessarily in this model - I would like to know if it "sub-stratifies" amongst the various different risk groups (although it is more common to see unmutated with 17p and 11q than the 13q cases so perhaps the model was just not big enough to take it all into account)
5) How do these markers hold up in the face of the new drugs. ABT-199, ibrutinib, CAL-101, GA-101 are so remarkable. Will traditional markers hold up in the "new era?" It is important to note that this model is based upon cases that have already been followed for quite a few years. Some didn't get rituxan with their first line of therapy. Presumably none were able to take advantage (since it is an Italian study) of the new drugs. By definition, this is a backwards looking model and does not capture what I see as a very optimistic future. For example, 29% 10 year survival for poor risk does not reflect the impressive durable control obtained in front line 17p patients treated with ibrutinib.
Though there are questions, the authors of this paper are to be thanked profusely for their remarkable effort to create a single predictive model of this magnitude. I would imagine that there were thousands of hours put into creating and analyzing the data. This paper will serve as a landmark for quite a few years and will help guide countless numbers of patients.
Thursday, December 6, 2012
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.”
Saturday, December 1, 2012
When to treat CLL
The "watch and wait" mantra in CLL can be a test of wills unlike most other cancer experiences.
Let's face it, sitting there and doing, "nothing" is hard enough when we are conditioned to believe "early detection saves lives" or "catching it early is your best chance to beat it." Those things are true in common cancers like breast, prostate, colon, lung, etc. but at least for now those do not necessarily hold true in CLL (I hope that will change).
Furthermore, the trip to the doctors office takes on new levels of anxiety when the WBC count keeps slowly ticking up - 20 - 30 - 50 - 80. I think a lot of patients see those numbers and experience a lot of angst. How high do you let it go? Shouldn't I do something about it? Watch and wait is hard enough, but getting run over by a steamroller in slow motion seems like a medical version of water boarding.
The first thing I tell patients is that there is no single number that tells me it is time to treat a patient. I think many docs start to get uncomfortable when things hit 100 or higher, but for the CLL specialists out there, 100 is often just another number and you will see things periodically go quite a bit higher. I suspect a number of CLL docs take a deep breath when things get much higher than 200 but for a stable patient without other problems - 200 isn't necessarily any worse than 50. I suppose we may need to take extra precautions when you treat someone with a sky high WBC to make sure they don't experience tumor lysis (when too many cells die all at once, it can cause the "gunk" to back up in the kidneys or cause your heart some electrical problems). The highest I've heard of in a stable patient was 500 on one of the ibrutinib studies - I am glad that wasn't my patient - I would have been pretty anxious.
In some of the "acute leukemias" which are very different conditions - such numbers would be terrifying. The biology is very different though - 100 CLL cells is very different than 100 AML cells.
So if we don't look at a single number - then what should we look at. In clinical trials we use the term, "clinically active disease" as a reason to start treatment. In my mind, "clinically active disease" is largely about trends. Here is where you need some judgement though.
It is one thing for a white blood count to go from 20 -30 - 50 - 80 over a two year period. It is another thing all together if that happens over four months. All too often, I hear people get anxious when the wbc goes from 30 to 50 without other changes. When that happens to my patients, I normally look for any signs or symptoms of infection or other abnormalities. I will often repeat it a few weeks later to make sure it is really a trend instead of a "blip." These things can jump around from time to time and I've seen plenty of cases where that 50 went back to 30 and I never knew why. When the WBC doubles over a several month period and that trend looks real / sustained - that is active disease. Often such a patient can still sit tight if other things are holding steady, but chances are that patient is headed for treatment in the next 2-6 months. It is another thing too if it doubles from 30 to 60 (often lots of room to spare) versus 100 to 200 (more likely your marrow might get compromised).
Other trends that are VERY important to me are the hemoglobin and platelets. When WBC keeps going up, those will often start to fall. The marrow can only do so much. If it is too crowded with CLL cells, there isn't enough room to make RBC and platelets. Here again, there is no single number that tells me to get started but when there is a sustained trend in the platelets and it gets under 100 or the hemoglobin falls to less than 11 under similar conditions it suggests treatment is coming soon. It is important to make sure it is an "overcrowding" phenomena and not an "autoimmune" situation. Sometimes CLL cells can go on a rampage and make antibodies that destroy RBC and PLT's. This can happen quite suddenly. When a hemoglobin goes from 11 to 7 in several weeks, chances are that is autoimmune.
There are other reasons to treat that are not based on trends. Sometimes a patient has overwhelming fatigue, other times lymph nodes can become really troublesome. Sometimes CLL really compromises somebodies immune system and they keep getting significant infections (see video link to Brian Koffman video we did together: Feeling run down from CLL.) Those are fair reasons though somewhat "softer" indications to start on treatment.
So why do we wait so long? In the past, our treatments were chlorambucil and fludarabine. There was an old study in follicular lymphoma (close cousin to CLL) where watch and wait was compared to chlorambucil. If anything the chlorambucil patients did a little worse in the long term. The idea took hold that nothing we did ultimately impacted how long a person survived so don't jump too soon. If taking "chemotherapy" didn't do anything more than make you feel better (not a typo), let's make sure you were feeling pretty bad before we got started. I've written in other posts about clonal evolution - another concern for jumping in too soon. One important thing to note however is that it can be very difficult to show that ANYTHING improves survival in CLL. For a condition that can often last over a decade, it takes a long time to prove your point. Even with the most exciting new research drugs, we may not see that they improve overall survival for average CLL patients for another 10 years!
Things have started to change though. Two studies in the past few years have shown we can improve overall survival in CLL (both started quite some time ago). Frontline fludarabine keeps patients alive longer than frontline chlorambucil in patients needing treatment and the Germans have shown us that FCR keeps patients alive longer than FC.
Those are milestone studies, yet I think the real change will happen when we get to a place where we have effective biologically informed treatments that are not chemotherapy based. We are spoiled to have a substantial number of these working through clinical trials now (ibrutinib, GS-1101, GA-101, ABT-199, and others). My personal conviction is that once we can start combining some of these treatments we will really be off to the races with the "new era in CLL."
In follicular lymphoma, things are changing for the better. Rituxan is "biologic therapy" that is a pretty effective treatment that does not necessarily need to involve chemotherapy. 70% of patients will respond to rituxan and disease control can be quite durable for some patients. Unfortunately, as a single agent, it is not nearly as effective CLL.
There are always exceptions to the definition of "active disease" I outlined above. I watch my patients with 17p a little more closely and may jump in a little earlier. I don't know that I am right for doing this, but I think a lot of docs do the same. Since these cells can be so resistant to treatment it might not be a good idea to collect so many of them before getting started. The same is true for 11q minus patients but perhaps not to the same degree. Another thing to consider is that patients with "unmutated" cells might on average go up faster than someone with "mutated" cells.
Things also change in patients with relapsed disease. It is not uncommon to see faster kinetics with relapsed disease (see clonal evolution post). Also, over time, lymph nodes become more problematic. Keep in mind that CLL cells in bone marrow and lymph nodes are considered more difficult to eradicate than the ones in the circulation. I think docs tend to jump on relapsed disease a little earlier than they do in untreated patients - even though the indications really do not change.
We spend a lot of effort as docs and probably freak out a lot of patients by looking at all sorts of expensive prognostic markers (BCR mutation status, b2 microglobulin, CD38, ZAP-70, etc.) Ultimately, we try to use these to tell us what the trends are going to look like in the future. Better yet, get an old blood test from the last time you had blood drawn. It is very common for me to meet a patient, dig up a three year old blood test and point out that their CLL was present way back when, just not enough to trigger the alarm bells. I think a lot of patients are relieved to know things haven't really changed a whole lot over a several year period.
Anyhow, hope that helps explain how I think a lot of docs think through this sort of question.
Let's face it, sitting there and doing, "nothing" is hard enough when we are conditioned to believe "early detection saves lives" or "catching it early is your best chance to beat it." Those things are true in common cancers like breast, prostate, colon, lung, etc. but at least for now those do not necessarily hold true in CLL (I hope that will change).
Furthermore, the trip to the doctors office takes on new levels of anxiety when the WBC count keeps slowly ticking up - 20 - 30 - 50 - 80. I think a lot of patients see those numbers and experience a lot of angst. How high do you let it go? Shouldn't I do something about it? Watch and wait is hard enough, but getting run over by a steamroller in slow motion seems like a medical version of water boarding.
The first thing I tell patients is that there is no single number that tells me it is time to treat a patient. I think many docs start to get uncomfortable when things hit 100 or higher, but for the CLL specialists out there, 100 is often just another number and you will see things periodically go quite a bit higher. I suspect a number of CLL docs take a deep breath when things get much higher than 200 but for a stable patient without other problems - 200 isn't necessarily any worse than 50. I suppose we may need to take extra precautions when you treat someone with a sky high WBC to make sure they don't experience tumor lysis (when too many cells die all at once, it can cause the "gunk" to back up in the kidneys or cause your heart some electrical problems). The highest I've heard of in a stable patient was 500 on one of the ibrutinib studies - I am glad that wasn't my patient - I would have been pretty anxious.
In some of the "acute leukemias" which are very different conditions - such numbers would be terrifying. The biology is very different though - 100 CLL cells is very different than 100 AML cells.
So if we don't look at a single number - then what should we look at. In clinical trials we use the term, "clinically active disease" as a reason to start treatment. In my mind, "clinically active disease" is largely about trends. Here is where you need some judgement though.
It is one thing for a white blood count to go from 20 -30 - 50 - 80 over a two year period. It is another thing all together if that happens over four months. All too often, I hear people get anxious when the wbc goes from 30 to 50 without other changes. When that happens to my patients, I normally look for any signs or symptoms of infection or other abnormalities. I will often repeat it a few weeks later to make sure it is really a trend instead of a "blip." These things can jump around from time to time and I've seen plenty of cases where that 50 went back to 30 and I never knew why. When the WBC doubles over a several month period and that trend looks real / sustained - that is active disease. Often such a patient can still sit tight if other things are holding steady, but chances are that patient is headed for treatment in the next 2-6 months. It is another thing too if it doubles from 30 to 60 (often lots of room to spare) versus 100 to 200 (more likely your marrow might get compromised).
Other trends that are VERY important to me are the hemoglobin and platelets. When WBC keeps going up, those will often start to fall. The marrow can only do so much. If it is too crowded with CLL cells, there isn't enough room to make RBC and platelets. Here again, there is no single number that tells me to get started but when there is a sustained trend in the platelets and it gets under 100 or the hemoglobin falls to less than 11 under similar conditions it suggests treatment is coming soon. It is important to make sure it is an "overcrowding" phenomena and not an "autoimmune" situation. Sometimes CLL cells can go on a rampage and make antibodies that destroy RBC and PLT's. This can happen quite suddenly. When a hemoglobin goes from 11 to 7 in several weeks, chances are that is autoimmune.
There are other reasons to treat that are not based on trends. Sometimes a patient has overwhelming fatigue, other times lymph nodes can become really troublesome. Sometimes CLL really compromises somebodies immune system and they keep getting significant infections (see video link to Brian Koffman video we did together: Feeling run down from CLL.) Those are fair reasons though somewhat "softer" indications to start on treatment.
So why do we wait so long? In the past, our treatments were chlorambucil and fludarabine. There was an old study in follicular lymphoma (close cousin to CLL) where watch and wait was compared to chlorambucil. If anything the chlorambucil patients did a little worse in the long term. The idea took hold that nothing we did ultimately impacted how long a person survived so don't jump too soon. If taking "chemotherapy" didn't do anything more than make you feel better (not a typo), let's make sure you were feeling pretty bad before we got started. I've written in other posts about clonal evolution - another concern for jumping in too soon. One important thing to note however is that it can be very difficult to show that ANYTHING improves survival in CLL. For a condition that can often last over a decade, it takes a long time to prove your point. Even with the most exciting new research drugs, we may not see that they improve overall survival for average CLL patients for another 10 years!
Things have started to change though. Two studies in the past few years have shown we can improve overall survival in CLL (both started quite some time ago). Frontline fludarabine keeps patients alive longer than frontline chlorambucil in patients needing treatment and the Germans have shown us that FCR keeps patients alive longer than FC.
Those are milestone studies, yet I think the real change will happen when we get to a place where we have effective biologically informed treatments that are not chemotherapy based. We are spoiled to have a substantial number of these working through clinical trials now (ibrutinib, GS-1101, GA-101, ABT-199, and others). My personal conviction is that once we can start combining some of these treatments we will really be off to the races with the "new era in CLL."
In follicular lymphoma, things are changing for the better. Rituxan is "biologic therapy" that is a pretty effective treatment that does not necessarily need to involve chemotherapy. 70% of patients will respond to rituxan and disease control can be quite durable for some patients. Unfortunately, as a single agent, it is not nearly as effective CLL.
There are always exceptions to the definition of "active disease" I outlined above. I watch my patients with 17p a little more closely and may jump in a little earlier. I don't know that I am right for doing this, but I think a lot of docs do the same. Since these cells can be so resistant to treatment it might not be a good idea to collect so many of them before getting started. The same is true for 11q minus patients but perhaps not to the same degree. Another thing to consider is that patients with "unmutated" cells might on average go up faster than someone with "mutated" cells.
Things also change in patients with relapsed disease. It is not uncommon to see faster kinetics with relapsed disease (see clonal evolution post). Also, over time, lymph nodes become more problematic. Keep in mind that CLL cells in bone marrow and lymph nodes are considered more difficult to eradicate than the ones in the circulation. I think docs tend to jump on relapsed disease a little earlier than they do in untreated patients - even though the indications really do not change.
We spend a lot of effort as docs and probably freak out a lot of patients by looking at all sorts of expensive prognostic markers (BCR mutation status, b2 microglobulin, CD38, ZAP-70, etc.) Ultimately, we try to use these to tell us what the trends are going to look like in the future. Better yet, get an old blood test from the last time you had blood drawn. It is very common for me to meet a patient, dig up a three year old blood test and point out that their CLL was present way back when, just not enough to trigger the alarm bells. I think a lot of patients are relieved to know things haven't really changed a whole lot over a several year period.
Anyhow, hope that helps explain how I think a lot of docs think through this sort of question.
Thursday, November 8, 2012
WVCI ASH 2012 Abstracts
ASH abstracts are out. I recently posted on how to carefully evaluate the news. Over next several weeks I want to draw attention to those abstracts that I think are most noteworthy. In the meantime, I thought I would put the links to the studies our center has participated in. Most of these represent collaborations with leaders in CLL and NHL. It has been a good year in CLL/NHL and I think we are really on the verge of substantial change in the field.
Monday, November 5, 2012
How I treat Diffuse Large B Cell Lymphoma (DLBCL)
In contrast to the debate about how to select initial
treatment for patients with follicular lymphoma, treatment in DLBCL is
considerably more straight forward.
These two lymphomas represent the most commonly diagnosed subtypes of
NHL. For further questions about thedifferent types of NHL link here.
Most patients with DLBCL are going to be treated with
R-CHOP. I have a lengthy post about this regimen that describes the regimen in detail for the interested reader. There are a number of considerations that may
individualize therapy for some patients so it is not just a blanket – one size
fits all.
When R-CHOP is the selected regimen, several important
questions need to be asked. The first
question is “how many cycles.” In most
patients the answer will be six. I
normally repeat CT scans after cycles two, four, and six. If the patient still has measurable disease
and it continues to shrink between cycles four and six – I will occasionally go
to eight cycles – but that is definitely the minority of patients. You cannot continue R-CHOP indefinitely
because the “H” which stands for “hydroxydoxorubicin” aka “Adriamycin” can be
hard on the heart and you can only give so many doses before running into long
term cardiac issues.
For the less common patient who shows up with “limited
stage” (ie. Stage I or stage II disease mostly in one spot), you can consider a
shorter duration of R-CHOP when combined with radiation. Usually 3 cycles followed by radiation is
enough. Sometimes that is more difficult
when the site of disease is less agreeable to radiation such as in the colon.
I will also use radiation in patients who present with stage
III, or IV disease provided there was one spot that was particularly bulky at
the start (>10cm) but this is a little more controversial. This tends to reduce the likelihood that
disease will relapse at the same site of disease, but does not necessarily
prevent distant spread of the lymphoma.
The next question is whether a patient is at risk for their
lymphoma coming back in their brain.
Since chemotherapy does not get into the brain very well, it is a site
of relapse in a minority of high risk patients.
This includes patients whose initial disease started in the testicle,
the nasal sinuses, or someone who has a lot of disease outside of their lymph
nodes (what we call extra-nodal disease).
For those patients with high risk of CNS relapse, we have the option of
administering a shot of a drug called methotrexate by way of a lumbar
puncture. When done by our radiology
colleagues using fluoroscopy, this doesn’t typically bother a patient too
much.
The problem with methotrexate is that we really don’t have a
lot of confidence that it works particularly well. It is one of those things we do by convention
when what is really needed is a change of convention. Some docs will actually give a much higher
dose of methotrexate into a vein. The
dose in this situation typically requires the patient be admitted to the
hospital for a few days. This may be a
more effective strategy, but obviously a lot more difficult to perform.
There are circumstances where R-CHOP may not be a good idea
for a patient. In patients with prior
exposure to Adriamycin (perhaps for a breast cancer many years ago), or who are
starting with a bad heart to begin with, you may need to substitute the
Adriamycin for something more “heart friendly.”
Sometimes these substitutions are done for patients that you think might
be a little too old or fragile to handle R-CHOP. I did recently treat a 92 year old with
DLBCL giving him six cycles of R-CHOP.
Granted, he was still out there chopping wood – but another example of
where age does not equal limitation. He
is two years out from therapy now and just celebrated his 70th
anniversary – way cool!
There are a number of ways to do swap things around. I know some docs who use a different
formulation of Adriamycin known as “Doxil” which is more heart friendly. Others have used a drug with a lot of
similarities to Adriamycin known as mitoxantrone. Unfortunately, this substitution reduces
efficacy and it isn’t totally clear that it protects the heart all that
much. I have periodically used a
substitute for Adriamycin known as etoposide.
The published study for this is pretty old and I cannot be certain it is
a great substitute. I try to use R-CHOP
as much as I can, but sometimes you just have to avoid the Adriamycin.
Another key group of patients for whom I choose a different
path are the patients with “double hit” lymphoma. I need to explain some biology here. There are common DNA abnormalities in
DLBCL. The most common is where a gene
known as BCL-6 gets abnormally activated by getting the chromosomes rearranged,
resulting in excessive protein. This can
happen with other genes including BCL-2 or Myc.
When a lymphoma has two of these (most commonly Myc and one of the
others), we think these patients do not do as well as our more common “single
hit” DLBCL. Most scientists agree this
group is considered “higher risk” but what to do about it is less agreed upon
and subject of practice patterns not necessarily scientifically proven to be
any better.
When Myc in locked on, the cells cannot stop dividing. We see exceptionally highly proliferative
tumors in this setting. We can measure a
“Ki67” which is just a marker for dividing cells. While normal DLBCL might be anywhere from
40-80% of cells staining positive, Myc affected cells are almost always >
90%. Myc is also a hallmark of a
particularly aggressive version of lymphoma known as Burkitt’s lymphoma. Unfortunately, if you show microscopic slides
of very aggressive lymphomas to a bunch of pathologists, you will find a
surprising degree of disagreement as to whether a lymphoma is Burkitt’s or
DLBCL. In fact there is even a new
category known as “Aggressive B Cell lymphoma with features indeterminant
between Burkitt’s and DLBCL.” The main
point for me, is that we sometimes under-diagnose either double hit lymphoma or
it’s close cousin Burkitt’s and instead call it DLBCL.
Clinical science gets a little thin here so please do not
take the following as the only acceptable strategy. For those patients with highly proliferative
tumors, I will use a regimen that has been studied in both DLBCL as well as
Burkitt’s. The regimen is known as
“R-EPOCH” A lot of the letters (as well
as the drugs) are actually the same. In
fact, there is only one new drug – etoposide.
The main difference is that all the drugs are infused over four days
through a pump followed by some injections on day five. This is different than R-CHOP which is
commonly given over just one day.
Since the regimen is good in Burkitt’s as well as DLBCL, I
use it when there is gray area with the diagnosis. I cannot say that this is definitively the
right thing to do but I know a number of academic physicians who do the same. There is a large research study currently
comparing R-EPOCH to R-CHOP but it is accruing slowly and I don’t know if it
will ever give us the answer as to which regimen is the best.
R-EPOCH is also my preferred regimen for those patients with
HIV who have been diagnosed with DLBCL.
This is a unique subpopulation that used to be a lot more common than it
is today. There have been a number of
studies using this regimen in this setting.
Hopefully that should cover a number of questions about how
to select a front line regimen in DLBCL.
It is not meant to be a replacement for your own doctors advice but
hopefully give you confidence that your doc is on the right track. I hope I’ve highlighted where things are
pretty clear and where they are controversial so that any differences in
strategy might be explainable.
Thanks for reading!
Jeff
Tuesday, October 30, 2012
ASH abstracts are coming... beware of the headlines
It seems like we hear a lot about clinical trial results that are “significant.” Yet, in many cases it feels like the outcomes of certain diseases really are not changing all that much. ASH abstracts will be out in the next few weeks and it is always a time for news. Unfortunately, much of the news is poorly reported because the language of science is not always the same as the language of the rest of the world. Nowhere is that more important as the word "significant." When the headlines scream "significant" it really helps to understand what is actually being communicated.
We often trumpet a study that has achieved a level of improvement to be
considered “statistically significant” yet what that really means is that when
two or more interventions were compared, the difference in outcome between the
interventions is unlikely to have occurred by chance (or more accurately
stated, likely to have occurred by random chance <5% of time should the
study be repeated multiple times under similar circumstances).
The problem with this definition is that a small difference
between interventions (say an improvement in response rate from 33% to 38% or
improvement in survival from 11 months to 12 months) can be “statistically
significant” if it is observed in a large enough population whereas most
patients might say – “who cares if it is such a small difference.” This is a key point, so I want to make sure
it is clear. If you see a 5% difference
in a study population of 70 patients, you might agree that there is a good
chance the difference is purely random.
On the other hand, if you see a 5% difference in a study population of
10,000 patients – chances are that is a real / reproducible difference. In the latter case, we would call that “statistically
significant” even if the patient says, “so what.” Take a 50% difference in outcome however, and
even if it is observed in a small population, it is a big enough difference to
make you think it isn’t a random chance observation.
When we design studies we go through an exercise known as
“powering the study” which enables us to project a difference between two interventions
and then calculate how many patients we will need to study to enrolled to
conclude that our difference is “statistically significant.” If we project that a new treatment improves
response rate from 20% to 80% that is a huge number and we need few patients to
prove our point. Similarly if we double
the duration of response with a new treatment – that doesn’t take many patients
either.
When the difference is small though, the studies have to get
very large. That is true when we already
have very effective treatments (hodgkin’s disease) and you don’t have a ton of
room for improvement (ie, can’t cure 130% of patients) or the incremental
benefit is small (different hormone manipulations in breast cancer improving
outcome by 1-2%). One good clue to how
meaningful a result is is simply to look at how many patients were
enrolled. If you have > 500 patients
per arm, chances are the improvement is fairly modest.
Patients want “clinically meaningful” results such as “Dad
survived 6 years instead of 6 months with his pancreatic cancer” or “everyone
who takes the new drug feels better and responses are dramatically
improved.” Who could blame patients for
wanting this.
Over the past 50 years most of our advances have fallen into
the “incremental gain” category. This is
where we had huge studies to show that we could prolong pancreatic cancer
survival by two weeks on average and this was trumpeted as “statistically
significant” – yuck! We’ve had a bunch
of these recently in colon cancer. Seethis link for a very good article about this.
Sadly, the route to approval of drugs requires
“statistically significant” even if it is not “clinically significant.” Of course, a new drug is going to be very
expensive and if you have to take $90,000 of treatment to prolong life by
several months, you might think twice if you were paying for it (provenge in
prostate cancer). The British have a
system that measures “clinical significance” as part of their approval
process. I have to say that I can see
some logic there – please look at this link for more.
I am pleased that many of the experimental treatments in CLL
fit the category of “clinically meaningful.”
It is important to note that randomized studies to measure the magnitude
of difference have not been completed with ibrutinib, CAL-101/GS-1101, ABT-199,
GA-101 and so forth – but they are underway.
Many thought leaders feel these agents will be both “clinically
significant” and “statistically significant” to boot. Hopefully we will gain broader access to
these soon and patients will live longer, happier lives.
ASH abstracts are just around the corner. You will probably hear a lot about “significant”
results. Pay close attention to the use
of the terms “statistically significant” and “clinically significant” – they are
different. Look for how large the sample
size is in the study. Lymphoid studies
tend to be smaller than breast / lung studies.
A big lymphoma study or CLL study might be >500 patients. Keep in mind that you cannot define “statistically
significant” unless you are comparing at least two groups – so they are either
randomized studies or looking at subgroups within a larger study.
Hopefully we will have a lot of studies to discuss that
really improve the quality of lives for patients with these disease.
Statistic vs real significance
drug cost vs efficacy
Friday, October 19, 2012
clonal evolution part 2
ASH plenary session link
I've written once previously about clonal evolution, but I think this is really an important topic and so I wanted to come back to it again.
There is a wonderful new technology called "next generation sequencing" that is turning cancer biology upside down. The human genome project took 13 years, 6 billion dollars, and sequenced (ie measured every single piece of human DNA) the genome of four healthy individuals. That is a lot of time and money. You can now do the same (actually much more) amount of work in about 2-3 weeks at a cost getting closer and closer to $1000.
When you can measure DNA at this level of depth at this cost you can start asking very important questions. Take the following image:
This looks at an individual with CLL who had their cancer cells sequenced at 5 different timepoints in their disease. I suspect this is true in lymphoma as well, but tissue is harder to get. For now, assume this applies to both diseases.
At the first timepoint analyzed (a) there are already three "subclones" and a population of normal B cells. The patient gets treated with chlorambucil and at timepoint (b) which is relapse following treatment, one clone has taken off as the major one (91%). The patient then gets treated with FCR and overall the disease largely goes away. Subclone 1 goes away forever. Unfortunately subclone 4 which was only 1% of all the cells prior to FCR really takes off and becomes the clone that eventually causes the patient to get into trouble.
This highlights how the behavior of disease can change over time. Different subclones may acquire different mutations (17p, 11q, BIRC3, SF3B1, NOTCH, etc.). Though it may be lurking in background, it can become the predominant clone when exposed to therapies that eliminate the "easy disease."
I am not sure just yet if that makes an argument for how we treat patients, but I do think we aught to be looking to see how certain therapies affect patterns of resistance....
I've written once previously about clonal evolution, but I think this is really an important topic and so I wanted to come back to it again.
There is a wonderful new technology called "next generation sequencing" that is turning cancer biology upside down. The human genome project took 13 years, 6 billion dollars, and sequenced (ie measured every single piece of human DNA) the genome of four healthy individuals. That is a lot of time and money. You can now do the same (actually much more) amount of work in about 2-3 weeks at a cost getting closer and closer to $1000.
When you can measure DNA at this level of depth at this cost you can start asking very important questions. Take the following image:
This looks at an individual with CLL who had their cancer cells sequenced at 5 different timepoints in their disease. I suspect this is true in lymphoma as well, but tissue is harder to get. For now, assume this applies to both diseases.
At the first timepoint analyzed (a) there are already three "subclones" and a population of normal B cells. The patient gets treated with chlorambucil and at timepoint (b) which is relapse following treatment, one clone has taken off as the major one (91%). The patient then gets treated with FCR and overall the disease largely goes away. Subclone 1 goes away forever. Unfortunately subclone 4 which was only 1% of all the cells prior to FCR really takes off and becomes the clone that eventually causes the patient to get into trouble.
This highlights how the behavior of disease can change over time. Different subclones may acquire different mutations (17p, 11q, BIRC3, SF3B1, NOTCH, etc.). Though it may be lurking in background, it can become the predominant clone when exposed to therapies that eliminate the "easy disease."
I am not sure just yet if that makes an argument for how we treat patients, but I do think we aught to be looking to see how certain therapies affect patterns of resistance....
Monday, October 15, 2012
17p Deletion in CLL
17p is the genomic alteration in CLL that triggers the
greatest concern in most patients. It can have a tremendous impact on CLL prognosis and the FDA has recently extended approval to ibrutinib in this population (even without prior treatment) and the European equivalent of the FDA (the EMA) will do the same for idelalisib in combination with rituximab. A lot of patients know that 17p deletions is one of the high risk markers in CLL – but there are a lot of things to consider
about CLL with 17p deletion before completely tearing your hair out.
When we say 17p deletion CLL, what we mean is that the short
(petit) arm of chromosome 17 is missing.
You have 23 pairs of chromosomes (46 total) and as you get higher in the
numbering, the chromosomes get smaller and smaller. It is probably an excessive simplification to
say that the biology of 17p is all about one particular protein called p53 –
but for the time being that is most of the story.
P53 is affectionately called “the guardian of the genome.” Every time I read about p53 I
discover some new function of the protein that I didn’t know about before. One of the most important
though is that it will bind to DNA in a bunch of places and turn on / off the
genes at those locations. In this role
it is known as a “transcription factor.”
Many of the proteins that are regulated by p53 have to do with cell
survival or cell death. When P53 decides
it is time for a cell to die – very few things can stop that. The most important signal that turns on p53
is DNA damage (hence – guardian of the genome).
When DNA damage occurs the cells have a lot of repair
mechanisms to try to fix the problem (including the ATM protein on chromosome
11q). P53 will halt cell proliferation
until that DNA damage is fixed. Some DNA
damage cannot be easily fixed and when that is the case, p53 triggers a
cell death cascade called apoptosis (one of several ways that cells can die).
I mentioned above that you have two copies of every chromosome
– so you ought to have two copies of P53.
We have been good at detecting absence of chromosome 17p for quite some
time (via routine cytogenetics or FISH), but we have not always been very good
at detecting p53 mutations which have been far more difficult to measure until recently. With new sequencing
technology, it is relatively easy to look for mutations and an increasing
number of laboratories are offering that service.
This is important because patients with 17P deletion are not the only individuals who have to be concerned about it. About 30 percent of patients with abnormality in P53 have a mutation BUT NO DELETION. Those have just as bad a prognosis but are not currently detected by FISH testing (nor SNP arrays which are one newer technology that is gaining popularity). There is a strong association between loss of chromosome 17p on one chromosome and mutation of the other copy (about 85% of cases with 17P deletion will also have P53 mutation on the other chromosome).
This is important because patients with 17P deletion are not the only individuals who have to be concerned about it. About 30 percent of patients with abnormality in P53 have a mutation BUT NO DELETION. Those have just as bad a prognosis but are not currently detected by FISH testing (nor SNP arrays which are one newer technology that is gaining popularity). There is a strong association between loss of chromosome 17p on one chromosome and mutation of the other copy (about 85% of cases with 17P deletion will also have P53 mutation on the other chromosome).
Another common misunderstanding has to do with “how many
deleted cells does it take to call a patient 17p deleted?” In other words, FISH will report the
percentage of cells lacking one copy of 17p.
That can range from 1% to 100%.
In simple terms, the more abnormal cells, the worse. For research purposes we say that 20% of
cells lacking one copy of 17p calls that person “17p deleted.” Some labs have lower thresholds (7%). Occasionally I will hear from a patient that has 2% of cells with 17p deletion who is worried about their future. By convention we would not group that patient into a 17p deletion category.
I think the 20% distinction is important – but gets more
emphasis than it deserves. We have prior
posts talking about clonal evolution and this is a topic that is very important
to understand (also covered in my "watch and wait" post. If you have a small
percentage of 17p deleted cells and you get chemotherapy that damages DNA –
requiring p53 to transmit death signals – guess which cells are going to survive. We know that one out of five patients will have a high risk molecular abnormality at relapse (11q/17p). If we look hard enough we can see that it was often there to begin with – but below our typical levels of detection. By giving therapy that removes the more sensitive cells, the resistant ones remain.
On the other hand, if you have a large number of 17p deleted cells, you
are less likely to respond to chemotherapy in the first place.
The question becomes, what to do clinically when a patient
has a 17p deletion. There are not a lot
of standard regimens that are particularly active when a patient has a high
load of 17p deleted cells. FCR and BR
are not very effective. Indeed, perhaps the most important clinical trial in this population right now is the frontline study of idelalisib in combination with rituximab. It is available here and here (can be opened at any of these locations)
Campath (an antibody that does not damage DNA) can work well, but does not clear bulky lymph nodes which are common with 17p
deletion. High dose steroids can shift
cells into the circulation where they can be removed by campath. Rituxan also does not damage DNA both rituxan
and campath combine well with high doses of steroids.
The new drugs CAL-101 (aka GS 1101), ibrutinib (aka PCI-32765), and ABT-199 (AKA GDC-0199) appear in preliminary reports to be
quite active in 17p deleted CLL.
Multiple clinical trials are available for those drugs. For untreated CLL with 17P, I think it is worth trying to get into this study
I have a particularly memorable patient who presented to my
clinic with bad stage IV 17p deleted disease.
He had bulky nodes, WBC count of 200, platelets of 20k and hemoglobin of
8. His FISH showed 100% 17p
deleted. Two cycles of FCR did nothing
except get him transfused every few days.
I switched him to campath with rituximab and got his marrow into better
shape but he still had bulky nodes. He
was young enough for transplant, but not eligible because he still had bulky
nodes. I sequentially gave him R-ESHAP,
bendamustine rituxan, revlimid rituxan, ofatumumab all without much
benefit. I started him on CAL-101 and
his disease melted away. His disease control lasted nearly two years.
When a patient is young enough, they should definitely
consider a stem cell transplant for 17p deleted disease. The challenge though is that CLL more
commonly affects patients too old for transplant. The engineered T cells hold some promise for being active in this setting.
I also have a lower threshold for starting treatment in
previously untreated CLL with 17p deletion (see "when to treat CLL").
Since those cells are likely to be resistant, I don’t see value in
getting too far behind before getting started. When I start, I might avoid FCR though some
would argue it is still the right choice (NCCN lists this as first choice but I do not agree).
In Europe, you would typically get steroids with campath and I tend to
think that is the right option. Unfortunately, not enough sound data to tell us one regimen is better than another in this situation. If a patient has access to ibrutinib in this setting that may be preferable.
Finally – one more biologic consideration. Richter’s transformation is the name given to
CLL that changes behavior and becomes a lot more aggressive – a different entity we call diffuse large B cell lymphoma.
It appears that p53 abnormalities are one of several key steps to
getting to Richters (the other possibly being abnormalities in Myc or a protein that turns on Myc called NOTCH). This is
part of the reason Richter’s can be so difficult – it has intrinsic resistance
to chemotherapy.
We are lucky to have a host of new drugs working through the
system. I will be very interested to see
if drugs work out in this setting!
Thanks for reading - I also discuss this in a video done by Brian Koffman. For anyone still interested, here is the link: High risk CLL
Thanks for reading - I also discuss this in a video done by Brian Koffman. For anyone still interested, here is the link: High risk CLL