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 In CLL/SLL I think rituximab monotherapy is mostly outdated as of late 2014.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

Building a better CD20 antibody?

Rituxan was an unbelievable breakthrough drug in the treatment of all sorts of B cell lymphoid cancers (CLL / NHL) as well as a lot of autoimmune conditions to boot.  At the time it was put into the patients, the idea of using therapeutic antibodies to treat cancer had not really been done.  Skeptics abounded.  As soon as it was tried, it was immediately obvious that there had been a breakthrough.  One theme I continually revist is that the immune system can be a very powerful cancer fighter when properly directed.  Rituxan was one of the first ways to focus this aspect of the immune system to fight off lymphoma.

You make antibodies to fight off the flu, e. coli, etc.  Instead of the naturally occuring variety of antibodies, rituxan is a synthesized antibody designed to fight off B-Cells (ie. the cells that give rise to lymphoma and CLL).  Rituxan binds onto the outside of the cancer cell (on a marker known as CD20) and has about 4-5 ways to kill the cell. 

15 years later, hundreds of thousands of patients have been treated.  As a single agent nearly 70% of patients with untreated follicular lymphoma will respond and in many cases the responses can be very durable.  In most situations where giving chemotherapy for CLL/NHL is good, giving it together with rituxan is better.  Not bad for a drug that has few of the side effects of traditional chemotherapy!

Not long after Rituxan demonstrated its value, lots of science went toward understanding why rituxan does or doesn't work.  With the accumulated knowledge, different companies have sought to make a better version of the drug.

Ofatumumab was the next CD20 antibody to be approved.  The main improvements in ofatumumab was more sturdy binding to CD20, binding at a different location on CD20, and a better job "fixing complement."  Complement is a set of "executioner proteins" that get recruited from the circulation when there is enough antibody bound to the outside of a cell.  "Fixing complement" just means it does a better job attracting those proteins to bind to the outside of the cell and punch holes through the membrane.

GA-101 is an ant-CD20 antibody currently in clinical trials in both CLL/NHL.  GA-101 (aka obinutuzumab) does several things new.  It binds to CD20 in a different orientation.  Imagine an antibody like the letter "Y"  The top of the "Y" is the little "grabber" part that identifies its target while the bottom part of the "Y" sticks out and alerts the immune system.  GA-101 binds more vertically which sticks the action end out there better for the rest of the immune system to see.  Rituxan binds more flat to the cell and the action end sort of gets burried on the surface of the cell.  GA-101 also has a more flexible "hinge region" (where the "Y" splits) which is supposed to help bring together the different proteins better.  GA-101 also "engineers out" the complement activity and instead "engineers in" better ADCC.  ADCC (antibody dependent cellular cytotoxicity) is the term that describes when a "killer cell" attackes a target cell because it is coated with antibody.  Finally there is a somewhat poorly characterized process by which antibodies can cause direct cell killing.  This is supposedly enhanced by antibodies known as "Type 2" antibodies (not really worth explaining this one, except that Rituxan / Ofatumumab are Type 1)

So far, there are not a lot of studies that clinically compare the different anti CD20 antibodies head to head.  Ofatumumab initially tried to get an FDA approval in follicular lymphoma patients considered refractory to Rituximab.  Results didn't really impress all that much.   Based upon FDA approval strategies, it also tried to gain approval in CLL patients were refractory to fludarabine AND campath (or bulky fludarabine refractory where campath doesn't work well).  This worked better and led to the approval of ofatumumab in CLL.  The drug has not yet gained a high utilization in CLL. 

GA-101 is owned by Genentech and with Rituxan likely to go off patent in the future, they are working hard to make GA-101 the standard-bearer.  At ASH 2011 there were a lot of clinical papers with GA-101 but the most notable was a head to head comparison of GA-101 to Rituxan in patients with relapsed follicular lymphoma.  GA-101 had twice the response rate though the duration of response was not a lot different.   Hard to say if that is a glass half full or half empty - trying to extrapolate to different NHL / CLL situations it may depend on the context.  Increasing a response rate in DLBCL might be very important whereas PFS prolongation may be more important in follicular lymphoma.  Furthermore, we should probably consider that the activity of one antibody may be better in CLL while a different set of characteristics may make a different antibody better in follicular lymphoma.

Perhaps the cleanest way to figure if a drug is active is in the previously untreated patients.  Ofatumumab was studied in this setting and reported at ASH.  GA-101 has been evaluated in front line CLL and I found this news story anecdote to be pretty exciting though you must be very careful with anecdotes and no formal reports are available.  Rituximab was evaluated in relapsed patients way back in the early 2000s with pretty modest single agent activity, though improved with higher dosing of the drug or greater frequency (another way of increasing the dose). 

You can bet you will hear a lot about "better versions of rituxan."  Look for head to head comparisons or results that are substantially different from prior series.  Rituxan was definitely a pioneer, but I fully expect we will be able to build a better treatment.  Here is a review published in ASH that goes over a lot of the information above and describes some of the other strategies to improve upon rituxan.