Some Treatment Approvals outside the U.S.

I've said more than a few times that I know my perspective on Follicular Lymphoma is very much an American one. I tend to focus on treatment approvals by the FDA in the United States, and write about issues that affect Amercan patients. Which makes sense, of course, since I live in the U.S.

But I also try to keep up with things that are happening outside my country when I can. I have readers from about 80 different countries, according to my Google analytics. I want to provide relevant information to as many of you as I can.

So here's some news from the last couple of weeks that may excite some you.

EU approves Odronextamab

First, the European Commission has approved Odronextamab for patients with relapsed or refractory Follicualr Lymphoma who have had at least two prior treatments. 

If you've been reading the blog lately, you know that Odronextamab is a bispecific antibody, a type of treatment that many oncologists are excited about. You also know that there was some slightly revised data published recently from the clinical trial that was used to approve the treatment. And you also know that in the U.S., the FDA denied approval (delayed approval, really) for Odronextamab a few months ago because they wanted to see more data from a larger trial. So you folks in Europe have access to this sooner than those of us in the U.S.

EU Approves Epcoritamab

The EC also granted "granted conditional marketing authorization" for the expanded use Epcoritamab for patients with relapsed or refractory FL who have had two or more treatments. Epcoritamab is also a bispecific antibody. It was approved by the EC for Diffuse Large B Cell Lymphoma, so this approval makes it "expanded use." The "conditional" part of the approval seems to come from a planned study that the makers of the treatment will conduct to try to cut down on Cytokine Release Syndrome. But the treatment is now available. 

Epcoritamab was approved by the FDA about two months ago. So it looks like we have a draw, as far as whether Europe and the U.S. approved a bispecific before the other. We may need to go to a shootout.

(See? A Football comparison. I can write for non-U.S. audiences. I didn't even call it Soccer.)

EU Approves Liso-Cel

Finally, the European Medicines Agency approved a Type II variation application for Liso-Cel (also known as Breyanzi) for r/r FL patients with at least two prior treatments.Liso-Cel is a CAR-T treatment. Before I get into the FDA approval, it might be important to know what a Type II variation is. Then we can determine who won this football/soccer match....

But wait. What's this? Japan is on the pitch!

Japan's Ministry of Health, Labor, and Welfare has also approved Liso-Cel for r/r FL patients, but with only one prior treatment, not two. 

This changes everything! We have to sort this out before we can determine a winner of this match! I'll need to get back to you!

That was silly, I know. But truly, the winners are all of the thousands of r/r FL patients in many countries who now have access to the some of the treatments that are most exciting these days. Expanded options are good for all of us. 

And while many FL patients have relapsed or refractory disease after two treatments -- and those are probably the patients who need treatment options the most -- some of us have r/r disease and just one treatment, and others are still benefiting from their first, or have yet to receive treatment. So I hope there are more approvals coming soon that I can share with you. 

That would be some World Cup-level stuff.

 

Liso-cel

https://www.cancernetwork.com/view/ema-validates-type-ii-application-for-liso-cel-in-r-r-follicular-lymphoma

Financial Problems, Mental Health, and Cancer

As I have said a few times in recent posts, I have been thinking a lot more lately about issues of survivorship -- not just what happens between diagnosis and treatment, but what happens after we're told we're "all better." 

That involves a lot of other issues, and they certainly include physical issues. We all deal with the physical issues that come with having cancer. And most of us also have to deal with the side effects of treatment -- short-term and long-term. (I'm dealing more and more with long-term side effects these days.)

But there are lots more non-physical side effects that we need to deal with, too. Emotional side effects are certainly prominent, and it's important to be aware of them and have a plan for dealing with them.

And then there are the financial side effects of having cancer. More and more advocates are using the term "financial toxicity" to describe these. Just as a clinical trial report will focus on "toxicity" (usually meaning the physical side effects of treatment), doctors and hospitals and pharma companies are being asked to pay attention to financial toxicity -- the side effects related to money.

This is an especially big issue in the United States, where for many people, our health insurance is tied to our jobs. Many other patients in the U.S. have some kind of government-sponsored health insurance, whether Medicare or a state- or federal-sponsored healthcare program. But even with health insurance, some treatments can cost a huge amount of money. CAR-T is a great treatment for many people, but also can cost close to a half million dollars. 

I can't say how much of a financial burden that cancer is for people outside the U.S. But even if treatment is paid for, there are so many other financial issues -- the cost of transportation to doctor appointments. Prescription medications for side effects. Loss of a job, and the cost of finding another one. Or loss of wages even if the job isn't lost. It all adds up.

This probably isn't news to any of you. Cancer is expensive.

But I also think it can be good to know that you're not the only one having problems. Blood-Cancer.org published a piece yesterday by Daniel Malito called "The Financial Cost of Cancer and How To Deal With It."Dan often writes about the funny things that have happened to him as a blood cancer patient. This article isn't so funny. He offers some advice about financial issues, such as disputing hospital bills. 

I thought it was a timely article, given how much I've been thinking about these kinds of issues lately, and given that the medical journal JCO Oncology Practice also published a piece a few days ago about financial toxicity.

The JCOOP article is called "Exploring the Relationship Among Financial Hardship, Anxiety, and Depression in Patients With Cancer: A Longitudinal Study."

In some ways, what the article says is not at all surprising -- basically, that there's a link between financial hardship and mental health in cancer patients, But I think it's important anyway, for a couple of reasons.

First, it's a longitudinal study -- it follows a number of patients for a long period of time (over a year), rather than doing a survey that measures what is happening at a particular moment (also important, but also much more common than a longitudinal study, which takes more effort to conduct). It's easy to say "Of course there is a link between financial issues and mental health." It's important to have a team of experts actually study it and write it up in a medical journal. It kind of makes it "official" that way.

And that's the second reason it is an important article -- it's in a medical journal aimed at clinical oncologists. Those are the doctors that see cancer patients every day. They are the ones that need to be aware of how a treatment will affect a patient's quality of life. They need to be aware of financial toxicity and its relationship to mental health. They need to know what survivorship means.

The JCOOP article is fairly easy to read, and I suggest you take a look if you're interested. But I'll mention one thing that I found most interesting -- financial hardship and mental health feed one another.

The researchers looked at data from 2,305 patients with cancer. They measured financial hardship, depression, and anxiety at 3, 6, 9, and 12 months after the study began. They found, for example, that having symptoms of depression at the beginning of the study and 6 months later, or having anxiety at 9 months, could predict that financial hardship was likely to happen later on. But it also predicted that having financial hardship at the 9 month point predicted that it was likely that symptoms of depression would come at the 12 month point.

In other words, financial problems can lead to mental health issues, but mental health issues can also lead to financial problems -- they are intimately related. 

In all, the researchers fund that about half of the patients in the study experienced financial hardship. As they say, "These findings underscore the need for a comprehensive approach in cancer care that concurrently addresses anxiety, depressive symptoms, and FH, recognizing their interconnected impact."

In other words, "Hey, doctors! Pay attention to patients' lives, even if their cancer seems to be getting better!"

And of course, survivorship also depends on us as patients. We need to be aware of the kinds of issues that we are likely to face -- physical, emotional, financial. And we need to make it a point to bring those issues up with our doctors, and ask if there is help available. Many cancer centers have survivorship programs, and many doctors don't know enough about them to make them effective.

So it's up to us as patients to make sure we are taken care of. 

Thanks for reading, and take care of yourselves.

New Data for Odronextamab

The medical journal Annals of Oncology published some updated data on the bispecific Odronextamab last week. It will be very interesting to see the implications.

You may remember Odronextamab being in the news a few months ago. It's a bispecific antibody, attaching to the CD20 protein on a Follicular Lymphoma cell and a CD3 protein on a T cell. (Read a little more about Bispecifics here as a reminder.)   In March, the FDA denied the application for Odronextamab to be approved, but only temporarily. The treatment had been granted accelerated review in October 2023, but in March, the FDA decided that it wanted to see more data. The application had been submitted with data from phase 1 and phase 2 trials.

The results from those trial were good. In the phase 2 trial, patients with Follicular Lymphoma had an Overall Response of 82% and a Complete Response of 75%. Durability was good, to, with a median duration of response of 20.5 months and median Progression Free Survival of 20 months. Safety was a potential issue, with 100% of the 131 patients with FL experienced side effects, with 78% of them experiencing grade 3 (serious) side effects, including Cytokine Release Syndrome (in over 50% of patients in the trial), low blood cell counts, diarrhea, fever, and joint pain. 

The article in Annals of Oncology is called "Safety and Efficacy of Odronextamab in Patients with Relapsed or Refractory Follicular Lymphoma," and the results are slightly different. It's looking at 3 fewer patients than the earlier data, with an ORR of 80% (vs 82%) and a CR of 73.4% (vs 75%). Meduan PFS is about the same, and the duration of CR is 25 months.

Still, the biggest concern seems to be safety. About 16% of patients had to stop the trial because of side effects, and the numbers for Cytokine Release Syndrome, Neutropenia (low whire blood ells), and Pyrexia (fever) are high. 

The advantage of having this published in a medical journal, even if the numbers haven't changed much, is that it has gone through peer review -- other experts have seen the data and confirmed it, and potentially approved the authors' assessment of their own data ("generally manageable safety.") The authors discuss safety issues in their conclusions, and point out that the trial happened during the Covid period before vaccines, which may have affected some patients results. They also say that, based on the safety data, they plan to conduct the trial on an out-patient basis. In other words, in the phase 2 trial, patients had to go to the hospital to receive the treatment and be monitored. They think side effects are manageable enough that hospitalization won't be necessary as they expand the trial to get more data.

So it looks like there isn't enough new data here to justify FDA approval. But having it all be reviewed by outside experts, and seeing the optimistic analysis from the authors, means that we might see another application soon -- within a couple of years, certainly, maybe sooner than that. (Assuming the phase 3 trial doesn't show any new safety issues.)

So this is overall good news, even if it's mostly old news.

 We'll definitely keep an eye on this one.

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.

Validating FL Symptoms

Interesting study last month from the Journal of Patient-Reported Outcomes.

Before I get into it, let me say how great it is that there is a medical journal called The Journal of Patient-Reported Outcomes. It's an official publication of the International Society for Quality of Life Research, which encourages research into Quality of Life with regard to health and medicine. They say this kind of research is important because it ill help us "Understand the potential benefits and risks of a proposed treatment;Weigh the impact of a decision on symptoms, function and life expectancy;Live their lives more fully." 

As you can see, all of this ties into all of the survivorship issues I've been thinking about so much lately. It's not enough to have a treatment that is effective, or even that is both effective and safe. There needs to be some idea of how the treatment, and the act of being given a treatment, and of receiving a cancer diagnosis in the first place, all affect our ability to live a happy life. 

Back to the article in the JPRO. It's called "Content validation of the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (NFLymSI-18) in indolent B-cell non-Hodgkin’s lymphoma."

It's a long title for a fairly simple idea -- are the physical and emotional symptoms that we think affect patients with indolent lymphomas actually the symptoms that affect them? 

You'd think that it would be obvious -- anytime we look up Follicular Lymphoma online, we get a list of symptoms -- swollen lymph nodes, fatigue, etc. But there are a couple of potential issues with whether or not that is accurate. The first is that the disease presents itself so differently for each of us. Some of us are diagnosed because the FL is causing big problems. But others of us are diagnosed with few or even no symptoms at all, or are diagnosed accidentally. It's a strange disease that way.

But the other issue is that sometimes a diagnostic tool can get in the way of the thing its trying to diagnose. I'm sure many of you have had this experience - you go to WebMD or some other site online that lets you enter your symptoms and then provides you with a range of possible diagnoses. In the end, they aren't helpful, because the at best, the tool presents too many possible options. At worst, the tool wasn't built well, and it doesn't accurately account for the variety of symptoms for a disease (you put in swollen lymph nodes but not fatigue, so it doesn't list FL as one of the choices). This is a doctor's nightmare, and why they don't like us going to "Dr. Google." (I hate that phrase -- it's used by some doctors to completely discount a patient's needs and experiences.)

There is a tool that can be used to measure symptoms called the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (NFLymSI-18). You can actually download a copy if you want to see it. The number 18 in the name comes from the 18 items that are on the list. It's a self-administered list of symptoms with a lickert scale (meaning you are asked whether or not you have experienced a symptom within the previous seven days on a scale from "not at all" to "very much." The survey begins with the statement "Below is a list of statements that other people with your illness have said are important."

The survey has been around for about 8 years, and has been used in clinical trials. But it hasn't been tested content validity specifically for people with indolent NHL (which can be a very different thing from ore aggressive types of lymphoma).

For the study, the survey was given to 18 patients with indolent lymphoma from a single cancer center. Of the 18 patients, 12 had been diagnosed with FL, 5 with Marginal Zone Lymphoma, and 1 with  lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia. They were given the survey, and then followed up with "cognitive debriefing," where they were interviewed in greater depth about their symptoms.

The results found that the NFLymSI-18 survey was accurate, and did indeed capture the symptoms that patients with indolent lymphomas experience. 

There were limitations to the study -- it was very small, the patients were all similar in race and educational background, and they all came from one single cancer center. So it's hard to say this is an accurate instrument for all indolent lymphoma patients. But it does provide a good start for a larger study.

More importantly, I think, it that it validates the importance of asking patients what they experiencing. The survey was initially created with input from patients, which is great. But continuous input is even better. It's good for all of us to have a sense that what we experience is common among other patients with out disease.

At the same time, it's also important to remember that the disease really does affect each of us differently. Not just in the way our symptoms present. But also in the way those symptoms affect us emotionally. The survey asks we have "emotional ups and downs" and if we "feel uncertain about our future health" -- excellent things to ask about. But it also doesn't ask things like "I worry about my family" and "I worry about how I'm going to pay for all of this treatment" or even "I worry about whether my friend will be able to pick me up after my appointment." That's probably all included in a general statement, but no survey will even really capture everything we feel.

And I think it's worth remembering that even those small worries that only we are experiencing individually are still "valid content." It's OK to feel how you feel, even if someone else isn't also feeling it.

There's no one way to be a cancer patient. Don't let anyone tell you different.

 

Oncologist Appointment

I had a six-month appointment with my oncologist yesterday. Everything looks good.

I knew this appointment was going to be a little bit different. My regular oncologist, Dr. H, has been on vacation, so when I made the appointment six months ago, I made with his Physician's Assistant. I don't know if other parts of the world have PAs.They do many of the same things that a medical doctor can do, though they don't go to school for as long, and the usually work under the supervision of a medical doctor. It makes sense that I would see a PA for an appointment like this -- I haven't been feeling any symptoms, and this was to get some blood tested and a physical exam. I don't have any problem with a PA (and you can usually get an appointment much sooner with a PA than you can with an MD).

I got to the appointment early, which I usually do, and made my way through the parking garage and the maze that my cancer center can be. It's kind of a strangely designed place. I have to park on a particular floor of the garage, then go into the building, then take an elevator up one floor, then go across a bridge, and then sign it at a desk and get a sticker that says I'm a patient or a visitor. And only then can I start looking for where I need to go.

So when I got into the elevator at the garage, I wasn't surprised when a couple about my age came into the elevator. "Are you going down?" the man asked. 

"No, I'm going up," I said.

The woman said to the man, "No, we're going up, too."

The man said, "Are you sure? I think we go down."

I asked if they were going into the hospital, and they said yes, so I assured them they needed to go up one floor.

As we were riding, the man said, "This place is so confusing."

"Yes," I agreed, and then I joked, "Yeah, kind of a bad choice to make a building so confusing when it's full of people with chemo brain."

They didn't laugh. 

I had to remind myself that not everyone likes cancer jokes, or just might not be in a place where they can appreciate them. 

So I made sure I got out of the elevator before the couple, and when we got to the desk to sign in, I made sure I was loud. "YES, I HAVE AN APPOINTMENT FOR A BLOOD DRAW AT 8:30. AND THEN I HAVE AN APPOINTMENT TO SEE MY ONCOLOGIST AT 9:00."

I just wanted to make sure they knew I was a cancer patient, and not some random weirdo who makes jokes about chemotherapy.  

I hope  they had a good appointment.

I went to get my blood draw, and the phlebotomist introduced herself as "an intern." She did a good job, and I made sure to tell her so, and to make sure her supervisor heard me. (I'm a teacher -- I know positive feedback is helpful.)

There was a short wait to see the PA, but he apologized and did the exam. It was a fairly short visit. He had read my file, and asked me about my history with FL. Only part of the bloodwork results were available when we met, but what he had looked good. (The rest of the results came in last night; they look good too.) The physical exam was fine, too.

It's interesting -- he gave me a little bit of background on Follicular Lymphoma and what it is. Nothing I didn't already know, basic stuff. But it made me think, "Wow -- he doesn't know who I am."

That sounds arrogant, and I don't mean for it to be. But I kind of chuckled to myself. I have never told a doctor about the blog, or about any of the other advocacy work that I do. I know from working with physicians that some of them can be very wary of a patient who thinks they know more than the doctor does. They say things like "Google didn't go to medical school. I did." I've never had a doctor say that to me so directly, but I have definitely had doctors try to "put me in my place" when I gave even a hint of medical knowledge. I absolutely DO NOT think I know as much as a medical doctor does. As I remind you all as often as I can, I'm not a doctor or a cancer researcher. But I do like to think I can have an informed conversation about cancer-related topics with an expert, and I know which questions to ask.

Anyway, that was going through my head as I listened to the PA tell me about FL. 

So it was a good appointment, despite my unsuccessful cancer joke, my student phlebotomist, and my own suppressed arrogance.

I hope all of you have good appointments in the near future as well.

We're moving past the post-ASCO research hangover, so I'm seeing more FL research results in my feed lately. I should have some good stuff to pass along soon.