Monday, November 10, 2014

Rituximab monotherapy in CLL

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

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

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 In CLL/SLL I think rituximab monotherapy is mostly outdated as of late 2014.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

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

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

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

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

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

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

So what are the key new data sets?

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

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

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

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

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

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

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

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

To summarize:

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

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

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

Thanks for reading

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 (expecting updates at publication)

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)