I expect this blog post is going to ruffle some feathers. I can’t wait to see the responses in CLL forum, ACOR and elsewhere.
Patterns of care databases report that during the course of CLL approximately one third of patients will receive mono-therapy with rituximab (ie. rituximab with NO OTHER CHEMOTHERAPY). In fact, it is one of the most commonly utilized therapies in the management of CLL but should almost completely disappear in light of new clinical trial data. Based upon information published within the last 6 months, I think any treatment recommendation for single agent rituximab should he held to some additional scrutiny.
I will admit that I have given this therapy a limited number of times in CLL/SLL before under circumstances where I thought it might be appropriate. In CLL/SLL I think rituximab monotherapy is mostly outdated as of late 2014. Newer drugs such as obinutuzumab and Ibrutinib or new combinations such as idelalisib with rituximab have taken the place of rituximab monotherapy and I have changed my practice patterns as a result.
I recently blogged about rituximab monotherapy in follicular lymphoma and highlighted several key papers published that show how well this immunotherapy drug works. I also blogged about how the addition of lenalidomide may alter the landscape of front line treatment in follicular / indolent lymphoma. Indeed, rituximab monotherapy in indolent NHL (follicular, marginal zone) is a good treatment and definitely appropriate in many circumstances - particularly low tumor burden disease. But what is true for some indolent lymphoma isn’t necessarily true for ALL indolent b-cell disorders.
Small lymphocytic lymphoma and chronic lymphocytic leukemia are often considered two different manifestations of the same disease. Indeed, they are often referred together as CLL/SLL and lumped in with the rest of the indolent lymphomas. But different lymphomas have different behaviors and the response to rituximab is one key difference. Unfortunately, many doctors don’t pay too close attention to this distinction.
Rituximab is often a very easy drug to administer (some uncommon exceptions apply). In most indolent lymphomas and even CLL, you can see things get better and everyone seems happy. Both doctors and patients can be lulled into a sense that they are getting good therapy when they see things going the right direction – but good can sometimes be the enemy of better and may not be best in long term.
When rituximab first came out as a new drug it was noted that it had fairly modest activity in the management of chronic lymphocytic leukemia. Response rates were lower than in follicular lymphoma and didn’t last as long. Two key papers were published in the Journal of Clinical Oncology in 2001 authored by John Byrd (linked here) and Susan O’Brien (linked here). Both of them looked at ways to increase the dose of rituximab in order to get a better response in patients with relapsed disease. Dr. Byrd's paper looked at more frequent dosing and Dr O’Brien’s paper looked at giving mega-doses. Despite these efforts the overall response rates were between 35-45% and generally lasted 8-10 months.
Two key caveats though should dampen even that modest efficacy. The first is that this was in a population that had largely not been exposed to rituximab previously. Rituximab works better in patients who have never received it before. Nowadays virtually all patients get rituximab added to their first line therapy. When their disease relapses, a sizable population is getting rituximab mono-therapy and it is less likely to work when used a second time. The second caveat is that in 2001 we had different criteria for response assessments and CT scans were not used the same way they are today. Since lots of patients have enlarged lymph nodes hanging out in their chest or abdomen that cannot be detected by physical exam, looking more closely with CT scan would influence the determination of response and progression.
To get a good estimation of how well rituximab or even ofatumumab actually works, I would suggest looking at the control arm of the recently reported studies that led to the approval of idelalisib and Ibrutinib (linked here and here respectively). In these studies patients were randomly assigned to one of the “tried and true” or one of the new drugs but looked at rituxan exposed patients and used CT scans to determine progression. In the rituximab alone arm of the idelalisib study, the lymph node response rate was only 6% and the median progression free survival was under six months. Those response rates are really lousy. In the ofatumumab alone arm of the ibrutinib study, patients didn’t fare much better.
CLL researchers look at the patterns of care data and look at the utilization of rituximab monotherapy with a measure of disdain. While in the past I might have argued back that CLL patients treated in academic centers are fundamentally different from those seen in community practice (an assertion which has good data to support). Indeed, community patients are on average older, have more medical issues, and less good baseline organ function, and several other key differences compared to patients seen in academic medical centers. In the past, I think you could have used that logic to support some utilization of rituximab monotherapy but new data sets strip that away.
So what are the key new data sets?
In previously untreated CLL, obinutuzumab is better than rituximab. These are both CD20 antibodies but obinutuzumab has a number of key modifications that make it more effective than rituximab. In a paper published late last year (linked here), the German group performed a three arm study comparing chlorambucil to chlorambucil in combination with either rituximab OR obinutuzumab. From progression free survival perspective these came in at 11, 16, and 26 months respectively with obinutuzumab the clear winner. If you only compared the chlorambucil arm to the obinutuzumab arm, you even saw an overall survival benefit (second paper to ever show this in CLL).
I have heard some people argue that the better performance of obinutuzumab was just based on differences in dosing in the study. I believe that is an argument made by people who are unfamiliar with obinutuzumab (gazyva). Clinically, it is a very different drug and the differences in dosing are pretty minimal.
This study was in CLL patients that are more typical for the disease (average age 71). Of course chlorambucil is somewhat of a pariah in the US and many have asked whether it is even a necessary part of the regimen. I was recently at the International Myeloma, Lymphoma, and Leukemia conference in NY where this topic was the subject of a one hour debate (hot Friday nights in the CLL research world). Hard to debate the topic given the lack of published data in this space but our group led a large study of obinutuzumab monotherapy that was presented at ASCO (link here) and will hopefully be published soon. My take on the data: you get a little more bang for the buck when you add the chlorambucil but not clear it is worth the cost, particularly with the agents available now in the relapsed setting.
Two years of average benefit in this disease can be meaningful. It will even be more meaningful if we can apply molecular data to pull out the patients less likely to benefit as well. There is new data from two studies that suggest the presence of NOTCH1 mutations makes CD20 antibody therapy considerably less effective (FC vs FCR and Chlorambucil vs chlorambucil-ofatumumab). Not sure if it applies yet to obinutuzumab yet, but hopefully that data will come out soon. You can test for NOTCH mutations here.
The second key data set (linked here) led to the approval of idelalisib. In this study, patients received either rituximab alone or in combination with idelalisib – a twice daily, non-chemotherapy pill. The difference was striking. Instead of a nodal response rate of 4% it was 96% and the difference in progression free survival was improved by 82%. In fact the difference was so striking the study had to be terminated for ethical reasons because the difference in overall survival started becoming too obvious to ignore (which we were not expecting to be different for technical reasons attributable to cross-over study design). This was the third study ever reported to show that there could be a survival difference in CLL with a new regimen.
I fundamentally believe that there is a significantly sized population of CLL patients who are not appropriate for an aggressive chemotherapy regimen. Let’s face it, the average age at first treatment in CLL is between 71-74 years old. Many are much older. Tack on heart and lung disease or multiple other medications, arthritis, etc which is entirely common in the population and things like FCR are absolutely prohibitive and even bendamustine-rituximab can be a stretch. If a CLL patient TODAY received the recommendation for rituximab therapy alone, I think it would be hard to justify why idelalisib isn’t included (note, I do not put rituximab or ofatumumab in combination with ibrutinib outside of a clinical trial as there is some suggestion that the ibrutinib may make the antibody work less well).
The third data set (linked here) compared Ibrutinib pills to ofatumumab infusions. Here too, the differences were so striking the study had to be terminated before it was planned to do so. In clinical research you set out to conduct studies when there is a sense of “equipoise.” That means there is an honest uncertainty about the difference between two therapies that you need to prove. The difference between ofatumumab and Ibrutinib in this particular study shatters the possibility of equipoise – the differences are too overwhelming. Response rates, progression free survival, and overall survival for patients treated with ibrutinib absolutely trounced ofatumumab.
So between these three papers the justification for rituximab monotherapy in either front line or relapsed CLL disappears. In front line, obinutuzumab is better than rituximab and in relapsed disease either adding idelalisib or swapping the two for Ibrutinib improve outcomes enough to fundamentally change the paradigm.
The remaining setting where CD20 antibody therapy such as rituximab or ofatumumab is used in CLL is as a “maintenance therapy” following some other chemotherapy. There have been several recent updates in this space and I think you could make a rational argument in support of maintenance though I’m not sure this is widely adopted in CLL treatment. I have provided a few links (here and here) but will leave this discussion for another time.
To summarize:
In previously untreated CLL, I think obinutuzumab has demonstrated sufficient clinical superiority over rituximab (either monotherapy or in combination with chlorambucil) to justify the swap in most cases - there is some debate about this point but I think the argument is settled. To date, there is not enough published data to routinely combine obinutuzumab with drugs like bendamustine or fludarabine outside of a clinical trial.
In patients with relapsed CLL, adding idelalisib to rituximab makes it work a whole lot better and Ibrutinib monotherapy trounces ofatumumab. Neither rituximab nor ofatumumab look nearly as good as single agents as we had believed in the past.
I anticipate the next several years of research will be about swapping out the various parts and putting them together again. Newer antibodies will be combined with newer pills and newer pills will be used earlier and earlier in the disease. It is a new era and we are quite fortunate to be in a time period where many of the “rules” are being re-written. Patients will live longer than our standard “prognosis” dictums and maybe we will even begin see a disease once considered incurable to be curable. Throw in BCL-2 inhibitors, CAR-T cells, bi-specific antibodies, and immune checkpoint inhibitors and I hope all patients will look to join in research studies so we can move the needle more quickly.
Thanks for reading
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Monday, November 10, 2014
Thursday, October 23, 2014
Lenalidomide and Rituximab in Lymphoma
In a recent post I outlined some of the important historical milestones of how we arrived at current standards of care in lymphoma. I ended my list with the advent of “immunotherapy.” Last week there was a paper published (link to article here) that
helps lay the groundwork for a paradigm change in indolent (slow/follicular) lymphoma – and I
want to highlight it here.
I think patients are instinctively drawn to the idea of
immunotherapy when they understand it.
Most clinicians use the term to describe some intervention that helps
shape the immune system to fight off a cancer rather than traditional
chemotherapy. Just about every patient I
meet asks me if there are some nutritional supplements that can “boost the immune system.” While maintaining healthy Vitamin D levels is a good candidate some of the new treatments that
are being developed are pretty fantastic.
At the most simple level, rituximab is an example of
immunotherapy. I have blogged about CD20 antibodies previously. You naturally make
antibodies to fight off bacteria and viruses.
Rituximab is merely an antibody that we give to you that fights off
lymphoma and CLL. When you give the
medicine, it binds to the outside of cancer cells and alerts the remainder of
the immune system to eliminate the cancer cells – no chemo involved.
For the last 15 years we have shown in study after study
after study that adding rituximab to just about any other sort of chemotherapy
makes that chemotherapy work better. I
have also recently blogged about giving rituximab by itself (link here).
There have also been a lot of other studies that have tried
to make better versions of rituximab. We
now have FDA approval ofatumumab and obinutuzumab which are all “CD20
antibodies.” In the case of obinutuzumab it has been shown to definitively work better than rituximab in chronic lymphocytic leukemia. There is also a
huge list of CD20 antibodies that are lingering in development or have been
killed off all together because they weren’t any better.
A different approach might be to ask if adding a second drug
can make rituximab work better. One
interesting theme that has evolved in research is the concept of “T cell pseudo-exhaustion.” Lymphocytes primarily come in three flavors (T cells, B
cells, and NK cells). Rituximab works in
part by recruiting the T/NK cells to kill the B cells. But B cells are crafty – they are able to use
cell surface receptors and micro-hormones to lull the T/NK cells to sleep – aka –
pseudo-exhaustion. It is as if the T/NK
cells identify a problem, but they have
a post thanksgiving turkey coma and can’t do anything about the
problem. We call it “pseudo” though
because it is entirely a reversible biochemical process. Give those T/NK cells a jolt of biochemical “coffee”
and now they can wake back up.
It has now been well shown in multiple laboratory studies
that lenalidomide can reverse T/NK cell pseudoexhaustion. Lenalidomide is a pill that is FDA approved
for treatment of multiple myeloma , another blood disorder called MDS, and even
mantle cell lymphoma but a handful of studies have shown it has substantial
activity in both follicular lymphoma and DLBCL.
More impressively when you give those T/NK cells a medicinal jolt and
then the rituximab helps tell them where to go, the results are pretty
spectacular.
The article I referred to at the start of this is (linked here). It reports the activity of
lenalidomide (revlimid) in combination with rituximab for previously untreated
indolent NHL. Here is the punch line, it
works extremely well.
When you use rituximab with chemotherapy for untreated
follicular lymphoma (like R-CHOP or R-Bendamustine), the overall response rate
is a health 90+% and the rate of “complete response” is about 35%. Somewhere between 50-60% of patients have
their disease still in remission at the 3 year mark (link to key article here).
When you use rituximab in combination with lenalidomide toe
overall response rate is also a healthy 90+% but the rates of complete response
are an astounding 87% in follicular lymphoma.
Furthermore the rates of three year remission are closer to 80%. If you look at rates of PET negative scans at
end of treatment (an important prognostic marker) it is virtually everyone and
looking at markers like “complete molecular response” they are extremely high.
All without chemotherapy!
A few caveats to note.
This study was a “single institution study” from the MD Anderson. In multiple prior studies things that came
out of MD Anderson didn’t pan out when tested in more diverse treatment
settings (selection bias, patient comorbidity, etc.). That said, this looks like it could herald a
paradigm change in low grade lymphoma.
So what does it take to change the status quo? For starters, insurance typically wouldn’t
cover lenalidomide in this setting because it is not yet approved for frontline
treatment. Some patients may be able to
get it paid for but it is extremely expensive so without coverage few will
probably take it. Fortunately a
prospective randomized multicenter phase III study that compares lenalidomide
and rituximab to either R-CHOP / R-Bendamustine (link here) has nearly completed accrual and
if the results from that study hold up, the drug will likely be approved in
this setting and insurance will have to cover it. If that happens, I think you will see a large
change in practice patterns as patients ask / push for non-chemo treatments
that may be better than chemo treatments.
In the meantime, there are still studies patients can
join. In PREVIOUSLY TREATED lymphoma
(including follicular, marginal zone, mantle cell) there is a study going on
where EVERYONE gets the combination of these two drugs and then there is a
randomization for the duration of lenalidomide treatment (link here).
There are also a handful of other studies using lenalidomide in lymphoma in a variety of combinations (see clinical trials webpage linked here)
When you can get the immune system to do its job, it can be
a fabulous thing.
Thanks for reading
Sunday, September 28, 2014
Immunotherapy for Indolent (low grade) Lymphoma
An academic mentor once told me, “scientific advances are a lot like a game
of baseball.” Curious, I asked him what
he meant. He shared with me, “most
advances are like getting a base hit. Doubles happen but are not terribly common, triples are
rare, home runs don’t happen all that often and genuine grand slams change the
field all together.”
As I shared with him my idea of turning off B cell receptor signaling using pills, he told me, “Jeff, it sounds like you are swinging for the fences, and for our Stanford fellows, we are happy if you just crowd the plate and get hit by a pitch…” Oh well, I suppose everything worked out fine, and I still don't really care much for baseball. I wanted to compile the history of home-runs in the field to highlight just where we are and point out where I think we are going.
If you look back over the last 60 years of advances cancer medicine, there are only a handful of clinical breakthroughs in low grade lymphoma (indolent) that fundamentally re-oriented our treatment strategies in the disease and upended the status quo of the time. It hasn’t necessarily been a story of slow and steady progress. Instead there are discrete episodes that shred through the treatment landscape and when the dust settles, the field has evolved into something new.
Cancer is a complex beast and many discoveries have only served to show us just how little we actually know. While the progress is now exponential, so too is the amount we realize we don’t know. Every so often something comes along that genuinely moves the needle and patients have longer and better lives. I am very excited about an emerging story in indolent NHL and I wanted to help put in context a story that I think we are going to hear about very soon.
Here is my short list – for the interested reader, I highly recommend the book The Emperor of All Maladies. It was written by one of my residency training classmates at MGH and has received the Pulitzer Prize. It is a fantastic read.
1) Way back in the 1940's local radiation therapy was the only treatment available. This really didn't work well in a disease that is typically "systemic." Since we didn't know much about radiation dosing, patients were burned and burned again until their disease became "radiation resistant" and they died of massive lymph node enlargement or complications from radiation.
2) In 1946 we had the introduction of "chemotherapy" which actually spun out of chemical warfare research during WWII. (The remarkable story of America’s “Second Pearl Harbor” and the birth of chemotherapy is one of the most amazing little known stories in medicine). Patients with lymphoma were the very first to be treated with modified versions of mustard gas. Responses were short-lived but merely 15 years after the introduction of penicillin the idea that “medicine” could treat cancer was born.
3) In the 1950's the drug Adriamycin was isolated from a soil sample of a 13th century Italian Castle and subsequently was shown to be effective in lymphoma. This drug became a "backbone" of many treatment strategies in lymphoma and is still commonly used today. It is the “big red” drug that makes many lymphoma patients lose their hair but is also commonly used in breast cancer, gastric cancer, sarcoma’s and other diseases.
4) For the next several decades, progress was built in many small steps. New drugs were found, developed, and tested one at a time. Vincristine was isolated from the Madagascar Periwinkle, Etoposide was isolated from the “mayapple” and so forth. Multiagent drug cocktails were assembled and tested. When you put as many drugs together as you possibly could, you got crazy names such as M-Bacod (6 drugs), Pro-Mace-Cytabomb (8 drugs), and CODOX-M-IVAC (7 drugs). While some of these were for more aggressive lymphomas, each had their loyal adherents and debates raged without much comparative data. That all ended however in 1993 CHOP (4 drugs) was declared the winner over several more "intensive" regimens.
5) In 1997 we saw the introduction of rituximab in lymphoma. This was the first time we used a therapeutic antibody (like the ones your body makes to fight the flu) to treat cancer. Rituximab administered alone has impressive single agent activity and has become increasingly utilized as monotherapy. It was also quickly added to CHOP to make the R-CHOP regimen. This was the first "chemo-immuno-therapy" regimen and led to substantial improvements in long term outcome of patients with both low grade and DLBCL. Until 2007, patterns of care data indicate that if you were going to get chemo for follicular lymphoma, 50% got R-CHOP, and another 25% got the same regimen without the Adriamycin which adds quite a punch in terms of side effects (R-CVP), and about 15% received rituximab alone.
6) In 2008, there was a US based study of a drug that had been floating around East Germany during the entire cold war yet remained unknown to western cancer doctors. This was the first that most US docs had heard of Bendamustine. The data was quite impressive for how effective the drug was compared to standard alternatives. In 2009, the German lymphoma study group initially presented data at ASH comparing bendamustine-rituximab to R-CHOP in follicular lymphoma. It was actually only published in Lancet last year. This showed improved efficacy with bendamustine, and far reduced side effects which led to the sweeping changes in patterns of care. Bendamustine with rituximab has upended practice patterns. In the last two years, US patterns of care data reveals approximately 1/3 of previously untreated follicular lymphoma patients needing treatment receive Bendamustine-Ritxuximab, 1/3 receive rituximab alone, and only about 1/5 receive R-CHOP in front line treatment and virtually nobody receives it following relapse. Fludarabine utilization is virtually gone (see attached slide presentation at the bottom of this post and my post on "How I treat follicular lymphoma).
7) As ASCO 2007, our lab at Stanford presented the first “pre-clinical” data showing that inhibition of B-Cell receptor signaling enzymes could have therapeutic effect in B cell malignancies. This theory was subsequently confirmed in a plenary session presention at ASH in 2008 utilizing the drug fostamatinib. The discussant at the time felt that the data met the criteria for “game-changing” and put it on his list of NHL history makers. While fostamatinib is no longer being actively developed, the proof of concept directly preceded / led to the exploration of ibrutinib and idelalisib in similar diseases. In heavily pretreated patients, both of these drugs have approximately 50% overall response rate (size criteria for response determination, many more actually shrink and benefit – just not enough to be considered “partial response”) and average a year of benefit for responding patients. Idelalisib was recently FDA approved in follicular lymphoma and we await data on ibrutinib in this population. While the impact in follicular lymphoma remains an evolving story, the impact in chronic lymphocytic leukemia and small lymphocytic lymphoma is nothing short of transformative.
8) I believe story 8 in indolent lymphoma will be “immunotherapy." Rarely a day goes by where I am not asked by a patient, “is there anything I can do to boost my immune system.” While my answer has always been, “not really” a number of very important new therapies are showing that harnessing the power of the immune system to attack cancer can be extremely powerful. Drugs have been either approved or are soon to be approved in melanoma, lung cancer, kidney cancer, and bladder cancer that help the immune system identify and destroy the cancer cells – without using chemotherapy. Some of these are antibodies that interfere with the “on/off” switches of the immune system. Others “re-program” T-cells using engineered viruses that can go absolutely crazy on B cells (see amazing video here). The most accessible and perhaps most exciting of these for patients with indolent lymphoma may very well be the combination of revlimid with rituximab. There are several very important studies that are poised to position this combination at the center of treatment pathways for patients with follicular lymphoma.
Nathan Fowler’s data from MD Anderson – link here
Nearly completed study in frontline follicular lymphoma Rev-Rituximab vs R-Chemo – link here
Open study of Rev-Ritux in relapsed follicular lymphoma – link here
I think of the combination of revlimid-rituximab (also called R2) as a road trip with a pot of coffee and a map. Rituximab helps orient the immune system to go after the cancerous b cells by coating the outside of them and serving as an alarm for the T cells (like a road map). Revlimid (lenalidomide) helps overcome what has been called T-Cell “pseudo-exhaustion” and get them to reactivate (ready for the road). B cell cancers have a remarkable ability to “put the t cells to sleep.” Whether though secretion of hormones, or actually manipulating the on/off switches of T cells, the cancerous B cells literally put the other half of the immune system into a post thanksgiving meal food coma. Revlimid acts like a cold splash of water to the face for the sleepy T cells. Not bad for a drug that really isn’t chemotherapy but is considered an “imid” for – immunomodulatory drug.
The combination has been explored in CLL. It can be so active at times that there can be problems with tumor lysis syndrome. The combination is not approved by the FDA in this setting and should be utilized very carefully due to the associated risks.
The combination has also been explored in follicular lymphoma with some pretty spectacular results… and that will be the subject of an upcoming post!
Thanks for reading
(Patterns of care data and a nice view of the Sisters volcanic range in Oregon from Mt Bachelor Ski area)
As I shared with him my idea of turning off B cell receptor signaling using pills, he told me, “Jeff, it sounds like you are swinging for the fences, and for our Stanford fellows, we are happy if you just crowd the plate and get hit by a pitch…” Oh well, I suppose everything worked out fine, and I still don't really care much for baseball. I wanted to compile the history of home-runs in the field to highlight just where we are and point out where I think we are going.
If you look back over the last 60 years of advances cancer medicine, there are only a handful of clinical breakthroughs in low grade lymphoma (indolent) that fundamentally re-oriented our treatment strategies in the disease and upended the status quo of the time. It hasn’t necessarily been a story of slow and steady progress. Instead there are discrete episodes that shred through the treatment landscape and when the dust settles, the field has evolved into something new.
Cancer is a complex beast and many discoveries have only served to show us just how little we actually know. While the progress is now exponential, so too is the amount we realize we don’t know. Every so often something comes along that genuinely moves the needle and patients have longer and better lives. I am very excited about an emerging story in indolent NHL and I wanted to help put in context a story that I think we are going to hear about very soon.
Here is my short list – for the interested reader, I highly recommend the book The Emperor of All Maladies. It was written by one of my residency training classmates at MGH and has received the Pulitzer Prize. It is a fantastic read.
1) Way back in the 1940's local radiation therapy was the only treatment available. This really didn't work well in a disease that is typically "systemic." Since we didn't know much about radiation dosing, patients were burned and burned again until their disease became "radiation resistant" and they died of massive lymph node enlargement or complications from radiation.
2) In 1946 we had the introduction of "chemotherapy" which actually spun out of chemical warfare research during WWII. (The remarkable story of America’s “Second Pearl Harbor” and the birth of chemotherapy is one of the most amazing little known stories in medicine). Patients with lymphoma were the very first to be treated with modified versions of mustard gas. Responses were short-lived but merely 15 years after the introduction of penicillin the idea that “medicine” could treat cancer was born.
3) In the 1950's the drug Adriamycin was isolated from a soil sample of a 13th century Italian Castle and subsequently was shown to be effective in lymphoma. This drug became a "backbone" of many treatment strategies in lymphoma and is still commonly used today. It is the “big red” drug that makes many lymphoma patients lose their hair but is also commonly used in breast cancer, gastric cancer, sarcoma’s and other diseases.
4) For the next several decades, progress was built in many small steps. New drugs were found, developed, and tested one at a time. Vincristine was isolated from the Madagascar Periwinkle, Etoposide was isolated from the “mayapple” and so forth. Multiagent drug cocktails were assembled and tested. When you put as many drugs together as you possibly could, you got crazy names such as M-Bacod (6 drugs), Pro-Mace-Cytabomb (8 drugs), and CODOX-M-IVAC (7 drugs). While some of these were for more aggressive lymphomas, each had their loyal adherents and debates raged without much comparative data. That all ended however in 1993 CHOP (4 drugs) was declared the winner over several more "intensive" regimens.
5) In 1997 we saw the introduction of rituximab in lymphoma. This was the first time we used a therapeutic antibody (like the ones your body makes to fight the flu) to treat cancer. Rituximab administered alone has impressive single agent activity and has become increasingly utilized as monotherapy. It was also quickly added to CHOP to make the R-CHOP regimen. This was the first "chemo-immuno-therapy" regimen and led to substantial improvements in long term outcome of patients with both low grade and DLBCL. Until 2007, patterns of care data indicate that if you were going to get chemo for follicular lymphoma, 50% got R-CHOP, and another 25% got the same regimen without the Adriamycin which adds quite a punch in terms of side effects (R-CVP), and about 15% received rituximab alone.
6) In 2008, there was a US based study of a drug that had been floating around East Germany during the entire cold war yet remained unknown to western cancer doctors. This was the first that most US docs had heard of Bendamustine. The data was quite impressive for how effective the drug was compared to standard alternatives. In 2009, the German lymphoma study group initially presented data at ASH comparing bendamustine-rituximab to R-CHOP in follicular lymphoma. It was actually only published in Lancet last year. This showed improved efficacy with bendamustine, and far reduced side effects which led to the sweeping changes in patterns of care. Bendamustine with rituximab has upended practice patterns. In the last two years, US patterns of care data reveals approximately 1/3 of previously untreated follicular lymphoma patients needing treatment receive Bendamustine-Ritxuximab, 1/3 receive rituximab alone, and only about 1/5 receive R-CHOP in front line treatment and virtually nobody receives it following relapse. Fludarabine utilization is virtually gone (see attached slide presentation at the bottom of this post and my post on "How I treat follicular lymphoma).
7) As ASCO 2007, our lab at Stanford presented the first “pre-clinical” data showing that inhibition of B-Cell receptor signaling enzymes could have therapeutic effect in B cell malignancies. This theory was subsequently confirmed in a plenary session presention at ASH in 2008 utilizing the drug fostamatinib. The discussant at the time felt that the data met the criteria for “game-changing” and put it on his list of NHL history makers. While fostamatinib is no longer being actively developed, the proof of concept directly preceded / led to the exploration of ibrutinib and idelalisib in similar diseases. In heavily pretreated patients, both of these drugs have approximately 50% overall response rate (size criteria for response determination, many more actually shrink and benefit – just not enough to be considered “partial response”) and average a year of benefit for responding patients. Idelalisib was recently FDA approved in follicular lymphoma and we await data on ibrutinib in this population. While the impact in follicular lymphoma remains an evolving story, the impact in chronic lymphocytic leukemia and small lymphocytic lymphoma is nothing short of transformative.
8) I believe story 8 in indolent lymphoma will be “immunotherapy." Rarely a day goes by where I am not asked by a patient, “is there anything I can do to boost my immune system.” While my answer has always been, “not really” a number of very important new therapies are showing that harnessing the power of the immune system to attack cancer can be extremely powerful. Drugs have been either approved or are soon to be approved in melanoma, lung cancer, kidney cancer, and bladder cancer that help the immune system identify and destroy the cancer cells – without using chemotherapy. Some of these are antibodies that interfere with the “on/off” switches of the immune system. Others “re-program” T-cells using engineered viruses that can go absolutely crazy on B cells (see amazing video here). The most accessible and perhaps most exciting of these for patients with indolent lymphoma may very well be the combination of revlimid with rituximab. There are several very important studies that are poised to position this combination at the center of treatment pathways for patients with follicular lymphoma.
Nathan Fowler’s data from MD Anderson – link here
Nearly completed study in frontline follicular lymphoma Rev-Rituximab vs R-Chemo – link here
Open study of Rev-Ritux in relapsed follicular lymphoma – link here
I think of the combination of revlimid-rituximab (also called R2) as a road trip with a pot of coffee and a map. Rituximab helps orient the immune system to go after the cancerous b cells by coating the outside of them and serving as an alarm for the T cells (like a road map). Revlimid (lenalidomide) helps overcome what has been called T-Cell “pseudo-exhaustion” and get them to reactivate (ready for the road). B cell cancers have a remarkable ability to “put the t cells to sleep.” Whether though secretion of hormones, or actually manipulating the on/off switches of T cells, the cancerous B cells literally put the other half of the immune system into a post thanksgiving meal food coma. Revlimid acts like a cold splash of water to the face for the sleepy T cells. Not bad for a drug that really isn’t chemotherapy but is considered an “imid” for – immunomodulatory drug.
The combination has been explored in CLL. It can be so active at times that there can be problems with tumor lysis syndrome. The combination is not approved by the FDA in this setting and should be utilized very carefully due to the associated risks.
The combination has also been explored in follicular lymphoma with some pretty spectacular results… and that will be the subject of an upcoming post!
Thanks for reading
(Patterns of care data and a nice view of the Sisters volcanic range in Oregon from Mt Bachelor Ski area)
Monday, September 22, 2014
Rituximab monotherapy in follicular lymphoma
When patients are diagnosed with follicular lymphoma, the
treating doc often uses the “eye ball” test on the CT scans, blood work, and
physical exam to figure out whether or not a patient has “a lot” or “a little” follicular
lymphoma.
While the “eyeball test” is an approximation that requires
individual physician judgment (ie. subject to considerable error), such
measurements have been codified by what we call the “GELF criteria” which is a
French acronym for “groupe d’Etude des lymphomes folliculaires” (ie. French
study group of follicular lymphoma).
You are considered “low tumor burden” provided you lack any
node > 7cm, have less than three nodes areas > 3cm each, no B symptoms
(night sweats, fever, weight loss), spleen below the belly button, circulating
follicular lymphoma, or bone marrow dysfunction from involvement (and a few
others).
The distinction between “low tumor burden” and “high tumor
burden” is relevant because clinical trials often distinguish between such
patients in terms of the appropriateness of certain therapies (see: how I treat follicular lymphoma part 1 and part 2). Patients with “low tumor burden” follicular
lymphoma have been studied in studies such as “rituximab vs watch and wait” or
the Resort trial (how much rituxan alone do you need), or even the SAKK study
(some rituxan vs some plus more rituxan) whereas patients with high tumor
burden are more likely to be studied in chemotherapy type studies such as bendamustine-rituximab
vs R-CHOP type studies or perhaps other new study designs.
I wanted to focus on the “low tumor burden” population
because I was preparing a talk and thought there were a number of important
statistics that such patients should be aware of. I want to simply list them here for your
consideration. They are drawn from three main studies linked here:
Resort Trial (Induction and Maintenance vs Induction and Retreatment when needed)
SAKK Trial (Four doses in one month vs eight doses in nine months)
From the study of “rituximab vs watch and wait”
Approximately 20% of patients with asymptomatic
advanced stage disease can be followed for over 10 years without requiring
treatment
Thus far NO study has shown that starting
treatment EARLIER (ie immediately at diagnosis vs when needed) improves overall
survival (very few studies have ever tried to prove this point
Patients who undergo watchful waiting may
experience spontaneous regression in 12% of patients by two year mark evenly
split between ones that completely disappear from CT scans and ones that
partially disappear (in no case do we think the body has “cured” it, we just
can’t detect it on scan
40% of patients with low tumor burden follicular
lymphoma on watchful waiting will have growth of their lymphoma by two year
mark.
Between 80-90% of patients with low tumor burden
follicular lymphoma who receive rituximab will experience a response when
evaluated several months post treatment
Between 10-30% of patients suitable for watch
and wait yet receive rituximab will experience progression within 24 months
(partially depends on how much rituximab is given)
Despite responses seen following rituximab,
after following patients on average four years after randomization there is no
apparent difference in overall survival or rates of histologic transformation
between patients assigned to watch and wait versus rituximab (perhaps will
change when data more mature?)
The average time a between diagnosis and disease
progression when following watch and wait is approximately two years.
The patients who have most emotionally stable reaction
to their lymphoma are patients who start rituximab and then continue on
maintenance compared to those who take four doses and stop or those on watch
and wait.
From the RESORT study (Rituxan followed by rituxan maintenance
versus four doses or rituxan and rituxan re-use when needed)
In the average patient with low tumor burden
indolent lymphoma who starts rituximab (whether with maintenance or reuse) it
will work for about four years before something new is needed.
Patients who stay on maintenance rituxan are
less likely to have disease progression, but those patients who “reuse” rituxan
are often able to keep the disease under control for about same amount of time
and use less rituxan (about 75% less rituxan)
From the SAKK study (which compared four doses of rituximab
over one month versus eight doses over nine months in both previously treated
and untreated follicular lymphoma)
If you don’t respond initially to rituxan,
continuing it for four more doses doesn’t help
In previously untreated follicular lymphoma
patients who respond to rituxan and get total of eight doses, almost half have
not experienced any progression by 8 years compared to about a quarter of
patients who only get four doses
There is a trend that does not reach the level
of “statistical proof” that any patient with follicular lymphoma who gets eight
doses compared to four might have better overall survival. Caution here – not clear if this is real or
statistical chance just making it look better
Long story short, you can slice and dice this info to do just about anything you want it to mean. In my own practice, I generally start with rituximab once per week for four weeks then give one dose every other month for four more doses if I am starting rituximab alone in previously untreated patients. I would not strenuously argue with others if they did it differently. Here are a few key slides that come from the representative papers as well as a beautiful view of Mt. Washington in the Cascades east of Eugene
Long story short, you can slice and dice this info to do just about anything you want it to mean. In my own practice, I generally start with rituximab once per week for four weeks then give one dose every other month for four more doses if I am starting rituximab alone in previously untreated patients. I would not strenuously argue with others if they did it differently. Here are a few key slides that come from the representative papers as well as a beautiful view of Mt. Washington in the Cascades east of Eugene
Friday, September 19, 2014
Idelalisib (Zydelig) Update
A funny thing happened when the Europeans evaluated the same trial data that led to the approval of idelalisib in the US. They saw things differently....
Doctors and patients alike are quite interested in knowing the "package insert" for a medication. Essentially it contains the prescribing information on how to use the drug and for what conditions it is approved. This is enormously important because it often determines when an insurance company will have to pay for it to be used.
The US FDA and the European Commission on Medicinal Products look at new drugs independently. They look at all the safety of all the clinical trials and the efficacy and come to their own conclusions about when such a drug could / should be used.
The FDA took a very conservative view of the trial data and highlighted the risks and gave a fairly narrowly defined set of circumstances where the drug can be used.
In the US - the FDA has stated that it can be used in patients with CLL:
1) in combination with rituximab in patients who are not suitable for chemotherapy on account of other medical problems.
In Europe - idelalisib has been recommended for approval:
1) in combination with rituximab in patients who have had one prior line of therapy (sounds very similar to the information for ibrutinib)
2) in front line treatment for patients with 17P deletion or TP53 mutation.
2a) The best way to test for TP53 mutation linked here
2b) See my link for the new molecular markers
2c) There is a clinical trial in US utilizing idela/rtx in this same population that can be accessed through our network at these locations
The labeled indications for follicular lymphoma following two prior lines of therapy is quite similar.
The other key differences were regarding the safety of the drug. The US prescribing information highlights the risks of a variety of side effects. Things that happened to 1-2 patients (and may have due to entirely other medications) out of the 1000 treated prior to approval were listed as "black box" warnings. It appears that several of those will be stripped entirely from the European guidelines - will try to update link when it becomes available.
"package inserts" can be "living documents." They get updated as new clinical trials are released. For instance, the role for ibrutinib in patients with 17P was recently updated in the US. I expect that the package insert for both of these agents will continue to expand over time. I think the additional insight provided by our European colleagues shed new perspective on how and where we might think to use the drugs here in the US.
Thanks for reading.
Doctors and patients alike are quite interested in knowing the "package insert" for a medication. Essentially it contains the prescribing information on how to use the drug and for what conditions it is approved. This is enormously important because it often determines when an insurance company will have to pay for it to be used.
The US FDA and the European Commission on Medicinal Products look at new drugs independently. They look at all the safety of all the clinical trials and the efficacy and come to their own conclusions about when such a drug could / should be used.
The FDA took a very conservative view of the trial data and highlighted the risks and gave a fairly narrowly defined set of circumstances where the drug can be used.
In the US - the FDA has stated that it can be used in patients with CLL:
1) in combination with rituximab in patients who are not suitable for chemotherapy on account of other medical problems.
In Europe - idelalisib has been recommended for approval:
1) in combination with rituximab in patients who have had one prior line of therapy (sounds very similar to the information for ibrutinib)
2) in front line treatment for patients with 17P deletion or TP53 mutation.
2a) The best way to test for TP53 mutation linked here
2b) See my link for the new molecular markers
2c) There is a clinical trial in US utilizing idela/rtx in this same population that can be accessed through our network at these locations
The labeled indications for follicular lymphoma following two prior lines of therapy is quite similar.
The other key differences were regarding the safety of the drug. The US prescribing information highlights the risks of a variety of side effects. Things that happened to 1-2 patients (and may have due to entirely other medications) out of the 1000 treated prior to approval were listed as "black box" warnings. It appears that several of those will be stripped entirely from the European guidelines - will try to update link when it becomes available.
"package inserts" can be "living documents." They get updated as new clinical trials are released. For instance, the role for ibrutinib in patients with 17P was recently updated in the US. I expect that the package insert for both of these agents will continue to expand over time. I think the additional insight provided by our European colleagues shed new perspective on how and where we might think to use the drugs here in the US.
Thanks for reading.
Thursday, September 11, 2014
Lymphoma and Leukemia Society
I am a huge fan of the Lymphoma and Leukemia Society.
I personally support their mission every year, I've done triathlon's for Team In Training (one of the ways they raise funds) and when I had more time, I served on their board of directors for the Oregon chapter. I encourage everyone who reads this blog to find some way to get involved with them.
One of my wonderful patients has found a way to support them financially by hosting an annual BBQ / silent auction / etc. Over several years he has raised close to $100,000 on behalf of LLS.
They made a video of him and his story. I think it is really quite good. Even though it is a call for support, his experience gives me great hope. I think you will enjoy watching this four minute story.
Thanks for watching. If having difficulty loading video, watch directly on YouTube by linking here. (Seems Internet Explorer not working well, but Firefox loads well)
I personally support their mission every year, I've done triathlon's for Team In Training (one of the ways they raise funds) and when I had more time, I served on their board of directors for the Oregon chapter. I encourage everyone who reads this blog to find some way to get involved with them.
One of my wonderful patients has found a way to support them financially by hosting an annual BBQ / silent auction / etc. Over several years he has raised close to $100,000 on behalf of LLS.
They made a video of him and his story. I think it is really quite good. Even though it is a call for support, his experience gives me great hope. I think you will enjoy watching this four minute story.
Thanks for watching. If having difficulty loading video, watch directly on YouTube by linking here. (Seems Internet Explorer not working well, but Firefox loads well)
Sunday, September 7, 2014
Can CLL be cured?
Question for you -
What is better, 10+ years free of CLL in exchange for 6 months of chemotherapy or 10 years of a pill taken daily? Go one step further: what if the chemo not only got rid of the disease for 10 years but actually cured some patients?
We are incredibly fortunate that there are new therapies approved by the FDA that are non-chemotherapy based - but we should be careful before abandoning something that can be extremely effective for some patients just because it is called "chemo."
Everyone desperately wants to find a cure for CLL so we need to be vigilant and avoid excessive optimism. The idea of "curable CLL" is debatable among the researchers who study the disease. For the purposes of this post, I need to be very clear that the difference between very long term remission and cure can become a little blurry. At what point is a patient with no signs of leukemia considered "cured?"
I am always careful to define "remission" when I am in the clinic. To me, it means, "we can't see the cancer but we know that it is there." That is very different from a cure, where one would assume it isn't. The only thing that really distinguishes between the two is the test of time. How much time needs to pass before you say it is no longer a remission but indeed a cure. In CLL we have never really talked about cure before, so I guess the answer is "a long time."
When carefully identified patients are treated with FCR chemo-immunotherapy, a decent fraction of them may not have any evidence of their CLL for over a decade. Two studies have now shown statistical outcomes to suggest that some of these patients may be cured (link here and here).
Frequent readers of my blog likely know that I have periodically taken a skeptical view of the FCR regimen. The multitude of new drugs such as ibrutinib and idelalisib have forced us to fundamentally re-think the best ways to treat the disease. After the widespread introduction of bendamustine and rituximab followed by the newer agents, the enthusiasm for FCR has been steadily diminishing. Database analysis would indicate that it is only utilized in the front line management of patients with CLL in about 20-35% of patients,
I think it is human nature to embrace things that are new and exciting - especially when that means moving away from chemotherapy. Yet as pendulums swing away from FCR 14 years after it was initially introduced, we may be ignoring some of the most impressive arguments in favor of the regimen that are only just now becoming evident.
The "chemoimmunotherapy regimens" such as FCR and Bendamustine-rituxan have constituted our treatment backbone for a number of years. Please see my prior blog post about choosing between the two. With the new non chemotherapeutic targeted drugs that are coming, there is likely to be quite a "turf war" over what regimens are right in which circumstances. While the new drugs are primarily approved in patients with relapsed disease, there will be considerable interest in moving them to the front line setting. Indeed, I've already had quite a few patients ask me if starting with one of the new drugs up front makes more sense than chemotherapy. I think that in some cases the answer may be yes, in other cases no. In many cases it is too early to tell.
So where is all this going?
CLL is biologically heterogeneous. Two patients who look very similar can have very different outcomes with treatment. Understanding that biologic heterogeneity is essential if you want to make the best choices on behalf of the patient. At the extremes, I think there are some patients where we need to make every effort to give effective chemoimmunotherapy and others where starting with a targeted agent makes more sense. Between those two extremes there is a lot of uncertainty. Over the next several blog posts, I hope to make that spectrum clear.
Let me start by coming back to the question that I began this post with: If you could get six months of chemotherapy and have 10 years free of disease and not require any treatment, would that be better than taking pills every day for ten years? What if I upped the ante and asked if that same six months of therapy cured a decent proportion of molecularly defined patients? Would chemotherapy be preferable to pills in that circumstance? What fraction of patients would need to be cured? Would 20% be enough? What if it was 60%? If 80% could be cured, would that make chemotherapy better than pills that are not thought to result in cure for anyone (yet)?
Let's start by defining "cure."
When we evaluate the performance of a new drug or a regimen, we plot the efficacy on a "Kaplan Meier" curve. On the "Y axis (up and down)" is a variable such as overall survival, or progression free survival. On the "x-axis (left to right)" is time. At time point zero the curve should be at 100% but then it keeps going down every time someone has an "event" such as disease progression or death. If a disease is really bad or a treatment really ineffective, the curve goes down very quickly toward the x-axis. If a disease is mild, or the treatment very effective, the curve stays very "flat" and doesn't drop from 100 much.
People who look at Kaplan Meier curves a lot get really excited when they see a "plateau." A plateau happens when you do some sort of treatment that is likely to cure a subset of patients. As time goes on, all those patients who are not cured either relapse or die until you are left with those patients who no longer have the disease and the events stop happening. When this happens, the curve may start at 100, slowly drop down to the percentage of cured patients (20%?-40%?) and then stays flat - or reaches a "plateau." If a plateau persists with updates of the data, researchers start to ask if those patients who are no longer relapsing are cured of their disease - particularly if you test them with MRD testing and they remain negative for CLL. Of course if you follow all patients long enough, it will always go down to zero as patients die of other causes, but few studies follow patients that long and a prolonged plateau is suggestive of something very important when considering a treatment.
At ASH 2012, the MDAnderson group put out an abstract entitled, "Is CLL still incurable?" This provocative question was asked in response to an apparent plateau in their long term follow up of the original 300 patient sample treated with FCR. After following their original group of patients treated back in 2000-2003 for thirteen years, a group of them still appear to have no evidence of any active CLL. That is a very impressive result for a therapy that only lasts six months.
Many researchers however regard data from MDAnderson with a degree of skepticism. It says a lot about a patient if they get on a plane and fly down to Houston for an opinion. It says even more if they do that every month for six months to get treated. Such patients necessarily have a degree of affluence, fitness, and education that makes them different from the average CLL patient. Multiple different studies have shown that such variables strongly influence outcome. It ends up being a biased sample set. Indeed, the average age of patients in the study was 57 years old while the average age of a patient requiring treatment for CLL in the United States is typically 74 years. That is a massive difference.
I have to admit, I was somewhat dismissive of the 2012 abstract on that basis - until the Germans gave an update of the CLL8 study which compared FC (fludarabine / Cytoxan without rituximab) versus FCR and evaluated outcome on the basis of molecular risk factors. They show that after six years of average follow up, several groups of patients start to achieve a plateau. Over the ensuing two years of follow up, if a patient has not already experienced a progression, very few such patients appear likely to do so.
Is this a cure? It is still probably too early to tell for sure. All Kaplan meyer curves are prone to becoming "unstable" the farther out in time that you go. Since fewer patients of the original cohort have been followed that long, single patient changes in status can have disproportionately larger effects on the curve than happens earlier in the follow up. Furthermore, bias influences become larger if there is a subset of patients with "better" follow up data. I am very interested though to see if this curve remains flat with subsequent follow up. It appears to mirror the single center MDA experience but in a multicenter population where the data is more reliable.
So who are these patients? It is interesting to know after the fact that some patients do very well, but it is far more helpful if we know before selecting a therapy if a cure is within reach. It would likely influence how you think about treating such a patient.
I previously wrote a post about the mutation status of the B-cell receptor, so called IgVH mutation analysis. The new update from the German CLL8 study did an impressive job looking at the multitude of new prognostic markers in CLL. They showed that patients with unmutated IgVH (bad), had a substantially higher rate of other negative prognostic markers (such as NOTCH, SF3B1, TP53 mutations) compared to those patients with mutated IgVH (better) to the tune of about 43% vs 24%. We also know from recent publications that newer technologies (next generation sequencing) can find a much higher frequency of adverse markers as it is a lot more sensitive to lower levels. These lower levels appear to be very important because they appear to confer similar overall prognosis. I wouldn't be surprised if "next-gen" could identify an even larger split between the IgVH mutated and unmutated groups.
Turns out that those patients with the mutated IgVH did MUCH better long term than those with unmutated IgVH. Indeed if the plateau in their data holds, it may occur in as many as 60% of patients with mutated IgVH whereas no clear plateau is seen in patients with unmutated IgVH.
Is 60% chance of long term disease control (maybe cure) good enough to take FCR? It is abundantly clear that not all patients are sufficiently "fit" to receive FCR and NCCN guidelines draw the line for full dose FCR at age 70. Are there other variables that you can look at to remove "bad actors" within this subset of better risk patients? If you focus on the "good risk" patients with IgVH mutated BCR and then exclude the patients with 17P or 11Q or bad molecular markers such as TP53, NOTCH1, SF3B1 mutations what is the long term disease control rate in that group - certainly a lot higher than 60% - probably closer to 80-90% chance of long term disease control - possible cure in this subset of patients.
These findings are very similar to those seen by the MD Anderson group. In their study just under 40% of patients had not experienced any progression at the 10 year point. If you look at the associated table however, it was strongly skewed in favor of those patients IgVH mutated BCR 49% vs 11%. They did not have access to FISH or molecular markers so that information is not available. I find it compelling though that the numbers were very similar between the two studies. It is also interesting to note that the change in the shape of the curve occurred right around the 6-7 year mark in both data sets. This implies that if you fit this highly favorable profile and make it that far out, your chance or progression over the next few years seems very unlikely.
The point I wish to make is this. The new drugs are very "sexy." It is very appealing to think of taking a non-chemo pill rather than chemotherapy, but if I am ever a patient with CLL and IgVH mutated BCR lacking 17P/11Q/TP53/NOTCH1/SF3B1 abnormality, I will absolutely take chemoimmunotherapy because there is a VERY GOOD chance I will not have to think about my CLL for many years, and based upon these two studies, I think he plateau in the survival curve is very provocative.
This blog post was originally intended to also talk about what I would do if I had 17P deletion, IgVH unumtated BCR, or other high risk markers but the post became too long and unwieldy. I will tackle those possibilities in upcoming posts.
Thanks for reading.
What is better, 10+ years free of CLL in exchange for 6 months of chemotherapy or 10 years of a pill taken daily? Go one step further: what if the chemo not only got rid of the disease for 10 years but actually cured some patients?
We are incredibly fortunate that there are new therapies approved by the FDA that are non-chemotherapy based - but we should be careful before abandoning something that can be extremely effective for some patients just because it is called "chemo."
Everyone desperately wants to find a cure for CLL so we need to be vigilant and avoid excessive optimism. The idea of "curable CLL" is debatable among the researchers who study the disease. For the purposes of this post, I need to be very clear that the difference between very long term remission and cure can become a little blurry. At what point is a patient with no signs of leukemia considered "cured?"
I am always careful to define "remission" when I am in the clinic. To me, it means, "we can't see the cancer but we know that it is there." That is very different from a cure, where one would assume it isn't. The only thing that really distinguishes between the two is the test of time. How much time needs to pass before you say it is no longer a remission but indeed a cure. In CLL we have never really talked about cure before, so I guess the answer is "a long time."
When carefully identified patients are treated with FCR chemo-immunotherapy, a decent fraction of them may not have any evidence of their CLL for over a decade. Two studies have now shown statistical outcomes to suggest that some of these patients may be cured (link here and here).
Frequent readers of my blog likely know that I have periodically taken a skeptical view of the FCR regimen. The multitude of new drugs such as ibrutinib and idelalisib have forced us to fundamentally re-think the best ways to treat the disease. After the widespread introduction of bendamustine and rituximab followed by the newer agents, the enthusiasm for FCR has been steadily diminishing. Database analysis would indicate that it is only utilized in the front line management of patients with CLL in about 20-35% of patients,
I think it is human nature to embrace things that are new and exciting - especially when that means moving away from chemotherapy. Yet as pendulums swing away from FCR 14 years after it was initially introduced, we may be ignoring some of the most impressive arguments in favor of the regimen that are only just now becoming evident.
The "chemoimmunotherapy regimens" such as FCR and Bendamustine-rituxan have constituted our treatment backbone for a number of years. Please see my prior blog post about choosing between the two. With the new non chemotherapeutic targeted drugs that are coming, there is likely to be quite a "turf war" over what regimens are right in which circumstances. While the new drugs are primarily approved in patients with relapsed disease, there will be considerable interest in moving them to the front line setting. Indeed, I've already had quite a few patients ask me if starting with one of the new drugs up front makes more sense than chemotherapy. I think that in some cases the answer may be yes, in other cases no. In many cases it is too early to tell.
So where is all this going?
CLL is biologically heterogeneous. Two patients who look very similar can have very different outcomes with treatment. Understanding that biologic heterogeneity is essential if you want to make the best choices on behalf of the patient. At the extremes, I think there are some patients where we need to make every effort to give effective chemoimmunotherapy and others where starting with a targeted agent makes more sense. Between those two extremes there is a lot of uncertainty. Over the next several blog posts, I hope to make that spectrum clear.
Let me start by coming back to the question that I began this post with: If you could get six months of chemotherapy and have 10 years free of disease and not require any treatment, would that be better than taking pills every day for ten years? What if I upped the ante and asked if that same six months of therapy cured a decent proportion of molecularly defined patients? Would chemotherapy be preferable to pills in that circumstance? What fraction of patients would need to be cured? Would 20% be enough? What if it was 60%? If 80% could be cured, would that make chemotherapy better than pills that are not thought to result in cure for anyone (yet)?
Let's start by defining "cure."
When we evaluate the performance of a new drug or a regimen, we plot the efficacy on a "Kaplan Meier" curve. On the "Y axis (up and down)" is a variable such as overall survival, or progression free survival. On the "x-axis (left to right)" is time. At time point zero the curve should be at 100% but then it keeps going down every time someone has an "event" such as disease progression or death. If a disease is really bad or a treatment really ineffective, the curve goes down very quickly toward the x-axis. If a disease is mild, or the treatment very effective, the curve stays very "flat" and doesn't drop from 100 much.
People who look at Kaplan Meier curves a lot get really excited when they see a "plateau." A plateau happens when you do some sort of treatment that is likely to cure a subset of patients. As time goes on, all those patients who are not cured either relapse or die until you are left with those patients who no longer have the disease and the events stop happening. When this happens, the curve may start at 100, slowly drop down to the percentage of cured patients (20%?-40%?) and then stays flat - or reaches a "plateau." If a plateau persists with updates of the data, researchers start to ask if those patients who are no longer relapsing are cured of their disease - particularly if you test them with MRD testing and they remain negative for CLL. Of course if you follow all patients long enough, it will always go down to zero as patients die of other causes, but few studies follow patients that long and a prolonged plateau is suggestive of something very important when considering a treatment.
At ASH 2012, the MDAnderson group put out an abstract entitled, "Is CLL still incurable?" This provocative question was asked in response to an apparent plateau in their long term follow up of the original 300 patient sample treated with FCR. After following their original group of patients treated back in 2000-2003 for thirteen years, a group of them still appear to have no evidence of any active CLL. That is a very impressive result for a therapy that only lasts six months.
Many researchers however regard data from MDAnderson with a degree of skepticism. It says a lot about a patient if they get on a plane and fly down to Houston for an opinion. It says even more if they do that every month for six months to get treated. Such patients necessarily have a degree of affluence, fitness, and education that makes them different from the average CLL patient. Multiple different studies have shown that such variables strongly influence outcome. It ends up being a biased sample set. Indeed, the average age of patients in the study was 57 years old while the average age of a patient requiring treatment for CLL in the United States is typically 74 years. That is a massive difference.
I have to admit, I was somewhat dismissive of the 2012 abstract on that basis - until the Germans gave an update of the CLL8 study which compared FC (fludarabine / Cytoxan without rituximab) versus FCR and evaluated outcome on the basis of molecular risk factors. They show that after six years of average follow up, several groups of patients start to achieve a plateau. Over the ensuing two years of follow up, if a patient has not already experienced a progression, very few such patients appear likely to do so.
Is this a cure? It is still probably too early to tell for sure. All Kaplan meyer curves are prone to becoming "unstable" the farther out in time that you go. Since fewer patients of the original cohort have been followed that long, single patient changes in status can have disproportionately larger effects on the curve than happens earlier in the follow up. Furthermore, bias influences become larger if there is a subset of patients with "better" follow up data. I am very interested though to see if this curve remains flat with subsequent follow up. It appears to mirror the single center MDA experience but in a multicenter population where the data is more reliable.
So who are these patients? It is interesting to know after the fact that some patients do very well, but it is far more helpful if we know before selecting a therapy if a cure is within reach. It would likely influence how you think about treating such a patient.
I previously wrote a post about the mutation status of the B-cell receptor, so called IgVH mutation analysis. The new update from the German CLL8 study did an impressive job looking at the multitude of new prognostic markers in CLL. They showed that patients with unmutated IgVH (bad), had a substantially higher rate of other negative prognostic markers (such as NOTCH, SF3B1, TP53 mutations) compared to those patients with mutated IgVH (better) to the tune of about 43% vs 24%. We also know from recent publications that newer technologies (next generation sequencing) can find a much higher frequency of adverse markers as it is a lot more sensitive to lower levels. These lower levels appear to be very important because they appear to confer similar overall prognosis. I wouldn't be surprised if "next-gen" could identify an even larger split between the IgVH mutated and unmutated groups.
Turns out that those patients with the mutated IgVH did MUCH better long term than those with unmutated IgVH. Indeed if the plateau in their data holds, it may occur in as many as 60% of patients with mutated IgVH whereas no clear plateau is seen in patients with unmutated IgVH.
Is 60% chance of long term disease control (maybe cure) good enough to take FCR? It is abundantly clear that not all patients are sufficiently "fit" to receive FCR and NCCN guidelines draw the line for full dose FCR at age 70. Are there other variables that you can look at to remove "bad actors" within this subset of better risk patients? If you focus on the "good risk" patients with IgVH mutated BCR and then exclude the patients with 17P or 11Q or bad molecular markers such as TP53, NOTCH1, SF3B1 mutations what is the long term disease control rate in that group - certainly a lot higher than 60% - probably closer to 80-90% chance of long term disease control - possible cure in this subset of patients.
These findings are very similar to those seen by the MD Anderson group. In their study just under 40% of patients had not experienced any progression at the 10 year point. If you look at the associated table however, it was strongly skewed in favor of those patients IgVH mutated BCR 49% vs 11%. They did not have access to FISH or molecular markers so that information is not available. I find it compelling though that the numbers were very similar between the two studies. It is also interesting to note that the change in the shape of the curve occurred right around the 6-7 year mark in both data sets. This implies that if you fit this highly favorable profile and make it that far out, your chance or progression over the next few years seems very unlikely.
The point I wish to make is this. The new drugs are very "sexy." It is very appealing to think of taking a non-chemo pill rather than chemotherapy, but if I am ever a patient with CLL and IgVH mutated BCR lacking 17P/11Q/TP53/NOTCH1/SF3B1 abnormality, I will absolutely take chemoimmunotherapy because there is a VERY GOOD chance I will not have to think about my CLL for many years, and based upon these two studies, I think he plateau in the survival curve is very provocative.
This blog post was originally intended to also talk about what I would do if I had 17P deletion, IgVH unumtated BCR, or other high risk markers but the post became too long and unwieldy. I will tackle those possibilities in upcoming posts.
Thanks for reading.
Wednesday, September 3, 2014
Predicting outcome to therapy
There is an interesting article out today via pubmed that talks about the ability to predict response to chemotherapy in CLL (summary editorial here, actual article here).
As I've been talking about quite a bit, it involves knowing the detailed molecular genetics associated with an individual patient which you can now test for.
I wanted to briefly point out the difference between "prognostic" and "predictive" biomarkers. First of all, a biomarker is any sort of test such as a blood test, type of scan, etc that correlates with a biologic behavior. Ideally those biomarkers can help influence treatment decisions to make more personalized treatment decisions.
"Prognostic biomarkers" give a general sense of how a patient is likely going to do with their disease. In CLL, you might look at things like ZAP-70 or CD38 to estimate how a patients disease is going to behave over time. You might say that they are "high risk patients" or "low risk patients" for progression / survival etc. but it doesn't necessarily tell you if a specific therapy is going to be useful.
"Predictive biomarkers" on the other hand help with specific therapeutic decisions. They can be either positive or negative predictors. Patients with 17P deletion for instance do not experience durable benefit from FCR therapy so in essence it "predicts" an inadequate response to this treatment. Patients with TP53 or BIRC3 mutations have similar negative outcomes therefore these are considered "negative predictive biomarkers."
On the other hand, some biomarkers may be "positive predictive biomarkers." I am VERY interested to find out if CLL patients with NOTCH1 mutations derive unique benefit from new research medications that target that mutation specifically. In other cancers like melanoma or lung cancer, the presence of BRAF or EGFR mutations are required before you can even use certain meds that have very high levels of activity in those specific settings but are useless or even harmful if a patient lacks the mutation.
This particular CLL paper looks at the German CLL8 study which compared FC to FCR and was the first paper to establish a survival benefit in CLL. It offers a wealth of new insight into the newer prognostic and predictive biomarkers that have emerged in CLL. We find out that patients with SF3B1 mutations respond well, but experience more rapid relapse. Patients with NOTCH1 mutations don't derive benefit from the addition of rituximab to FC. Patients with 17P deletion / TP53 mutation and IgVH unmutated CLL have shorter survival following FCR therapy compared to patients lacking these abnormalities.
Both the technical article and the associated editorial are worth the read.
Thanks
As I've been talking about quite a bit, it involves knowing the detailed molecular genetics associated with an individual patient which you can now test for.
I wanted to briefly point out the difference between "prognostic" and "predictive" biomarkers. First of all, a biomarker is any sort of test such as a blood test, type of scan, etc that correlates with a biologic behavior. Ideally those biomarkers can help influence treatment decisions to make more personalized treatment decisions.
"Prognostic biomarkers" give a general sense of how a patient is likely going to do with their disease. In CLL, you might look at things like ZAP-70 or CD38 to estimate how a patients disease is going to behave over time. You might say that they are "high risk patients" or "low risk patients" for progression / survival etc. but it doesn't necessarily tell you if a specific therapy is going to be useful.
"Predictive biomarkers" on the other hand help with specific therapeutic decisions. They can be either positive or negative predictors. Patients with 17P deletion for instance do not experience durable benefit from FCR therapy so in essence it "predicts" an inadequate response to this treatment. Patients with TP53 or BIRC3 mutations have similar negative outcomes therefore these are considered "negative predictive biomarkers."
On the other hand, some biomarkers may be "positive predictive biomarkers." I am VERY interested to find out if CLL patients with NOTCH1 mutations derive unique benefit from new research medications that target that mutation specifically. In other cancers like melanoma or lung cancer, the presence of BRAF or EGFR mutations are required before you can even use certain meds that have very high levels of activity in those specific settings but are useless or even harmful if a patient lacks the mutation.
This particular CLL paper looks at the German CLL8 study which compared FC to FCR and was the first paper to establish a survival benefit in CLL. It offers a wealth of new insight into the newer prognostic and predictive biomarkers that have emerged in CLL. We find out that patients with SF3B1 mutations respond well, but experience more rapid relapse. Patients with NOTCH1 mutations don't derive benefit from the addition of rituximab to FC. Patients with 17P deletion / TP53 mutation and IgVH unmutated CLL have shorter survival following FCR therapy compared to patients lacking these abnormalities.
Both the technical article and the associated editorial are worth the read.
Thanks
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.
Tuesday, June 3, 2014
Management of CLL in Elderly CLL - ASCO Presentation
I gave a talk with the Clinical Care Options Team at ASCO this year. I am still trying to figure out what content to add to the blog and am hoping some find this useful. Since the slides are already made, thought I might as well just put them in here. If this works, I will add others.
The topic was management of older individuals with CLL. There is really a distinction between the age groups and the average patient with CLL will fall into this category.
Hopefully the links work.
Enjoy
The topic was management of older individuals with CLL. There is really a distinction between the age groups and the average patient with CLL will fall into this category.
Hopefully the links work.
Enjoy
Friday, May 16, 2014
ASCO 2014
Another ASCO season is upon us. Seems the highlights are likely to be many of the new immunotherapies in various solid tumors. These drugs are really cool and do a fantastic job tricking the immune system to go after cancer. Merck, BMS, and Genentech are leading the way in the solid tumors.
CLL and NHL promises to be "HOT" again. Someday the ASCO organizers will move us out of our small closet where we present the data in Chicago. At the last ASH meeting, one of the CLL sessions filled up the original presenting room AND four different big overflow halls. As the session started, we shuttled around like cattle with many of the most important research physicians trying to find a place to sit.
Below are links to projects that I am a part of this year. ASCO limits you to only TWO first author presentations. For me, they both relate to CLL this year with GS-9973 (Syk inhibitor) and another idelalisib presentation. I was able to be senior author on several other presentations including obinutuzumab, lenalidomide, and CD-79/22 Antibody drug conjugates.
Overall a very productive year and many exciting things to come.
Independent evaluation of ibrutinib efficacy 3 years post-initiation of monotherapy in patients with chronic lymphocytic leukemia/small lymphocytic leukemia including deletion 17p disease.
A phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of idelalisib (GS-1101) in combination with bendamustine and rituximab for previously treated chronic lymphocytic leukemia (CLL).
Second interim analysis of a phase 3 study evaluating idelalisib and rituximab for relapsed CLL.
Health-related quality of life (HRQL) impact of idelalisib (IDELA) in patients (pts) with relapsed chronic lymphocytic leukemia (CLL): Phase 3 results.
Obinutuzumab (GA101) 1,000 mg versus 2,000 mg in patients with chronic lymphocytic leukemia (CLL): Results of the phase II GAGE (GAO4768g) trial.
Efficacy of idelalisib in CLL subpopulations harboring del(17p) and other adverse prognostic factors: Results from a phase 3, randomized, double-blind, placebo-controlled trial.
MAGNIFY: A phase 3B, randomized trial of lenalidomide plus rituximab induction and maintenance therapy followed by lenalidomide single-agent versus rituximab maintenance in patients with relapsed/refractory indolent non-Hodgkin lymphoma (NHL).
Effect of clinical NGS-based cancer genomic profiling on physician treatment decisions in advanced solid tumors.
Phase 2 trial of GS-9973, a selective Syk inhibitor, in chronic lymphocytic leukemia (CLL).
Preliminary results of a phase II randomized study (ROMULUS) of polatuzumab vedotin (PoV) or pinatuzumab vedotin (PiV) plus rituximab (RTX) in patients (Pts) with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL).
CLL and NHL promises to be "HOT" again. Someday the ASCO organizers will move us out of our small closet where we present the data in Chicago. At the last ASH meeting, one of the CLL sessions filled up the original presenting room AND four different big overflow halls. As the session started, we shuttled around like cattle with many of the most important research physicians trying to find a place to sit.
Below are links to projects that I am a part of this year. ASCO limits you to only TWO first author presentations. For me, they both relate to CLL this year with GS-9973 (Syk inhibitor) and another idelalisib presentation. I was able to be senior author on several other presentations including obinutuzumab, lenalidomide, and CD-79/22 Antibody drug conjugates.
Overall a very productive year and many exciting things to come.
Independent evaluation of ibrutinib efficacy 3 years post-initiation of monotherapy in patients with chronic lymphocytic leukemia/small lymphocytic leukemia including deletion 17p disease.
A phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of idelalisib (GS-1101) in combination with bendamustine and rituximab for previously treated chronic lymphocytic leukemia (CLL).
Second interim analysis of a phase 3 study evaluating idelalisib and rituximab for relapsed CLL.
Health-related quality of life (HRQL) impact of idelalisib (IDELA) in patients (pts) with relapsed chronic lymphocytic leukemia (CLL): Phase 3 results.
Obinutuzumab (GA101) 1,000 mg versus 2,000 mg in patients with chronic lymphocytic leukemia (CLL): Results of the phase II GAGE (GAO4768g) trial.
Efficacy of idelalisib in CLL subpopulations harboring del(17p) and other adverse prognostic factors: Results from a phase 3, randomized, double-blind, placebo-controlled trial.
MAGNIFY: A phase 3B, randomized trial of lenalidomide plus rituximab induction and maintenance therapy followed by lenalidomide single-agent versus rituximab maintenance in patients with relapsed/refractory indolent non-Hodgkin lymphoma (NHL).
Effect of clinical NGS-based cancer genomic profiling on physician treatment decisions in advanced solid tumors.
Phase 2 trial of GS-9973, a selective Syk inhibitor, in chronic lymphocytic leukemia (CLL).
Preliminary results of a phase II randomized study (ROMULUS) of polatuzumab vedotin (PoV) or pinatuzumab vedotin (PiV) plus rituximab (RTX) in patients (Pts) with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL).