CAR-T for Transformed FL Gets Priority Review from FDA

The FDA has granted a faster-than-usual review for yet another Follicular Lymphoma treatment. This one is for KTE-C19, a type of CAR-T therapy, and it is for transformed Follicular Lymphoma, as well as Diffuse Large B Cell Lymphoma (DLBCL) and Primary Mediastinal B Cell Lymphoma (PMBCL).

(We're taking a quick break from ASCO Previews for this one. The review is based on results that were presented at a different convention -- the AACR last month. The results come from the phase 2 ZUMA-1 trial, though a few other different aspects of that trial will be discussed at ASCO.)

CAR-T therapies, in general, involve removing T cells from the patient. T cells are part of the immune system, and their job is to find invaders (like cancer cells) and get rid of them. The problem is, T cells can't recognize cancer cells. So after the T cells are removed, they are changed so they will recognize the cancer cells, and then they are put back into the patient so they can do their job.

Now, KTE-C19 works the same way. It gets its name from its target: the protein called CD19, which appears on the surface of the cancer cells being targeted (and lots of other cells). When those new, changed T cells find the cancer cells, they destroy them, the way they were supposed to.

The Zuma-1 trial looked at two groups of patients, one of them including transformed FL patients. Out of 101 total patients, 24 of them had transformed FL or another type of lymphoma. In that group, the Overall Response rate was 83%, and the Complete Response rate was 71%. After 8.7 months, the OR rate remained high -- 67%, and the CR stayed at 61%.

Patients in the trial were chemorefractory, meaning chemotherapy was no longer working for them. They had had a median of 3 treatments before the trial.

Side effects included things like anemia, decreased white blood cell counts of different types. Several patients had Cytokine Release Syndrome, which occurs when the body is overwhelmed with an immune response. There were 4 fatalities during the trial, 3 of them related to the treatment. Most of the  non-fatal side effects were reversed within a month.

Based on these results, the FDA is granting Priority Review (as it did with Copanlisib earlier this month).  This means that the FDA plans to take action on approval within 6 months, and that it considers the treatment important enough (and doing something that other treatments aren't doing) to speed it along a few months early.

If this is approved, it will give us another tool for transformed Follicular Lymphoma -- we can never have too many.

CAR-T is definitely hot this year at ASCO, with trials and experiments targeting a bunch of different cancers. I know there are a few folks who read regularly who have some experience with it, and who are very excited about CAR-T. Let's hope this one continues to give us all something else to be excited about.

anemia (43%), neutropenia (39%), decreased neutrophil count (32%), febrile neutropenia (31%), decreased white blood cell count (29%), thrombocytopenia (24%), encephalopathy (21%), and decreased lymphocyte count (20%). - See more at: http://www.targetedonc.com/news/ktec19-granted-priority-review-by-fda-for-nonhodgkin-lymphoma#sthash.schjRozT.dpuf

The 8.7-month ORR rate was 67 percent, with a CR rate of 63 percent. - See more at: http://www.curetoday.com/articles/agent-granted-priority-review-to-treat-nonhodgkin-lymphoma#sthash.V9EN38YB.dpuf

ASCO: Lenalidomide plus Obinutuzumab in Relapsed FL

Another ASCO preview.

This time, a look at the results from phase I and phase II trials for Lenalidomide plus Obinutuzumab.

This seems like a natural pairing. Lenalidomide is one of the ingredients in  in the R-squared combination that has so many FL experts so excited (Lenalidomide also goes by the name of Revlimid, and combining it with Rituxan gives us R-squared).

Obinutuzumab is a kind of Rituxan substitute. Like Rituxan, it targets the CD20 protein on B cells. Unlike Rituxan, it is humanized -- basically, Rituxan is made from mouse cells, and Obinutuzumab is made from human cells, which may cut down on the allergic reactions that some patients have with Rituxan (including me).

So the Lenalidomide plus Obinutuzumab combination makes sense, given how successful the Lenalidomide plus Rituxan combination works.

This fairly small study (just 36 patients) was divided into two parts. All of them had relapsed Follicualr Lymphoma (a treatment had worked, but the FL had returned).

In phase I, 6 FL patients helped to determine dose escalation -- how much Lenalidomide could be taken and still be both safe and effective. After that was figured out, in phase II, the other 30 patients were given that full amount, along with the Obinutuzumab.

Results were excellent -- 100% of patients showed a response, with 78% of them getting a Complete Response.

Side effects were manageable, and included fatigue, diarrhea, and rash, as well as neutropenia (low white blood cells that can lead to infection).

Longer term, with a median follow up of 14 months, 10 of the 36 patients had progressed. The researchers estimated that the Progression Free Survival rate at 24 month will be 61%. 

So overall, this seems like an effective and safe combination. The researchers are looking at the successful patients to see if there are any biomarkers that will help identify which other patients might have success with this combination. They also say that this combination is being studied as an initial treatment for FL patients, too.

I'll keep looking for more good FL news in the ASCO abstracts.

ASCO: Copanlisib for Follicular Lymphoma

It's that time of year! ASCO abstracts are out!

In early June every year, the American Society of Clinical Oncology (ASCO) holds its annual meeting. It's a big meeting, meant for clinical oncologists -- the people that we see in their offices -- so the research that gets presented is usually pretty practical. It's a meeting for oncologists of all specialties, so there aren't always as many Follicular Lymphoma presentations as there are at a conference like ASH, which focuses on blood cancers. But because it's a big meeting, the presentations are usually significant.

I like to preview some of the more interesting sessions, looking at the abstracts for stuff that gets me excited. Once the conference happens, pharmaceutical companies and universities will start to send out press releases, bragging about their stuff (good clinical trial results, for example). Sometimes, the news is so good, they start talking about it weeks before the meeting.

And that happened this year (sort of). There will be a session called "Copanlisib in Patients with Relapsed or Refractory Follicular Lymphoma." That's good stuff, but even better is the news that the FDA has granted Priority Review to Copanlisib, based on the clinical trial results that are going to be discussed at ASCO.

So let's look at the ASCO abstract first. Copanlisib is a PI3K inhibitor.There are lots of different inhibitors out there for cancer, and for FL. Haters hate, as they say, and inhibitors inhibit -- they keep something important from happening in a cell. Different inhibitors focus on different things.

PI3K inhibitors focus on the PI3K enzyme, which is needed for a cell to do some important things like grow normally. When there is a problem with the pathway, the cell grows uncontrollably (resulting in cancer). By inhibiting the enzyme, the uncontrollable growth is stopped.

(There's more to it than that -- it involves something called the PI3K/AKT/mTOR pathway, which is really important to cell growth. But we'll just keep it simple. Let's all agree that this is a really important thing to target with an inhibitor.)

Another really important thing about Copanlisib that makes this a big deal is that PI3K actually comes in a few different forms (called isotopes). Most inhibitors only target one of those forms -- Copanlisib targets two of them.

So, the ASCO presentation is going to discuss the results of a phase II clinical trial. A total of 141 patients were in the trial, but the 104 with Follicular Lymphoma are the real focus. These patients were relapsed/refractory (their last treatment didn't work, or stopped working), and had at least 2 prior treatments.

The results were impressive -- Overall Response was 58.7% (14.4 % had a Complete Response and 44.2% had a Partial Response), with another 33.7% having stable disease. The median duration of response was just over 1 year.

Side effects were "manageable," and included diarrhea, reduced neutrophils, fever and fatigue. There were 6 deaths in the group, with "3 attributed to Copanlisib" (a lung infection, a respiratory failure, and a blood clot).

Even with those problems, the researchers point out that Copanlisib did not show some of the problems that other PI3K inhibitors have shown, including infections, colitis (inflammation of the colon), and hepatic enzymopathy (problems with liver enzymes).


Which brings us to the big news about the FDA granting Copanlisib a Priority Review designation. This designation means that the FDA plans to take action within six months (a regular review takes 10 months). Getting the designation means that the FDA thinks it is important that the treatment becomes available quickly, because it's doing something that other treatments aren't doing.

In this case, it seems like the combination of effectiveness and safety is what makes this a better option than some others that are available. I'm guessing that the lack of problems that get seen in other PI3K inhibitors was a big factor.

The question that I had (and that you might have too) is something like "Wait -- didn't it say that 3 people died?" Yes, and that does seem to be downplayed in the reports that I have seen about the FDA approval (though it is certainly mentioned in the ASCO abstract).

It's important to remember that this is a fairly narrow FDA approval, and that is still pending -- it is only for FL patients with refractory/relapsed disease, and who have had at least 2 prior treatments. In other words, this is potentially being approved for patients who are running out of options. So the deaths among trial participants might not be quite as significant. If this were an approval for a first-line treatment, there would be much more attention paid to those unfortunate "adverse events."

So, there's your first ASCO preview. I'll keep looking at the abstracts for more interesting news. Stay tuned.

Impact of Treatment in Long-Term Survival of FL

The journal PLOS ONE just published an article called "Impact of Treatment in Long-Term Survival Patients with Follicular Lymphoma: A Spanish Lymphoma Oncology Group Registry." As the article title implies, it looks at FL patients from a lymphoma registry in Spain, and tries to assess factors related to long-term survival.

I'll be honest -- I've kind of struggled with this article. I've read it over a few times, and I'm still not sure what to get out of it. I thought about just not writing about it (I'd rather do that than write something I wasn't comfortable with), but I decided the things that I do understand are important, and the lesson I get is worth sharing.

The study looks at a large group of 1074 Follicular Lymphoma patients in Spain who were diagnosed between 1980 and 2013. But it also looks at a smaller group of those patients who were still alive over 10 years after they were diagnosed, to see what those patients had in common.

There is a lot of statistical analysis in the article (which might be one of the things that gives me trouble), but the important statistic (mentioned in the title) is Overall Survival.

Looking at their large sample of 1000+ patients, they found that the Overall Survival was over 20 years.

If nothing else, that is important: OS for this group was over 20 years.

To give that some context, when I was diagnosed 9 years ago, I read that the OS was 8-10 years. That actually was probably low -- it might have been 12-15 years at best. But for this group, it was over 20 years. As a whole, Follicular Lymphoma patients are living longer. That should give us all something to celebrate.

Now, researchers tried to answer the question "Why do some patients live longer than others?"

To do this, they looked at 166 patients in their study who had been diagnosed over 10 years ago and were still alive. It's an important grouping. The larger study involved patients who were diagnosed before Rituxan was introduced in Spain (in 2004), and we know that Rituxan has played a HUGE role in making our lives better. So looking at more recent patients who have had long-term success makes a lot of sense.

They looked at a bunch of stuff to try to figure out what makes these patients have a longer OS. They found that the following were statistically significant:stage

• age under 60 years at diagnosis
• low FLIPI (they used FLIPI, and not FLIPI2 or m7-FLIPI, which are much newer)
• normal Beta2 microglobulin (found in blood -- higher than normal levels are bad)
• no B symptoms at diagnosis (things like fever and night sweats that might indicate a more aggressive form of FL)
• combines treatments with Rituxan and anthracyclines (the patient had R-Chop or R-Bendamustine)

So, statistically, patients who survived more than 10 years were more likely to have had one or more of those things.

But let's keep things in perspective -- those are statistical measures only, and don't predict an individual patient's disease or survival.

And to me, none of them are very surprising. Low FLIPI and  lower stage are, by definition, measures of a less aggressive FL. Same with no B symptoms and normal Beta2 microglobulin. These things are not news.

What I did find interesting was some of the factors that do NOT correlate with longer Overall Survival:

• gender
• number of nodal areas affected (more isn't necessarily bad)
• bone marrow involvement
• origin (whether it started in lymph nodes or organs)
• LDH levels (lactate dehydrogenase -- high levels are a problem)
• presence of bulky mass (nodes are really big)
• or transformation to an aggressive lymphoma

That first group included a bunch of things that I expected to be there. But this group includes things that I didn't expect to be there. The big lesson, for me as a patient, is to be really careful looking at statistics.

I've said before that I'm not a big fan of statistics. Every time my disease has gotten me depressed, it's because I focused too much on statistics, and where my place was within those numbers. And these statistics are a good explanation of why that happened.

It would be easy for someone to look at that first list and think they were in trouble, maybe regretting that they decided to watch and wait or take just Rituxan instead of R-CHOP. Or that their FLIPI score was too high. But, again, those things don't really tell us anything about an individual patient.

When I do look at statistics, I try to focus on the good numbers -- the things that make me happy. That's probably not fair, and it certainly isn't the way a statistician or scientist would do things. Fortunately for me, I am not a statistician or scientist, so I can look at numbers any way I want.

And the good number in this study says that our Overall Survival is trending up. People with Follicular Lymphoma are living longer with their disease. That's something we should all be hopeful about.

And the title of this article tell us why -- it's about the impact of treatment. Rituxan seems to be the common factor here, though they also tie it to Rituxan + chemotherapy. But again, the big lesson  here: Treatments are getting better. And they'll keep getting even better.

As I said, there's a lot more that could be analyzed in this study, I know. there's more to it than just saying we're living longer. Adn if anyone wants to point out other lessons to be learned, please do so.

But I'm sticking with what makes me happy. It's what I need today.

Does Chemo Still Have a Role in FL?

Healio posted a short debate a few days ago, asking the question: Does chemotherapy still have a role in follicular lymphoma treatment?

The idea behind the debate is to look at where we are with Follicular Lymphoma treatments.  Newer treatments approved n the last few years are not traditional chemotherapies. Chemo tends to take a broader approach to killing cancer cells, killing some normal healthy cells as well. Newer treatments are more targeted, and focus their efforts on the cancer cells themselves, and mostly leave healthy cells alone. If we have so many of these newer, targeted treatments available, is it time to stop using traditional chemo? Does chemo still have a place in treating FL?

Answering "Yes" is Dr. Stephen M. Ansell of the Mayo Clinic in Minnesota. He points out that clinical trials of R-squared (Rituxan + Revlimid/Lenalidomide), this non-chemo combination got great results (overall response of 90% of patients, with a complete response for 63%). However, that trial had only a small number of high-risk patients, the kind that chemo will benefit. Comparing results from trials means paying close attention to which type of FL patients were being treated (those with lower risk, slow-growing FL, versus those with higher-risk, extensive, aggressive FL). It's hard to do a real comparison, otherwise.

In other words, for a fairly large part of the Follicular Lymphoma population, chemotherapy might be a better choice.

Answering "No" is Dr. Bruce Cheson of Georgetown University. He points to the many new treatment options that have become available in the last few years (or are in trials) that are more focused, very effective, and with fewer side effects. He, too, talks about R-squared, and uses it an example of a focused, non-chemotherapy treatment that has great results. And there are others, too, like possible improvements on Rituxan such as Obinutuzumab, pathway treatments like Ibrutinib, Idelalisib, and Venetoclax, CAR-T therapies, and others. With those targeted treatments available, there's no reason to put patients through traditional chemo.

So where do I stand on this?

Well, if you've read Lympho Bob for a while, you know how fond I am of  Dr. Cheson. And you also know that I get frustrated when I see clinical trials for traditional chemo, because, as a patient, I'd rather see resources being put into testing newer treatments, because they are without a doubt our future.

With that said, I have to say there's still a place for chemotherapy in Follicular Lymphoma, mostly for the reasons that Dr. Ansell points out. Again, as a patient, I like to keep my options open. There is still plenty of evidence that R-CHOP, for example, is a great option for transformed FL. And as I have seen in lots of patients, more aggressive types of FL (even if they haven't transformed) seem to do better with chemo. I want R-CHOP and Bendamustine available to me if I ever need them.

Now, can I see a time in the future when they aren't necessary any more? Sure. But that means more clinical trials that test newer treatments on more aggressive types of FL, ideally in trials that put those newer treatments up in direct comparison to older chemos that we know will work. But that means chemo needs to stick around until we know for sure that we don't need them any more.

So it's my hope that one day they'll be gone. But for now, I like having those options -- I like having those arrows in my quiver (as I have liked to say for a long time).

Of course, any treatment choices are best discussed with your doctor. The good news is, with lots of treatment options available, it could be a nice long conversation.

Maintenance Rituxan Improves Overall Survival in FL?

New research published in the European Journal of Cancer suggests that Rituxan Maintenance after chemotherapy might improve Overall Survival in Follicular Lymphoma patients.

The idea of Rituxan Maintenance has been controversial since it was approved. The idea is that, after getting some kind of treatment (usually chemotherapy of some sort), the patient is given Rituxan at regular intervals for a period of time -- usually 2 years. The additional Rituxan is supposed to clean up any remaining FL cells and keep the disease away for longer than the initial treatment.

Previous studies of Rituxan Maintenance have shown mixed results -- there seems general agreement that Maintenance improved Progression Free Survival, and some suggest that it improves Overall Survival, though others say the opposite, and it does not improve OS. Maintenance also has its problems -- because it suppresses the immune system, it can raise the risk of infections. And because it is given for a long time, it increases the chances of Rituxan Resistance -- basically, Rituxan just stops doing its job if it is used too much.

So there is some debate about whether or not Maintenance Rituxan is worth doing. As with most Follicular Lymphoma treatments, Overall Survival is an important factor -- if it's not going to keep us alive any longer than other treatments, do the positives outweigh the negatives?

So that's where this new study comes in.

The authors of the study did a IPD meta-analysis -- an Individual Participant Data study. Basically, that means that they didn't look at any new patients. Instead, they went back to the researchers from 7 previous studies of Rituxan Maintenance in FL, and asked to look at their original data. This allowed the researchers of the new study to have a much wider group of patients to look at.

The 7 combined groups involved studies that looked at the same thing -- some patients were given Maintenance after their first treatment, and some were not. The new study looked at 2315 patients -- 1145 received Maintenance, and 1170 did not. Most of them received either chemotherapy (CHOP, CVP, or Fludarabine) or Chemoimmunotherapy (R-CHOP, R-CVP, or R-Fludarabine). Overall, patients who received Maintenance had a better Overall Survival -- 12 years, instead the 11.5 years for patients who did not receive Maintenance.

But the breakdown of different categories makes things less clear. Patients who had Maintenance after one initial treatment of chemo or R+chemo (not just straight chemo) had an Overall Survival about the same as patients who didn't receive Maintenance. But patients who received Maintenance after a second round of R + chemo had a 30% higher OS than those who didn't receive Maintenance.

Complicating things further is that the meta-analysis confirmed that Maintenance raises the risk for infections. And the researchers also point out that the analysis doesn't include any studies that looked at Bendamustine + Rituxan as a pre-Maintenance treatment (important since Bendamustine has become a pretty popular form of chemo for FL patients).

Despite all of that, the authors of the article recommend that all Follicular Lymphoma patients receive Rituxan Maintenance.

The site Cancer Therapy Advisor ran a good summary and commentary about the study (and was very helpful to me in understanding some of the EJC article). It ends with some comments from an oncology researcher, who questions whether the study justifies that all FL patients should get maintenance.

I would tend to agree. (Not that I'm an oncologist or researcher or scientist.) As a patient, I don't think the analysis would have been enough for me to justify Maintenance in my situation (Rituxan but no chemo). That's easy to say, looking back 7 years later, though even back then, I had accepted my oncologist's idea that we should do the minimum necessary, and keep the long road ahead in mind.

Of course, the point of all of this is to not listen to me when you need to make these kinds of decisions, but to listen to your doctor, and know enough to have an informed conversation about it.

Unfortunately, we still have no easy answers when it comes to decisions about Follicular Lymphoma.

Lymphoma Canada's Watch and Wait Guide

A few days ago, I came across a really nice link on Twitter about Watching and Waiting.

(Did I mention I'm on Twitter now? Yes, I did. Follow me at @Lymphomaniac if you're on Twitter, too.)

It's a pamphlet put out by Lymphoma Canada on Watching and Waiting. I have to say, I think it's the best patient-focused explanation of Watching and Waiting that I've seen. I wish I had been given something like this when I was diagnosed. I remember my first frantic internet search of "Follicular Lymphoma," trying to figure out what kind of treatment I could expect. One of the options was "watch and wait," and the idea of doing nothing seemed so ridiculous to me that I didn't bother to try to understand it.

That's why I like this pamphlet -- it explains in simple terms what the strategy is and why it's worth considering.

But what I like most is that it encourages patients to be proactive. It's easy to think that Watching and Waiting means doing nothing. That's a mistake. We really do need to watch.  The pamphlet includes a place to track your symptoms -- writing down physical changes that you can share with your doctor. (The danger, of course, is that you can become obsessed with even the smallest of changes. That gets better with time, in my experience.)

I also really like the list of lifestyle changes that you can make -- eating better, exercising, reducing stress, doing things that make you happy -- and, of course, taking the time to learn more about Follicular Lymphoma so you can make an informed choice about treatment when the time comes. (Like reading Lympho Bob). Those kinds of active changes might help you feel more in control of your life, at a time when it feels like you're not in control.

(And I really appreciate the line "There's no evidence to suggest that you can do anything to keep your FL from progressing." That's important, too -- taking care of yourself is important, and as you are reading around, learning about Follicular Lymphoma, you might find something that promises a "miracle cure" or some way of keeping your Follicular Lymphoma from getting worse. Don't believe it. Eat better, exercise, and stop smoking because it will help you feel better, physically and psychologically. But don't expect any of it to cure you.)

So if you are recently diagnosed, and been told to Watch and Wait, then consider reading the pamphlet. Even if you've been doing it for a while, take a look -- it's a good reminder to take care of yourself and be proactive.

As for the rest of you, you might want to look at some of the other publications that Lymphoma Canada offers. Good stuff, especially if you're from Canada.