Wednesday, December 30, 2015

Rituxan Maintenance: Shorter is Better?

The current Journal of Clinical Oncology has the results of a study of Rituxan Maintenance in Follicular Lymphoma. In some ways, the study helps clarify the best way to use Rituxan Maintenance, though it raises some questions as well.

(We wouldn't really expect any kind of clear answer when it comes to treating Follicular Lymphoma, would we?)

The study is published in the article called "Rituximab Maintenance for a Maximum of 5 Years After Single-Agent Rituximab Induction in Follicular Lymphoma: Results of the Randomized Controlled Phase III Trial SAKK 35/0." Medical journal articles are pretty good about using straightforward titles, and this one is no different:

The article reports the results of a phase III clinical trial that looked at short-term and long-term use of Rituxan Maintenance after Rituxan induction therapy. In other words, patients were first given Rituxan for four weeks, and then if it seemed to work, they were split into two groups, with some getting Rituxan Maintenance every two months for 4 doses (or 8 months), and some getting it every two months for up to 5 years (or until they had an event). The measurement here was Event Free Survival (EFS), which is a little less common than many FL trials, which often use Progression Free Survival (which measures the disease getting worse) or Overall Survival (which measures death from any cause). EFS is a little broader, and the "events" can include death or disease progression, but also things like a secondary cancer, unacceptable toxicity, or using other treatments related to cancer.

The authors say that, while there are lots of studies that look at Rituxan Maintenance, those studies use lots of different time periods. Their aim here was to compare two different time periods directly to see which one worked best.

The plan had been to stop the study at about 5 years, with the expectation that there would have been 99 events to count. However, they stopped when they had reached 95 events, because the events stopped coming. I think that's good news -- both types of Maintenance seemed to work well.

In the end, though, they found that longer isn't necessarily better -- there was no real difference in Event Free Survival between the two groups -- neither approach seemed better than the other. There was also no difference in Overall Survival between the two groups, though the researchers want to continue looking at data for a longer time to see if that remains true.

However, the long-term group had a Progression-Free Survival that was much longer than the short-term group. (They kind of down-play this, though it seems significant to me. It's probably because their primary measure was EFS, and because the OS was the same, so it doesn't really matter on its own.)

The researchers point out several important things in their conclusion:

First, if there is no difference in EFS or OS between the two, then short-term seems the better option. It will be less expensive and cause less toxicity.

Second, there were more patients with "adverse events" in the long-term arm than the short-term. These include things like infections, which makes sense, since Rituxan kills off the B cells that fight infections.

Finally, they point out some of the limitations of their study, including their not measuring quality of life. It is possible that, for lots of reasons, long-term Maintenance could result in lower quality of life.

So in the end, the results are mixed. If anything, the study seems to back up the idea that Rituxan Maintenance can be a good thing (though they weren't trying to prove that it is better than waiting until Rituxan is needed before giving it), and the idea that short-term Maintenance is just as good as long-term, and maybe better, if you consider the cost.

Sorry, folks -- no Big Answers here. But I still feel OK knowing that even a small piece of the puzzle is being put into place.

Friday, December 25, 2015

Merry Christmas

Today is Christmas for a large part of the world. I know that not everyone who reads the blog celebrates this day, so for those of you who do, I say Merry Christmas.

And for all of you, whether you celebrate or not, I offer another traditional greeting for the day: Peace on Earth.

It seems like more than ever, we could use some peace on our planet. For those of us with Follicular Lymphoma, or any type of cancer, we have enough inner turmoil. We don't need all of that outer turmoil, too. It won't go away just by wishing you peace, but maybe all of our good feelings will add up and make a small difference together. Just a little less turmoil in our own tiny little parts of the world.

I don't know how many of you celebrate Christmas, but I do know you come from lots of countries besides my own, and I love seeing comments that identify where you are from. It's easy to see how different we are, just from the name of a country. But it's so much easier to see how much we are the same. Every one of us has had the same experience -- being told (or having a loved one be told) that we had cancer. There isn't much worse than hearing those words, and it's not a happy thing to have in common with so many other people.

So lets all try to spend just one day thinking about all of the other things we have in common with the people we encounter today, whether we're celebrating Christmas or not. Everyone hurts in some way, whether it's from cancer or not. But everyone celebrates those small joys, too. So find some way to celebrate with them. Or, even better -- give them some reason to feel just a little spark of joy.

Contribute to some peace on earth.

Have a good day, everyone.

Sunday, December 20, 2015

ASH: Ofatumumab

Still looking at some of the research that was presented at ASH this year.

This one is called "Phase II Trial of Ofatumumab (OFA) in Previously Untreated Follicular Non-Hodgkin Lymphoma (NHL): CALGB 50901 (Alliance)."It looks at Ofatumumab as a first treatment for Follicular Lymphoma.

Ofatumumab is a lot like Rituxan -- a monoclonal antibody that targets the protein CD20 on the surface of B cells. The key difference is that Ofatumumab fully humanized. Rituxan was developed using mouse cells, but Ofatumumab was developed using human cells. The thinking is that this might cut down on some of the allergic reactions that people have when they are first given Rituxan. (I had chills and a lot of itching.)

In the ASH study, the researchers try to compare Ofatumumab to Rituxan in patients who haven't been treated yet and who have low or intermediate risk FL. Since this is a comparison to Rituxan, they were looking to show that Ofatumumab would do a better job than Rituxan, so they considered a repsonse rate below 60% to essentially be a failure, and over 80% to be a great success.

Since it was a phase II study, it was fairly small, with just 51 patients. Some received a dose of 500mg, and others 1000mg, all once a week for four weeks, and then four more times every 8 weeks. For the patients with the 1000mg dose, the Overall Response Rate was 86.7%, and 1 year Progression Free Survival was almost 100%. For the patients with the 500mg dose, the OR was 60%, and the 1 year PFS was 85.1%.

The researchers conclude that Ofatumumab was effective and well-tolerated. The side effects were not too far out of line with Rituxan. However, they also concluded that  "Activity appears to be in a range comparable to that reported with other anti-CD20 antibodies in this setting, suggesting that significant improvements in efficacy will require novel combinations." In other words, it did about as well as Rituxan, but not much better than Rituxan, so it seems unlikely to replace it. Maybe it will be used with some other treatments in ways that are more effective than Rituxan.

Ofatumumab isn't the first attempt to replace Rituxan, and so far, no monoclonal antibody has shown to be better than it. I find that fascinating. There has to be something about the mechanism of monoclonal antibodies that has a limit, which is who combining it with something else might be the way to go. we've known for a long time that Rituxan works well, and CHOP and other chemos work well, but it's when they are put together that they really shine. Research into which combinations work best to attack cancer from different angles seems to be a very effective strategy.

Ofatumumab was actually in the news for something else recently, too. In late November, the company that makes Ofatumumab announced that it was stopping a phase III trial before it was done because the early results showed that it wasn't going to be much of an improvement over Rituxan. This was a little different from the ASH study -- it compared Ofatumumab and Rituxan directly, but involved patients who had previously been treated with Rituxan. But the big picture was still the same thing -- it's hard to do better than Rituxan.

If monoclonal antibodies do have a long-term future in Follicular Lymphoma treatment,  it looks like it will be in combination with other. newer treatments.

Monday, December 14, 2015

More on CAR-T for FL

I got a nice comment on my last post (about the CAR-T study at ASH), and I thought it was worth sharing here because sometimes things get lost in the comments section. The comment is from Ben, who has had some success with CAR-T.


Hi Bob,

Thanks for covering this topic. This is the second time I am commenting on one of your posts. The first time was when you mentioned Revlimid/Rituxan, the so-called "R-Squared", as I was being treated with it.

And now you've done it again. I can provide more insight to you and anyone else reading this, as I myself am a CAR-T patient. I was infused with my "re-engineered" T cells in July, and was discharged in August after some unfortunately rather severe CRS (I needed to be in ICU for 5 days).

However, my follicular lymphoma is now in a Partial Remission (PR), with minimal activity showing in my most recent PET/CT. This is after getting minimal response from the aforementioned R-squared, and a subsequent HYPER-CVAD regimen, before entering the CAR-T trial.

We've since recommended CAR-T to another fNHL patient we learned about through a family member. He was diagnosed only a year ago, but got only a minimal response from R-CHOP and R-Bendamustine, and his lymphoma got progressively more active. He may have even started transforming.

This fellow was also infused over the summer, and now has a Complete Remission (CR), and did not have any of the CRS symptoms that I experienced. He was even able to do this as an out-patient at his facility, since his fever remained low and only lasted a couple of days.

So for anyone reading this, please know that another option exists for follicular lymphoma patients who are no longer getting good responses from their current therapies, which is of course often the nature of this disease.

I had mentioned in my first R-Squared post almost a year ago that I was considering starting a blog as you have done, and you had encouraged me to do so. I unfortunately never got around to it, but now I am re-considering. Hopefully this time I'll get around to it. I'll keep you posted...

Thanks so much for your continued coverage of current events re fNHL!


-- Ben 


 There are a few things worth mentioning here:

First, thank you, Ben, for the comment, and I hope you don't mind my highlighting it here.

Second, I think it's really valuable to hear stories from people who have actually had the treatment. I have been fortunate enough to not need treatment for several years now, so I can't talk much about any of these new treatments, so I really appreciate Ben sharing his story.

I especially appreciate him talking about the side effects he experienced. I sometimes ignore that part of the research I describe. I get so excited about results sometimes that I don't give the bad part of the research. And every treatment does have some kind of side effects. in Ben's case, it was a bad bout of CRS, which is Cytokine Release Syndrome. Basically, with CRS, T-cells release a protein called Cytokines, which can cause an inflammation response in the body. The CRS can be fairly mild, and not too dangerous, making the patient feel really horrible, but not doing much damage. But it can also be pretty severe, as it seems to have been with Ben, who was Intensive Care for a few days.

That's really important to remember (and for me to remember when I write about these things) -- every treatment has some side effects, and it's important to understand them fully.

Finally, Ben mentions blogging. It's not for everyone, but if you have something to share, I think you should try writing (that includes you too, Ben). I like this introduction to blogging from The Minimalists, posted about a month ago. It gives some basic general steps to getting started.  I get lots of comments from people who were glad they found Lympho Bob (and I love reading those comments), and it kind of lets me know that people are hungry for information and stories about Follicular Lymphoma. So if you are moved, pick a platform and a blog name and start writing.

Thanks again for the comment, Ben.

Saturday, December 12, 2015

ASH: Early CAR-T results for Follicular Lymphoma

Before I get to the cancer stuff, a couple of personal items:

First, I had my annual physical exam a couple of weeks ago. This wasn't an oncologist appointment, just my regular doctor, and she was pleased overall, especially with the 20 or so pounds I have lost since the summer. Everything looked good. I got my blood test results yesterday, and everything looks fine there (other than a little blood cancer, of course). My cholesterol is still low, and my vitamin D is high. My B12 is "on the lower end of normal," so I'm going to start a supplement. But otherwise, I think I have retaned my title as the healthiest cancer patient in town.

Second, today is my dog's birthday. She's nine years old.

She's a standard schnauzer, but unlike George, she's useless when it comes to sniffing cancer. But we love her anyway.


Now, on to the Follicular Lymphoma stuff.

The pharmaceutical company Novartis announced at the ASH conference that they are seeing good results with their treatment CTL019, a Chimeric Antigen Receptor T cell therapy, or CAR-T therapy.

CAR-T therapies are one of those treatments that are getting lots of cancer people excited these days. They seem to be working on lots of different types of cancer, liquid and solid, but seem especially suited to blood cancers like Follicular Lymphoma.

CAR-T is really cool. It's a type of immunotherapy, so it uses the body's own immune system to fight the cancer. Usually, cancer works because the body can't recognize that it doesn't belong there, so the usual immune system defenses (like T cells) just look the other way when they encounter a cancer cell.

CAR-T therapy makes sure that doesn't happen. T cells are removed from the body and given a reprogramming so they recognize the cancer cell as something to be destroyed. In the case of CTL019, the T cells recognize CD19, a protein on the surface of the cancerous cells (kind of like Rituxan recognizes CD20).  Once it recognizes the CD19 and hooks on to the cancer cell, it beats the crap out of it. says the CAR-T cells act like the antibodies that are naturally present in our blood, and expand to become a "living drug." They are effective as long as they stay in the blood and keep doing their job (which might be the tricky part). You can read more about CAR-T therapies for lymphomas at

The Novartis folks are working on a phase II clinical trial involving 15 patients with DLBCL and 11 with Follicular Lymphoma. All of the patients have advanced disease and "have not responded to standard treatment."

The Overall Response Rate for CTL019 was 47% for DLBCL patients, and 73% for the Follicular Lymphoma patients, which is pretty good. Apparently, they plan to apply for FDA approval in 2017; I assume they will applying for accelerated approval, since they are only on a phase II trial at the moment and it seems a little early in that trial, and even that might only be for DLBCL. The FDA gave CTY019 a "break through" designation for ALL last year.

One problem with all of this -- we're talking about a personalized treatment, so each batch will need to be made specially for each individual patient. Only your own T cells can fight your cancer. So it will be expensive, at least at first -- about $450,000 per treatment. (Yikes.) That price will come down eventually, but it's hard to say when, and how much.

But it's a really promising concept. We'll keep an eye out for future news about it.

Monday, December 7, 2015

Dr. Cheson's ASH preview

Well, the ASH conference is almost over now -- it finishes up tomorrow. But there is still lots to talk about from the conference.

It might seem like it's too late at this point, but here is an ASH preview from Lymphoma Rock Star Dr. Bruce Cheson from Georgetown University.

Dr. Cheson is always entertaining, and this video is no exception -- watch until the end for his surprise guest.

The video is a general preview of things that he is looking forward to from the conference, so he talk about more than just Follicular Lymphoma. But he does mention FL, specifically some of the studies that looked at Ibrutinib in various combinations for FL. (I think CLL is, once again, generating most of the excitement this year, but that's OK. We'll take what we can get.)

We'll see some press releases soon from university hospitals and pharmaceutical companies bragging about their ASH results. I'll pass anything along that looks interesting.

Enjoy Dr. Cheson's video.


OK, I had saved the link to Dr. Cheson's video, and now I'm having trouble accessing that link, so I don't know if the one above will work for everybody. But if you do a quick Google search for "Bruce Cheson ASH," you should find it (it's from Medscape). If you still have trouble accessing the video, or if you are looking for the text for translation purposes, Medscape was good enough to provide a transcript, which I am pasting below:

Hey, there. This is Bruce Cheson from Georgetown University Hospital, speaking to you for Medscape Hematology. It's that time of the year again: the American Society of Hematology (ASH) Annual Meeting preview for 2015.
I guess the people at ASH feel obliged to give us a few chemotherapy studies. There will be the third iteration of RCHOP-14 vs RCHOP-21 in diffuse large B-cell lymphoma. Will it be any better this time around?
As you know, there are two basic types of diffuse large B-cell lymphoma. There is the ABC, or activated B-cell type, and the germinal center type. The activated B-cell type traditionally does not do as well with standard therapy. However, certain drugs are preferentially active in this subtype, such as ibrutinib, lenalidomide, and bortezomib. At ASH, we're going to see the first results in large cell lymphoma of RCHOP with or without bortezomib in this population. Will it improve outcomes? I will not spoil the suspense.
We're also going to see results of bortezomib as either consolidation or maintenance following aggressive chemotherapy for untreated mantle cell lymphoma. There are interesting data there as well.
But what everybody wants to hear about are the novel targeted drugs. They're not even so novel anymore; there are so many of them out there. They want to hear about the non-chemotherapy approach for patients with lymphoma and chronic lymphocytic leukemia (CLL). There will be some single-agent data, including ibrutinib vs chlorambucil—the RESONATE-2 trial.
They're always trying to beat up chlorambucil. It's like the sick puppy out there that always gets drugs approved because everything is better than chlorambucil. We'll see in this trial with untreated CLL patients that the results are extremely impressive.
We'll see the results of ibrutinib in relapsed refractory follicular lymphoma. There was a previous abstract that showed a response rate of 28%, but there may be implications of a dose-response effect. Stay tuned for that one. We'll see the results of ibrutinib vs temsirolimus in mantle cell lymphoma, and we will see the results of venetoclax, or ABT-199, in CLL and non-Hodgkin lymphoma.
And now, we're into the second- and third-generation drugs. We're going to see some very exciting data on ACP-196, the new BTK inhibitor, in patients with relapsed refractory CLL. We will also see the idelalisib frontline data in chronic lymphocytic leukemia. There are lots of interesting single agents, but that's not where the action is, my friends.
The action is in combinations. We will see ibrutinib and rituximab in untreated follicular lymphoma. We're going to see a regimen that we developed in Alliance with R-squared: rituximab plus lenalidomide plus ibrutinib in untreated follicular lymphoma. We'll see various agents in combination with bendamustine, rituximab, bendamustine and rituximab, and we will also see venetoclax and the second-generation anti-CD20 antibody obinutuzumab. Promising data.
Speaking of obinutuzumab, it was approved for CLL on the basis of the CLL11 trial, in which it was rituximab/chlorambucil vs obinutuzumab/chlorambucil vs chlorambucil. Both combination arms were better than chlorambucil, but the obinutuzumab arm appeared to be superior to the rituximab arm. Okay, that's nice, but why don't we use a regimen in a study that's actually used to treat patients in this country? Well, we'll see preliminary data from the GREEN trial, in which there will be, as one of the arms, bendamustine and obinutuzumab. Let's see what happens with that study.
The excitement continues to mount for another class of drugs: the checkpoint inhibitors. There are lots of these in clinical trials. We saw at the last ASH meeting some astounding data with nivolumab in relapsed/refractory Hodgkin lymphoma and with pembrolizumab in a similar population. We will see at this meeting an update of those data. Do they really hold up over time? Let's hope so.
Again, combinations are where it's at. There will be a presentation on brentuximab vedotin (Adcetris®), the anti-CD30 antibody drug conjugate, plus a checkpoint inhibitor in relapsed/refractory Hodgkin's lymphoma. Those data will be of particular interest to me because I'm getting ready to activate a study of brentuximab vedotin plus nivolumab in patients with untreated Hodgkin disease. We'll also see data on checkpoint inhibitors in the treatment of patients with that really awful condition, Richter transformation.
I hope to see you in Orlando. Perhaps you'll also see this friend of mine. Excuse me while I move this camera. There he is. He's vacationing for the winter there, so Mr Mick and I will be running into you down there. Have a good ASH meeting, for those of you who go. For those of you who don't, we'll have a wrap-up session with Medscape Hematology afterwards.
Thank you very much. See you there. Bruce Cheson, signing off.