R-CHOP is one of the most commonly used regimens out there for lymphoma. I wanted to briefly write about what the different ingredients are - how they work - what patients experience - etc. R-CHOP actually is a cocktail of 5 different drugs. Each letter represents one of the drugs. Here goes...
R=Rituxan. Rituxan is an antibody. You make antibodies to fight colds, flu, e.coli, etc. Instead of a naturally occurring antibody, this one is "engineered" to bind to the outside of a lymphoma/leukemia cell and alert the immune system to go after it. See my other post "Building a better CD20 antibody." People can often have "infusion reactions" with the first dose (chills, shaking, shortness of breath, rash, etc). If you actually measure "b-cells" in the blood while administering the antibody, you can see them disappear from the blood during the infusion. As those b-cells go away they release little hormones that cause the symptoms. Often the symptoms do not recur with subsequent doses as the B cells are gone. Overall, most people tolerate the drug extremely well and are not even aware they are getting a very effective anti-cancer treatment. Those patients with side effects can often be managed by extra tylenol, benadryl, steroids, etc.
C=Cyclophosphamide. This is an old school chemotherapy that has been around for quite a few years. It binds to DNA in the nucleus of the cancer cell and prevents effective replication of the cells genome. Those cells that divide more rapidly are more sensitive to the treatment. Therefore cancer cells and normal bone marrow are most affected. It lowers healthy blood cells as well as bad ones. Fortunately the good guys recover more quickly. It can also cause nausea but our nausea medications are so good, that is rarely a problem. There can be bleeding in the bladder but I have given a ton of cytoxan and I've never seen it as a problem.
H=Hydroxyrubicin (which we call Adriamycin). Some call this drug "Big Red" as it has a pinkish / red color and can make your urine discolored for 24-48 hours. When you talk about R-CVP the only difference is that this drug is missing. Hydroxyrubicin "intercalates" or "slips between" the base pairs of DNA. DNA is a coiled structure. In order to copy it, you need to unzip the two strands. This creates a lot of "torque" or "strain" that needs to be released. It is like a hair dryer cord that gets turned around and bound up in knots. To relieve the strain there are enzymes called "topoisomerases" which nick the DNA so it can spin around and release the tension and then get re-attached. Adriamycin prevents that and results in "double stranded DNA breaks." These are harder for the cancer cell to repair than single stranded breaks. The side effect profile is notable for hair loss and low blood counts. The fear of adriamycin is that it can weaken the heart muscle. You can usually get away with 6-8 doses of the drug, but after that point the risk of heart damage really goes up. In uncommon situations, it can cause some permanent injury to your bone marrow stem cells and in extremely rare circumstances even cause a second cancer.... aargh!
O=Oncovin (which we call vincristine). Vincristine is what we call a "microtubule inhibitor." Other microtuble drugs include vinblastine, taxol, taxotere, eribulin, etc. Microtubules are like the cellular "skeleton." It helps hold all the pieces of the cell where they want to be. When cells need to separate their chromosomes into daughter cells they use microtubules to help pull them apart to the opposite sides of the cell. They chew up one end and add pieces to the other which creates a sense of "movement." Vincristine freezes that process and cells don't like that. If they stay frozen too long they trigger cell death. It causes some numbness in finger tips and toes and possibly constipation.
P=Prednisone (yes the good old fashioned steroid). You are probably familiar with prednisone for things like rashes or arthritis etc. We use it to lower the immune system. Lymphoma is simply a cancer of the immune system. I have had occasion to "cool off" a patient while trying to collect additional tests. I can sometimes give them a slug of steroids while I am waiting and see their lymph nodes shrink.
Sometimes when we tell patients about potential side effects, I get the impression the cure sounds a lot worse than the disease. Doc's probably practice defensive medicine more than we realize. If we tell you everything that can go wrong, then we feel we are less likely to get sued if something bad happens. Unfortunately you see some patients go through the side effect list and freak out - understandably.
I often say that chemotherapy is a lot like a "stereo dial." We can turn it up to 10 (unbearable) or down to 1 (was that chemo you just gave me?). R-CHOP is somewhere between a 4-6. Nausea isn't often much of an issue. Fatigue is considerable. Many people can work while getting chemo, but some folks are better off taking the time off of work (if they can). Somehow the hair loss makes you feel like a cancer patient. After you have had one dose of chemo (a cycle is every three weeks you get one dose) I tell patients that they have seen 80% of the side effects. Yes there is some degree to which things are cumulative, but for the most part you have seen the side effects.
Hopefully that helps. In another post, I will talk about how I approach DLBCL and when I choose alternatives.
Friday, August 31, 2012
Friday, August 24, 2012
Making sense of all the different lymphomas
I am not sure if there is a single person on the planet who can tell me exactly how many different types of lymphoma exist. I live and breath lymphoma and I can't. Perhaps Elaine Jaffe M.D. could since she is the pathologist in charge of the world health organization committee responsible for lymphoma nomenclature, but I would wager that she might pause before giving you an answer. I think the number is somewhere between 70-100 different types - but it sort of depends how far into the weeds you want to get with your counting.
Take the most common form of NHL known as Diffuse Large B Cell Lymphoma (aka DLBCL) and you could have such variants as primary CNS (brain) DLBCL, primary mediastinal (between the lungs) DLBCL, intravascular DLBCL, gastric (stomach) DLBCL, activated B cell DLBCL, germinal center DLBCL, DLBCL of leg, etc. Remarkably each of these entities has a fairly significantly different biology / prognosis and they warrant unique classification. It is not merely the part of the body where they show up, they are actually different diseases.
If you even venture to take a single entity like "activated B-cell DLBCL" there may be key molecular differences that could split this disease into multiple subtypes depending on whether there is a CD79b mutation versus a CARD11 mutation or a MYD88 mutation which could be the key difference in responses to drugs like ibrutinib.
This bewildering complexity is one of the reasons I most enjoy being involved in lymphoma / CLL. Even amongst seasoned oncologists, you can often look like the brightest person in the room when you talk about subtle patient management differences in uncommon variants.
Unfortunately this bewildering complexity can also be overwhelming for a patient who is told by their surgeon that they have lymphoma and need to see an oncologist. The delay between the diagnosis and the consult is often filled with an internet search that feels like a trip through Alice in Wonderland.
When I meet a patient with lymphoma I always explain how these different diseases fall into a few limited categories and how those categories are unique. Hopefully you will find this useful.
The first "branch point" is the difference between Hodgkin's Lymphoma and Non-Hodgkin's Lymphoma. Patients always ask, "Which is better?" Of course there are a lot of variables that determine the answer to that so I usually say, "stick with me for a minute... we will get there."
Among the patients with Non-Hodgkin's Lymphoma (which outnumber Hodgkin's by about 5:1), my next branch point is T cell versus B cell. In normal physiology, B cells are responsible for making antibodies and T cells are either the "brains" of the immune system or the "cellular assassins" that go around looking for a rogue cell to annihilate. B cell lymphoma outnumbers T cell by about 9:1 so when most people talk about lymphoma they are talking about one of the subtypes of B cell Non-Hodgkin's Lymphoma.
So if we focus for now on the different types of B cell Non Hodgkin's Lymphoma the next branch point splits into three categories based more on clinical behavior. I call them "slow, medium, and fast." In official parlance they are "indolent, aggressive, highly aggressive." Within each category, there is one form of NHL that is the most common and it becomes the "prototype" of the category - for better or for worse. Slow = Follicular Lymphoma (all my FL posts can be linked here), Medium = Diffuse Large B Cell Lymphoma, Fast = Burkitt's. There are a bunch of other slow lymphomas such as Marginal Zone Lymphoma, MALT lymphoma, Small Lymphocytic Lymphoma, etc. There can be considerable differences in management between these, but there is still value in lumping them together as a category. For example, if you learn the basic features of follicular lymphoma (slow prototype), you have a good place to start then you can learn how your specific disease is different or unique.
It is important to recognize however that even a singular entity like Follicular Lymphoma can range from a disease that never needs treatment to a disease that is immediately life threatening. There are other diseases like Mantle Cell Lymphoma that don't fit nicely into a singular category and can take on properties of both "slow" or "medium" lymphomas.
Back in medical school, they always taught us how important a patients history is. In oncology I find this to be most true when I evaluate a new patient with lymphoma. If that lymph node sprung up in 6 days, that is very different than a lymph node that sprung up in 6 months, or even the occasional patient who comes in and says that the lymph node has been there for 6 years. Yes there are categories, but you cannot take a variable that has a continuous distribution and neatly put it into discrete categories!
With all those limitations, I still want to make an effort to say how the categories are different.
If you go from slow to medium to fast I tell patients that the "curability" increases and the "managability" decreases. You are probably not going to cure a slow lymphoma, but for quite a few patients you can manage it for many years. In the Rummel presentation at ASCO 2012, the median (half of patients do better, half do worse) progression free survival after bendamustine / rituxan was almost 7 years - even without rituxan maintenance. That doesn't even take into account survival based on second line regimens and beyond. Slow lymphoma is often very manageable. I have quite a few patients out many years who have NEVER REQUIRED ANY TREATMENT! This is the group where you often hear "watch and wait." I understand that patients want to be "cured." Sadly, with our current treatment regimens I don't think patients with slow lymphoma often get there (ok ignore the minority of limited stage slow lymphoma that gets radiated doesn't have their disease come back elsewhere). I often use the analogy of having a "quiver of arrows." You use the arrows as you need them and count on research to add arrows to your quiver as you go. With survival that is often over a decade, that does not feel to me like a false hope.
If you go the other direction from fast to medium to slow, "managibility" increases. On the highly aggressive end of the spectrum are Burkitt's lymphoma or Lymphoblastic Lymphoma. Here you are aiming for cure but if you don't get there you are in trouble because it is unlikely to be very manageable. Often you don't meet a patient with Burkitt's in the clinic. They often get hospitalized because something has gone terribly wrong and they are hospitalized before the diagnosis is made. Other times, you get a call from a primary care physician who has made the diagnosis and is requesting a consult. I tell them to send the patient straight to the hospital, I will meet them there! From the outset, you are fighting a high stakes battle. With these diseases you often have one chance to get it right. If things go wrong, your chance for cure gets a lot more difficult.
DLBCL is somewhere in between. It is the most common form of NHL (about half of all cases). The disease is quick, but often you have enough time to dot all your "i's" and cross all your "t's" before launching into chemotherapy which probably cures a little more than half of all patients. "Watch and Wait" does not apply to this group, but you often have time to get your PET scan, bone marrow biopsy, echocardiogram, etc. as an outpatient. For those patients not cured, it can often be in remission for years. Even if it comes back, you often have a back-up plan that can cure them the second time around (albeit with a "auto stem cell transplant"). Not surprisingly though there is a broad range of behavior among cases of DLBCL. In some cases it acts like a bad case of Follicular and at other times it can give Burkitt's a run for the money.
I've largely ignored T cell NHL to this point. Though there are "highly aggressive" T cell lymphomas they are fairly rare. Most of the systemic T cell disease fall into the same "intermediate / medium" category as DLBCL. There are a variety of skin T cell lymphomas that are in the "slow" category. Start talking T cell lymphoma variants and you often get a glazed look from oncologists who don't think about NHL all that often.
To summarize: we often lump NHL into one of three categories. Though there can be a significant range within an individual category, our clinical approach to each category is unique and the expectations of patient outcome varies by category. The prototypes (most common per category) are follicular (30%), DLBCL (40-50%), Burkitt's (5%). The remainder of cases make up the bewildering complexity of NHL and explain why my job will likely never be outsourced....
Take the most common form of NHL known as Diffuse Large B Cell Lymphoma (aka DLBCL) and you could have such variants as primary CNS (brain) DLBCL, primary mediastinal (between the lungs) DLBCL, intravascular DLBCL, gastric (stomach) DLBCL, activated B cell DLBCL, germinal center DLBCL, DLBCL of leg, etc. Remarkably each of these entities has a fairly significantly different biology / prognosis and they warrant unique classification. It is not merely the part of the body where they show up, they are actually different diseases.
If you even venture to take a single entity like "activated B-cell DLBCL" there may be key molecular differences that could split this disease into multiple subtypes depending on whether there is a CD79b mutation versus a CARD11 mutation or a MYD88 mutation which could be the key difference in responses to drugs like ibrutinib.
This bewildering complexity is one of the reasons I most enjoy being involved in lymphoma / CLL. Even amongst seasoned oncologists, you can often look like the brightest person in the room when you talk about subtle patient management differences in uncommon variants.
Unfortunately this bewildering complexity can also be overwhelming for a patient who is told by their surgeon that they have lymphoma and need to see an oncologist. The delay between the diagnosis and the consult is often filled with an internet search that feels like a trip through Alice in Wonderland.
When I meet a patient with lymphoma I always explain how these different diseases fall into a few limited categories and how those categories are unique. Hopefully you will find this useful.
The first "branch point" is the difference between Hodgkin's Lymphoma and Non-Hodgkin's Lymphoma. Patients always ask, "Which is better?" Of course there are a lot of variables that determine the answer to that so I usually say, "stick with me for a minute... we will get there."
Among the patients with Non-Hodgkin's Lymphoma (which outnumber Hodgkin's by about 5:1), my next branch point is T cell versus B cell. In normal physiology, B cells are responsible for making antibodies and T cells are either the "brains" of the immune system or the "cellular assassins" that go around looking for a rogue cell to annihilate. B cell lymphoma outnumbers T cell by about 9:1 so when most people talk about lymphoma they are talking about one of the subtypes of B cell Non-Hodgkin's Lymphoma.
So if we focus for now on the different types of B cell Non Hodgkin's Lymphoma the next branch point splits into three categories based more on clinical behavior. I call them "slow, medium, and fast." In official parlance they are "indolent, aggressive, highly aggressive." Within each category, there is one form of NHL that is the most common and it becomes the "prototype" of the category - for better or for worse. Slow = Follicular Lymphoma (all my FL posts can be linked here), Medium = Diffuse Large B Cell Lymphoma, Fast = Burkitt's. There are a bunch of other slow lymphomas such as Marginal Zone Lymphoma, MALT lymphoma, Small Lymphocytic Lymphoma, etc. There can be considerable differences in management between these, but there is still value in lumping them together as a category. For example, if you learn the basic features of follicular lymphoma (slow prototype), you have a good place to start then you can learn how your specific disease is different or unique.
It is important to recognize however that even a singular entity like Follicular Lymphoma can range from a disease that never needs treatment to a disease that is immediately life threatening. There are other diseases like Mantle Cell Lymphoma that don't fit nicely into a singular category and can take on properties of both "slow" or "medium" lymphomas.
Back in medical school, they always taught us how important a patients history is. In oncology I find this to be most true when I evaluate a new patient with lymphoma. If that lymph node sprung up in 6 days, that is very different than a lymph node that sprung up in 6 months, or even the occasional patient who comes in and says that the lymph node has been there for 6 years. Yes there are categories, but you cannot take a variable that has a continuous distribution and neatly put it into discrete categories!
With all those limitations, I still want to make an effort to say how the categories are different.
If you go from slow to medium to fast I tell patients that the "curability" increases and the "managability" decreases. You are probably not going to cure a slow lymphoma, but for quite a few patients you can manage it for many years. In the Rummel presentation at ASCO 2012, the median (half of patients do better, half do worse) progression free survival after bendamustine / rituxan was almost 7 years - even without rituxan maintenance. That doesn't even take into account survival based on second line regimens and beyond. Slow lymphoma is often very manageable. I have quite a few patients out many years who have NEVER REQUIRED ANY TREATMENT! This is the group where you often hear "watch and wait." I understand that patients want to be "cured." Sadly, with our current treatment regimens I don't think patients with slow lymphoma often get there (ok ignore the minority of limited stage slow lymphoma that gets radiated doesn't have their disease come back elsewhere). I often use the analogy of having a "quiver of arrows." You use the arrows as you need them and count on research to add arrows to your quiver as you go. With survival that is often over a decade, that does not feel to me like a false hope.
If you go the other direction from fast to medium to slow, "managibility" increases. On the highly aggressive end of the spectrum are Burkitt's lymphoma or Lymphoblastic Lymphoma. Here you are aiming for cure but if you don't get there you are in trouble because it is unlikely to be very manageable. Often you don't meet a patient with Burkitt's in the clinic. They often get hospitalized because something has gone terribly wrong and they are hospitalized before the diagnosis is made. Other times, you get a call from a primary care physician who has made the diagnosis and is requesting a consult. I tell them to send the patient straight to the hospital, I will meet them there! From the outset, you are fighting a high stakes battle. With these diseases you often have one chance to get it right. If things go wrong, your chance for cure gets a lot more difficult.
DLBCL is somewhere in between. It is the most common form of NHL (about half of all cases). The disease is quick, but often you have enough time to dot all your "i's" and cross all your "t's" before launching into chemotherapy which probably cures a little more than half of all patients. "Watch and Wait" does not apply to this group, but you often have time to get your PET scan, bone marrow biopsy, echocardiogram, etc. as an outpatient. For those patients not cured, it can often be in remission for years. Even if it comes back, you often have a back-up plan that can cure them the second time around (albeit with a "auto stem cell transplant"). Not surprisingly though there is a broad range of behavior among cases of DLBCL. In some cases it acts like a bad case of Follicular and at other times it can give Burkitt's a run for the money.
I've largely ignored T cell NHL to this point. Though there are "highly aggressive" T cell lymphomas they are fairly rare. Most of the systemic T cell disease fall into the same "intermediate / medium" category as DLBCL. There are a variety of skin T cell lymphomas that are in the "slow" category. Start talking T cell lymphoma variants and you often get a glazed look from oncologists who don't think about NHL all that often.
To summarize: we often lump NHL into one of three categories. Though there can be a significant range within an individual category, our clinical approach to each category is unique and the expectations of patient outcome varies by category. The prototypes (most common per category) are follicular (30%), DLBCL (40-50%), Burkitt's (5%). The remainder of cases make up the bewildering complexity of NHL and explain why my job will likely never be outsourced....
Wednesday, August 22, 2012
Campath is going away?
I was quite surprised today to hear that Campath is being withdrawn from the oncology marketplace. This will affect some patients with CLL and some patients with cutaneous lymphoma
Campath is a "bit player" in the management of CLL/NHL but for docs comfortable using it - it can be quite handy. It is one of the few drugs that clearly works in the group of patients with 17p deletion and can be effective when other drugs have failed provided the patient does not have bulky lymph nodes (Campath is good at marrow and circulating cells but doesn't often resolve big nodes).
We have always known that Campath profoundly lowers the immune system. Unfortunately, some of the initial studies were done in patients who were already heavily pre-treated. It probably made the drug look worse than it really is to study it in patients whose immune system was already beaten up by multiple rounds of fludarabine. None the less, you have to be on guard for all sorts of unusual infections such as CMV, PCP, shingles, etc.
Viagara was initially supposed to be a drug to treat hypertension and when men had an unusual "side effect" while taking the drug, it quickly got repurposed and became an extremely valuable asset for Pfizer. Similarly, there are reasons other than CLL where you may wish to lower the immune system. Multiple Sclerosis is just such a reason.
As is the case with lots of drugs - dose matters! They are hoping to show that lower campath doses can treat MS and avoid the infectious complications. If that works, it will probably be a much more valuable drug for its owners. Campath will be "re-branded" so I am not sure if it will still be available for patients with CLL.
To me, this is potentially bad news because although it was never much more than 5% of CLL patients ever treated with the drug - for that 5% it was quite good. It sounds like there may be patient access programs for patients with CLL - hopefully those materialize. Rumor has it that it may even be given away for free to patients with CLL - obviously that would be a good thing - but I will believe it when I see it. Furthermore, additional barriers may just make a hard to use drug even harder to get.
We are lucky that the CAL-101/GS-1101, ibrutinib drugs appear to have activity in 17p deleted cases - these drugs are coming just in time to help.
Campath is a "bit player" in the management of CLL/NHL but for docs comfortable using it - it can be quite handy. It is one of the few drugs that clearly works in the group of patients with 17p deletion and can be effective when other drugs have failed provided the patient does not have bulky lymph nodes (Campath is good at marrow and circulating cells but doesn't often resolve big nodes).
We have always known that Campath profoundly lowers the immune system. Unfortunately, some of the initial studies were done in patients who were already heavily pre-treated. It probably made the drug look worse than it really is to study it in patients whose immune system was already beaten up by multiple rounds of fludarabine. None the less, you have to be on guard for all sorts of unusual infections such as CMV, PCP, shingles, etc.
Viagara was initially supposed to be a drug to treat hypertension and when men had an unusual "side effect" while taking the drug, it quickly got repurposed and became an extremely valuable asset for Pfizer. Similarly, there are reasons other than CLL where you may wish to lower the immune system. Multiple Sclerosis is just such a reason.
As is the case with lots of drugs - dose matters! They are hoping to show that lower campath doses can treat MS and avoid the infectious complications. If that works, it will probably be a much more valuable drug for its owners. Campath will be "re-branded" so I am not sure if it will still be available for patients with CLL.
To me, this is potentially bad news because although it was never much more than 5% of CLL patients ever treated with the drug - for that 5% it was quite good. It sounds like there may be patient access programs for patients with CLL - hopefully those materialize. Rumor has it that it may even be given away for free to patients with CLL - obviously that would be a good thing - but I will believe it when I see it. Furthermore, additional barriers may just make a hard to use drug even harder to get.
We are lucky that the CAL-101/GS-1101, ibrutinib drugs appear to have activity in 17p deleted cases - these drugs are coming just in time to help.
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