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. 

 

My Many Doctors

I had my annual physical exam this morning. Everything looks good. 

To be clear, this is the exam I do every year with my "regular" doctor, the GP (general practitioner), not my oncologist. The point of the exam is to make sure everything is working properly, and my mental and physical health are OK. If something doesn't seem right, or if I have complaints, then this appointment is the time where I'd be referred to a specialist. 

The doctor asked the usual questions at first, about my smoking and drinking habits, if I'm exercising enough, how work is going, any new sources of stress, etc. All good there. 

The she asked, "Do you have any questions for me?"

I laughed. "No. I have so many other doctors that I see, that I get all of my questions answered by them."

And it's true. As she was doing the physical exam, taking my blood pressure, and all that, I tried counting the number of doctors that I see on a regular basis.

There's the oncologist, my cancer doctor. I see him every six months or so. I have an appointment coming up next month.

I also see a dermatologist, my skin doctor. The oncologist encouraged me to see her at least once a year, though it seems like a see her twice a year to check up on something that came up when I see her once a year.

Then there's the cardiologist, my heart doctor. My heart is actually in pretty good shape. I had a stress test a few months ago, and the report came back as "excellent." But I do have an "electrical problem," with a strange fast heartbeat that comes around every few months. Plus some high blood pressure.

The cardiologist sent me to a pulmonologist/sleep specialist. There's a not in my online medical records that I'm supposed to make a follow-up appointment with her soon.

Which reminds me -- I'm also due for a 10 year colonoscopy with my gastroenterologist. I don't see him as often as I used to, which is nice. But I do see the Otalaryngologist for my ears a couple of time a year. Too much Black Sabbath at high volume when I was young.

But it all got me thinking about how amazing the body is. Amazing enough that we need a whole bunch of people whose focus is on just one thing.We are such complex creatures. It's kind if fascinating.

At the same time, it's easy for doctors to see us as individual body parts, and not as one whole, amazing, complex creature. I don't know how much one of my health conditions affects the others, but it's certainly possible. Rituxan can cause heart rhythm issues -- did my cancer treatment affect my heart? Or was it sleep problems that cause the heart issue? And that medication the gastro doctor had me on for years -- will I end up with the kidney problems, or the dementia, or the bone loss, that I'm at higher risk of by taking the medication for so long?

And that's the problem. To one doctor, I might be just lymph nodes. To another, I'm just ears. To another, a weirdly beating heart. 

That's the danger, and I know people in a similar situation (seeing lots of different specialists) who don't ever seem to have their many doctors communicate with one another. I'm lucky that I do have a few doctors who at least who see me as more of a whole -- making sure I talk to someone else about potential problems.

For me, as someone who sees lots of doctors (and nurses, physician's assistants, etc.) to just kind of let it all wash over me. Another day, another appointment, something to get over with and move on. 

And it's also easy to think about everything that's wrong with me, and wish that I had a better heart, smaller lymph nodes, a shoulder that didn't act up if I sleep the wrong way.

It's nice to stop and marvel, for just a minute, at how amazing the human body is, in all its complexity. And to think about how much we don't know about it yet. And about how wonderful it will be when we learn those new things, and use that knowledge to make us feel better. 

World Lymphoma Awareness Day

 Today is World Lymphoma Awareness Day.

The World Lymphoma Coalition, which is made up of 80 lymphoma-related organizations in over 50 countries, has chosen a theme for this year: "We Can't Wait." They are looking to highlight the ways that the Covid-19 pandemic has affected lymphoma patients around the world.

And there have certainly been many ways we have been affected. A lot of us have compromised immune systems, which make us more vulnerable to the disease. Others have tried a vaccine, but have not gotten a benefit from it, because of their "imperfect" immune systems. All of us are affected in the long-term by the slowing down of research, when hospitals and university labs were closed last year, and by research money that was shifted to pandemic-related causes.

We can't let people forget about us. We can't wait for things to get back to "normal," whatever that was, and whatever is now is.

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I almost always say the same thing on World Lymphoma Awareness Day: personally, I don't need the reminder. I'm aware of my lymphoma every day. I think about it and read about and write about. Every day.

But it's other people who need to be made aware.

Yesterday, we got the news that the comedian Norm MacDonald died. I liked his comedy. I saw one obituary that described him as a "patient" comic. He would spend a full five minutes on a story that had a goofy punchline, the kind of thing my kids would tell me when they were 8 years old. But he could also tell jokes that were incredibly caustic and biting and adult. Someone once described him to me as saying he really liked to make people "uncomfortable" with his comedy. He was unpredictable that way. that's partly why I liked listening to him. I like to laugh at uncomfortable things. It's helped me deal with cancer.

Yesterday, I heard a replay of an interview he did once, where he was critical of people (particularly celebrities) who publicized their illnesses. He thought talking about it was just a way of getting sympathy. The braver choice, he thought, was to not talk about it or burden others with it. "I might have a specific ailment," he said. "Maybe I do. You don't know. But I wouldn't talk about it."

Of course, he did a specific ailment. The obituaries and tributes mention that he died of cancer (I don't know what type). A friend of his confirmed that he had been keeping his diagnosis private for about 10 years.

Now, given that I write a lot about my own cancer, I obviously disagree with Norm MacDonald on this. I'm more of a "shout it from the roof tops" kind of person when it comes to cancer.

And let me be clear: I am not in any way criticizing Norm MacDonald for wanting to keep it to himself. I've known as many roof-top-shouters as I have people who wanted to keep their diagnoses private. And they keep things private for many, many reasons. I would never tell another cancer patient that they were somehow "doing it wrong." We all need to find the best way to deal with our diagnosis -- our own best way. Every cancer patient has had one common experience: we've heard the words "You have cancer." That's enough to unite us. What happens after that is whatever makes sense to each of us individually.

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And that's why "awareness" matters so much. I shout so Norm MacDonald, and others like him, didn't have to.

Someone has to tell the stories, because as individual as our stories are, there's always something in them that someone else -- maybe just one person -- can connect to. One small detail to make another cancer patient realize that they aren't alone in feeling a certain way.

Someone has to ride the bike or run the marathon or sell the lemonade, or whatever else gets done to raise money for research.

Someone has to share the meme, or take the quiz, or post the story on social media. 

Those of us who are able to do those things need to do them, so other people don't have to. So they can deal with things in the way that makes most sense to them, that helps and supports them in their own best way.

That's what "awareness" is really about. Not making yourself aware, but using yourself to make it easier for others, even in small ways.

As I always say, there's lots to be hopeful about in the world of lymphoma. Do what you can to let others know that, too.

 

Some Thoughts on Being "Cured"

I appreciate the comments on my last post about how hopeful it was. I always love hearing a Lymphoma expert get excited about a treatment. And I love it even more when two experts are fighting over which of two great treatments is better. 

Jacquline's comment was interesting: "I belong to several Follicular Lymphoma groups on various social media sites. There is a gentleman who swears that CAR-T cures fNHL. He apparently was "cured" because of it. I know someone who was not helped by CAR-T and eventually passed away. As with all treatments, some work for some people and don't work for others. That is why this article was so uplifting, it offers us many wonderful and promising treatments that are in the "pipeline". It is an exciting time, I feel fortunate to be living during all of this." 

As much as I want to be as enthusiastic as the gentleman that Jacqueline describes, I'm with Jackie on this one -- hopeful but a little skeptical. I do think CAR-T is a miracle for a lot of people, and may very well cure them (whatever that means -- it's a complicated word). But I also know that there are a lot of patients who don't get a long-term benefit from it. 

I want to focus on the word "cure." It truly is a complicated thing, and has a few different meanings. Some cancers are considered "curable," meaning there are treatments that have a very good chance of working, for a long time, for a large number of patients. I don't think there's an official definition of "cured" for cancer (not one that I can find). But there are certainly some patients who have received a treatment that lasts for their lifetime. That's "cured." And there are some cancers that have a larger number of patients in that situation. that makes the cancer "curable."

Follicular Lymphoma is, unfortunately, considered not curable. We just don't have treatments that work for many years on a large percentage of FL patients. 

Here's where it gets complicated. Some Lymphoma specialists talk about patients being "functionally cured." In other words, they might not have entirely eliminated all of their cancer cells, but they haven't needed treatment again. Think about someone who is diagnosed at age 70 (pretty common), has B-R and then R-maintenance, and then a scan turns up some cancer cells at age 80. Not enough to need treatment again -- it's still growing slowly. That patient then dies a few years later, at age 84, about average life expectancy for the general population.

Was the patient "cured"? No -- there were still some cancer cells in their body. BUT, that B-R + maintenance lasted a very long time, long enough that they didn't need another treatment. Which is the definition of "cured," isn't it? This is called a "functional cure." Not technically cured, but living the same life as someone who was "cured."

(Incidentally, this is where I am now. 13+ years without treatment, but still had some bright spots on my last PET. I do not consider myself cured. There's always going to be a little part of me that expects it to come back.)

So while there aren't enough patients who will get treatment, and then go for their lifetime without cancer, to have FL be considered "curable," there are individual patients who may very well be "cured." But because the disease isn't considered "curable," it's hard to know for sure.

How does CAR-T fit into all of this?

Well, when CAR-T treatments were first approved, the clinical trial results were kind of 33/33/33. About one third of patients did not respond to treatment, one third had a response that lasted a year, and one third had a response that lasted longer than a year. (Those are very rough numbers.) Those numbers are improving, slowly, especially those whose response lasts longer than a year. In my last post, I write that Dr. Cheson says about 35% of patients in one study had a PFS of 5 years. In another follow-up, 10 patients with indolent (slow-growing) lymphoma who were given CAR-T had a median Complete Response rate of 5 years -- that's no cancer at all. The range for those 10 patients was between 1 and 114 months. So for at least one patient, it really didn't work at all. And for at least one more, it lasted almost 10 years.

To get back to Jacqueline's comment: the gentleman who believes CAR-T is a "cure" might very well be the patient who has had a 10 year response from it.  The patient with the 1 month response would probably disagree.

So, as I said, a "cure" is complicated. Some patients might very well be cured.

But for me, the numbers are a little less hopeful. Too many patients who don't get the benefit.

Which isn't to say that there will never be a cure, or even that CAR-T won't be the treatment that turns out to be a cure. I'm still hopeful that the day, and the treatment, will come. I think there's even a good chance it will come during my lifetime. (Remember, I plan on living a very long life.)

In the meantime, I'll stay hopeful, keep learning all I can about this disease, and be ready when the time comes to choose a treatment to give me the best chance at a cure.

CAR-T versus Immunotherapies in Lymphoma

ASCO Post has another video from the 2021 Pan Pacific Lymphoma Conference took place in Hawaii last month. This is a discussion between Lymphoma two experts, Dr. Bruce Cheson and Dr. Stephen Ansell. (If you've been reading a while, you now how fond I am of Dr. Cheson.) 

The video clip is called "Bruce D. Cheson, MD, and Stephen M. Ansell, MD, PhD, on Non-Hodgkin and Follicular Lymphomas: Integrating Non–CAR T-Based Treatments." 

Basically, as Dr. Ansell says, the Lymphoma treatment landscape seems to be about "drugs versus cells." On the one hand, there is lots of excitement about CAR-T (that's the "cells" part of this discussion), but also lots of alternatives that are worth being excited about, too (the "drugs" part).

Dr. Ansell points out that Dr. Cheson has spent lots of his long career as a cancer researcher looking at Immunotherapies and other non-chemotherapy options for lymphoma. He asks, where is the place for CAR-T in all of that?

Dr. Cheson points out some of the problems he sees with trying to make CAR-T the default treatment for lymphoma. For one thing, there us geography. There are very few CAR-T treatment centers in the United States that are easy to get to for most people. (He says about 75% of the patients in the U.S. would have a hard time traveling to a CAR-T center). It's also expensive. And while the data about its effectiveness looks good, it's worth taking a closer look.

For example, for patients who are not eligible for clinical trials, the numbers show that CAR-T is about half as effective as for people who are in clinical trials. (To make that clear: sometimes trials will reject patients who have health issues that might mess with the data. Someone might have heart problems, and if they died of a heart issue during the trial, it still cunts toward the Overall Survival statistics for the trial, since OS measures overall survival, not survival related to cancer. So, ironically, healthy people sometimes have an easier time getting into trials, especially phase 2 and 3 trials.)

Dr. Ansell points out that this is probably true of any treatment, not just CAR-T. In the real world, people have health issues that might make a treatment less effective.

Dr. Cheson then turns to the ZUMA-1 trial to make his point about drugs versus cells. The ZUMA-1 trial was the clinical trial that resulted in the first CAR-T approval for aggressive lymphomas. As great as the results were, Dr. Cheson points out the the 5 year Progression Free Survival for that trial was about 31%, and the 4 year PFS was 35%. Still good numbers. But a different treatment combination (a "drug"), Tafasitamab + Lenalidomide, had a very similar (34%) PFS at 4 years. For Dr. Cheson, that drug combo would be a much easier choice for many patients -- a monoclonal antibody and a daily pill, instead of travel to a CAR-T center and great expense for the "cell" treatment.

(If you're not familiar with the combo, Tafasitamab/Lenalidomide was approved for relapsed or refractory diffuse large B-cell lymphoma, including transformed FL, last summer. It's in a trial for Follicular Lymphoma, but no results yet.)

Dr. Cheson admits that, if a patients came to him very excited about CAR-T, was willing and able to travel and afford the treatment, he would certainly recommend it. He's not anti-CAR-T by any means. But he also thinks that a patient in that situation would be likely to do just as well with the other combo, without the hassle. 

He also mentions that there are a number of other promising treatments in the pipeline that may challenge CAR-T, including several bispecifics.

The upside to it all is that, as both of these experts agree, things are evolving fast -- there are lots of new and exciting treatments coming our way. We're still learning about the genetics of Follicular Lymphoma, and the more we learn, the more researchers will be able to target those cancer cells effectively.

As much as they seem to be "debating" these two choices, they also are clear that both are great choices for certain patients, and we'll have more great choices in the future.

I'll add this -- with the choices we have, and knowing that some will work better than others for certain patients, it's important to get second opinions when we can, especially from lymphoma experts. General oncologists can be great, but a specialist might see something that makes them think that a newer treatment might be especially effective, something a general oncologist might miss.

Lots to be hopeful for. Watch the video if you can (and, again, sorry -- there's no transcript for translating. But you might enjoy the Hawaiian music at the beginning, anyway).