Tazemetostat: Official FDA Alert

The big news in my inbox this week was the official FDA Alert for Tazemetostat. 

Tazemetostat had been voluntarily pulled from the market a couple of months ago by its manufacturer after results from a trial showed that there were concerns about patients developing new cancers. The news from the FDA gives more detail about that.

Tazemetostat had been given accelerated approval by the FDA, based on results from a phase 2 trial. It is an EZH2 Inhibitor, meaning it stops or inhibits an enzyme called EZH2, controlled by the EZH2 gene, which is part of process in calls that keeps them from dying as they normally would. About 20% of Follicular Lymphoma patients are effected by this issue with EZH2, and Tazemetostat was the first treatment that specifically targeted EZH2. That was enough to have the FDA give accelerated approval, which means patients could start taking Tazemetostat outside of a trial while the larger phase 3 trial went on to confirm the results of the phase 2 trial. 

But even  when they grated accelerated approval, the FDA was aware of potential issues with secondary cancers. About 1.7% of patients in the trial had developed a new cancer.

The FDA's alert gets into more detail about this. During the phase 3 trial, the rate of new cancers went much higher, with 18 of 318 patients (about 5.7%) developing new cancers, some as soon as 7.5 months after they began treatment, though most developed them 1-3 years after beginning treatment. 

Most of the new cancwrs were Myelodysplastic Syndrome and Acute Myeloid Leukemia, though there were some other blood cancers as well. 

The phase 3 trial isn't taking new patients, but it will remain open so doctors can follow up on long-term side effects of the patients in the trial.

Obviously, there is lots of bad news all around, but most especially for the patients in the trial who developed new cancers. The rest of the patients in the trial will also have to deal with the uncertainty of long-term side effects. And the rest of us have one less treatment to rely on.

The good news, if we can still see good news, is that things were handled as well as they could be, with the trial sponsors shutting it down as soon as they could, and then making sure they are following up with the patients in the trial and making sure they are taken care of. Let's all hope they are doing OK.

I think it's very important to state, though, that this doesn't mean we shouldn't take part in clinical trials. 

It's a natural reaction to read something like this and get nervous about serious side effects. But that's going to be the case no matter what treatment we end up taking. It's worth a conversation with your oncologist about whether or not a trial is right for your situation. I talk about trials with my oncologist at least every other visit, so I know what 's available.

Trials are the only way new treatments can become available. There is no other way. I remember very early on, soon after I had been diagnosed, someone in the online support group that I belonged to said that patients who agreed to be a part of a clinical trial are "heroes." I agree. 

If you are still concerned about clinical trials, or even if you just have questions about them, the Follicular Lymphoma Foundation has a webinar coming up on Tuesday, May 26, called "What No-one tells you about clinical trials and why it matters for your care."  It's going to be an excellent webinar. Click on the link to read more about it and register. 

More coming soon. Those ASCO abstracts must be just about ripe. 

 

Treatment Selection in R/R Follicular Lymphoma

The oncology website OncLive has another of their interesting video series on Follicular Lymphoma. They post these every few months -- a small panel of experts discussing issues related to FL. A lot of times, they discuss current treatments. I find it helpful to hear different Lymphoma specialists talk about how they handle particular situations, and explain their reasoning. 

The current video series is called "Optimizing Sequencing Strategies in R/R Follicular Lymphoma," though so far they only have one video posted. It's called "Navigating Treatment Selection in R/R Follicular Lymphoma," and as the title suggests, the Lymphoma experts talk about some of the factors that they consider when they are deciding on treatment for a patient who has Refractory or Relapsed disease (that is, the treatment they already had stopped working or didn't work at all).

The experts are Dr. Loretta Nastoupil from Southwest Oncology in Colorado, and Dr. Amitkumar Mehta from the University of Alabama - Birmingham. This is just the first part of a longer conversation, but they still had some good things to say.

Their focus here is on how they make decisions about which treatments to consider for a R/R FL patient. Dr. Nastoupil lists a few factors that she considers. She points out that FL is a very heterogeneous disease -- each patient is different. She says she sees patients in their 30s up to their 80s. Those groups will have very different goals. Some patients are extremely fit, with few comorbidities or other health issues to consider, which some are very frail. Some may have received single agent Rituxan (like me) while others had aggressive treatment that may have caused additional health issues. And of course, there is the issue of patient preference. Some patients want an aggressive treatment that gives them a chance at a very long remission. Others might prioritize a less aggressive treatment that does not affect their day-to-day lives as much but also is likely to mean treatment will be necessary within a few years. All of those factors make it hard say that there is an ideal second treatment.

Dr. Mehta briefly discusses the treatment landscape. He points out that two approved treatments have been pulled from the market for different reasons (PI3K inhibitors and Tazemetostat), but that some newer treatment regiments are also very promising. (He teases two of them, and says they will be discussing them later, probably in another video in the series. I assume they are Epcoritimab + R-squared and Tafasitamab + R-squared.) He says that in choosing a treatment, he tries to balance several factors -- how effective the treatment is, what kinds of side effects can be expected, and how those things  fit with a patient's individual goals. 

(I always like when Lymphoma experts make a priority of patient goals.) 

The rest of the series should be very good. It's not necessarily a presentation of anything new. That's usually how these video series work. It's more of  summary of where we are. I think that's really valuable, too.

One more thing that's worth pointing out. Dr. Mehta makes a comment about patient survival. He said when he was in training, they used to say that FL patients had a 10-15 year median survival. (He must be young. It was 8-10 years when I was diagnosed.) But he says that FL patients these days will probably have a "normal life span." Think about it. If the typical FL patient is 60-65 years old, and FL has a median Overall Survival of 20 years, that puts you right into the average lifespan of someone in the U.S.

And for you younger folks, remember that "median" means the midpoint. So if the median OS for FL is 20 years, that means half of FL patients will live longer than 20 years. I was diagnosed at 40. I fully expect to live to a normal life span. Dr. Mehta attributes this to having more and more effective treatments for R/R FL than we had in the past.

I've mentioned this before, and it's worth mentioning again.  Several years ago, I had a reader tell me that her oncologist said "If we can keep an FL patient alive for 5 years, we can keep them alive for 50." It's the same logic as Dr. Mehta's. The number of available treatments these days is so much greater than when I was diagnosed 18 years ago. We have options. And we have even more options being developed all the time.

That's what I like most about these videos. They give me hope. 

No More Tazemetostat

The news came out this week that the makers of Tazemetostat will no longer offer this treatment to patients, including patients with Follicular Lymphoma. There are too many concerns about patients developing new, different cancers.

They made an announcement about a month ago that they were stopping a clinical trial that was testing it, and now they have decided to just pull it from the market completely.  

Tazemetostat is an EZH2 inhibitor. It works by inhibiting or stopping an enzyme called EZH2, or Enhancer of Zeste Homolog 2." This enzyme is controlled by the EZH2 gene. EZH2 keeps tumors growing, so when it's not doing its job, it needs to be inhibited -- stopped by Tazemetostat. About 20% of FL patients have an issue with their EZH2, though it can also be effective on patients that don't have that particular mutation.  

Tazemetostat was approved by the FDA in 2020 based on its ability to help that 20% of FL patients -- it was the first treatment that successfully helped that group of patients. The FDA approval was accelerated, meaning it was approved based on a small phase 2 clinical trial, rather than the usual, larger phase 3 trial. The accelerated approval, as always, is based on continuing research. A larger phase 3 confirmatory trial must be run to make sure the treatment is as effective and as safe as the smaller trial suggested.

Accelerated approval can be great. But sometimes the phase 3 trial that comes after approval shows some problems. And in this case, that problem was that the treatment may be causing secondary cancers. I haven't seen anything about how many patients developed the new cancers, or what kind of cancers. 

If you're wondering what happens to the patients in a cancelled trial: in this case, they will continue to receive treatment. The trial (called SYMPHONY-1) involved 2 groups. One received R-Squared (Rituxan and Revlimid) + Tazemetostat, and the other received just R-Squared. So patients who were enrolled in the trial will all continue to receive R-Squared. They won't be left without treatment. 

I have mixed feelings about accelerated approvals. They make new treatments available to patients who might need them. But they also risky in that they haven't gone through the full process that other treatments have gone through. On the other hand, even if there had been a phase 3 trial, the patients who volunteered for it would still be dealing with the same risks. It's all very complicated.  

The unfortunate part for all of us is that we have one less treatment available to us. And for those with the EZH2 mutation, that's even more unfortunate.  

But we can stay hopeful. There are lots of treatments available to us, and many more potential treatments on the way. 

 

 

Tazemetostat Trial Pulled

 Yesterday (February 4) was World Cancer Day. It's a day to encourage research, prevention, and awareness. The link will give you more information about some of the events that took place around the world yesterday, and some that will continue to take place. I had planned to post something about it, but I've been so busy lately that I never got the chance. I had forgotten all about the day until I saw a notice from the Follicular Lymphoma Foundation last night.

It wouldn't have been much of a post anyway. I mostly would have wished you a good day and encouraged you to eat some ice cream. So I hope it really was a good day for everyone.

*****************

Instead, I want to comment on a news item that I saw a couple of days ago.

It's a post from a pharma investing site called "Ipsen’s Tazemetostat Trial in Tough Lymphoma Group Withdrawn: What Investors Should Know." I've written recently about my feelings about investment and finance with regards to my disease. This is an example of the kind of different perspective that a financial site brings over a medical site. 

It reports on a clinical trial involving Tazemetostat that was withdrawn -- stopped before it was really started.

Tazemetostat is an EZH2 Inhibitor that was given accelerated approval by the FDA in 2020. EZH2 is short for "Enhancer of Zeste Homolog 2," an enzyme that is controlled by the EZH2 gene. The job of EZH2 is to keep tumors from growing, so when it's not doing its job, it needs to be inhibited -- stopped by Tazemetostat. The EZH2 abnormality involves about 20% of FL patients, though it can also be effective on patients that don't have that known mutation. 

But "accelerated approval" really means "approval for now." It is usually given based on data from a smaller trial, and must then go through a confirmatory trial -- a larger trial, with more patients, that can show the same results as the small trial. 

The official web page for Tazemetostat says that the confirmatory trial has not yet been completed.  

The clinical trial that was stopped was called "NCT06068881: A Study to Assess Efficacy and Safety of Oral Tazemetostat in Adult Participants With Relapsed/​Refractory Follicular Lymphoma That Does Not Have an "EZH2 Gain-of-function" Genetic Mutation (Mandolin)."

This is not the confirmatory trial. The title is clear that it is meant to study patients who do not have the EZH2 mutation and who have had previous treatment.

What I find so interesting is that there is so little information about this. And that's true of pretty much every failed clinical trial. It is very rare that a researcher or a company will be brave enough to discuss their failures, which is too bad, because we learn so much from failure. (I'm sure the researchers learned a lot -- they just aren't sharing it with us.)

And failure is certainly common. Of all of the potential cancer treatments that start the process of getting approval (lab tests, then animal tests, them stage 1, stage 2, and stage 3 clinical trials on people), less than 10% ultimately get approved. 

As the article says, there was no announcement about this, just some changes to the official clinical trial page that indicated it had been stopped. Most clearly, there is a red box that says "Withdrawn" where there would normally be a green one that says "Recruiting." It also says "Never Started."

There are many reasons why this could have been the case. It's possible that some issues with Tazemetostat have come up that we don't know about yet. I'm not saying that's true, just that it's a reason -- but it does seem unlikely, since the trial was supposed to have started last September. It's also possible that funding was pulled and there was just not enough money to complete the trial in the way they wanted. It's also possible that they just had trouble getting participants (there is no information about locations for the study) -- with so many other exciting possible treatments, maybe there just weren't enough folks for this one. 

My big point here is that this is an example of how much we don't know as patients. There is so much to be excited about, especially around ASH and ASCO, as early research gets discussed. And much of that just never finds success. No one has to tell us about failures, even though I wish they would. 

The other pint is, sometimes those folks who look at this from a financial perspective can give us something good. I can imagine someone who is invested in the company that makes Tazemetostat, looking a couple of times a week at the clinical trials site, trying to get some insight as to whether it's a good investment. their financial incentive makes it worth talking about, even if someone with a medical interest doesn't pay any attention to it.

Perhas we'll get some updated information about Tazemetostat's confirmatory trial soon. In the meantime, the good news is, we have lots of options, and lots of reasons to be hopeful, even when the failures are invisible (or perhaps because they are invisible). 

New Research on FL Subtypes

Some very cool and potentially important research in Blood Cancer Journal this month. It's called "Identification of Genetic Subtypes in Follicular Lymphoma." It's a straightforward title for some research that is fairly complicated, though its implications are easier to understand. There is a lot of genetics in here, and I found myself getting lost at times, but as I said, its implications are easier to understand. I'll do my best to give you the important stuff.

Some background, first. Cancer researched changed for the better about 20 years ago, when the Human Genome Project finished mapping al of the genes in the human body. That mattered because it allowed researchers to start looking more easily at the genetic basis for cancer. That is, once they saw where genes were supposed to be, they could more easily see that they had moved or changed, and they could figure out that some changes caused health issues like certain cancers. 

Over time, that has made it easier for researchers to identify specific genetic bases for certain cancers. Knowing the genetic basis for something allows other researchers to create targeted treatments. I don't go into much detail when I talk about these things here, because it's usually not necessary. I'll say something like "This treatment helps stop the cancer cell from growing because it shuts off a switch that tells a gene to create an enzyme that enables a protein to tell the cancer cell to keep growing." But that, in a very oversimplified way, is how genetics works in cancer treatments. It's about figuring out which gene is giving instructions that cause a long chain that lets cancer cells grow an survive.

So one of the many types of cancer research is trying to classify certain cancers based on their genetics. As I said, lots of cancers have had this happen (including DLBCL). But so far, that hasn't happened for Follicular Lymphoma. Until now, possibly.

The researchers who wrote this article looked at DNA samples of 713 FL patients before they had treatment. Then they did some DNA analysis and found that there were 5 different genetic subtypes for FL -- 5 different ways that certain genes were expressed. This is important. FL is often thought about as a single disease. But at the same time, if you talk to any other FL patient, you see just how heterogenous the disease is -- how different it shows up. Some us (like me) can watch and wait for a couple of years. Others need treatment immediately. But we both might be stage 3 grade 1/2. And those two people will respond to the same treatment in very different ways.

I don't want to confuse things too much with a lot of detail (which will confuse me, too). But these are the 5 subtypes that the researchers identified:

CS, with affected genes CREBBP and STAT6

TT, with affected genes TNFAIP3 and TP53

GM, with affected genes GNA13 and MEF2B

Q, which stands for quiescent, which means "motionless" or "resting." This genetic subtypes often included patients with stage 1 disease and showed fewer mutations than the other types.

AR, with mutations of the mTOR pathway. This genetic subtype was the one most often associated with advanced-stage disease.

If you google those specifc genes (like CREBBP), you can find more information about what they do. But they generally boil down to the general description I wrote above -- they tell a protein to allow something to happen that leads to a chain of events that keeps a cell alive and growing longer than it should be.

The researchers looked at a second database of FL patients who had received treatment to verify all of this, and to figure out the outcomes for these subtypes. 

That's where it gets really interesting. They can speculate what the implications might be for these genetic subtypes. For example, they think mTOR inhibitors might be an effective treatment for the AR subtype. The CS and GM subtypes might respond to epigenetic modulation (like Tazemetostat). TT might do well with chemotherapy-free treatments. Their hope is that future research will help sort all of that out. But this is a good start.

One other interesting bit from the research -- they were able to look at a group of patients with transformed FL (slow-growing disease that turns into a different, fast-growing disease like DLBCL). They found that early transformation (soon after diagnosis) had stable genetics, while late transformation had unstable genetics. In other words, the subtype that might have shown up on a genetic test soon after diagnosis wouldn't be the same as one that shows up years later at transformation. This is just my speculation, but that would seem to be why it's so hard to find a biomarker to identify transformation (or even POD24) before it happens. The tests miss it because it isn't there yet. They do recommend genetic testing often to pick up on these changes.

All of this is very early research, and most of the practical stuff (like which subtypes will result in certain treatments being more successful) is just guessing. And even if further research confirms the subtypes, it's still not that simple -- there are lots of other factors that go into why a treatment does or doesn't work (otherwise, everyone with a EZH2 positive FL would respond to Tazemetostat, which isn't the case). 

But it's a start, and possibly a good start, in figuring out why we can all have such different forms of the same disease when so many things look the same.

Great Debates: Alternatives to CAR-T

There's a really interesting speaker series that happens every year in New York City called "Great Debates and Updates in Hematological Malignancies." Basically, a bunch of famous oncologists get together, two of them pick sides of a debate about blood cancer, each one speaks for a while, some others comment on what they said, and they move on to the next debate.

It's probably a little bit misleading to call them "debates." I'm not sure they really expect there to be winners and losers. It's more like they are exploring together, looking at issues that don't have definite answers, and offering there thoughts. It's really an alternative format for the kinds of "update videos" that I like to post every now and then.

Follicular Lymphoma seems like a natural fit for something like this, since there really aren't any clear answers when it comes to our disease. Usually at ASH or ASCO every year, someone makes a presentation that looks at the last 10 years or so of FL diagnoses in a database, and how the patients were treated. And the treatment choices will be all over the place -- some watch and wait, some Rituxan, some traditional chemo (some of them Bendamustine and some R-CHOP), some R-squared, plus a bunch of treatments in clinical trials. You see what I'm getting at, I'm sure. There is still no clear treatment path for FL that everyone can agree on. That's partly because FL patients present differently, but also because all of those treatments work, so oncologists just go with what they've always used.

So there's lots to debate, if two oncologists are looking to have a friendly debate.

At this year's "Great Debates" (which happened about a week ago), the FL debate feature Dr. Peter Martin of Weill Cornell and Dr. Caron Jacobson or Dana Farber. The debate centered on Relapsed FL and CAR-T. Dr. Martin's presentation was called "CAR-T Cells Should Be Rarely Used in Relapsed Follicular Lymphoma," while Dr. Jacobson's was "CAR-T Cells Should Be More Often Used in Relapsed Follicular Lymphoma." Pretty straightforward.

Unfortunately, I don't have access to Dr. Jacobson's talk, but I do have an interview with Dr. Martin, where he summarizes what he said at "Great Debates." It's an interesting talk, and worth the 5 minutes it takes to view it (or read the transcript, both of which you can find here.)

I'll give you a summary. Dr. Martin's role in this debate is to argue in favor of "all of the other treatments" besides CAR-T, which seems to me to be the easier side to take. But he focuses in particular on 3 treatment options (and remember, these are for relapsed FL, not for first treatment). Traditional chemotherapy is not one of the options -- "we're al moving beyond that," he says.

The first of the three is R-Squared, or Rituxan + Revlimid (also known as Lenalidomide). In its favor is the fact that we have data from two large trials now, so we know a lot about side effects and effectiveness. As he says, R-squared will work for between 2 and 5 years on average, and it's well-tolerated.  A good option.

Second is Tazemetostat, an EZH2 inhibitor. It works especially on B cells, keeping them from growing, which makes it very well-suited to FL. About 20% of patients have a mutation in EZH2 that makes Tazemetostat a very good option, and it has very few serious side effects. For patients who have the particualr mutation, t can be very effective, especially given the low side effects.

Finally, and "most exciting," according to Dr. Martin, are the bi-specifics. He compares them especially to PI3K inhibitors, saying bi-specifics are geared toward the same population as those who tried the PI3K inhibitors, but the bi-specifics are twice as effective. They can be tricky to administer, and their most serious side effect is Cytokine Release Syndrome. But bi-specifics are also (like Rituxan) open to combinations with other treatments, which could increase effectiveness. 

It's interesting to me that this once again comes down to bi-specifics vs. CAR-T, but that's not a surprise.

What's most important is this statement from Dr. Martin: "I think we're at a very fortunate time in the history of follicular lymphoma to have a number of excellent options."

That's absolutely true, and the most important take away from this "great debate." We do have some excellent options, and more likely on the way.

I'm going to keep an eye out for Dr. Jacobson's talk on why CAR-T should be used more often. She's great, and I'm sure it will be worth sharing. 

But for now, we can remember that we have some other options, and they're very good.

Peace

Sometimes I write a message on this day, Christmas Day. I know many of you celebrate and many don't. I do. But the message I like to send on this day is one that, I hope, is appropriate no matter what faith one follows, if any.  

As I've said in the past, there are lots of phrases and greetings associated with Christmas. You see them on gift tags and bags, on cards, on posters in stores. Of all of them, my favorite has always been "Peace on Earth." It's usually a wish, a desire, rather than an observation. This year is no different. Maybe even worse than usual -- there's so much division in the world. Some people can't even agree on which greeting to use for Christmas. And that's not even considering the war and violence going on in the world, and the division that happens as a result, thousands of miles away from it. 

This is a tough time to find peace.

And my message on this day usually connects that desire for peace on earth with a need for peace inside ourselves. That hasn't changed. In fact, with so much going on outside of us, there's probably a greater need for peace inside of us. Stress takes its toll on a cancer patient. We all need a break. Now more than ever.

After almost 16 years of living with Follicular Lymphoma, I wish I had some better words of wisdom than I do. But it seems like the wiser I get, the harder the problems around me seem to get. 

I just re-read that last paragraph, and I corrected a word I had misspelled -- I had said "After almost 16 years of loving with Follicular Lymphoma." And I suppose that's true, too. I've been doing my best to spread some love for all of that time. It's strange how writing a blog post about radioimmunotherapy or tazemetostat can be an act of love, but here we are.

And I suppose that's the message, in the end. When it comes to living with Lymphoma, we need to find our own path to inner peace. I've always believed that we each need to live our lives as cancer patients in the way that makes most sense to us. Our path to inner peace has to be our own path. It needs to make sense to us.

So on this day, my biggest wish for you is that you find your path to peace, whatever it might be. 

And maybe, if enough of us find our own peace, it makes the world just a little more peaceful. Not entirely peaceful -- I'm nothing if not a realist. Just a little more peaceful. I'll be happy with that.

Merry Christmas to those of you who celebrate it. Happy holidays to those of you who celebrate other days, weeks, and months this time of year. 

And peace to all of you.

 

New Combinations for Follicular Lymphoma

Targeted Oncology ran a nice piece last week called "Exploring Novel Combinations in Indolent Lymphomas." It highlights a bunch of studies that are being conducted that involve trying different combinations of treatments to find something that improves outcomes without increasing side effects too much.

A lot of the research being done centers around R-Squared, the combination of Rituxan and Revlimid (also known as Lenalidomide). As you may know, R-Squared was approved with much celebration. It was the first treatment that was shown to be as effective as traditional chemotherapy. As such, it showed that it was possible for treatments that are more targeted to be a viable alternative to chemo. (Traditional chemotherapy likeR-CHOP and Bendamustine is often very effective for Follicular Lymphoma. The problem is, while chemo kills cancer cells, it often kills healthy cells as well.)

So while R-Squared is effective, it's not better. And that's an important distinction. It doesn't have the same side effects as chemo, but it also doesn't have fewer side effects. Just different ones. The official term for this is "non-inferior." That was the outcome of the large clinical trial that led to R-Squared being approved by the FDA -- it's not better than chemo, but it's not worse, either. But if it isn't better (that is, either more effective or safer), then it can't really replace chemo.

That's kind of where this article begins -- R-Squared came close to knocking chemo off the throne, but it didn't quite do it. So the next step is to find some way to make R-Squared more effective. That's what will make it superior to chemo, not just not inferior.

An example of this is the combination Tazemetostat + R-Squared, as I wrote about last month. R-Square is great, but adding a third treatment that goes after cancer cells in a different way just might make it better. Again, the problem is that it can also introduce a third set of side effects that can make things worse (though that doesn't seem to be the issue with Tazemetostat + R-Squared).

The article looks at a few others, though they aren't all being tested for Follicular Lymphoma. (The article is about indolent, slow-growing lymphomas, not just FL). This article is a summary of a presentation from the annual meeting of the Society of Hematologic Oncology (SOHO).

Some of the highlights:

• R-Squared is being combined with Epcoritamab, a bispecific antibody. The research is very early, in stage 1 and 2 trials, involving 66 previously untreated FL patients, but the results are good, with about 80% of patients in the trial getting a response.
• Another bispecific, mosunetuzumab, is also being combined with Lenalidomide (but not Rituxan) in a phase 3 trial with similar results. 
• Some other combinations focus on what are known as protumoral macrophages. Macrophages are another type of immune system cell, like the B cells that turn cancerous in FL. When macrophages become pro-tumorous, they allow cancer cells to grow. Some treatments target this process, including the BTK inhibitor Acalabrutinib. It is being combined with R-Squared in an early trial with 29 patients. It's doing well in the trial, with no new side effects when compared with R-squared, but it's also not much more effective. 
• Another BTK inhibitor called Zanubrutinib is being combined with Obinutuzumab (a monoclonal antibody like Rituxan). In a phase 2 trial, the combination is more effective than just Obinutuzumab.
  

A lot of these combinations are in early trials, as the article points out. But it does show that the approach is still very much on the minds of researchers. As exciting as CAR-T and bispecifics are on their own, there might be even more reasons for excitement if they are combined with other treatments. As long as the side effects remain manageable -- not worse than the side effects of the individual parts of the combination -- then there's some promise. 

All some fun things to keep an eye on.

Recent Treatment Guideline Updates [video]

A few weeks ago, OncLive did another of their short videos series, featuring oncologists exchanging ideas.

This one is called "Recent Treatment Guideline Updates in Follicular Lymphoma," and it features Dr. Sameh Gaballa of the Moffitt Cancer Center and Dr. Matthew Lunning of the University of Nebraska. (Unfortunately, there's no written transcript of the conversation, just a video.)

The two of them talk briefly about some of the changes that have been made to NCCN Guidelines. Those are the general guidelines for oncologists for which FL patients should receive which treatments, and in which order, if necessary. If you've been paying attention to FL research, you can guess that the guidelines are very flexible -- lots of options. That's good in a way, but less good because it means none of them are perfect.

Anyway, the two oncologists talk about how the guidelines have influenced their ways of diagnosing FL patients. 

Dr. Gaballa discusses testing patients for EZH2. It's an interesting idea -- as I mentioned a couple of posts ago, we have very few biomarkers that tell us that a particular treatment will work, but EZH2 is one of them. But relatively few FL patients have the marker, so it is limited in its usefulness. But for those who do have the biomarker, Tazemetostat is a good option -- especially for patients who have already had multiple treatments, given its less aggressive side effects.

They continue their conversation in a second video, "Evolving Treatment Landscape of Relapsed/Refractory Follicular Lymphoma." 

It's interesting to hear them talk about the kind of choices they make, and why. They are based on individual patients' needs, which is great, but also things like the recent pandemic, and making sure that their patients ' immune systems can handle the potential side effects of certain treatments.

It's a short, fast conversation, almost like sitting at a table in a restaurant and overhearing two oncologists talk about their work. But it's a very interesting bit of eavesdropping, and I always enjoy hearing oncologists get a little bit excited about what they do.

SYMPHONY-1 Trial (Tazemetostat plus R Squared)

OncLive has a nice interview with Dr. Jennifer Effie Amengual of the Columbia University Irving Medical Center in New York. She discusses the SYMPHONY-1 trial, which is testing a promising treatment combination -- Tazemetostat plus R Squared.

Tazemetostat was approved by the FDA a few years ago for a subset of Follicular Lymphoma patients. Tazemetostat is an EZH2 inhibitor. EZH2 stands for "Enhancer of Zeste Homolog 2. EZH2 is an enzyme that is controlled by the EZH2 gene that controls tumor growth. Because Tazemetostat is an inhibitor, it stops EZH2 from allowing cancer cells to grow. 

As the interview with Dr. Amengual points out, one of the great things about Tazemetostat is its safety profile -- the side effects are comparatively mild (at least compared to traditional chemotherapy). To be clear -- there are side effects, and they can be serious. But they seems to be different from, say, CAR-T, especially cytopenias (that is, low blood cell counts, whether they are red or white blood cells or platelets). 

And that seems to be why the combination with R-Squared is appealing. R-Squared, as you may know, is the combination of Rituxan and Revlimid (also known as Lenalidomide). As I mentioned in my last post, R-Squared is a big deal because it was the first treatment that was shown to be as effective as traditional chemo, but with different side effects.

So you can see the pattern here -- effective treatments with different side effects that don't pile up on each other. 

One of the interesting things that Dr. Amengual discusses is a kind of comparison between this combination and CAR-T. The trial doesn't specifically compare the two, but she does bring up which patients she would recommend for each of them. She uses the phrase "younger, fit patients" to talk about who she might recommend CAR-T to. Particularly because CAR-T patients had likely been heavily pre-treated, already having received a few treatments already that would have potentially weakened their immune systems, a combination like Tazemetostat and R-Squared might be easier on older, less fit FL patients. 

The trial is now in phase 2, so they are testing how effective the combination is. Half of the patients in the trial will get Tazemetostat and R-Squared, and the other half will just get R-Squared. Definitely worth paying attention this one.

The interview on OncLive seemed pretty accessible to me, if you're interested in reading it. It's worth a look. 

Relapsed and Refractory Follicular Lymphoma (Video)

The Lymphoma Research Foundation sponsored an online webinar last month on Relapsed and Refractory Follicular Lymphoma, featuring Dr. Bruce Cheson. If you've been reading the blog for a while, you might recognize the name. I believe he is retired now, but still very active in the Lymphoma community. I've always found him to be very informative and very entertaining.

This webinar (which you can watch by clicking the link above) is aimed at R/R FL patients, and Dr. Cheson addresses them directly. It's a very good overview of the landscape of what is happening for R/R patients -- those whose first treatment stopped working, or didn't work at all. (I think the webinar took place last November, but was posted online last month.)

Some highlights:

He begins by giving some statistics about R/R FL: the overall survival rate at 10 years is about 80%, and patients who are not POD24 have a lifespan that is very similar to the overall population.

He also shows some statistics that discuss older treatments (that is, it doesn't include things like CAR-T and bispecifics). At one time -- and I remember this very well -- it was thought that the typical path for most FL patients was that we would need many different treatments over time, and that each treatment would give us a shorter Progression Free Survival. In other words, we might have chemo, which would put us in remission for maybe 5 years. Then another treatment would work for 3 years. Then another for 1 year. That was definitely what I expected to happen 15 years ago. But that's not the case anymore. We get much longer times between treatments these days.

Dr. Cheson also spends some time discussing current treatment options, with their strengths and weaknesses: Rituxan/Obinutuzumab, RIT, Bendamustine, R-squared, Tazemetostat, PI3K inhibitors (no longer available), CAR-T, and Bone Marrow Transplants (which Dr. Cheson hasn't used in a very long time). He discusses many of these in detail, including PI3K Inhibitors. He is enthusiastic about Zandelisib, though this isn't being studied much anymore.

He moves on to some of the "more exciting stuff," including bispecifics. He's careful to spend some time on side effects of these treatments, as well as their effectiveness. It's nice to hear the excitement in his voice. He gives a similar discussion of CAR-T, explaining what it is, and reviewing some studies and discussing their effectiveness and side effects. He also gives a nice comparison between CAR-T and bispecifics.

Finally, he looks at some of the treatments that are currently in development. His conclusion about Relapsed and Refractory FL: chemo should not be considered an option, because there are so many non-chemo options. And with more options coming available, "newer approaches will clearly improve outcomes." Patients should consider clinical trials as a way of getting access to these treatments and helping them along the process. 

It's a nice overview of where we are with R/R FL, and as I said, I have always found Dr. Cheson to be entertaining. [Watch for his joke about "transformation" at about the 10 minute mark.] Most importantly, he is hopeful, and that's what I like most about him (and his presentations) -- he sees a very big picture, knows where the world of Lymphoma has been, and can see where it is going, and he is very happy about the direction it is moving in. 

This is a useful video for anyone with FL, but especially those who have had a first treatment. It should give you lots to be positive about.

Managing Relapsed/Refractory Follicular Lymphoma

As I mentioned in my last post, the journal Haematalogica published a nice piece recently called "Prospects in the Management of Patients with Follicular Lymphoma Beyond First-Line Therapy." It's a nice summary of where we are and where we might be going. (And by "we," I mean those of us who have already had some kind of treatment.)

The article basically goes through the options that are available for patients who have already had a treatment, and whose FL has come back, or whose treatment failed. In the last 10 years or so, we've seen new treatments types become available -- PI3K inhibitors (Idelalisib, Copanlisib, and Umbralisib) , Immunomodulators (Lenalidomide), Epigenetic Therapies (tazemetostat), and CAR-T. Add these to the ones that were already available -- traditional chemotherapy (CHOP, Bendamustine, and CVP), Rituxan, radiation (for some stage 1 and 2 patients), RadioImmunoTherapy, and Stem Cell Transplants -- and you have a pretty good bunch of choices for FL patients.

One of the main points that the authors make is, despite all of these choices, there is still no clear Best Choice for R/R Follicular Lymphoma. It seems like all of our situations are just a little bit different from one another, and with so many choices, and so much incomplete data from clinical trials, it's impossible to handle it any way than to consider each patient's individual situation. and make a choice from the list.

(This is worth mentioning -- the authors say that "the flood of data derived from phase II studies, and the lack of randomized studies comparing treatment strategies" are part of the problem. There are so many new types of treatments that the FDA gives special consideration to many of them, allowing them to be used on patients even though they have only gone through a smaller phase 2 trial. The good thing is that they get to patients sooner; the bad thing is they don't come with the large amount of data that a phase 3 trial would bring. Same with the lack of "randomized studies." Clinical trials can be run in two basic ways -- give a bunch of patients the new treatment, or "randomize" the trial and give half the patients the new treatment and half an old treatment, and compare the two groups directly. Randomized trials are a little harder and more expensive to run, so they aren't used as often. Same deal as relying on phase 2 trials -- less information to use later on. So we have more treatments available to use in the last 10 years, since they got to us faster, but not as much information as we'd have if we'd spent 15 years on them. Nothing is easy with this disease.)

It's probably not worth going through every one of the available options. (I've pretty much been doing that for 14 years.) But there is a really cool-looking image in the article with many of the different treatments going after an FL cell, of you want to take a look.

I think it's more important to think about some of the other points the authors make about treatments for R/R FL patients.

One important point they make has to do with sequencing therapies. (It's important to remember that this is written by Lymphoma experts for other doctors.) For many of us, that first treatment won't be the last treatment, and neither will the second treatment. If that's the case -- we might live a long time, but those years will involve a bunch of treatments -- doctors need to think carefully about how side effects might build on the side effects of treatments that have come before. They might also need to consider things like "location and socioeconomics." Not every treatment is available at every cancer center, and even the expense of traveling for a couple of hours once a week might need to be considered. Not everyone can travel easily, and not everyone can afford to take a day off of work once a week, let alone being able to afford an expensive treatment itself. I like to think that doctors keep those things in mind, but it's good for them to be reminded of factors like that. 

And just as important, an treatment recommendations should "incorporate the patient’s goals." Some of us might be OK with taking a pill every day for a year or two (like with some inhibitors). Others might want to just "get it over with" and do all of the treatment at once (like with RIT). As patients, we have goals for how our lives will be lived. Doctors need to consider those goals. The "best" treatment isn't always the best treatment.

Which is related to the next point that the authors make -- Quality of Life matters, and needs to be preserved. If an FL patient has the potential to live for years with the disease, the treatment shouldn't cause such severe side effects that those many years are difficult. A treatment might offer the possibility of a cure, but with long-term side effects that case nerve damage of make the patients more vulnerable to infection. There needs to be an honest and careful conversation about that before a treatment is decided on.

Finally, the authors look to the future. Even as we have lots of good options available to us, there are still more on the way. (They mention bispecifics as an example.) There are also lots of combinations being studied. Sometimes, two treatments work together in ways that are better than the two individual treatments -- R-Squared is a good example.

The hope is that the newer treatments will mean fewer or less severe side effects, and longer times between treatments. We're learning more about the biology of FL, too -- more potential biomarkers, and more about the pathways that cancer cells take to live and grow. All of that knowledge may lead to better treatments.

There's a lot here to be hopeful about. The treatment options really have changed a lot in a pretty short amount of time -- even in the almost 14 years since I was diagnosed. The article isn't written to us patients in particular, but that lesson is definitely worth learning.

The other lesson here for patients is also important -- with so many options, it's important that we know what they are, and what the implications are for each of them. I don't think we need to know all of the science behind every treatment -- we're not doctors or researchers. But we should know which questions to ask, and we should insist that our doctors take the time to answer them and explain what we need to know. A very good place to start is to think about your goals -- what kind of life you hope to live after the treatment is successful. That's a good place to start, and a good doctor should be able to start a conversation from that point.

I'm looking forward to exploring more of this with you all this year.

Use of Tazemetostat in R/R FL

Cancer Network has a new video series on Follicular Lymphoma. You all know I like these kinds of things, since they usually involve a Lymphoma expert giving their take on what is happening in the world of Lymphoma research. I enjoy watching an expert talk about what they think is exciting.

This series features Dr. Connie Batlevi from Memorial Sloan Kettering Cancer Center in New York. (Dr. Batlevi is a "double doctor" -- she has an MD and a PhD, which I always find impressive as heck. Not only smart, but willing to stick with two programs.)

What I found most interesting about the series is video #3, "Use of Tazemetostat in R/R FL." That link will take you to the video series, which includes transcripts, in case anyone wants to read and/or translate the text.

When Tazemetostat was approved for Relapsed/Refractory Follicular Lymphoma last year, I was kind of unimpressed with the numbers, and a little unsure of why everyone was so excited about it. It seemed like a relatively small number of patients would benefit from it. And the company that makes Tazemetostat was fairly aggressive in marketing it; I was seeing ads for it all over the place.

(And before I go on, this is a good time to remind everyone that I am not a doctor or a cancer researcher. I'm a patient who reads a lot and tries to stay informed. So when I say I was "unimpressed with the numbers," take that for what it's worth. An informed opinion, but not an expert opinion.)

The video does a good job of explaining why Tazemetostat is something to be excited about.

Tazemetostat is an EZH2 inhibitor. We know that inhibitors work by inhibiting things -- stopping something from doing what it wants to do. In this case, it stops EZH2, an enzyme that is involved with winding and unwinding DNA, and helping cancerous B cells to grow. So inhibiting, or stopping EZH2 will help stop FL cells from growing. (I think Dr. Batlevi does a very good job of explaining this.)

Not every FL patient has mutated EZH2, and Tazemetostat works best on the 25% or so of FL patients that do have this mutation -- about 70% of those patients had a response, and about 20% of those had a durable response, one that lasted more than 18 months. About 35% of patients with a "wild type" EZH2 had a response, with about 20% of those having the same 18 month response.

So why the excitement? Two reasons.

First, as Dr. Betlavi explains, Tazemetostat is one of the first truly targeted treatments for FL. There needs to be some genetic testing to figure out if the patient has mutated EZH2. Having a treatment that uses this kind of approach successfully "opens doors in terms of how we can use genetic profiling and personalized medicine to do more treatments in lymphoma," as she says. That happens a lot -- someone shows that a particular approach works, and other researchers build on that approach in new ways. 

The other important thing is that Tazemetostat has a good safety profile -- there aren't many side effects, and those that exist aren't too severe. That makes it a good candidate for combination with other treatments. If two treatments kill cancer cells in different ways, and their combined side effects aren't too harsh, then we may have a treatment combination that is effective and helps maintain quality of life -- something very important in a cancer like FL that may involve many treatments over many years.

So it's a good video. I like video series like this because they usually reinforce what I know about FL, but this one was great because it taught me some new things.

And since I'm a non-cancer professional who shares my opinions about cancer, that's good for all of us. 

 

2020: The Lympho Bob Year in Review

This is probably my last post of 2020, so I'll use it to first say Goodbye to a pretty bad year. 

I don't need to tell you why it's bad. So much worry and anxiety. Poor health for many of us (I added a new health issue my list this year. It's not cancer-related. I'm not going to get into it.) Loss of loved ones for some of us. Loss of Quality of Life for all of us, with nowhere to go and no one to see. A lot of that is likely to continue, for a few more months, anyway.

But you know me -- I don't dwell on the bad stuff for long. Hope, even a little bit of hope, always shines through.

So in looking back at a bad year, I want to focus on the good stuff.

Here are my five biggest Follicular Lymphoma stories from 2020. They're not all completely great, but I can find some happy hopeful stuff in there somewhere.   

#5: Covid-19

Like I said, it's not all happy news. I couldn't ignore this, given the way it changed our lives this year. But I won't put it any higher than #5 on this list, either. 

Looking back on the blog, I started writing about Covid back in March. I really didn't have a lot to say about it, because so much was unknown, other than how it was making me feel. We got a little bit of guidance early on, but there was still so much unknown.

And there's still a lot we don't know, especially about how a vaccine will affect Follicular Lymphoma patients -- those who are immuno-compromised because they are currently in treatment, or who recently had treatment, or even whose immune systems have been affected by treatment long ago. No real answers. Maybe we'll get more information as more people are vaccinated and we have more data. I see FL patients online debating this, with some saying their oncologists think they should hold off and others thinking they should get it as soon as possible. Everyone's situation is different. Trust your doctor's advice.

But find some hope in the vaccine, even if you can't get it right away. Trust science. Encourage others to get it. Hang in there. We'll get through this.

 

#4: R-Squared

R-Squared is the combination of Rituxan and Revlimid (which is also known as Ledalidomide). It made news in 2019 when it was approved by the FDA for use on previously treated Follicular Lymphoma patients. It was an important approval because it showed that a non-chemotherapy treatment could be as effective as traditional chemo. Side effects were different, but not better or worse. 

The big news for R-squared in 2020 was that it was also shown to be effective in FL patients who have not yet received treatment. An ASCO presentation on Complete Metabolic Responses confirmed that untreated FL patients did very well with R-Squared. 

But what really puts it on the list is just how excited Lymphoma specialists are about it. I like to post articles and videos of experts kind of summing up what we know about Follicular Lymphoma, and R-Squared is always something they talk about, whether for the approval for Relapsed or Refractory FL, or the future approval for untreated FL. I don't know of any attempt to seek FDA approval  for untreated FL right now, but my guess is that it will come in the next couple of years. We're going to keep hearing about this for a while.

 

#3: Tazemetostat

Tazemetostat was approved by the FDA in June (as far as I know, it is still in trials in other parts of the world) for two groups of Follicular Lymphoma patients. The first is those with an EZH2 gene mutation. The EZH2 gene is important in telling cells that they are supposed to die, so a mutation mans those cells keep on growing and living, which is of course how cancer develops. Tazemetostat is an EZH2 inhibitor, meaning it stop EZH2 from keeping cancer cells alive. 

The other group is a little larger and less specific -- FL patients who do not have any other alternatives. It's good that they have an approved treatment to try, even if they don't have the EZH2 gene mutation. 

This one is really interesting to me. Lymphoma experts are very excited about it. But only about 25% of FL patients have the EZH2 mutation, and about 69% of patients had a response. To me, those aren't really spectacular numbers, at least compared to some other treatments.

On the other hand, those 25% of FL patients have a really good chance of being helped, and if I was one of that group, I'd want the option. 

I also think that, like many inhibitors, Tazemetostat may end up having a life as part of a combination therapy, along with one or more other treatments. 

But, really, it's the excitement from Lymphoma experts that puts this on the list. If they're excited, then I'm excited, too.

 

#2: CAR-T: ZUMA-5

There has been a whole lot of news about CAR-T for a few years now (see the CAR-T and Follicular Non-Hodgkin's Lymphoma blog for more up-to-date info -- I can't keep up with them).

And there's too much CAR-T news from 2020 to mention here, so I'll focus on what I see as the Big News, and what, once again, seemed to get experts so excited -- the ZUMA-5 trial.

A couple of different CAR-T treatments have already been approved for aggressive lymphomas, including Transformed Follicular Lymphoma. The ZUMA-5 trial focuses on indolent lymphomas -- the kind of slow-growing, less aggressive FL that many of us live with (including me). The phase 2 trial involves a fairly small number of Follicular Lymphoma patients (80), but the results have been very positive, with 94% having a response, including 73% with a Complete Response.

This is, once again, one of those treatments/trials that experts are very excited about. ZUMA-5 is a phase 2 trial, so we're probably not going to see this approved very soon (though, who knows? The makers may give it a shot). With numbers like those, it seems pretty likely to be approved. We're looking forward to that.

#1: Survival

In some ways, "survival" should be #1 on the 2020 list because we've all survived it. It's a low bar -- "I made it out alive" -- but I think it's an OK one in a year like this.

But that's not really why I put it at #1.

Looking back at what I wrote this year in the blog, I see a bunch of research on survival in Follicular Lymphoma.

Trends in Treatment and Survival in Follicular Lymphoma.

 

New Information on FL Survival.

 

Improved Lymphoma Survival Over 20 Years.

 

Plus a couple more articles with advice on how FL patients should think about their post-treatment lives. 

 

The overall message in all of this is the same --

 

Follicular Lymphoma patients are living longer lives.

 

Treatments are getting better. Newer treatments are allowing patients to live with a better Quality of Life. When I was diagnosed in 2008, the median overall survival for FL patients was still considered to be 8-10 years. Most research these days that looks at long-term follow-up of FL patients hasn't even reached a median OS yet. Patients are living too long to measure it. But many experts guess that it's about 18-20 years. 

 

How great is that?

 

There have been enough reminders this year that survival has to be #1. Not just because we made it through this tough year. But because it's getting easier for more FL patients to live longer and better lives.

 

We made it through this year. We'll make it through the tough few months at the start of next year, and we'll move beyond it. Remain hopeful. That's not just an empty saying. There are so many reasons for hope.

 

Thanks again for being with me during this tough year. I look forward to sharing more with you in 2021.

Trends in Treatment and Survival in Follicular Lymphoma

The journal Leukemia recently published an article online called "Stage-specific trends in primary therapy and survival in follicular lymphoma: a nationwide population-based analysis in the Netherlands, 1989–2016." Unfortunately, I can only see the abstract (the paragraph summary that highlights what the authors think are the main ideas). But there's still some interesting things to see there.

The article looks at a very large group of Follicular Lymphoma patients -- 12,372 of them, who were diagnosed in the Netherlands between 1989 and 2016.

That's an interesting group -- it includes some who were diagnosed before Rituxan made its way to the Netherlands (which was 2003, according to the article, a few years after the U.S., in 1997). But, of course, it doesn't include patients who were diagnosed in the last few years, which I think is significant.

 The researchers were interested in primary therapy (the first treatment that patients received), and in Overall Survival. Given the large number, and the fairly large span of time they looked at (27 years), they also broke the data down into age groups (18-60 years old, 61-70 years old, and over 70), and time periods (1989-1995, 1996-2002, 2003-2008, and 2009-2016), and then looked at trends within those periods, and for those age groups.  

I'd love to see the full set of data, but the article is behind a pay wall, and I don't want to spend $10 to read it (though I might get free access to it a little later). Still, what the abstract says is pretty interesting anyway.

As far as primary therapy goes, one of the trends they noticed was that, for stage I patients, radiation has always been a very popular treatment. This makes sense -- because stage I disease is only present in one place in the body, very often a beam of radiation can reach it and get rid of it. That dosn't work as well with later stages.

For stage II, III, and IV, the trend they noticed was that starting chemotherapy within 12 months after diagnosis became less popular over time. They see this as showing that watch-and-wait was becoming more popular as time went on.  This is kind of interesting to me (especially as someone who watched and waited for two years). I don't know what trends are in different parts of the world, but there are a lot of oncologists in the U.S. who say we shouldn't watch and wait anymore, since there are so many options now for treatment, especially non-chemotherapy options. (The argument for watch and wait has always been that there were limited options, so it was best to hold off on using them until it was necessary.) 

I think it's kind of interesting that they say "before starting chemotherapy," specifically. This is where I'd love to see the full set of data. For much of that 27 year period, traditional chemo was really the only option. But I don't know if this study accounts for other first treatment options, like straight Rituxan, or RadioImmunoTherapy, or some newer inhibitors. I have no idea of those treatments are even available in the Netherlands, though I'm guessing they are, since they have had EU approval. But the wording is pretty interesting to me, none the less.

As far as survival trends go, the news is very good -- "Relative survival improved considerably over time." They say this is especially true since 2003 (thanks, Rituxan), and in older groups.

They look at five-year relative survival rates for this study. For the time period 2009 to 2016, the 5 year survival rate for stage I and II patients was 96% for the 18-60 year old group, 93% for the 61-70 group, and 92% for the 70+ group. The numbers are lower for stage III and IV patients, but still good -- 90%, 83%, and 68%.  

This makes sense; as patients get older, they are more likely to have co-morbidities -- other health issues that may impact their lymphoma, or may have nothing to do with their lymphoma. In other words, it's very important to remember what Overall Survival measures -- death by any cause (cancer, but also heart attack, getting hit by a bus, choking on food, whatever). As we age, we typically accumulate health issues. It doesn't necessarily mean the lymphoma is worse is older people. 

(Please read this post on Overall Survival if you're not sure what that statistic means, or if you need a refresher on how to read cancer statistics without being thrown into a panic -- especially you folks who have been recently diagnosed.)

It's noteworthy, though, that the numbers for the oldest group (over 70 years) is different in stage I and II patients (92% five year survival) and stage III and IV patients (68% five year survival). Remember, these numbers are measurements for 2009-2016. And this where I think that few years makes a difference.

The authors say "There remains, however, room for improvement among elderly stage III-IV FL patients." They're right, if you look at those statistics. But some of those patients in that 68% were diagnosed in 2009, 2010, 2011 -- the options available to them were so different from what we have today. (I know, as someone diagnosed in 2008, who pays attention to these things.) Someone with stage IV disease in 2009 was likely going to get CHOP chemotherapy, a treatment which does a great job, but has some nasty side effects, including potential damage to the heart. So a doctor who is deciding how to treat that patient, say a 72 year old with some health issues (pretty likely in a 72 year old) has to consider giving, perhaps, fewer rounds of the chemo (less effective, but also fewer side effects) or full chemo (more effective, but greater side effects that could harm someone who already has health issues). 

In other words, there are lots of reasons why that 70+ group has a lower survival rate. And, 10 years later, my guess is that some of those 72 year olds from 2009 would not get CHOP today. They'd get R-Squared, perhaps, or an inhibitor, something that is less taxing on the body and may extend their survival by a few years. 

The big lesson from this study, for me as a patient, is this -- it's interesting to look back at what happened in the past, because it's almost always going to show how much things have improved. We are so much better off now than we were 27 years ago, or even 10 years ago, with newer, better, and more treatments available. And even the best study that looks back on history (and this one is pretty good, looking at 2016) is still out of date. 

Care to guess how many treatments the FDA has approved for Follicualr Lymphoma since the beginning of 2016?

The answer is seven: 

Obinutuzuman + Bendamustine (2016), Rituxan Hycela (2017), Copanlisib (2017), Obinituzumab + Chemo + O Manintenance (2017), Duvelisib (2018), R-Squared (2019), and Tazemetostat (2020). 

And that doesn't count the CAR-T treatment for transformed FL, or any biosimilars for Rituxan.

Again, the point is -- history is interesting, but this study doesn't tell us everything we need to know. And as much as I'd like to see the full data for this study, what I really want to see is the historical study of patients from 2016 to 2026. Because it will be about 2030 then, and I'll be older and grayer but still saying the same thing -- "Interesting, but it doesn't account for the treatments that were approved last year!"

(I also assume that I won't have to type any more in 2030, and I can just use brain waves or whatever to write my blog.)

 Lots  to be hopeful about, folks. Lots.

 

Tazemetostat: The Official Numbers

Last June, the FDA approved Tazemetostat for Follicular Lymphoma patients with the EZH2 mutation who had already had treatment, and for FL patients who were essentially out of other options.

The approval was based on the results of a phase 2 clinical trial involving patients in 38 clinics or hospitals in France, the UK, Australia, Canada, Poland, Italy, Ukraine, Germany, and the United States. 

This week, the results of that phase 2 trial were published in The Lancet Oncology journal. This is important, because the data has now been peer-reviewed -- other experts in the field have looked at the data and have given it their approval. The study was designed and conducted well, and the results are valid. 

The article, "Tazemetostat for Patients with Relapsed or Refractory Follicular Lymphoma: An Open-Label, Single-Arm, Multicentre, Phase 2 Trial," presents data that is similar to what was reported when Tazemetostat was approved: 69% of patients with the EZH2 mutation had a response to Tazemetostat, and it lasted a little under 11 months.

EZH2 is an enzyme that controls the EZH2 gene, which controls whether a cell should die like it is supposed to. When EZH2 mutates, the cell doesn't know it is supposed to die which, of course, leads to cancer. Tazemetostat is an EZH2 inhibitor, which means it inhibits or stops mutated EZH2 from keeping cancer cells alive.

Roughly 25% of FL patients have the EZH2 mutation, so Tazemetostat might not be in everyone's future. But for those who do have the mutation, it seems like it should give them some hope. It works on FL in ways that no other treatment does, currently. 

It will be interesting, too, to see how Tazemetostat works in combination. As you probably know, there are lots of treatments for FL and other cancers that do a decent job on their own, but then do a much better job when combined with other treatments that work on cancer cells in a different way (like Rituxan, which works well on its own but also makes some chemo even better). I look forward to seeing results from some of those trials soon.

I also look forward to seeing results from the phase 3 trial that will look at how Tazemetostat works on a larger group. 

Lots to be hopeful about.

  

 

 

Updates on Follicular Lymphoma from SOHO 2020

Last month, the virtual meeting for SOHO (The Society of Hematologic Oncology) held its annual meeting online.  Dr. Nathan Fowler from MD Anderson in Texas posted a video with a summary of what was said about Follicular Lymphoma.

Dr. Fowler is a certified Lymphoma Rock Star; he was the researcher who presented the data for R-Squared. He was one of the main speakers at SOHO 2020 for lymphoma.

(By the way, cool name for a group of cancer doctors -- SOHO.)

The SOHO meeting isn't like ASCO or ASH, where people are presenting brand new research. It's more about education -- collecting all of that recent research and showing doctors why it's useful.

I mention this because it's kind of the spirit of Dr. Fowler's video. He very nicely sums up some of the more recent research on Follicular Lymphoma (and he's doing it for the website Lymphoma Hub, a site for oncologists).

So what does Dr. Fowler think are the major developments in FL that oncologists should know about?

There are some new options for untreated FL (the first treatment a patient receives):

Obinutuzumab has been shown to be a good substitute for Rituxan in combination with chemo (a little better Progression Free Survival, balanced with slightly worse side effects).

The RELEVANCE trial, which compared R-Squared with Rituxan + Chemo, showed that a non-chemotherapy option could work as well as chemo (though with a different set of side effects).

As Dr. Fowler says, we're seeing new options for first treatments, but it's important to consider side effects, since they can be different for different treatments, and the choice of treatment might not depend so much on effectiveness (since they are about the same), but Quality of Life (how side effects will play out).

For Relapsed FL, there are some recent options, too, including a third Kinase inhibitor Umbralisib, curently under review. All three have PFS of about a year (not great, but another option for people who need the option).

R-Squared is also approved for relapsed FL.

And then there is  Tazemetostat,the EZH2 inhibitor approved this summer.

And of course, there is CAR-T.

The various newer treatments, he says, have different mechanisms of action -- they work on the cancer cells in different ways. That's important -- we still don't now why exactly, but some patients' Follicular Lymphomas do very well with certain types of treatments, and others do better with a different type of treatment. Options are good.

Once again, this video isn't presenting anything new, but I always like seeing a Lymphoma expert getting excited about what's happening in his world.

 

New Approaches for R/R Follicular Lymphoma

It's been a busy week. Work has picked up again. That explains why I haven't written in almost a week. I've barely had time to think, let along write.

(But, as I've said for 12 years or so, I'm lucky to be healthy enough to work, and to have a job to work at. So this isn't a complaint.)

In the spirit of being busy, and of the kind of "wrap up the summer" feeling that I've been getting this week, as kids go back to school (staying safe, I very much hope), I'm going to link to a nice interview published on OncLive a couple of days ago.

It's called "Emerging Approaches Seek to Expand the Relapsed/Refractory Follicular Lymphoma Treatment Arsenal," and the person interviewed is Dr. Lori Leslie of the John Theurer Cancer Center in New Jersey. 

Dr. Leslie discusses some of the recent research on Relapsed/Refractory FL -- treatments that are used after a treatment has stopped working, or that didn't wok at all. It's a subject that I care about a lot, of course; like many of you, my next treatment will be one that has been approved for R/R FL patients, or is in a trial that group.

She mentions Bendamustine and CHOP, two traditional chemotherapies. They are usually combined with Rituxan, though they are also being combined with Obinutuzumab more and more these days (it's similar to Rituxan, but with some changes that should make it more effective and less likely to produce allergic reactions, for some patients).

Dr. Leslie also discusses Tazemetostat, recently approved for patients with EZH2 mutation, or for whom there are no others options available. 

She is also hopeful that CAR-T will become available for R/R FL patients (that's still in a phase 2 trial; I'm guessing we'll see results in a few months at the ASH conference). She hopes it will someday be effetcive and safe enough to become the "standard of care" -- the default option.

The interview touches on a few other topics -- watching and waiting, for example, and R-Squared.

It's a good summary of what's happening in the lymphoma world for R/R patients right now. An end-of-summer-summary. (Sorry if that didn't translate well.)

I hope all of you are staying safe and healthy, especially as kids start going back to school.

More soon, when things calm down a little bit.

 

ASCO Part 2: Non-Chemo Treatments for Follicular Lymphoma.

This weekend, ASCO continues its virtual conference, with the 2020 ASCO Virtual Education Program. I'm calling this ASCO Part 2.

(I really wanted to call it ASCO Part 2: Electric Bugaloo, but I don't know how many of you would get that reference, so never mind.)

As I'm sure you remember, the ASCO conference (from the American Society of Clinical Oncology) takes place every year in early June. This year, the conference was split in two, since it is al taking place online -- the Scientific Program happened in late May, and focused on clinical trial results and other scientific research. ASCO was very generous this year and allowed patient advocates to "attend" for free. I was able to look in on sessions for the first time (since I can't ever afford to attend the conference in person).

And since I was registered for the Scientific Program, I am able to the Virtual education Program, which takes place this weekend. While the Scientific Program focuses more on giving results of research, the Education Program is more about how oncologists can use all of that research to be better doctors. So while it has sessions that focus on things like how Bispecifics might change the way Non-Hodgkin's Lymphoma patients are treated, it also has sessions on the specific cultural needs of cancer patients who serve in the military, or how COVID-19 is changing cancer care practices, or how to better care for LGBTQ cancer patients and survivors, or how financial toxicity can affect patient choices.

So while the sessions are focused on helping oncologists become better doctors, I can already see a bunch of sessions that look fascinating to me, even if they don't affect me directly. I'll try to share the ones that you might like, too, over the next few weeks.

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I'll start out with the only presentation that specifically addresses Follicular Lymphoma. (There are only 90 sessions for the whole program, and a bunch of those are speeches or award presentations, so it's no surprise that there is only one for FL.)

(Also, since this conference isn't presenting the results of new research, this presentation is more of a summary of previous research. Remember, the idea here is to educate oncologists, probably non-specialists who need a summary of research.)

The presentation is called "Chemotherapy-Free Approaches in Follicular Lymphoma and Mantle Cell Lymphoma." I'm including a link, though I don't know if you can access it without being registered for the conference.

The idea of the presentation is probably familiar to many of you (being patients who like to be well-informed). Traditionally, lymphomas have been treated with chemotherapy. And chemo still plays a big role in our treatment choices, with Bendamustine, CHOP, and CVP being very common. 

But more and more, researchers are focusing on non-chemotherapy treatments. Since traditional chemo kills some healthy cells as well as cancer cells, leading to a range of side effects, there is a preference for many newer treatments, which do a better job of targeting cancer cells and leaving healthy cells alone. There are still some side effects, but they are different from those that we might experience with chemotherapy. (Less hair loss, more nerve damage, for example.) We are likely at "maximum impact" from chemo -- what we have now is as good as it's going to get. Non-chemo treatments are the future.

And we do have several options.

For patients who are "treatment naive" (that is, who will be getting their first treatment), the options include Rituxin (which I received 10 years ago). But there are several others with a lot of promise, including R-Squared (Rituxan + Revlimid/Lenalidomide). Just a few weeks ago, updated research on R-Squared showed that it is effective for untreated FL patients. Other research on Lenalidomide + Obinutuzumab (a cousin of Rituxan) also shows promise.

There are a few more options for patients who have Relapsed/Refractory disease (they already had treatment, and it stopped working, or didn't work at all).  R-Squared is the one that seems to excite most oncologists. It's already been approved by the FDA. There's also the trio of inhibitors (Idelalisib, Copanlisib, and Duvelisib). Another, Umbralisib, is undergoing FDA review. And ME-401 is another inhibitor under review. While the inhibitors have had some success as individual agents, they tend to do better when they are combined with other things. Of course, that also means the chances are higher for more side effects. 

And finally, there's Tazemetostat, which was approved for Refractory/Relapsed FL patients with EZH2 mutations.  

The take-away from the session is that there are now chemo-free options for all Follicular Lymphoma patients, no matter where they are in their treatment life. 

One thing I noticed as I was creating the links is just how many of them have been in the news in the last few months. We are definitely in the middle of a real change in the way FL gets treated.

I can see an important issue for oncologists, though maybe it matters less in reality -- for many (most?) cancer patients, any treatment they get is "chemo." I don't know if it matters to them that Rituxan isn't technically chemotherapy, but maybe knowing the difference might also ease their anxiety a bit, if they see "chemo" as something scary. Understanding the distinction might also lead more patients to consider clinical trials.

As I said, I'll comment on some more of these ASCO 2 sessions in the next few weeks (I'm looking at a presentation on diet and another on CBD oil). There are some other Follicualr Lymphoma news items from the last week that could use commentary, too.

Stay tuned.

More FDA News for Follicular Lymphoma

A follow-up to my last post on Tazemetostat, an newly approved EZH2 inhibitor:

At the same time it was approved by the FDA, a new test to detect EZH2 mutations was also approved. The test takes a DNA sample (the mutation is to a gene that is part of the DNA) and is able to find the mutation very quickly -- results will come in less than a day. If a mutation is detected, the patient would be eligible for Tazemetostat, and may benefit from it.

Another piece of FDA news: The makers of Umbralisib  have submitted a Rolling New Drug Application for previously treated Follicular Lymphoma (and Marginal Zone Lymphoma, another indolent blood cancer).

A "Rolling Submission" for the FDA means the makers can submit parts of the application one at a time, rather than all at once. As you might guess, an FDA application is pretty large. Being able to submit parts of it, and get feedback tat can help with the other parts still to come, is a great advantage.

Umbralisib is a dual inhibitor of PI3 kinase-delta and CK1-epsilon proteins, both of which are necessary for cancer cells to grow. The application to the FDA is based on results from the phase 2b UNITY-NHL trial, which looked at Umbralisib in combination with some other agents, in a few different types of Non Hodgkin's Lymphoma, including Follicular Lymphoma.

As always, we'll keep an eye on this one.