The CLL landscape continues to change very quickly. I have previously written about picking a first line therapy, but my post from 2013 has become quickly outdated.
I recently had the opportunity to participate with a group called "Clinical Care Options" on a decision support tool that allows you to plug in a variety of variables that are central to picking out a treatment regimen and then seeing what therapy would be selected by a handful of experts.
To use the tool, you have to register for an account - but I thought it would be worth it for a number of patients who are at the point of picking out a particular therapy.
Here is a link to the tool
I also serve on the CLL Steering Committee for Medscape. We have recently conducted several taped interviews discussing how to pick therapy in both the front line and relapsed / refractory setting. Here again, you need to sign up for an account - but worth it if you want more color commentary regarding the tool outlined above.
Here is the link for the frontline video with me and Steve Coutre
Here is the link for the the relapsed / refractory video with Stephen Schuster, Matthew Davids and Amy Goodrich
I would like to predict that these will remain relevant tools for the foreseeable future but I am happy to report that they will only be valuable for another 12-24 months before the world changes again.
I tried to embed these tools directly on the blog but unfortunately was not able to do so. I hope you find them helpful.
Thanks for reading / viewing / tooling.
Showing posts with label ibrutinib. Show all posts
Showing posts with label ibrutinib. Show all posts
Wednesday, February 1, 2017
Thursday, June 4, 2015
Frontline Survival Benefit for Ibrutinib
NEWSFLASH:
Resonate-2, the randomized phase III study comparing frontline ibrutinib against chlorambucil met its primary endpoint of progression free survival (how long you are both alive AND without progression) and ended early. More importantly, the secondary endpoint of overall survival was improved as well
Meeting the primary endpoint was a virtual certainty. Everybody knew this study would be positive - but the study had to be done in order to get FDA approval for frontline ibrutinib. Single agent chlorambucil is a dead dog. It has served as the control arm that has been beaten up by just about every new drug in CLL in the last ten years (including campath, bendamustine, fludarabine, obinutuzumab, and now ibrutinib).
Meeting the secondary endpoint is a little more provocative. This study was built with a crossover design - meaning if you were randomized to chlorambucil and experienced disease progression, they gave you ibrutinib at that point. If there is an overall survival benefit, it means that early ibrutinib saves lives compared to ibrutinib after progression. This was also true in the Resonate study comparing ibrutinib to ofatumumab and the Gilead study that led to approval of idelalisib in combination with rituximab. That is three studies that show that patients die faster when they get ineffective therapy compared to novel agents. It remains to be seen if that is true with standard regimens that actually work like bendamustine-rituximab or FCR where the bar will be much higher than chlorambucil.
Presumably this will be presented at ASH if it isn't already published by then. It will also lead to FDA approval of frontline ibrutinib but that is probably still a ways off and the exact prescribing "label" will determine who can get it in the frontline. I have no particular insight, but suspect that is still 4-8 months away.
There will be several key details I want to see in the presentation:
1) In this "elderly" subset of patients - how well was ibrutinib tolerated? In most clinical trials it appears that about 5-10% of patients discontinue drug for poor tolerance. Age has also been shown to be biggest variable leading to drug discontinuation - and the median age in this study is likely to be a fair bit higher than other studies due to the nature of the control arm
2) How good is good? Our group helped contribute to the "frontline ibrutinib" data published in the Lancet. In that cohort of about 40 patients, only one patient experienced disease progression and several others discontinued for intolerance. In this larger - multicenter study, it will be the largest to date of previously untreated patients to go on ibrutinib. Is the progression rate still that good? Are there more progressions or is it still in the low single digits?
3) What happens to patients who discontinue ibrutinib? In the relapsed / refractory setting, patients who discontinue ibrutinib have been extremely sick and many have died very quickly. There has been a fair bit of discussion about "ibrutinib discontinuation syndrome." Some have argued that these patients had already failed every other therapy which is why they died so quickly. In this treatment naïve cohort - that excuse cannot hold. If the overall survival curve looks like the progression free survival curve - I will be worried.
4) Dose intensity. Do patients start 3 pills per day and stay on three pills per day without dose reduction or interruption? The ASCO data just presented really gives me considerable apprehension about big dose interruptions. As a patient, I would be trying to keep skipped doses to a minimum. Obviously you may need to do that for surgery etc. but if I had the choice, I would not want to do that early in a treatment course when there are a lot more CLL cells running around.
5) Cytogenetics and high risk markers: While chlorambucil is such a dog it really isn't worthy of a comparison arm, it will be interesting to look at the subgroups treated on ibrutinib. While comparing across trials is always dangerous, we have expectations for the outcomes of patients with markers like TP53, 11Q, and IgHV mutated/unmutated. This will serve as some interesting food for thought with those higher risk populations.
This news release follows two positive randomized phase III trials presented at ASCO for ibrutinib in combination with bendamustine/rituximab and idelalisib in combination with ofatumumab. These latter two studies are important but may not have as much practice impact as the study discussed above.
With a frontline indication for ibrutinib likely available within a year, it begs the question who to treat with chemotherapy and who to treat with targeted agents. I've attached some slides from a talk I recently gave on this topic but please note that these reflect my approach and guidelines are rapidly changing in this disease.
Thanks for reading. To leave a comment, click on the title of this post and it will open up the post in a new window with a comment section at the bottom.
Resonate-2, the randomized phase III study comparing frontline ibrutinib against chlorambucil met its primary endpoint of progression free survival (how long you are both alive AND without progression) and ended early. More importantly, the secondary endpoint of overall survival was improved as well
Meeting the primary endpoint was a virtual certainty. Everybody knew this study would be positive - but the study had to be done in order to get FDA approval for frontline ibrutinib. Single agent chlorambucil is a dead dog. It has served as the control arm that has been beaten up by just about every new drug in CLL in the last ten years (including campath, bendamustine, fludarabine, obinutuzumab, and now ibrutinib).
Meeting the secondary endpoint is a little more provocative. This study was built with a crossover design - meaning if you were randomized to chlorambucil and experienced disease progression, they gave you ibrutinib at that point. If there is an overall survival benefit, it means that early ibrutinib saves lives compared to ibrutinib after progression. This was also true in the Resonate study comparing ibrutinib to ofatumumab and the Gilead study that led to approval of idelalisib in combination with rituximab. That is three studies that show that patients die faster when they get ineffective therapy compared to novel agents. It remains to be seen if that is true with standard regimens that actually work like bendamustine-rituximab or FCR where the bar will be much higher than chlorambucil.
Presumably this will be presented at ASH if it isn't already published by then. It will also lead to FDA approval of frontline ibrutinib but that is probably still a ways off and the exact prescribing "label" will determine who can get it in the frontline. I have no particular insight, but suspect that is still 4-8 months away.
There will be several key details I want to see in the presentation:
1) In this "elderly" subset of patients - how well was ibrutinib tolerated? In most clinical trials it appears that about 5-10% of patients discontinue drug for poor tolerance. Age has also been shown to be biggest variable leading to drug discontinuation - and the median age in this study is likely to be a fair bit higher than other studies due to the nature of the control arm
2) How good is good? Our group helped contribute to the "frontline ibrutinib" data published in the Lancet. In that cohort of about 40 patients, only one patient experienced disease progression and several others discontinued for intolerance. In this larger - multicenter study, it will be the largest to date of previously untreated patients to go on ibrutinib. Is the progression rate still that good? Are there more progressions or is it still in the low single digits?
3) What happens to patients who discontinue ibrutinib? In the relapsed / refractory setting, patients who discontinue ibrutinib have been extremely sick and many have died very quickly. There has been a fair bit of discussion about "ibrutinib discontinuation syndrome." Some have argued that these patients had already failed every other therapy which is why they died so quickly. In this treatment naïve cohort - that excuse cannot hold. If the overall survival curve looks like the progression free survival curve - I will be worried.
4) Dose intensity. Do patients start 3 pills per day and stay on three pills per day without dose reduction or interruption? The ASCO data just presented really gives me considerable apprehension about big dose interruptions. As a patient, I would be trying to keep skipped doses to a minimum. Obviously you may need to do that for surgery etc. but if I had the choice, I would not want to do that early in a treatment course when there are a lot more CLL cells running around.
5) Cytogenetics and high risk markers: While chlorambucil is such a dog it really isn't worthy of a comparison arm, it will be interesting to look at the subgroups treated on ibrutinib. While comparing across trials is always dangerous, we have expectations for the outcomes of patients with markers like TP53, 11Q, and IgHV mutated/unmutated. This will serve as some interesting food for thought with those higher risk populations.
This news release follows two positive randomized phase III trials presented at ASCO for ibrutinib in combination with bendamustine/rituximab and idelalisib in combination with ofatumumab. These latter two studies are important but may not have as much practice impact as the study discussed above.
With a frontline indication for ibrutinib likely available within a year, it begs the question who to treat with chemotherapy and who to treat with targeted agents. I've attached some slides from a talk I recently gave on this topic but please note that these reflect my approach and guidelines are rapidly changing in this disease.
Thanks for reading. To leave a comment, click on the title of this post and it will open up the post in a new window with a comment section at the bottom.
Sunday, May 17, 2015
Take your pills - ibrutinib dosing matters!
When we are investigating new drugs that have never been tested before, we start with what's called a phase 1 study. Historically, the goal of a phase 1 study was to define the "maximum tolerated dose." In the era of traditional cytotoxic chemotherapy, you knew you had arrived at that dose when patients simply couldn't handle any more - it was just to much. Perhaps they had too much nausea or vomiting, or the liver couldn't handle it anymore, kidneys failed, or some other toxicity made it clear that you had reached the limits of human tolerance. As researchers, we just hoped we could get the drug levels high enough without causing too much damage. If we achieved blood levels that we expected to kill the cancer cells without irreparably harming the patient in the process - that was victory.
Many of the new drugs challenge that paradigm. When treatments effectively target the specific molecular abnormality with a cancer cell we can see considerably more efficacy while at the same time reducing toxicity. This has led to the concept of "optimal biologic dose." Instead of pushing the dose to the max, you only increase the dose as far as you need to - often with substantially less side effects than the traditional therapies.
Unfortunately, "optimal biologic dose" is much harder to define than "maximum tolerated dose." It presumes that we have effective and accurate means of actually measuring what were trying to do. While it may come as a surprise to many patients, the unfortunate reality is that there is an enormous amount of human judgment as well as a paucity of clear data involved in early clinical trials. Things are not as scientifically certain in early trials compared to the level of data we have later in a drugs like cycle. Furthermore, we often need to generalize to the larger population from a very small subset of patients that are appropriate for a phase I study.
There is new data regarding the dosing of Ibrutinib that I think is really important to consider.
Most drugs inhibit enzymes in what we call a "reversible" fashion. This means that the particular target is turned off only when you have high enough levels of the drug in the blood. Ibrutinib is a little bit different, it is what we call a "covalent" inhibitor. When you swallow a pill of Ibrutinib it gets into the bloodstream and either quickly binds to the BTK protein or it gets eliminated from the body. Within just a few hours of taking a pill there is virtually no free drug in the blood. Instead, it is all bound to the BTK protein - completely shutting down that signaling pathway until the cell makes more BTK. This is very different than most oral drugs where we are trying to make sure the levels are still high enough right before you take your next dose.
When you had a sore throat as a kid, the doctor always said to be sure to take all your pills so that the bacteria didn't become resistant. It is virtually a scientific paradigm that exposing bacteria to inadequate antibiotic dosing creates resistance. The same is probably true in leukemia and lymphoma with some of the new drugs. A CLL cell that has its B-cell receptor signaling pathway completely inhibited has a hard time escaping that inhibition. If that same pathway is only partially inhibited however, it will try to find ways to escape. This is why the discovery of mutations in the BTK protein that confer resistance to Ibrutinib or so important. These can only arise in cells that have survived the BTK inhibitor long enough to figure out how to thrive under the suppressive influences of Ibrutinib.
Dose intensity can be measured in two key ways. The first is how many days you take it out of how many days you are supposed to take it. We already know in other chronic leukemias like CML, adherence to Gleevec (imatinib) is the biggest predictor of treatment success. Heck, it is even true in breast cancer with hormonal agents. Now it looks like the same is true in CLL. Sometimes side effects force you to hold therapy - but prolonged drug holds are undesirable. Patients who had drug holds in excess of 8 days were almost three times more likely to experience a disease progression (link to ASCO 2015 abstract here).
The second way dose intensity is measured reflects what dose you take daily compared to the "optimal biologic dose." There was a very compelling presentation at AACR a few months ago (I am still trying to figure out how to link to the actual poster, but here is link to the session). The study title was "Population Pharmacokinetic-Pharmacodynamic (PKPD) Modeling of Ibrutinib in Subjects With B-Cell Malignancies" by Poggesi et al. (prize to the first person who figures out how to find the actual poster). I need to get a little technical for a minute - stick with me.
As I wrote above, ibrutinib has a cool property that is unique compared to most drugs. Since it covalently (or irreversibly) binds to BTK, we can do a blood draw, isolate the CLL cells, purify the BTK protein, and look to see how many molecules of the BTK protein are "bound" to a molecule of ibrutinib. This is what we call, "receptor occupancy." The higher the occupancy, the more drug is bound to the protein, and the more the pathway is shut off.
You can then ask how many people have how much of their BTK protein "occupied" or inhibited by ibrutinib at different doses. If we set the bar pretty low at 75% occupancy, any dose above 280mg (two pills) is pretty effective. 96% of patients achieve that level of occupancy at any of those doses. that may seem good but unfortunately, that low bar means that the pathway is only 75% "turned off." It is more like a dimmer switch on the lights instead of an on/off. 75% occupied means that there is a lot of room for cells to try to discover ways to become resistant. If you set the bar much higher at 90% occupancy, the standard CLL dose of 420mg (three pills) can accomplish that in 86% of patients but only 75% of patients who take two pills and 53% of patients taking on pill. In short - dose matters. You get more complete pathway inhibition with higher doses of ibrutinib.
What we don't really know what level of pathway inhibition is optimal for CLL treatment. It is tempting to think that 100% occupancy in 100% of subjects might be much better at preventing eventual resistance - but honestly, we do not know if that might mean higher levels of side effects. How could we get there? Well, perhaps we didn't actually define the "optimal biologic dose" correctly in the original phase I study. We pretty much stopped escalating dose because it seemed to be doing what we wanted it to do in the relatively small population of patients we were studying.
I would be curious to go back and do a "dose optimization" study to see if we could modify either the dosing schedule or the actual dose taken to see if we could make ibrutinib work better than it already does. I also worked on another BTK inhibitor that is no longer in development called CC-292. We never really got it to behave as well as ibrutinib until we started giving it to patients twice daily. Other BTK programs are looking at this as well. Another way of potentially addressing such drug limitations is by adding a second drug that acts through different mechanisms. This should ONLY be done in the context of a research study. We have three such studies within the US Oncology network of sites (and here as well) including the addition of ublituximab (an updated version of rituximab), the combination of a BTK and PI3K inhibitor, or even BTK in combination with one of the new immune checkpoint inhibitors - pembrolizumab.
Doctors tend to reduce doses when there are problems. It is how we think about so many different clinical problems, that we tend to assume it is smart decision making. In my own patients, I am concerned that dose reductions or prolonged dose interruptions may be causing ibrutinib to be less effective than if we can maintain the dose intensity.
To leave a comment, click on the title of this blog post. It will open up the blog post in a separate window with a comment field at the bottom. All comments are reviewed by myself before being allowed to be posted - be patient, I'm a busy guy.
Thanks for reading.
Many of the new drugs challenge that paradigm. When treatments effectively target the specific molecular abnormality with a cancer cell we can see considerably more efficacy while at the same time reducing toxicity. This has led to the concept of "optimal biologic dose." Instead of pushing the dose to the max, you only increase the dose as far as you need to - often with substantially less side effects than the traditional therapies.
Unfortunately, "optimal biologic dose" is much harder to define than "maximum tolerated dose." It presumes that we have effective and accurate means of actually measuring what were trying to do. While it may come as a surprise to many patients, the unfortunate reality is that there is an enormous amount of human judgment as well as a paucity of clear data involved in early clinical trials. Things are not as scientifically certain in early trials compared to the level of data we have later in a drugs like cycle. Furthermore, we often need to generalize to the larger population from a very small subset of patients that are appropriate for a phase I study.
There is new data regarding the dosing of Ibrutinib that I think is really important to consider.
Most drugs inhibit enzymes in what we call a "reversible" fashion. This means that the particular target is turned off only when you have high enough levels of the drug in the blood. Ibrutinib is a little bit different, it is what we call a "covalent" inhibitor. When you swallow a pill of Ibrutinib it gets into the bloodstream and either quickly binds to the BTK protein or it gets eliminated from the body. Within just a few hours of taking a pill there is virtually no free drug in the blood. Instead, it is all bound to the BTK protein - completely shutting down that signaling pathway until the cell makes more BTK. This is very different than most oral drugs where we are trying to make sure the levels are still high enough right before you take your next dose.
When you had a sore throat as a kid, the doctor always said to be sure to take all your pills so that the bacteria didn't become resistant. It is virtually a scientific paradigm that exposing bacteria to inadequate antibiotic dosing creates resistance. The same is probably true in leukemia and lymphoma with some of the new drugs. A CLL cell that has its B-cell receptor signaling pathway completely inhibited has a hard time escaping that inhibition. If that same pathway is only partially inhibited however, it will try to find ways to escape. This is why the discovery of mutations in the BTK protein that confer resistance to Ibrutinib or so important. These can only arise in cells that have survived the BTK inhibitor long enough to figure out how to thrive under the suppressive influences of Ibrutinib.
Dose intensity can be measured in two key ways. The first is how many days you take it out of how many days you are supposed to take it. We already know in other chronic leukemias like CML, adherence to Gleevec (imatinib) is the biggest predictor of treatment success. Heck, it is even true in breast cancer with hormonal agents. Now it looks like the same is true in CLL. Sometimes side effects force you to hold therapy - but prolonged drug holds are undesirable. Patients who had drug holds in excess of 8 days were almost three times more likely to experience a disease progression (link to ASCO 2015 abstract here).
The second way dose intensity is measured reflects what dose you take daily compared to the "optimal biologic dose." There was a very compelling presentation at AACR a few months ago (I am still trying to figure out how to link to the actual poster, but here is link to the session). The study title was "Population Pharmacokinetic-Pharmacodynamic (PKPD) Modeling of Ibrutinib in Subjects With B-Cell Malignancies" by Poggesi et al. (prize to the first person who figures out how to find the actual poster). I need to get a little technical for a minute - stick with me.
As I wrote above, ibrutinib has a cool property that is unique compared to most drugs. Since it covalently (or irreversibly) binds to BTK, we can do a blood draw, isolate the CLL cells, purify the BTK protein, and look to see how many molecules of the BTK protein are "bound" to a molecule of ibrutinib. This is what we call, "receptor occupancy." The higher the occupancy, the more drug is bound to the protein, and the more the pathway is shut off.
You can then ask how many people have how much of their BTK protein "occupied" or inhibited by ibrutinib at different doses. If we set the bar pretty low at 75% occupancy, any dose above 280mg (two pills) is pretty effective. 96% of patients achieve that level of occupancy at any of those doses. that may seem good but unfortunately, that low bar means that the pathway is only 75% "turned off." It is more like a dimmer switch on the lights instead of an on/off. 75% occupied means that there is a lot of room for cells to try to discover ways to become resistant. If you set the bar much higher at 90% occupancy, the standard CLL dose of 420mg (three pills) can accomplish that in 86% of patients but only 75% of patients who take two pills and 53% of patients taking on pill. In short - dose matters. You get more complete pathway inhibition with higher doses of ibrutinib.
What we don't really know what level of pathway inhibition is optimal for CLL treatment. It is tempting to think that 100% occupancy in 100% of subjects might be much better at preventing eventual resistance - but honestly, we do not know if that might mean higher levels of side effects. How could we get there? Well, perhaps we didn't actually define the "optimal biologic dose" correctly in the original phase I study. We pretty much stopped escalating dose because it seemed to be doing what we wanted it to do in the relatively small population of patients we were studying.
I would be curious to go back and do a "dose optimization" study to see if we could modify either the dosing schedule or the actual dose taken to see if we could make ibrutinib work better than it already does. I also worked on another BTK inhibitor that is no longer in development called CC-292. We never really got it to behave as well as ibrutinib until we started giving it to patients twice daily. Other BTK programs are looking at this as well. Another way of potentially addressing such drug limitations is by adding a second drug that acts through different mechanisms. This should ONLY be done in the context of a research study. We have three such studies within the US Oncology network of sites (and here as well) including the addition of ublituximab (an updated version of rituximab), the combination of a BTK and PI3K inhibitor, or even BTK in combination with one of the new immune checkpoint inhibitors - pembrolizumab.
Doctors tend to reduce doses when there are problems. It is how we think about so many different clinical problems, that we tend to assume it is smart decision making. In my own patients, I am concerned that dose reductions or prolonged dose interruptions may be causing ibrutinib to be less effective than if we can maintain the dose intensity.
To leave a comment, click on the title of this blog post. It will open up the blog post in a separate window with a comment field at the bottom. All comments are reviewed by myself before being allowed to be posted - be patient, I'm a busy guy.
Thanks for reading.
Tuesday, July 29, 2014
Ibrutinib in 17P deleted CLL
Yesterday the FDA expanded the "label" (or the set of conditions that the drug is approved for) for ibrutinib. See the ASCO news release here.
I think the news coverage missed the most important aspect of the change in the label. Most of the coverage focused on the usefulness of the drug in patients with the dreaded 17P deletion (which I have written about quite a bit). The analysis was based upon the RESONATE trial (summarized here) in which the benefit of ibrutinib over ofatumumab was particularly striking and one other unpublished study in abstract form here.
Since ibrutinib is already approved for patients with "one prior regimen" at first blush, this would not change the group of people eligible for the drug. I actually like to read the specifics of labeling information so I read the updated "label" (linked here) and was surprised that the language didn't distinguish between those patients who have been previously treated or not.
I was able to verify today that indeed, previously untreated patients with the 17P deletion are considered appropriate for the drug. That is much bigger news than what I read.
I have a huge blog post I've been working on for some time - hopefully ready to go in next few weeks about utilizing newer molecular diagnostics to select therapy in CLL. This new information corresponds to trends I have seen emerging where many of my CLL researcher colleagues have started using this drug in this setting. Keep in mind, quite a few patients have abnormalities in TP53 (on 17P) and may not be aware of it due to insufficiency of current FISH testing.
Another key trial in this population involves the recently approved idelalisib and rituximab in patients with untreated 17P deleted CLL (linked here). In addition to those sites listed on clinical trials.gov it is also available at most of the places on this map (linked here).
Although the number of CLL patients with 17P treated with this combination in the frontline setting is small, the overall response rate is 100% and the European Agencies have recommended frontline status for idelalisib in this setting as well.
Thanks for reading
I think the news coverage missed the most important aspect of the change in the label. Most of the coverage focused on the usefulness of the drug in patients with the dreaded 17P deletion (which I have written about quite a bit). The analysis was based upon the RESONATE trial (summarized here) in which the benefit of ibrutinib over ofatumumab was particularly striking and one other unpublished study in abstract form here.
Since ibrutinib is already approved for patients with "one prior regimen" at first blush, this would not change the group of people eligible for the drug. I actually like to read the specifics of labeling information so I read the updated "label" (linked here) and was surprised that the language didn't distinguish between those patients who have been previously treated or not.
I was able to verify today that indeed, previously untreated patients with the 17P deletion are considered appropriate for the drug. That is much bigger news than what I read.
I have a huge blog post I've been working on for some time - hopefully ready to go in next few weeks about utilizing newer molecular diagnostics to select therapy in CLL. This new information corresponds to trends I have seen emerging where many of my CLL researcher colleagues have started using this drug in this setting. Keep in mind, quite a few patients have abnormalities in TP53 (on 17P) and may not be aware of it due to insufficiency of current FISH testing.
Another key trial in this population involves the recently approved idelalisib and rituximab in patients with untreated 17P deleted CLL (linked here). In addition to those sites listed on clinical trials.gov it is also available at most of the places on this map (linked here).
Although the number of CLL patients with 17P treated with this combination in the frontline setting is small, the overall response rate is 100% and the European Agencies have recommended frontline status for idelalisib in this setting as well.
Thanks for reading
Wednesday, July 23, 2014
Idelalisib / Zydelig approved
There is a new kid on the block!
First it was called CAL-101. It is common for a drug company to use letters from the name of the company. In this case, it was originally Calistoga Pharmaceuticals. The 101 part is a little more funny. I understand one of the early investors in the company was driving in Palo Alto California and turned from University Drive onto the 101 highway and decided to call the drug CAL-101. True? False? Not sure.
Then Gilead bought up the drug from Calistoga. Next step? Change the numbers. CAL-101 became GS-1101. GS = Gilead Science. Not sure where the extra "1" came from. Perhaps it was an effort to differentiate from GA-101 which became obinutuzumab before it became Gazyva.
Next step is to give the letter / number combo an actual name. In this case it was idelalisib. As difficult as that seems, it actually makes perfect sense.
Idelalisib (pronounced I-Dela-Lisib)
I=inhibit
Dela= delta isoform of PI3K
Lisib = that is the mandatory suffix of drugs that inhibit PI3K enzymes
I have heard this drug mispronounced so many ways that it is almost comical -I-del-isilib, I-dela-mab, etc. I think I would have chosen Ideltalisib if I were in control of all things as that would make a lot of sense (inhibit-delta-PI3K).
Every drug has two names (brand name vs generic name). You would be amazed how much effort goes into coming up with a name for a drug. You would also be amazed how often drug names begin with the letter "Z." Some sort of market research I don't know about I suppose. So idelalisib is now called Zydelig. I think this is a combo of the "z" and the "delta" but not sure I know where the "ig" comes from.
As if we were not already spoiled by approvals of the latest treatments for CLL including the addition of obinutuzumab and ibrutinib within the last 12 months, now we have yet another new agent that is simultaneously remarkably effective, well tolerated, and has proven to prolong survival for patients with CLL and show efficacy in hard to treat low grade lymphoma!
It has been an interesting race for approval between ibrutinib and idelalisib. These two drugs entered human clinical testing at nearly exactly the same time and in the grand cosmos of time and were approved nearly simultaneously in blinding speed. Idelalisib was the first to present randomized phase III study showing dramatically improved progression free survival (being alive and without progression) as well as improved overall survival against a control arm in CLL. I think ibrutinib ended up crossing the finish line first because they got the early papers published more quickly creating a strong buzz in the literature. Idelalisib was sold from Calistoga pharmaceuticals to Gilead pharmaceuticals midway through the development. This results in enormous changes on the development team that probably caused some regulatory delay while ibrutinib was held onto by Pharmacyclics all the way through development (sparing a joint venture with Jannsen).
We are lucky in NHL/CLL that we have discovered an entire new PATHWAY in which many of the enzymes make good targets for drugs. Since this pathway travels several key enzymes like Syk, BTK, PI3K, we will probably have a multitude of new drugs for these diseases. Indeed, there are several BTK inhibitors, several PI3K inhibitors, several Syk inhibitors all working their way through development.
What is so special about idelalisb?
I've had the opportunity to work with this drug quite a bit over the last several years all the way from the early phase I combination studies through helping the team at Calistoga write the main phase III protocols in relapsed disease. I would like to highlight two patients I have treated with the drug because they both illustrate something really remarkable.
The first patient came into my clinic shortly after I started in Eugene. He had some of the nastiest CLL I've ever seen. He presented with a white blood cell count of about 140 thousand, enormous lymph nodes, and red blood cells and platelets so low that I had to transfuse him weekly. Worse yet, all of his cells had the 17P deletion.
I started him on FCR but after two cycles he had made zero progress and indeed his transfusion requirement went up. I gave him campath and rituximab which at least cleared his marrow enough to stop transfusions but he still had big bulky nodes and was considered ineligible for transplant. From there we quickly cycled through R-ESHAP, R-Bendamustine, high dose steroids, revlimid and ofatumumab. Unfortunately that list of drugs took quite a toll on him and he was back to weekly transfusions.
We got him enrolled onto an idelalisib study and it was magic. His white blood cells shot up immediately (typical for these drugs), and his nodes shrank. His marrow began to "wake up" and we got him off of his transfusions again. Indeed, he went two and a half years almost completely normal taking only his idelalisib before his disease became problematic again. It was amazing to see him take advantage of the time this drug gave him - his life was completely changed by idelalisib in a way that was profoundly meaningful.
The second patient is an older gentleman with mantle cell lymphoma. He had a few lines of therapy before his MCL became a problem and we got him enrolled into the first ever clinical study of ibrutinib. He had several years of fantastic disease control on ibrutinib before he began having problems. He developed a cough and was short of breath. We found that one of his lungs had filled up with fluid from his lymphoma. We sent the sample for analysis and found that he had the BTK Cys481Ser mutation that inactivates ibrutinib. We were able to get him enrolled on an idelalisib study and that was over a year ago. His lungs cleared up, cough improved, fluid was dramatically reduced, etc.
Zydelig is approved in combination with rituximab for patients with relapsed CLL AND as a single agent (no rituximab) for patients with follicular lymphoma / small lymphocytic lymphoma who have become refractory to rituximab AND alkalating agents (bendamustine, chlorambucil, Cytoxan). Ongoing studies are likely to expand the circumstances where it is approved.
These are good times indeed!
Thanks for reading.
First it was called CAL-101. It is common for a drug company to use letters from the name of the company. In this case, it was originally Calistoga Pharmaceuticals. The 101 part is a little more funny. I understand one of the early investors in the company was driving in Palo Alto California and turned from University Drive onto the 101 highway and decided to call the drug CAL-101. True? False? Not sure.
Then Gilead bought up the drug from Calistoga. Next step? Change the numbers. CAL-101 became GS-1101. GS = Gilead Science. Not sure where the extra "1" came from. Perhaps it was an effort to differentiate from GA-101 which became obinutuzumab before it became Gazyva.
Next step is to give the letter / number combo an actual name. In this case it was idelalisib. As difficult as that seems, it actually makes perfect sense.
Idelalisib (pronounced I-Dela-Lisib)
I=inhibit
Dela= delta isoform of PI3K
Lisib = that is the mandatory suffix of drugs that inhibit PI3K enzymes
I have heard this drug mispronounced so many ways that it is almost comical -I-del-isilib, I-dela-mab, etc. I think I would have chosen Ideltalisib if I were in control of all things as that would make a lot of sense (inhibit-delta-PI3K).
Every drug has two names (brand name vs generic name). You would be amazed how much effort goes into coming up with a name for a drug. You would also be amazed how often drug names begin with the letter "Z." Some sort of market research I don't know about I suppose. So idelalisib is now called Zydelig. I think this is a combo of the "z" and the "delta" but not sure I know where the "ig" comes from.
As if we were not already spoiled by approvals of the latest treatments for CLL including the addition of obinutuzumab and ibrutinib within the last 12 months, now we have yet another new agent that is simultaneously remarkably effective, well tolerated, and has proven to prolong survival for patients with CLL and show efficacy in hard to treat low grade lymphoma!
It has been an interesting race for approval between ibrutinib and idelalisib. These two drugs entered human clinical testing at nearly exactly the same time and in the grand cosmos of time and were approved nearly simultaneously in blinding speed. Idelalisib was the first to present randomized phase III study showing dramatically improved progression free survival (being alive and without progression) as well as improved overall survival against a control arm in CLL. I think ibrutinib ended up crossing the finish line first because they got the early papers published more quickly creating a strong buzz in the literature. Idelalisib was sold from Calistoga pharmaceuticals to Gilead pharmaceuticals midway through the development. This results in enormous changes on the development team that probably caused some regulatory delay while ibrutinib was held onto by Pharmacyclics all the way through development (sparing a joint venture with Jannsen).
We are lucky in NHL/CLL that we have discovered an entire new PATHWAY in which many of the enzymes make good targets for drugs. Since this pathway travels several key enzymes like Syk, BTK, PI3K, we will probably have a multitude of new drugs for these diseases. Indeed, there are several BTK inhibitors, several PI3K inhibitors, several Syk inhibitors all working their way through development.
What is so special about idelalisb?
I've had the opportunity to work with this drug quite a bit over the last several years all the way from the early phase I combination studies through helping the team at Calistoga write the main phase III protocols in relapsed disease. I would like to highlight two patients I have treated with the drug because they both illustrate something really remarkable.
The first patient came into my clinic shortly after I started in Eugene. He had some of the nastiest CLL I've ever seen. He presented with a white blood cell count of about 140 thousand, enormous lymph nodes, and red blood cells and platelets so low that I had to transfuse him weekly. Worse yet, all of his cells had the 17P deletion.
I started him on FCR but after two cycles he had made zero progress and indeed his transfusion requirement went up. I gave him campath and rituximab which at least cleared his marrow enough to stop transfusions but he still had big bulky nodes and was considered ineligible for transplant. From there we quickly cycled through R-ESHAP, R-Bendamustine, high dose steroids, revlimid and ofatumumab. Unfortunately that list of drugs took quite a toll on him and he was back to weekly transfusions.
We got him enrolled onto an idelalisib study and it was magic. His white blood cells shot up immediately (typical for these drugs), and his nodes shrank. His marrow began to "wake up" and we got him off of his transfusions again. Indeed, he went two and a half years almost completely normal taking only his idelalisib before his disease became problematic again. It was amazing to see him take advantage of the time this drug gave him - his life was completely changed by idelalisib in a way that was profoundly meaningful.
The second patient is an older gentleman with mantle cell lymphoma. He had a few lines of therapy before his MCL became a problem and we got him enrolled into the first ever clinical study of ibrutinib. He had several years of fantastic disease control on ibrutinib before he began having problems. He developed a cough and was short of breath. We found that one of his lungs had filled up with fluid from his lymphoma. We sent the sample for analysis and found that he had the BTK Cys481Ser mutation that inactivates ibrutinib. We were able to get him enrolled on an idelalisib study and that was over a year ago. His lungs cleared up, cough improved, fluid was dramatically reduced, etc.
Zydelig is approved in combination with rituximab for patients with relapsed CLL AND as a single agent (no rituximab) for patients with follicular lymphoma / small lymphocytic lymphoma who have become refractory to rituximab AND alkalating agents (bendamustine, chlorambucil, Cytoxan). Ongoing studies are likely to expand the circumstances where it is approved.
These are good times indeed!
Thanks for reading.
Sunday, July 13, 2014
ASCO Ibrutinib Update 2014
So I am a little late again. I started writing this blog post on my way back from ASCO (6 weeks ago) but upon landing in the whirlwind I call life this was put on hold. Take yourself back in time (at least 6 weeks) and this may seem like news that is "hot off the press."
As I make my way back from ASCO, it is hard to digest the pace with which CLL is changing. In three years we have gone from the FCR supremacy to a coming tidal wave of well tolerated pills that are a lot easier to take and are seeking to both displace chemotherapy entirely and change the rules of the game.
Ibrutinib had a lot of important data and I thought I would just update a few things we learned. Susan O'Brien presented the long term data from the original phase II ibrutinib study. There were a few take home points:
1) In patients who have had 4 different rounds of chemotherapy on average who then went on this study, ibrutinib has probably saved many of their lives. They were a really beaten up group of patients and many of them are still doing incredibly well after 3+ years on the drug.
2) Patients with 17P deletion really have the worst disease still. Over half such patients who have been treated with ibrutinib have progressed. While ibrutinib is likely better than anything else they could have gotten, this population will still likely need new agents. Patients with 11Q deletion are also experiencing progression
3) There has occasionally been concern about risk of infections in patients treated with ibrutinib. It looks like the longer you are on the drug, the better the immune system works because the rate of infections seems to go down over time.
4) The patients treated with ibrutinib in the front line have really done quite well. While a handful of patients stop the drug early, those patients who are able to stay on the drug are doing remarkably well. It remains to be seen if ibrutinib is better than chemotherapy in the frontline setting but with each new update of the data it gets more and more impressive.
Dr. Jennifer Woyach from Ohio State presented a poster that was simultaneously published in the New England Journal of Medicine about ibrutinib resistance. It fits well with the data I've blogged about once previously. Several things are worth noting:
1) In "evolutionary biology" we think that any strong "selective pressure" likely has influence over the nature of resistance. Ibrutinib binds to the BTK protein at a very specific location called "Cysteine 481." The bond is very specific, so the way to get around that is for the cancer cell to change it's BTK at position 481 from cysteine to serine. Ibrutinib has a much harder time binding to the protein and shutting it down. Genentech has a drug they are developing that is supposed to "get around" this mutation and still inhibit BTK.
2) An alternative route to resistance is to activate an enzyme in the "signaling cascade" downstream of BTK. PLC-gamma is just such a protein and can be artificially "turned on" by the cancer cell. It is like the electrical circuit has a short and is locked in the on position below the level of BTK so ibrutinib still binds but doesn't stop the electricity.
3) Neither of these are terribly common. In the Ohio State experience, they have treated something like 250 patients and only 15% have stopped the drug because it wasn't working.
Dr. John Byrd presented the results of the Resonate trial in which patients with relapsed CLL were randomized to either ibrutinib OR ofatumumab. Patients who progressed on ofatumumab could then receive ibrutinib (cross over).
1) Thank goodness for randomized data. There were rumors about ibrutinib causing Richter's transformation and kidney problems. When you don't have a similar group of patients observed under similar circumstances, you don't necessarily know the rate at which things actually happen. Turns out that changes in kidney function while on ibrutinib are no different than kidney changes for patients receiving ofatumumab
2) Ibrutinib beats the socks off ofatumumab. The overall response rates (10x higher), progression free survival (80% better), and even overall survival (60% better) all favored ibrutinib.
3) There did seem to be a slightly higher rate of atrial fibrillation (irregular heart rate) and possibly bruising / bleeding on ibrutinib which may be something to watch over time. Sometimes it is hard to strike the right balance between blood clotting and bleeding.
4) Multi-center data is NEVER as good as single center data. I was surprised to see how high the number of patients that had stopped ibrutinib by the one year mark. While it is still a relative minority of patients, it leaves a window for other drugs to be developed. In some cases this was due to progression or in other cases patient / clinician choice.
We are hoping to have approval of idelalisib quite soon - another drug that makes a dramatic impact for patients with relapsed CLL. It will be very interesting to see how we decide to use these two remarkable breakthroughs - perhaps a topic for an upcoming blog post
Thanks for reading.
As I make my way back from ASCO, it is hard to digest the pace with which CLL is changing. In three years we have gone from the FCR supremacy to a coming tidal wave of well tolerated pills that are a lot easier to take and are seeking to both displace chemotherapy entirely and change the rules of the game.
Ibrutinib had a lot of important data and I thought I would just update a few things we learned. Susan O'Brien presented the long term data from the original phase II ibrutinib study. There were a few take home points:
1) In patients who have had 4 different rounds of chemotherapy on average who then went on this study, ibrutinib has probably saved many of their lives. They were a really beaten up group of patients and many of them are still doing incredibly well after 3+ years on the drug.
2) Patients with 17P deletion really have the worst disease still. Over half such patients who have been treated with ibrutinib have progressed. While ibrutinib is likely better than anything else they could have gotten, this population will still likely need new agents. Patients with 11Q deletion are also experiencing progression
3) There has occasionally been concern about risk of infections in patients treated with ibrutinib. It looks like the longer you are on the drug, the better the immune system works because the rate of infections seems to go down over time.
4) The patients treated with ibrutinib in the front line have really done quite well. While a handful of patients stop the drug early, those patients who are able to stay on the drug are doing remarkably well. It remains to be seen if ibrutinib is better than chemotherapy in the frontline setting but with each new update of the data it gets more and more impressive.
Dr. Jennifer Woyach from Ohio State presented a poster that was simultaneously published in the New England Journal of Medicine about ibrutinib resistance. It fits well with the data I've blogged about once previously. Several things are worth noting:
1) In "evolutionary biology" we think that any strong "selective pressure" likely has influence over the nature of resistance. Ibrutinib binds to the BTK protein at a very specific location called "Cysteine 481." The bond is very specific, so the way to get around that is for the cancer cell to change it's BTK at position 481 from cysteine to serine. Ibrutinib has a much harder time binding to the protein and shutting it down. Genentech has a drug they are developing that is supposed to "get around" this mutation and still inhibit BTK.
2) An alternative route to resistance is to activate an enzyme in the "signaling cascade" downstream of BTK. PLC-gamma is just such a protein and can be artificially "turned on" by the cancer cell. It is like the electrical circuit has a short and is locked in the on position below the level of BTK so ibrutinib still binds but doesn't stop the electricity.
3) Neither of these are terribly common. In the Ohio State experience, they have treated something like 250 patients and only 15% have stopped the drug because it wasn't working.
Dr. John Byrd presented the results of the Resonate trial in which patients with relapsed CLL were randomized to either ibrutinib OR ofatumumab. Patients who progressed on ofatumumab could then receive ibrutinib (cross over).
1) Thank goodness for randomized data. There were rumors about ibrutinib causing Richter's transformation and kidney problems. When you don't have a similar group of patients observed under similar circumstances, you don't necessarily know the rate at which things actually happen. Turns out that changes in kidney function while on ibrutinib are no different than kidney changes for patients receiving ofatumumab
2) Ibrutinib beats the socks off ofatumumab. The overall response rates (10x higher), progression free survival (80% better), and even overall survival (60% better) all favored ibrutinib.
3) There did seem to be a slightly higher rate of atrial fibrillation (irregular heart rate) and possibly bruising / bleeding on ibrutinib which may be something to watch over time. Sometimes it is hard to strike the right balance between blood clotting and bleeding.
4) Multi-center data is NEVER as good as single center data. I was surprised to see how high the number of patients that had stopped ibrutinib by the one year mark. While it is still a relative minority of patients, it leaves a window for other drugs to be developed. In some cases this was due to progression or in other cases patient / clinician choice.
We are hoping to have approval of idelalisib quite soon - another drug that makes a dramatic impact for patients with relapsed CLL. It will be very interesting to see how we decide to use these two remarkable breakthroughs - perhaps a topic for an upcoming blog post
Thanks for reading.
Thursday, February 6, 2014
Copayment Assistance
I had the opportunity to visit Pharmacyclics headquarters today. It was the first time I've been there since 2007 when I was helping them design their original first in human phase I protocol (read part of that story here).
Thanks to all the nice people who took time out of their day to chat! It was fun to see the excitement brewing within a company that has developed a really remarkable drug. It felt to me a lot like the fun anticipation of Christmas Eve with kids (except with well behaved adults of course).
One thing I learned will be of considerable interest to a bunch of patients, so I thought I would throw a quick blog post up while awaiting my flight (back to a snowy Eugene... Lord help me).
Many of you know that the new drugs are pretty darn expensive. I've posted about drug costs previously for the interested reader. I think a lot of patients are reasonably apprehensive of the cost of care. For a drug that costs over $10K/month, that can potentially put the hurt on you really fast.
Fortunately the team at Pharmacyclics / Jannsen have put together a pretty fantastic copayment assistance program. Many drug manufacturers have such a program and sometimes these can remain stubbornly hidden to patients who have to fork out the cash every month for their drugs unaware that funding assistance may be available with a little work.
There are really two different mechanisms depending on what sort of insurance you have. For NON-MEDICARE patients (ie. the Blue Cross, Aetna, etc), you can apply for a grant if you are taking your ibrutinib for an FDA approved indication (see post on off label drug use). Currently that is just mantle cell lymphoma, though the approval in CLL is eagerly anticipated by many. Once approved in CLL, the grant program will cover that disease as well.
Long story short, a NON-MEDICARE patient should be able to get their drug for $25/month under most circumstances when using the copayment assistance program. The link to that program is here.
Medicare patients have a slightly more difficult situation, but by no means impossible. Since CLL frequently affects older patients, quite a few patients are likely to fall into this category. Medicare has policies that make it more difficult for manufacturers to provide copayment assistance. The work around is for the companies to make large grants to third party organizations like Lymphoma and Leukemia Society that can then make structured grants to patients. The copayment assistance webpage can help direct patients to such organizations.
US Healthcare is an ungodly mess when it comes to who pays for what, what things cost, and who gets paid for it - but it is nice to know the patients are not getting caught in the crossfire on this one.
Thanks for reading
Thanks to all the nice people who took time out of their day to chat! It was fun to see the excitement brewing within a company that has developed a really remarkable drug. It felt to me a lot like the fun anticipation of Christmas Eve with kids (except with well behaved adults of course).
One thing I learned will be of considerable interest to a bunch of patients, so I thought I would throw a quick blog post up while awaiting my flight (back to a snowy Eugene... Lord help me).
Many of you know that the new drugs are pretty darn expensive. I've posted about drug costs previously for the interested reader. I think a lot of patients are reasonably apprehensive of the cost of care. For a drug that costs over $10K/month, that can potentially put the hurt on you really fast.
Fortunately the team at Pharmacyclics / Jannsen have put together a pretty fantastic copayment assistance program. Many drug manufacturers have such a program and sometimes these can remain stubbornly hidden to patients who have to fork out the cash every month for their drugs unaware that funding assistance may be available with a little work.
There are really two different mechanisms depending on what sort of insurance you have. For NON-MEDICARE patients (ie. the Blue Cross, Aetna, etc), you can apply for a grant if you are taking your ibrutinib for an FDA approved indication (see post on off label drug use). Currently that is just mantle cell lymphoma, though the approval in CLL is eagerly anticipated by many. Once approved in CLL, the grant program will cover that disease as well.
Long story short, a NON-MEDICARE patient should be able to get their drug for $25/month under most circumstances when using the copayment assistance program. The link to that program is here.
Medicare patients have a slightly more difficult situation, but by no means impossible. Since CLL frequently affects older patients, quite a few patients are likely to fall into this category. Medicare has policies that make it more difficult for manufacturers to provide copayment assistance. The work around is for the companies to make large grants to third party organizations like Lymphoma and Leukemia Society that can then make structured grants to patients. The copayment assistance webpage can help direct patients to such organizations.
US Healthcare is an ungodly mess when it comes to who pays for what, what things cost, and who gets paid for it - but it is nice to know the patients are not getting caught in the crossfire on this one.
Thanks for reading
Tuesday, November 26, 2013
Off label drug use
How do you get access to a hot new drug if it isn't approved in your condition? With recent or pending approvals of ibrutinib, idelalisib, lenalidomide, obinutuzumab, etc. lots of people are asking these questions.
In the past, a drug that got approved by the FDA could largely be used by oncologists without much regard to the the specific "labeled indications" (see ibrutinib / imbruvica here) When a clinical trial is done that leads to the approval of a drug, the FDA evaluates the data and creates a "label." That label defines what the drug is approved for and that is generally based upon the specifics of the study that led to the approval (ie. the specific population, what other drugs were used, etc). There is a lot of attention to how broadly or narrowly a label is written because it will have enormous downstream impacts on utilization.
When brentuximab was approved in Hodgkin's lymphoma, it was originally approved for patients with relapse following stem cell transplant, or for patients ineligible for transplant who had received two prior regimens. Some were hoping the label would be more inclusive (ie to get patients to transplant, or in first relapse etc). That is why the stock initially went down substantially immediately after approval. Since it was a more narrow label doc's couldn't go prescribe it as frequently as some had hoped.
Many of the same questions surround ibrutinib. It was given "breakthrough designation" for patients with relapsed CLL that has the 17P deletion. Recall that 17P is one marker for high risk CLL among several others that determine prognosis. If I read the press releases correctly though, pharmacyclics submitted for approval in patients with relapsed CLL (irrespective of the 17P deletion). That sets up a potential scenario where the specifics of the label can make a huge difference in the initial approval in CLL. In relapsed CLL patients with 17P represent only about 20-30% of all patients. So if you don't have that marker will you be able to get the drug? What if you have a P53 mutation without the deletion? That is essentially the same population? How will insurance make that decision? If the drug is approved for relapsed disease only, what would stop a patient from taking a single dose of rituximab and then saying their disease is "previously treated?"
So who governs what can or can't be prescribed? That is complicated. For patients with medicare, it is hard to prescribe any of the "new" medications "off label." This is because medicare won't pay for it. For some of the older drugs though, they really got established into disease management before they became super expensive. If a drug gets "NCCN compendia listing" (which is an association of leading academic medical centers who agree on standards of care) it often gets covered by medicare. Nowadays it is pretty hard to get "compendia" listed unless a specific trial proves that a drug has a role in a very specific situation.
It is possible to prescribe a drug and administer it, but if it goes for ten thousand dollars per dose and medicare won't reimburse you for it, you can put yourself into enormous financial pain very quickly as an oncologist by getting too adventurous.
For patients with private insurance, it can be a lot more difficult to predict. If ibrutinuib or lenalidomied are currently approved for mantle cell lymphoma, what would stop you from prescribing them in CLL? Since the drugs can cost 10K/month, getting insurance to pay for it is the biggest issue. These drugs have been clearly well studied in these diseases, it is not like a doc would just be "flying by the seat of their pants" to recommend such a drug. The reality is that some insurance will cover it and some won't. In the case of ibrutinib, it will likely be approved in CLL in a few months so it may not be as much of an issue, but for a patient who needs therapy for CLL NOW and wants ibrutinib it all comes down to whether insurance will pay for it or not.
Since the doses are a little different between the two diseases, it shouldn't be a surprise that insurance could figure it is being given "off label." When you submit a "prior authorization" to insurance for a drug, they also ask for a diagnosis code (ICD-9) that is specific to the disease - i.e. CLL vs MCL vs other. If the code and the drug don't match, that is another red flag.
Does that mean it can't be done? I've had success giving patients unusual drugs off label where it was clear to the patient, insurance, and everyone else that we were off label. In some cases there was something uniquely compelling such as a specific mutation that matched a specific drug in a patient who had received all the available therapies already. In short - there really are not rules - just financial realities. In the UK, Europe, and Canada, it is a lot more strict and "off label" use is a lot less frequent. I guess our reputation as cowboys in the US has some truth.
For patients who are determined, a careful, thoughtful letter to the insurance company by the patient or the doctor citing relevant medical literature can sometimes help. I would suggest strongly that a respectful dialogue goes a lot farther than yelling and screaming in such a situation.
With a bunch of new drugs coming, the landscape of CLL and NHL are going to change dramatically. It will move fits and spurts. With all the dramatic changes coming in health care (that I have written and tweeted about quite a bit) it is really hard to predict how it is going to play out.
Thanks for reading
In the past, a drug that got approved by the FDA could largely be used by oncologists without much regard to the the specific "labeled indications" (see ibrutinib / imbruvica here) When a clinical trial is done that leads to the approval of a drug, the FDA evaluates the data and creates a "label." That label defines what the drug is approved for and that is generally based upon the specifics of the study that led to the approval (ie. the specific population, what other drugs were used, etc). There is a lot of attention to how broadly or narrowly a label is written because it will have enormous downstream impacts on utilization.
When brentuximab was approved in Hodgkin's lymphoma, it was originally approved for patients with relapse following stem cell transplant, or for patients ineligible for transplant who had received two prior regimens. Some were hoping the label would be more inclusive (ie to get patients to transplant, or in first relapse etc). That is why the stock initially went down substantially immediately after approval. Since it was a more narrow label doc's couldn't go prescribe it as frequently as some had hoped.
Many of the same questions surround ibrutinib. It was given "breakthrough designation" for patients with relapsed CLL that has the 17P deletion. Recall that 17P is one marker for high risk CLL among several others that determine prognosis. If I read the press releases correctly though, pharmacyclics submitted for approval in patients with relapsed CLL (irrespective of the 17P deletion). That sets up a potential scenario where the specifics of the label can make a huge difference in the initial approval in CLL. In relapsed CLL patients with 17P represent only about 20-30% of all patients. So if you don't have that marker will you be able to get the drug? What if you have a P53 mutation without the deletion? That is essentially the same population? How will insurance make that decision? If the drug is approved for relapsed disease only, what would stop a patient from taking a single dose of rituximab and then saying their disease is "previously treated?"
So who governs what can or can't be prescribed? That is complicated. For patients with medicare, it is hard to prescribe any of the "new" medications "off label." This is because medicare won't pay for it. For some of the older drugs though, they really got established into disease management before they became super expensive. If a drug gets "NCCN compendia listing" (which is an association of leading academic medical centers who agree on standards of care) it often gets covered by medicare. Nowadays it is pretty hard to get "compendia" listed unless a specific trial proves that a drug has a role in a very specific situation.
It is possible to prescribe a drug and administer it, but if it goes for ten thousand dollars per dose and medicare won't reimburse you for it, you can put yourself into enormous financial pain very quickly as an oncologist by getting too adventurous.
For patients with private insurance, it can be a lot more difficult to predict. If ibrutinuib or lenalidomied are currently approved for mantle cell lymphoma, what would stop you from prescribing them in CLL? Since the drugs can cost 10K/month, getting insurance to pay for it is the biggest issue. These drugs have been clearly well studied in these diseases, it is not like a doc would just be "flying by the seat of their pants" to recommend such a drug. The reality is that some insurance will cover it and some won't. In the case of ibrutinib, it will likely be approved in CLL in a few months so it may not be as much of an issue, but for a patient who needs therapy for CLL NOW and wants ibrutinib it all comes down to whether insurance will pay for it or not.
Since the doses are a little different between the two diseases, it shouldn't be a surprise that insurance could figure it is being given "off label." When you submit a "prior authorization" to insurance for a drug, they also ask for a diagnosis code (ICD-9) that is specific to the disease - i.e. CLL vs MCL vs other. If the code and the drug don't match, that is another red flag.
Does that mean it can't be done? I've had success giving patients unusual drugs off label where it was clear to the patient, insurance, and everyone else that we were off label. In some cases there was something uniquely compelling such as a specific mutation that matched a specific drug in a patient who had received all the available therapies already. In short - there really are not rules - just financial realities. In the UK, Europe, and Canada, it is a lot more strict and "off label" use is a lot less frequent. I guess our reputation as cowboys in the US has some truth.
For patients who are determined, a careful, thoughtful letter to the insurance company by the patient or the doctor citing relevant medical literature can sometimes help. I would suggest strongly that a respectful dialogue goes a lot farther than yelling and screaming in such a situation.
With a bunch of new drugs coming, the landscape of CLL and NHL are going to change dramatically. It will move fits and spurts. With all the dramatic changes coming in health care (that I have written and tweeted about quite a bit) it is really hard to predict how it is going to play out.
Thanks for reading
Wednesday, November 13, 2013
Ibrutinib gets first approval in Mantle Cell Lymphoma
Not sure if you caught the news (see NY Times) but the FDA has now approved ibrutinib (now called Imbruvica) for treatment of patients with mantle cell lymphoma (see my post on the different types of NHL).
ASCO has put out a broadcast so that you can see the data here.
The label is fairly broad (approved for patients who have had one prior therapy). That is significant because historically drugs that have been approved on the basis of single arm phase II studies (read NEJM article here) have required patients to have had exposure to all approved drugs in a particular disease. In mantle cell lymphoma, that would include bortezomib which does not have a huge role in the management of the disease. Keep in mind that lenalidomide was also recently approved in this disease. You can tell by stock price that the analysts think this is a good result for the company.
This is great news for MCL patients as it will give another treatment option. Furthermore, once approved it will allow for a lot more research to begin taking place. Not sure how much off label use will be allowed (will vary from insurance to insurance), but certainly hoping that the CLL indication comes soon.
ASCO has put out a broadcast so that you can see the data here.
The label is fairly broad (approved for patients who have had one prior therapy). That is significant because historically drugs that have been approved on the basis of single arm phase II studies (read NEJM article here) have required patients to have had exposure to all approved drugs in a particular disease. In mantle cell lymphoma, that would include bortezomib which does not have a huge role in the management of the disease. Keep in mind that lenalidomide was also recently approved in this disease. You can tell by stock price that the analysts think this is a good result for the company.
This is great news for MCL patients as it will give another treatment option. Furthermore, once approved it will allow for a lot more research to begin taking place. Not sure how much off label use will be allowed (will vary from insurance to insurance), but certainly hoping that the CLL indication comes soon.
Wednesday, October 9, 2013
The race tightens
In case you missed it, Gilead put out a major press release today:
Gilead to Stop Phase 3 Study 116 of Idelalisib in Chronic Lymphocytic Leukemia Early Because of Positive Risk-Benefit
Idelalisib is a very promising experimental agent for both NHL and CLL. I've written about it quite a few times previously. In CLL there is overwhelming enthusiasm regarding the multitude of new drugs on the very near horizon.
Obinutuzumab is an exciting new antibody that has been granted "breakthrough status" with the FDA. Most readers will be familiar with Ibrutinib which carries the same FDA designation. Idelalisib is another important experimental new therapy but was not awarded the same breakthrough status and was therefore considered by some to be "third place" in the horse race of approval. This announcement will really give them a significant boost.
The FDA is charged with determining if a new therapy is both, "safe" and "effective." The absolute best way to do that is perform a randomized / blinded / controlled phase III study in which half of patients are given a "standard of care" and the other half are given the experimental treatment. If patients do better on the experimental treatment the drug can be approved.
It is fair to ask, "what is a standard of care?" Sometimes in CLL - particularly in elderly individuals it isn't exactly clear from any real source what is "standard." Is "standard" what is commonly done by doctors or is "standard" the most rigorously studied and published "treatment regimen." In CLL, single agent rituximab does not have the enthusiastic endorsement of many thought leaders, but if you look at what is done in practice it represents nearly 30% of the treatment offered to elderly individuals. Is single agent rituxan therefore a good control? That will be answered by the FDA.
Another way drugs may be approved is on the basis of an "accelerated approval" where a drug company identifies an "unmet medical need." This is a population of patients with a specific disease who have exhausted all of their therapies and lack any good remaining / approved options. If you can show that your new drug is active in this setting, the FDA can give you a "conditional approval." The "condition" is that your approval depends upon you then completing an appropriate randomized phase III study.
This route of approval can be perilous. A really promising breast cancer drug was rejected by the FDA while going down this road because it was felt that not every patient had truly exhausted every single approved drug. After the company then completed a randomized phase III study with the same drug, they got approval this year. Unfortunately nearly three years passed between these two events.
If anyone is following the story closely - here is where things stand:
Obinutuzumab conducted a randomized phase III trial in FRONTLINE ELDERLY patients with CLL. The antibody has some pretty significant advantages and the FDA has granted both "breakthrough status" and "priority review"
Ibrutinib submitted their application to the FDA on the basis of a non randomized study and the FDA has granted breakthrough status in the 17P deleted population. I am not participating in the subsequent randomized phase III studies with this molecule but there are quite a few of them and accrual has been brisk. Will it be approved in this smaller subgroup of patients or all patients with relapsed CLL? The FDA will soon tell.
Idelalisib had taken the single arm strategy in follicular lymphoma refractory to both rituximab and an alkalating agent chemotherapy. They had seemed a little behind in CLL but now this announcement gives them a lot of new momentum. They reported that a randomized phase III study in CLL had to be terminated early because the benefit of the experimental arm was so significant.
The study consisted of half patients getting single agent rituximab WITH a placebo while the other half got rituximab WITH idelalisib (CAL-101 or GS-1101). This strategy would only be appropriate for older individuals with medical reasons not to give chemotherapy.
It is always nice when a study stops early for positive results - but keep in mind that the DSMB (data safety monitoring board) is NOT the same group as the FDA. Now the study closes. It sounds like patients on the control arm will be allowed to receive idelalisib. This may minimize the magnitude of the benefit that would have occurred if the study were to continue. Other drugs have been stymied at the FDA under similar circumstances.
Can't wait to see how this all plays out.
Thanks for reading
Jeff
Gilead to Stop Phase 3 Study 116 of Idelalisib in Chronic Lymphocytic Leukemia Early Because of Positive Risk-Benefit
Idelalisib is a very promising experimental agent for both NHL and CLL. I've written about it quite a few times previously. In CLL there is overwhelming enthusiasm regarding the multitude of new drugs on the very near horizon.
Obinutuzumab is an exciting new antibody that has been granted "breakthrough status" with the FDA. Most readers will be familiar with Ibrutinib which carries the same FDA designation. Idelalisib is another important experimental new therapy but was not awarded the same breakthrough status and was therefore considered by some to be "third place" in the horse race of approval. This announcement will really give them a significant boost.
The FDA is charged with determining if a new therapy is both, "safe" and "effective." The absolute best way to do that is perform a randomized / blinded / controlled phase III study in which half of patients are given a "standard of care" and the other half are given the experimental treatment. If patients do better on the experimental treatment the drug can be approved.
It is fair to ask, "what is a standard of care?" Sometimes in CLL - particularly in elderly individuals it isn't exactly clear from any real source what is "standard." Is "standard" what is commonly done by doctors or is "standard" the most rigorously studied and published "treatment regimen." In CLL, single agent rituximab does not have the enthusiastic endorsement of many thought leaders, but if you look at what is done in practice it represents nearly 30% of the treatment offered to elderly individuals. Is single agent rituxan therefore a good control? That will be answered by the FDA.
Another way drugs may be approved is on the basis of an "accelerated approval" where a drug company identifies an "unmet medical need." This is a population of patients with a specific disease who have exhausted all of their therapies and lack any good remaining / approved options. If you can show that your new drug is active in this setting, the FDA can give you a "conditional approval." The "condition" is that your approval depends upon you then completing an appropriate randomized phase III study.
This route of approval can be perilous. A really promising breast cancer drug was rejected by the FDA while going down this road because it was felt that not every patient had truly exhausted every single approved drug. After the company then completed a randomized phase III study with the same drug, they got approval this year. Unfortunately nearly three years passed between these two events.
If anyone is following the story closely - here is where things stand:
Obinutuzumab conducted a randomized phase III trial in FRONTLINE ELDERLY patients with CLL. The antibody has some pretty significant advantages and the FDA has granted both "breakthrough status" and "priority review"
Ibrutinib submitted their application to the FDA on the basis of a non randomized study and the FDA has granted breakthrough status in the 17P deleted population. I am not participating in the subsequent randomized phase III studies with this molecule but there are quite a few of them and accrual has been brisk. Will it be approved in this smaller subgroup of patients or all patients with relapsed CLL? The FDA will soon tell.
Idelalisib had taken the single arm strategy in follicular lymphoma refractory to both rituximab and an alkalating agent chemotherapy. They had seemed a little behind in CLL but now this announcement gives them a lot of new momentum. They reported that a randomized phase III study in CLL had to be terminated early because the benefit of the experimental arm was so significant.
The study consisted of half patients getting single agent rituximab WITH a placebo while the other half got rituximab WITH idelalisib (CAL-101 or GS-1101). This strategy would only be appropriate for older individuals with medical reasons not to give chemotherapy.
It is always nice when a study stops early for positive results - but keep in mind that the DSMB (data safety monitoring board) is NOT the same group as the FDA. Now the study closes. It sounds like patients on the control arm will be allowed to receive idelalisib. This may minimize the magnitude of the benefit that would have occurred if the study were to continue. Other drugs have been stymied at the FDA under similar circumstances.
Can't wait to see how this all plays out.
Thanks for reading
Jeff
Wednesday, September 11, 2013
Video update from IWCLL
I had the chance to meet up with Andrew Schorr in Germany at the IWCLL meeting. We taped this interview to provide an overview of where the new CLL drugs may best fit into an individuals treatment plan. Hopefully it is a good summary for you and puts things into a more focused perspective.
Andrew does a great job collecting the voices of many experts and putting them into one place. If you haven't made a contribution to his efforts, you might want to think about doing so. We are lucky to have him out on the front lines.
I apologize for being a little long winded in response to his questions. So much exciting stuff to talk about, I had a hard time containing myself.
Andrew does a great job collecting the voices of many experts and putting them into one place. If you haven't made a contribution to his efforts, you might want to think about doing so. We are lucky to have him out on the front lines.
I apologize for being a little long winded in response to his questions. So much exciting stuff to talk about, I had a hard time containing myself.
Wednesday, July 10, 2013
ASCO update 2013
Andrew Schorr and Brian Koffman have done a fantastic job putting together videos to help educate CLL patients about the state of the art in CLL. I appreciate the opportunity to interview with them - they are a great team and a fantastic resource for CLL patients looking for good information about what is out there.
In this interview we talked about a number of new investigational medications that many CLL patients have heard of including ibrutinib, idelalisib, obinituzumab, and ABT-199. Hopefully this gives some new insight into the importance of research participation.
In this interview we talked about a number of new investigational medications that many CLL patients have heard of including ibrutinib, idelalisib, obinituzumab, and ABT-199. Hopefully this gives some new insight into the importance of research participation.
Thursday, June 20, 2013
Ibrutinib for CLL and MCL in New England Journal of Medicine
It is with considerable pride that I get to report our ibrutinib study was published today in the most prestigious medical journal out there.
Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia
Time magazine says:
I've written extensively on my blog about ibrutinib because I have been working with it and other similar drugs since 2005. I got to treat the first two CLL patients in the world with ibrutinib and also one of the very first mantle cell lymphoma patients. It is fun to see the world waking up to the significance of these therapies.
It was a cool experience treating the first two CLL patients because it was immediately clear that the drug was doing something significant (though in the first few days it wasn't clear if it was good or bad). The patient had a white blood cell count of 50k and the next day she came back feeling great with nodes that had shrunk tremendously and her WBC had risen to about 150K.
I remember discussing it with the medical monitor and we hastily got a scan to make sure we were not making the patient worse. I had thought this might happen because of our prior experience with fostamatinib but the monitor at the time was uncertain of what it meant. After a few months we became aware of just how special this drug might be - the rest they say is history (recorded here)
There is also an article about ibrutinib in mantle cell lymphoma in the same journal and a fantastic editorial about why these drugs work. For patients with mantle cell lymphoma over age 65 there is a critically important new study to be aware of - linked here.
There is never a good time to get CLL, but if you had to pick one, now would be the time to get it! Lots of cool change coming.
Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia
Time magazine says:
I've written extensively on my blog about ibrutinib because I have been working with it and other similar drugs since 2005. I got to treat the first two CLL patients in the world with ibrutinib and also one of the very first mantle cell lymphoma patients. It is fun to see the world waking up to the significance of these therapies.
It was a cool experience treating the first two CLL patients because it was immediately clear that the drug was doing something significant (though in the first few days it wasn't clear if it was good or bad). The patient had a white blood cell count of 50k and the next day she came back feeling great with nodes that had shrunk tremendously and her WBC had risen to about 150K.
I remember discussing it with the medical monitor and we hastily got a scan to make sure we were not making the patient worse. I had thought this might happen because of our prior experience with fostamatinib but the monitor at the time was uncertain of what it meant. After a few months we became aware of just how special this drug might be - the rest they say is history (recorded here)
There is also an article about ibrutinib in mantle cell lymphoma in the same journal and a fantastic editorial about why these drugs work. For patients with mantle cell lymphoma over age 65 there is a critically important new study to be aware of - linked here.
There is never a good time to get CLL, but if you had to pick one, now would be the time to get it! Lots of cool change coming.
Wednesday, May 15, 2013
Ibrutinib Resistance
ASCO abstracts are out. It feels like Christmas Morning and I am 5 years old (that is probably a very sad commentary about myself).
I'm part way through the CLL stack and Abstract 7041 jumps out at me as a MAJOR discovery:
They took CLL cases treated with ibrutinib and sequenced the entire exome in patients who became resistant (an exome sequence is not as comprehensive as a genome but it is still pretty dang impressive).
In resistant cases, they found that the binding site for ibrutinib on BTK had been mutated in two cases and in a third case, an enzyme downstream of BTK acquired a mutation that turned the protein on.
This is big because it can tell us why patients become resistant to the drug. It is always a good sign that you have hit a very important target when the mechanisms of resistance show how important the pathway actually is. In other words, you know the BCR is important because the CLL cells that become resistant have discovered a way to reactivate the BCR. The next step is figuring out how to get those patients to be sensitive again (perhaps using idelalisib?)
The other significant finding of the paper is that ibrutinib does not result in a bunch of new genetic changes in the same way FCR might.
I'm part way through the CLL stack and Abstract 7041 jumps out at me as a MAJOR discovery:
They took CLL cases treated with ibrutinib and sequenced the entire exome in patients who became resistant (an exome sequence is not as comprehensive as a genome but it is still pretty dang impressive).
In resistant cases, they found that the binding site for ibrutinib on BTK had been mutated in two cases and in a third case, an enzyme downstream of BTK acquired a mutation that turned the protein on.
This is big because it can tell us why patients become resistant to the drug. It is always a good sign that you have hit a very important target when the mechanisms of resistance show how important the pathway actually is. In other words, you know the BCR is important because the CLL cells that become resistant have discovered a way to reactivate the BCR. The next step is figuring out how to get those patients to be sensitive again (perhaps using idelalisib?)
The other significant finding of the paper is that ibrutinib does not result in a bunch of new genetic changes in the same way FCR might.
Sunday, April 7, 2013
History of Ibrutinib
Where do drugs come from?
Sometimes they come from places far removed from where they were
originally intended to go. The history
of ibrutinib development is detailed in this article published in Forbes
magazine. As David aptly points out –
these drugs can come out of left field with wild histories. Lots of people played important roles – and I
think it is a fantastic read. I would
highly encourage any patient with CLL or NHL take the time to read it (yes I am
proud to get a couple of personal mentions).
Unfortunately the initial approval will not serve as broad
permission for any oncologist to prescribe it to any patient. It will probably have a narrow, “indication”
at first for patients with relapsed Waldenstrom’s Macroglobulinemia and MantleCell Lymphoma having received some specific prior therapies. Second – I predict that patients with 17pdeleted CLL will get the next, “indication.”
Over the next 1-3 years we will see the “indications” slowly expand in
different patient populations
“Indications” matter because insurance companies pay close
attention to what the FDA has approved.
Different insurance companies take very different attitudes regarding
“off label” prescribing of drugs. For a
drug likely to cost nearly $90k per year (my guess only) – insurance will
likely look quite closely at who is receiving it. While CLL patients will greet the approval –
it may still take a while for them to access the medicine. That is why getting involved in research
studies is so important!!!!
Wednesday, January 30, 2013
Clinical Oncology News: Ibrutinib
We finally published the phase I study of ibrutinib in NHL/CLL. The article was written up in the Journal of Clinical Oncology. This paper will probably be cited quite a few times and is worth the read for the interested reader.
For readers interested in B-Cell Receptor signaling, they might like to read the original fostamatinib study we published in Blood a few years ago.
Hopefully we will get some of the CAL-101 data written up soon.
A lot of this might seem like Greek, but I was asked to write a summary article for "Clinical Oncology News." Here is a link to that article
Here is a small quote:
"The BCR signaling pathway is central to B-cell survival. In laboratory conditions where B-cell signaling could be genetically eliminated, B cells disappeared.1 Pharmacologic intervention in downstream signaling pathway proteins intuitively followed, and inhibition of the proximal signaling enzyme spleen tyrosine kinase (Syk) by fostamatinib was initially proposed in only 2007.2
I have a bunch of posts I want to write but haven't had time to write them. Hopefully something more soon.
For readers interested in B-Cell Receptor signaling, they might like to read the original fostamatinib study we published in Blood a few years ago.
Hopefully we will get some of the CAL-101 data written up soon.
A lot of this might seem like Greek, but I was asked to write a summary article for "Clinical Oncology News." Here is a link to that article
Here is a small quote:
"The BCR signaling pathway is central to B-cell survival. In laboratory conditions where B-cell signaling could be genetically eliminated, B cells disappeared.1 Pharmacologic intervention in downstream signaling pathway proteins intuitively followed, and inhibition of the proximal signaling enzyme spleen tyrosine kinase (Syk) by fostamatinib was initially proposed in only 2007.2
Since that time, numerous clinical investigations have validated the importance of inhibition of BCR signaling. After Syk activation, BTK propagates the signal leading to downstream activation of phosphoinositide-3 kinase. These latter two proteins are inhibited by ibrutinib and CAL-101 (subsequently GS-1101, now idelalisib), respectively. Following the initial clinical reports of fostamatinib activity,3 the present paper by Advani et al represents the first published report of the clinical activity of ibrutinib.
In CLL, virtually all patients experience a rapid reduction in lymph node size and disease-related cytokines concurrently with a rapid rise in white blood cells (WBCs) as cells redistribute from their protective niches in nodes and marrow into the circulation. Over time, WBCs fall, nodes remain reduced, and improvement in marrow function is common, even in high-risk refractory disease. Different NHLs have been observed to respond as well. Some cases of diffuse large B-cell lymphomas may respond in dramatic fashion, although prospective identification of these patients is an area of intense interest. Patients with mantle cell lymphoma have enjoyed durable disease control with ibrutinib. Follicular lymphoma appears to respond to both ibrutinib and idelalisib, yet the clinical significance in this more indolent population requires further study.
Investigators and patients alike are excited because these oral drugs provide unique activity while being well tolerated in most cases. These drugs will alter the clinical management landscape of patients with B-cell malignancies in the near future and practicing clinicians will need to be aware of this emerging class of therapies.
References
- Kraus M, Alimzhanov M, Rajewski N, et al. Survival of resting mature B lymphocytes depends on BCR signaling via the Igalpha/beta heterodimer. Cell. 2004;117:787-800, PMID: 15186779.
- Sharman J, Irish J, Coffee G. Targeting syk kinase for the treatment of b-cell lymphoma. J Clin Oncol. 2007;25(18s):Abstract 3600.
- Friedberg J, Sharman J, Sweetenham J. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2010;115:2578-2585, PMID: 19965662.
I have a bunch of posts I want to write but haven't had time to write them. Hopefully something more soon.
Tuesday, January 22, 2013
Patient Power: "What is Hot in CLL"
I had the pleasure of meeting Andrew Schorr at ASH this past December. Andrew is a CLL patient who has an absolutely fantastic website called patientpower. I highly encourage you look through his material.
He asked me, "What is hot in CLL?" There is a lot going on in CLL. Here is the interview (I will try to directly embed this on my blog once I figure out how)
He asked me, "What is hot in CLL?" There is a lot going on in CLL. Here is the interview (I will try to directly embed this on my blog once I figure out how)
An Expert's Perspective: Why New CLL Treatments Supersede FCR from Patient Power® on Vimeo.
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.
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