Epcoritamab + R-Squared (+ Pharmacists)

In my quest for some Follicular Lymphoma-related reading material during this slow news time, I found an article in Pharmacy Times called "Epcoritamab Plus Lenalidomide and Rituximab in Practice: A Focus on EPCORE FL-1." 

As you can guess, Pharmacy Times is aimed at pharmacists, the folks who manage and sometimes advise on medications. That's the angle that makes it kind of interesting.

It's mostly a summary of the EPCORE FL-1 clinical trial results. EPCORE is the general name for a series of studies that have looked at the bispecific Epcoritamab. The EPCORE NHL-1 study looked at patients with several types of Non-Hodgkin's Lymphoma who were treated with just Epcoritamab. The EPCORE  FL-1 study is the one described here, and is the one that got people very very excited at last year's ASH conference.  This trial involves only FL patients, and combines Epcoritamab with R-Squared (Rituxan + Revlimid, also known as Lenalidomide).

The article provides a good overview of all of the successful trials for Epcoritamab, and especially for EPCORE FL-1. This was a phase 3 global study, with 488 patients from 30 countries. Patients had refractory or relapsed disease and had previously received a monoclonal antibody + chemotherapy. Patients were divided into two groups: one received R-squared and the other received R-squared plus Epcoritamab. 

Results were very positive. After a median follow-up of 14.8 months, The Epcoritamab group had a 95% Overall Response Rate (versus 79% for the R-squared only group). Most other measures were better in the Epcoritamab group did better than the R-squared only group -- including Progression Free Survival, Duration of Response, and Time to Next Treatment. It's easy to see why people were so excited at ASH.

Safety was also good, with low white blood cells counts (neutropenia) and infections being the most common side effects. Cytokine Release Syndrome, a major concern, occurred in 26% of patients, but all cases were manageable. Other side effects are described in the article. This isn't really providing any new data, just a summary of what was already reported.

What I found so interesting, though, were the "pharmacy" aspects of the article.

For instance, the article goes into some detail about dose escalation, something that gets mentioned in most oncology articles, but not in much detail.

In the EPCORE FL-1 trial, the dosing was changed partway through. At first, patients received a smaller dose first, and then a larger second dose. But in later studies, it was divided into three steps instead of two, so patients received it more gradually. Researchers think this probably helped lessen the severity of some side effects, including CRS. 

It also goes into some detail about "premedications" -- intravenous hydration, an antihistamine, an antipyretic (like acetaminophen), and corticosteroids (preferable dexamethasone) -- as well as "postmedications," including two to three liters of oral fluids within 24 hours after receiving Ecoritamab, plus corticosteroids (dexamethasone again) for 3 days.

I can picture an oncology pharamacist reading the results of the EPCORE FL-1 in an abstract, and thinking "That's nice, but what were the premedications?!" 

And I say that with great admiration, from one amateur Cancer Nerd to a professional one.

I don't really think about the role that pharmacists play in our treatment. 

When I had my Rituxan infusions, I had a blood draw first. Then I met with the oncologist to make sure everything was OK and I was well enough for the day's dose. Then I went to the treatment room, where the excellent Nurse Sue took care of me for a few hours. But somebody had to prepare the Rituxan. Somebody had to worry about my premedication hydration and the antihistamine I needed when I had an allergic reaction. 

It's kind of cool to think that there's someone else behind the scenes, keeping an eye on things. The size of our care team is really large.

I don't ever remember talking to a pharmacist when I needed treatment, but education is certainly a job for pharmacists, and the article discusses the role that pharmacists can play when a patient needs education about any of the medications that are a part of this treatment process. 

It's just kind of nice to have a broader perspective on things. It's one more person who cares about us, and who is looking out for us. We're lucky to have these hidden angels.  

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. 

 

 

R-CHOP 15 Year Follow-Up: A Cure for FL?

The big news in the world of Follicular Lymphoma this week is an article in JAMA Oncology describing results of a 15 year follow-up of FL patients who received R-CHOP (or CHOP + Radioimmunotherapy). The study suggests that 42% of the patients in the cohort have been cured of their FL. It's a big deal because it's really the first time anyone had seriously suggested that FL might be curable.

There's a lot going on in this study. It's worth looking into a little further.

The article is called "Treatment of Follicular Lymphoma With CHOP and Anti-CD20 Therapy: 15-Year Follow-Up of the SWOG S0016 Trial." The goal of this analysis was to see how many of the patients in the trial were cured after 15 years. They determined which patients were cured by a statistical method called "cure modeling," which provides an estimate of how many patients were cured.

I think that's important to note here. Part of the problem with determining whether someone is cured has been the nature of FL. With many other cancers (as I'm sure you are aware), if a patient is disease free after 5 years, they are often considered cured. That's harder with FL, since some patients will have the disease return after 6 years, or 10 years, or 15 years. So it's risky to say someone has been "cured" of their FL. 

And it's why many FL experts use the term "functional cure" instead. Someone can be diagnosed at 65, get a Complete Response, and never need treatment again, and die of something unrelated at 85 years old. Were they "cured"? It's hard to say. But they lived a life as if they were cured -- it was a "functional cure."

So this study defined "cure" using statistical methods because it's really difficult to say whether or not someone was cured the way they could for patient with something like colon cancer.

I won't pretend to understand the statistical analysis of the cure modeling, but I will say that since the article was peer-reviewed, it would have been approved by other experts in statistics before it was published, so I don't have any doubts about the analysis.

The SWOG study itself involved 531 patients. They received either R-CHOP or CHOP-RIT between May 2001 and October 2008. I don't write about CHOP much these days, so a reminder: CHOP is a traditional chemotherapy made up of four components (Cyclophosphamide, Hydroxydaunorubicin/doxorubicin, Oncovin, and Prednisone). It's been around for a while, and it's still a very popular treatment. R-CHOP is CHOP combined with Rituxan (rituximab/mabthera). When R was added to CHOP about 30 years ago, it increased its effectiveness. It's pretty standard now to include R with CHOP. RIT, RadioImmunoTherapy, is a treatment like Zevalin. It's essentially something like Rituxan, which can find the CD20 protein on a Lymphoma cell, but with a tiny bit of radiation attached to it, so the radiation can be delivered directly to the cancer cell. 

So of the 531 patients in the study, 267 received R-CHOP and 264 received CHOP-RIT. The 15 year Overall Survival rate was 70%, about the same for each of the two groups, though the RIT group had a better 15 year Progression Free Survival (the cancer didn't come back for 15 years for 47% of the CHOP-RIT patients, versus 34% of the R-CHOP patients). 

The cure modeling estimated that 42% of the patients in the study had been cured. The highest cure rates were in patients with low FLIPI scores and normal β2 microglobulin levels, essentially the patients with the lowest risk. (You can read more about FLIPI levels here, but keep in mind that it doesn't say anything about you as an individual, even though it seems like it does.) This isn't a surprise, really -- we expect less aggressive version of FL to be less problematic and more successful with treatment.

One important finding of the study was that the rate of relapse declined over time. For the first 5 years after treatment, 6.8% of patients in the study relapsed. But between years 15 and 20, just 0.6% of patients relapsed. So the longer the patients went in the study without relapsing, the less likely it was that their disease would come back. 

That's really important. Think back to the idea of "functional cure." It's hard to say someone is "cured" because the disease might come back after 10 or 15 years. But this study shows that it's much less likely to happen, so someone can be more confident after 15 years that the "functional cure" is an actual cure.

Te conclusion to all of this from the researchers is that maybe FL isn't incurable after all. The call this a "paradigm shift" -- a complete change in the way we think and thus the way we act. It could mean that doctors have very different conversations with patients, and that maybe R-CHOP is presented as a possibility for someone who might want a cure. It also has implications for future research.

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

As I said, there's a lot happening here. This article was published about 4 days ago, and I've been waiting to hear what other FL experts have to say. So far, I haven't seen or heard much, but I think everyone is trying to take some time and digest it all. Paradigm shifts don't happen in 4 days -- they take years for everyone to break out of the way they have been thinking for so long (at least according to Thomas Kuhn).   

And I absolutely understand that. We (meaning much of the Lymphoma community) get so locked in to the idea that "newer is better" -- that every new CAR-T or bispecific or inhibitor must be an improvement over chemotherapy -- that's it hard to see a study like this and not be skeptical. It's certainly my own reaction to it, and I immediately start with a long list of "Yes, but" statements. "Yes, but it's just a statistical estimate, not an actual look at the patients." Or "Yes, but 42% is hardly a cure for all of us." Or, "Yes, but it's still a fairly small number of patients in the study, compared to the thousands that are diagnosed every year."

Particularly for me as a patient who was diagnosed 18 years ago, and who has been told this is incurable for all of that time, it's pretty tough to suddenly think otherwise, and even tougher to think the cure might be from chemotherapy.

That's why I'm especially impressed with the statement from Dr. Jonathan Friedberg from the University of Rochester Wilmot Cancer Institute. He was one of the authors of the study, and he's the one who is talking about paradigm shift (see the story that came out of the Fred Hutch cancer center where he is quoted). He's a Lymphoma Rock Star, doing cutting edge research on FL, and he's willing to look at the data and say "Maybe it's chemotherapy after all." 

The few comments from Lymphoma specialists that I have seen have been positive. It's clear that no one expects R-CHOP to suddenly replace bispecifics and CAR-T. But it could mean that conversations with patients are different. For some patients with low risk disease, and who are otherwise healthy and can tolerate the side effects, maybe R-CHOP is an option. CHOP contains an anthracycline, a type of drug that can be very effective but can also cause long-term heart issues. That kind of factor will need to be taken into consideration. 

I saw one commentor who said this study will have an effect on future research in a couple of ways. First, long-term studies of FL treatments will be measured against this. It's really interesting that this come out just after a 15 year follow-up of R-Squared. It's a much smaller study -- only 79 patients. But could the same cure analysis be applied to it? Could it be applied to a larger study of 500+ patients? If it was, could we make a direct comparison between the two treatments? It will be hard to look at any long-term study of an FL treatment now and think "Yeah, but....does it have a better cure rate than 42%?"

Another way this might change research is that there might be a greater emphasis on second-line treatments. That emphasis already exists, in some ways -- most new treatments get approved for relapsed/refractory disease first, and then as first-line treatments. But this cut back on the number of treatments that do that second step and get approval as a first-line treatment. In other words, we could possible have something closer to an agreement on how newly diagnosed patients are treated, and that treatment could be traditional chemotherapy. 

That's not to suggest that everyone will be getting chemo from now on. There are and will be lots of options out there, and more to come, for a long time. But I expect those conversations to happen.

I'm going to keep an eye open for more commentary about this. I expect some of the oncology websites to have videos of experts discussing this. I'm hoping for more debate-style videos, with multiple experts arguing for and against using R-CHOP. They would be more enlightening to me.

But I think the main take away for all of us should be the same thing. For at least some FL patients, a cure may be possible. For the first time, people seem willing to say so. 

R-Squared 15 Year Follow-Up

A couple of weeks ago, a reader named Johnatan sent me a link to an article from Blood and asked if I'd seen it yet. I had not seen it -- it came out while I was reading all of those ASH abstracts. But it's worth taking a look at.

The article is called "Phase II Trial of lenalidomide plus rituximab (R2) in previously untreated follicular lymphoma: 15-year follow up data from MDACC Trial." 

It's an important study for a couple of reasons. 

First, it's always great when we get long-term data about a treatment. And 15 years is a long time. I love the idea that this study was starting when I was just out of treatment, and I had no idea it was even happening. Just think about how many amazing clinical trials are happening right now that we won't even hear much about for a few years.

But that 15 year follow-up is great. We always assume that a new treatment will continue to be good, but it's great to see the actual data that shows it.

Second, a long-term study of R-Squared (Lenalidomide + Rituxin) is especially important because it seems that R-squared is becoming the base treatment for lots of new combinations. In other words, researchers used to say "What would happen if I added thing new thing to CHOP or Bendamustine?" Now they're saying "What would happen of I added this new thing to R-Squared?" Just look at the excitement over Epcoritimab. It's not on its own -- it's in combination with R-Squared.

The original study that the article discusses was a phase 2 clinical trial at MD Anderson Cancer Center. It involved 79 patients with Follicular Lymphoma who had not yet had treatment. The participants were broken into two groups, one receiving six cycles of the combination and one receiving 12 cycles. The participants had a range of risks, based o FLIPI scores. The Overall Response Rate was 99%, with the Complete Response Rate at 87%.  Even with the long-term follow-up, a large number of patients could not be evaluated, with almost half not showing up for clinical visits after a while, particularly during the Covid pandemic.  

Despite that, the long-term follow-up numbers look great. The median Progression-Free Survival (the time it took from diagnosis for the disease to progress) as 16.5 years, with 61% of patients having their disease not progress for 10 years. At 30 months, 76% of the patients were in Complete Response. The patients who were in the group that received 12 cycles of the treatment had a longer median 10 year PFS than the 6 cycle group (75% vs 70%). And while 9 of the patients being followed died during the 15 year follow-up, only one was for a cause related to Lymphoma. The 10 year median Overall Survival was 95%. There were 11 patients who experiences POD24, progressing with 24 months, and 5 whose disease transformed, with the time to transformation ranging from 9 months to 15 years).

I would have loved to tell you that every patients was doing great after 15 years, but that's not how things work, unfortunately. But I can tell you that these 15 year follow-up numbers are excellent. A 10-year median Overall Survival of 95% is kind of amazing. 

So it's easy to see why R-Squared is becoming the base treatment for other combinations. I have still not seen numbers that show that R-Squared has become kind of the default treatment for patients (the most recent one I can think of had R-Squared being given to less than 10% of FL patients).  But things change over time. 

Thanks, Johnatan, for sharing the link to the article. I'm always happy to receive things like this, in comments or by email. Always feel free to contact me if you think I can be helpful, and I'll do my best to help.

 

More ASH Reviews

 I'm going through all of the links I have saved from the last month or so, and I have a few more related to ASH that are worth sharing, Not necessarily any new information, but at the very least, it's confirmation that some good things were presented at the conference last month.

The website Medscape published two video reviews of the conference.  The first is called "ASH 2025: The Clinical Impact of New Therapies and Long-Term Outcomes in Follicular Lymphoma." It features Dr. Kami Maddocks of The Ohio State University. She discusses some of the more important presentations at ASH, and focuses on clinical impacts -- how the new information might directly affect current patients.

Of course, she focuses on the data related to Epcoritamab + R-Squared, which she says is "going to change practice." In other words, we're likely to see it recommended for patients who have Relapsed or Refractory disease who are need of a treatment option. She also mentions Tafasitamab plus R-Squared, and the issues related to sequencing CD19-directed therapies. That is, patients who received Tafasitamab kept the CD19 protein on their cancer cells, meaning a teatment like CAR-T, which targets CD19, should be used after Tafasitamab, not before. (The presentation that discussed this was also on The Leonard List for this year.)

Dr. Maddocks also mentions the research that looked at long-term (20 year) follow-ups of FL patients, which found that 40% of patients who received immunochemotherapy (like R-CHOP or R-Bendamustine) were still disease-free after 15 years. And about 20% of patients who watched and waited continue to do so for 15 years. Finally, this study also showed that the risk of Transformation to a more aggressive Lymphoma decreases after 10 years. Dr. Maddocks says this is all important information when oncologists counsel FL patients about long-term outcomes. (This all sounds very familiar to me, but I can't find a link for this presentation, unfortunately, and the video doesn't include it. But it's great news -- I love a good long-term follow-up.) Finally, she discussed the research about GLP-1s and indolent Lymphomas including FL, something else that was on The Leonard List. (You might remember that I was hesitant to discuss that one. Dr. Maddocks thinks it looks very interesting, but there needs to be more data collected about it.)

So lots of good information, with the focus on how it all plays out right now in the doctor's office.

The second video review from Medscape is called "New Options in Follicular Lymphoma From ASH 2025," and features Dr. Michael R. Bishop from the University of Chicago. As the title suggests, Dr. Bishop is interested in some of the new treatments that were presented at ASH. Of course, he starts with Epcoritamab (because that's what everyone is excited about -- he calls it "The Big News" from the conference. He also mentions the presentation on Epcoritamab + R-Squared in untreated FL. He wants to see long-term follow-up to make sure the excellent responses will last, and he points out that it was a very small trial.

 Dr. Bishop also looks at a presentation on the CAR-T known as Liso-cel. In this research, Liso-cel was given to FL patients who were "heavily pre-treated" -- who had already received at least two other treatments. The results were great -- a 97% Overall Response Rate, including a 94% Complete Response. After 36 months, 75% of patients had not yet needed another treatment.  (Sorry -- I don't have a link for this one, either, but it's no surprise that a CAR-T was effective, though Dr. Bishop did point out that there were some secondary cancers in some patients.)

He also discussed another of The Leonard List presentations, this one looking at the Gallium Trial, showing that mutations in EZH2 and CREBBP could help predict success with Bendamustine. This research is important in showing how biomarkers can help guide treatment.

So, again, not much that hasn't been covered already, but I do think it's important to show that multiple Lymphoma experts see certain research as moving us forward. It's hard to see that when just reading abstracts. I enjoy hearing experts tell me what excited them after the conference is over. If you've ever been to a professional conference of any kind, there's a special kind of magic that you feel afterwards, when you have all of this new knowledge that's really exciting. These videos capture just a little bit of that.

More soon. 

 

A Few Approvals

Hello all, and welcome to 2026.

It's been a week since I have posted. I usually try to get something up a little sooner than that. But I started the new year with some computer problems, and it's taken a few days to get things fixed. Thankfully, I'm back to writing. I supposed I could have written a blog post on my phone, but honestly, I'm just too old for that. The buttons are too small, the words are too small, and my patience is too small. I wear progressive lenses for a reason. 

On a related note, Spotify gave me my "Listening Age." If you are unfamiliar, the music steaming service Spotify ends the year by giving you some data about your listening -- the songs or artists you listened to most -- that kind of thing. But they also give you a "Listening Age," a measurement of how old the music is that you listen to. So if you listen to a lot of contemporary music, you'll have a young Listening Age. My Listening Age is 69. I'm not only too old to write with my phone, I'm also too old to listen to anything that wasn't played at my high school prom.

So, just to sum up: 

My biological age is 58.

My Listening Age is 69.

My Lymph Node Age is about 93.

Just so you know what you're dealing with as we enter the new year.

**********

Unfortunately, I also have a hard time reading on my phone, so I'm behind on Lymphoma news to share with you.

So I'll pass along some of the approval news that has happened in the last few weeks. I haven't been able to share it because I have been focused on ASH.

The big Follicular Lymphoma approval news has been the FDA approval of subcutaneous Mosunetuzumab.  Mosunetuzumab was the first bispecific approved for FL (though Epcoritamab has been in the news a lot more lately). A quick reminder -- bispecifics work by attaching themselves to cancerous B cells, and then also to T cells, which are immune cells that can eliminate the cancer cells. Up until now, Mosunetuzumab has been administered intravenously, through a vein in the arm, over a period of 2 to 4 hours. With the subcutaneous injection, that time is reduced to about 1 minute. A clinical trial showed that the subcutaneous version was as effective and as safe as the IV version. This is, if nothing else, a Quality of Life issue, with less time spent in a hospital or clinic, and more time doing other things. Ideally, this will also bring the cost down. 

In non-USA approval news, the European Union approved Minjuvi (Tafasitamab) plus R-Squared (Revlimid/Lenalidomide and Rituxin) for patients with Relapsed or Refractory Follicular Lymphoma. I wrote about this in November, when it had been given it's almost-approval, but now it's official.

Also, Japan's Japan's Ministry of Health, Labour and Welfare approved the same Tafasitamab for the same population. I briefly mentioned both of these approvals in my "predictions" post, but I thought they deserved a little bit more attention than I gave them then.

There are a few more interesting FL-related articles that I have seen fromm the last few weeks. My old eyes will have an easier time reading them, and my old fingers will have an easier time writing about them, so look for them soon. And of course, look for my diagnosiversary post next week. I'll have some things to say.

 

How Were My 2024 Predictions?

This will be my last post for 2025, so I want to revisit my last post from 2024, called "Year-End Predictions." Just for fun, I made three predictions about Follicular Lymphoma for 2025.

I'm guessing a lot of you saw the calendar turn to December a few weeks ago and thought, "I wonder how Lympho Bob's year-end predictions went? I've been dying to know if he was right, because he's always so right about everything!"  Well, here we go. Your wish is about to come true.

My first prediction was "Tafasitamab won't be the 'game-changer' that the headlines predict it will." I was right about this.

At last year's (2024) ASH conference, there was a lot of excitement about Tafasitamab (also known as Monjuvi). Tafasitamab is a monoconal antibody, and the results of a stage 3 clinical trial were presented at ASH, where Tafasitamab was combined with R-Squared (Rituxan and Lenalidomide).  I had written about it a few times after ASH. There were lots of commentaries that talked about how great the combination was, and how it would most likely mean Tafasitamab + R-Squared would become the default treatment for Relapsed/Refractory Follicular Lymphoma. That hasn't happened. As I wrote a year ago, it takes a lot to change an oncologist's habits, and unless there is a huge change in survival statistics, there will probably be some change, but not a lot of change. The "game-changer" headlines are often clickbait, getting people like me and the rest of you Cancer Nerds all excited and reading their articles. It seems like there is always some new great treatment that will change things for us. To be sure, treatments are getting better over time (the difference in the choices I had when I was diagnosed about 18 years ago, and those available now, is incredible.) But as I get older, I get more suspicious of news articles that are a little too excited about these things. Tafasitamab may end up being an important part of our treatment choices, but it isn't yet. It was approved by the EU a week ago, and by the Japanese health ministry about the same time.

My second prediction was "Epcoritamab will cause some concerns." Epcoritamab was another treatment that caused some excitement at the 2024 ASH conference. But it also caused some controversy. The effectiveness numbers were great, but the safety raised some questions. There were a few more deaths than were expected, but they were explained by the fact that the trial took place during the Covid pandemic, when some of the trial participants had lowered immunity. As I said in the post, "my gut tells me those concerns haven't been completely answered." Well, as you know if you've been reading lately, Epcoritamab was this year's darling at ASH, and the "game changer" language for Tafasitamab from last year was applied to Epcoritamab for this year. So I'm going to say I was wrong about this one. There were no new safety issues in the year that followed, and Epcoritamab might well be the great treatment that the headlines say it will be. I sure hope so -- the numbers are fantastic. But time will tell.

My third prediction was "There won't be any major changes to the FDA approval process." I'm thinking I'm right about this one, too. Last year, there was talk that the FDA might cut back on surrogate endpoints and focus more on Overall Survival. In other words, they would ask for more long-term data before making decisions, That didn't happen, but there was plenty of controversy at the FDA anyway. I won't get into it. If you live in the U.S. and you follow health news, then you know. There has been a change in leadership, some instability in key positions, and controversies in many areas of pubic health. I was hoping to find a link to an objective source that described the year that the FDA had, but I couldn't find one. I will say, despite the controversies, it doesn't seem to me that the oncology world was effected negatively by it. FL treatments were approved, and people remain excited. The approval process has been largely the same as it was before. We'll stay hopeful that it stays that way, and if it does change, it will be change for the good.

There are a couple of lessons here.

First, I'll say what I said last year when I made the predictions -- remember that I'm not an oncologist or a cancer biologist. When it comes to cancer advice, the best person to talk to is your own oncologist. It's fun to make predictions, but I'd never make a prediction that I thought would affect an individual's life. I wouldn't want that responsibility -- that's not fun. Sure, I got two right, but the one I got wrong, I got really wrong. If your oncologist is a Lymphoma specialist, ask them what gets them excited about Lymphoma research these days. Then watch their eyes get big and their voice get a little louder from excitement. That's the real fun.

The other lesson is a reminder that one year is not a lot of time when it comes to cancer research. We move forward, but in small steps -- rarely in giant leaps. And we don't know for a while just how big a leap it is. Best to enjoy the small victories when we get them, and hope they turn into something big.

I hope your 2025 finishes up wonderfully, and your 2026 brings you good health and happy times.

I'll be back next year. Still lots of small victories to write about.

Take care.

ASH Review: Epcoritamab

If there was a Big Winner for Follicular Lymphoma at ASH this year, it was without a doubt Epcoritamab.

Epcoritamab is a bispecific antibody, meaning it has two mechanisms working. On one side, it attaches to a protein on the surface of the cancerous B cell, and then also attaches to a protein on a T cell, an immune cell. In this way a bispecific uses the body's immune system to treat the cancer.

The research that has everyone so excited is the results of a phase 3 clinical trial, also published in the prestigious medical journal The Lancet, as "Epcoritamab, lenalidomide, and rituximab versus lenalidomide and rituximab for relapsed or refractory follicular lymphoma (EPCORE FL-1): a global, open-label, randomised, phase 3 trial."

The results really are pretty exciting. This is a phase 3 randomized trial, which means the researchers split a large group of patients into two, so they could directly compare the results of two different  treatments. This kind of trial is considered the most accurate (rather than comparing one group to the results of a trial that happened a few years ago). In this case, one group was given R-squared (Rituxan + Lenalidomide/Revlimid), while the other was given R-Squared plus Epcoritamab. There were 448 patients in the trial (a pretty large number), and all had relapsed or refractory disease (they had already had treatment, and it didn't work or no longer worked).

With a median follow-up of 14.8 months, the Overall Response rate for the Epcoritamab group was 95% (versus 79% for the R-squared group). The Complete Response Rate was 83% for Epcoritamab and 50% for R-squared. 

The Progression-Free Survival for the Epcoritamab group was higher, with estimated PFS of 16 months in 85.5% of that group versus 40.2% in the R-squared group. (They had to use an estimate because some patients hadn't reached the median time yet.)

With a "triplet" -- a combination of three different treatments -- like this one, safety is always an issue. Three treatments might mean three times the effectiveness, but can also mean three times the side effects or adverse events. Grade 3 (serious) adverse events were higher for the Epcoritamab group (219 of 243, or 90% of that group, versus 161 of 238, or 68% of the R-squared group), which was to be expected. Cytokine Release Syndrome, which can be very dangerous, was low grade for the Epcoritamab group, and was managed by the doctors.

I was going to link to a few videos of Lymphoma experts talking about the results, but they're kind of all the same thing, with the expert repeating the numbers and talking about how exciting this could be (like this one from OncLive). And I do think it's exciting, having finally seen all of the data.

Any skepticism I have comes from whether or not patients will have access to it. It does seem to me that bispecifics are probably more accessible than CAR-T (the two are often talked about together, including by me). CAR-T is great, but more expensive (as one recent bit of research pointed out), which is going to make bispecifics a more popular choice for those who make those decisions about cost. But there are going to be still less expensive options for R/R patients, probably. I hope FL patients can get the best treatment available, no matter the cost.

This isn't the last we're going to hear about Epcoritamab. There were many ASH presentations on this treatment, for many different types of Lymphoma. Two that I thought were interesting were the results of a phase 2 trial of Epcoritamab and Rituxan for untreated FL patients (97% Complete Response Rate in a small trial), and Epcoritamab and R-squared in untreated FL patients (95% Overall Response Rate). 

But it's that randomized, phase 3 trial that really makes me think that Epcoritamab will be around for a while. A large number of patients over a long period of time. It seems pretty likely that it will be a regular part of treatment programs. It might take a while to get to that point, but it probably will.

I'm still looking at ASH abstracts and watching and reading commentaries. I'll have more soon. 

ASH Review from the Follicular Lymphoma Foundaton

The ASH meeting ended yesterday, so no more previews. Now we're into reviews. Over the next few weeks, there will be lots of Lymphoma experts writing articles and making videos that talk about what they found most exciting at ASH. They're helpful. They often provide more detail and analysis than I could get from the abstracts, and it's usually easy to see patterns when they all talk about the same thing.

For this first review, we'll look at a video sponsored by the Follicular Lymphoma Foundation. It features Dr. Jessica Okosun, a Lymphoma specialist and professor at Bart's Cancer Institute in London. (Prof. Okosun was one of the panelists for the FLF's webinar, "Charting Our Progress Toward a Cure" last summer.) 

You can watch Dr, Okosun's video here on YouTube, or go to the FLF's website and see it there with some additional commentary. 

The thing that excited Dr. Okosun the most was the research on Epcoritamab and R-Squared (Rituxan + Revlimid or Lenilidomide). If there was a standout for FL reseach at ASH this year, it was this one. Since it was presented a few days ago, I've seen about 20-30 articles about it, with phrases like "game changer" and "new standard." (I'm always a little skeptical about new treatments being talked about so excitedly. I'll get more into that at some point.) The results were also published in the prestigious medical journal The Lancet a couple of days ago, which is a bigger deal, since it means the data has been peer-reviewed by other experts. 

As Dr. Okosun says in the video, the research was a randomized trial with about 400 patients, half of them getting R-squared and the other half getting R-squared + Epcoritamab. The R-Squared group had a Progression Free Survival of about 11 months, with the Epcoritamab group had not reached its median after almost 15 months (meaning fewer than half of the patients had their Lymphoma return). 

She was excited about bispecifics in general -- there was additional research at ASH on Mosunetuzumab as well -- but she also pointed out some safety concerns. Bispecifics tend to increase the risk of infection in some patients, so as with any treatment, there needs to be some caution when giving it. 

Dr. Okosun was also excited about the research on the biology of FL that was presented at ASH. We still have some basic questions that we don't have answers to, like why FL comes back after it seems to have been treated successfully. She was excited especially about research by Dr. Karen Tarte, who presented data that looked at differences between FL cells at diagnosis and then at relapse. You can see that abstract here; I'll try to look at it and comment on it soon. 

As I said, there will be more commentary from Lymphoma experts in the next few weeks about what they found exciting at ASH. And I'm sure a lot of it will be about Epcoritamab. I have no doubt that it has the potential to make things better for Relapsed and Refractory FL patients. It will be a matter of getting it to them. 

More ASH reviews to come.  

 

Two Approvals and a Story

My email notifications have been very busy over the last few days, with news of treatment approvals in the US and in Europe. If I get that many notices, it must be a big deal. I'll tell you about them, but first, a story.

A couple of days ago, I went for my first CT scan in many years. It wasn't for cancer, but for a heart-related issue. (Everything is fine -- just needed to check on something to make sure it really is fine.)  I haven't had a cancer-related scan in a while because I haven't needed one, and my oncologist is pretty firm in his belief that if there isn't a reason to do a scan, we shouldn't do one. "Surveillance" scans, just looking to see if there are any problems, don't usually work that way. Something else happens that calls for a scan, and the scan confirms the problem. 

So that's what happened with my heart-related issue -- something else showed a problem that CT scan could confirm. It was different than any of my cancer-related scans. It was just a CT scan, not a PET scan, so there was no nasty liquid to drink, no IV with a contrast in my arm, no getting undressed. Just me on a table, gliding into a big donut. It took about 5 minutes. 

I've been so busy lately that I really hadn't had time to even think about getting this scan. So it wasn't until I was on the moving table that I even thought "Wow -- it's been a long time since I had a scan. I really don't like scans. There is way too big a chance that a scan is going to bring bad news." That little bit of scanxiety didn't kick in until I was in the middle of it.

And then the voice came on, the one that gives you instructions. So a male voice started speaking to me: "Take a deep breath....now let it all the way out.....take another breath.....now let it all the way out......Now breath in deeply and hold," but his voice went way up when he said "hold," like he was asking a question. Then he continued, "Now you may release your breath." This happened three times.

I almost messed up the scan because I started laughing a little.

The whole "hold" like it was a question was kind of funny. But then I started thinking about the last scan I had, several years ago, at my cancer center. The voice that spoke to me there had a British accent. So instead of saying "Now you may release your breath, " the British voice said "Carry on breathing."

"Carry on breathing" is not a phrase that we use in the US. I remember telling my kids about it, years ago, and them thinking it was very funny. 

So there I was in the CT machine, already smiling at the guy say "hold" like it was question, and now I'm also thinking about the British guy saying "Carry on breathing," and I know I'm about to laugh out loud and ruin this whole scan. 

Thankfully, I was able to hold in my laughter until I was done (thank goodness it was a short scan). But I did tell the technician about it, since she was looking at me funny when I was chuckling a little bit when she came back into the room. She thought it was amusing.

So it's nice to be in a place where I can laugh during a CT scan. I hope that's someplace we can all be someday, with no worries about anything. 

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

Now, on to those approvals.

The first is from the US. The FDA approved Epcoritamab for two different situations involving Follicular Lymphoma.  

Epcoritamab is a bispecific, attaching itself to B cells with the CD20 protein, ans then to a T cell (an immune cell) with the CD3 protein. In this way, it brings the immune cell close to cancer cell, so the immune cell can take out the cancer cell. Epcoritamab was accelerated approved by the FDA for relapsed/refractory FL in 2024. Accelerated approval is kind of temporary, allowing the treatment to be used on patients while additional data is collected. So the first of the two new approvals is making the accelrated approval into a permanent approval. Epcoritamab can be given as a single agent for patients with Relapsed/Refractory FL who have had at least two treatments already.

The second approval is for Epcoritamab to be used with R-Squared -- Rituxan and Revlimid/Lenalidomode. R-Squared is being used more and more as a substitute for traditional chemotherapy, so just as there are combinations of chemo with new agents, there are also combinations with R-Squared. The potential problem with that kind of combination is that with three treatments, you have the potential for triple the side effects. In fact, safety was a concern when research on Epcoritamab was presented at the ASCO conference in 2024. But apparently there was enough data to lessen those concerns.

So we have a couple of more treatment possibilities in the US. (It has already been approved in Europe and Japan.)

The second approval is for Tafasitamab in Europe. This isn't a full approval just yet, but it's very close. This approval is the last step before it becomes official. It was recommended by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP), which approved it for use with (again) R-Squared for Relapsed/Refractory FL who have had at least one other treatment. It needs to get its final approval from the European Commission.

Tafasitamab (also known as Monjuvi) is a monoclonal antibody, like Rituxan. But unlike Rituxan, which binds to the CD20 protein, Tafasitamab binds to the CD19 protein. So in theory, it should work well with R-Squared, since it works in a slightly different way. The same potential problems with safety can happen with this combination, but the clinical trial data seems to show that it was OK. Given how many notices I received about this, it seems like there won't be any major issues with it getting approval from the European Commission. 

I know that there is going to be some new data for Epcoritamab at ASH in a couple of weeks. I haven't looked to see if there will be anything new for Tafasitamab. I know I need to get moving on ASH previews. I hope to have some for you soon.

FDA Fast Track Designation for EO2463

Last week, the FDA grated Fast Track designation for a new immunotherapy treatment called EO2463. (It will probably get a cooler name soon.)

Some reminders before we go any further: Fast Track designation means that a proposed treatment has the potential to do something new, and so it gets extra help from the FDA to help it through the approval process. Its a way of trying to get treatment to a group that has great need for treatment. In this case, that group is Follicular Lymphoma patients. (The news article about this is not clear about the specific population of FL patients, though the National Cancer Institute page for the clinical trial specifies relapsed/refractory patients with FL and some other indolent blood cancers.)

 Immunotherapy is a group of treatments (like chemotherapy is a group of treatments) that uses the body's immune system to work against the cancer. Our immune systems are usually good at fighting off invaders, like bacteria or viruses). But cancer cells aren't invaders -- they are our own cells, but they refuse to die like they are supposed to. So immunotherapy treatments usually work by either changing our immune cells to find and fight the cancer c ells, or changing the cancer cells so they can be recognized by our immune system as invaders.

EO2463 is a very interesting treatment that takes a unique approach to identifying tumor cells. It's a little complicated, so I've tried to do a bunch of reading and watching to help me understand it. (This video helped.)

The company that makes the treatment focuses on bacteria in our guts. Gut bacteria is kind of big news these days, as researchers are looking into all kinds of ways that our gut biome affects our health. (Though not all of those claims have solid evidence.)

The role of gut bacteria in this treatment is different. The company uses Artificial Intelligence to identify over 20 million different proteins that exist in the gut. Their AI program can help identify proteins that are very similar to those that exist in the body, especially proteins that exist on certain cancer cells.

That distinction between the gut bacteria proteins and the human proteins is important. The bacteria in our gut play important roles, but they aren't meant to leave the gut. If they do leave it, our immune system takes over. Immune cells are meant to recognize and fight off invaders (like bacteria or viruses). When they encounter one, they eliminate it and then remember it, so if they encounter it again, they can eliminate it very quickly. Gut bacteria are included on that list of invaders. As long as they stay in the gut, they are welcome to hang around, and the immune system leaves them alone.

So we have two things happening here. First, you have gut bacteria that are considered invaders if they leave the gut. Second, you have proteins from the bacteria that are very similar to proteins on cancer cells, like the CD20 protein that is on the surface of Follicular Lymphoma B cells. 

When you put those two things together, you can develop a cancer treatment. Create a treatment that targets CD20 (and some other proteins) but create it in such a way that it tells immune cells that the cancer cell is really a bacteria that escaped from the gut and needs to be eliminated. Because the treatment is engaging an immune cell called a Memory T Cell, which remembers invaders, the thinking is that the treatment will be long-lasting.

[A note to you language nerds: I know that "bacteria" is the plural form of "bacterium," but I'm calling a single one a "bacteria" anyway because I think it sounds better. Shakespeare made up words, too, and it's my blog, so I do what I want.] 

The Fast Track designation was earned by the results of the SIDNEY clinical trial. This is a phase 2 trial involving 60 patients split into 4 cohorts. As I said above, there are several different blood cancers being targeted in the trial. Patients are given EO2463 on its own and in combination with R-Squared or one of its components, Rituxan or Lenalidomide/Revlimid. 

The early results are promising. The first 13 patients have an Overall Response rate of 46%, with no severe side effects. The makers of the treatment see this as a possible alternative to watching and waiting (though it's not clear if they are targeting untreated patients.)

I have to say, I'm kind of fascinated by the approach, using AI to identify possible targets based on gut bacteria. But there are also lots of questions to be answered -- as is always the case with a phase 2 study. My guess is that there will be more information at the ASH conference, which is happening in less than 2 months. 

But Fast Track is no guarantee of success. This is definitely one that I will keep an eye on.

 

Acalabrutinib + R-Squared for FL

The journal Nature Communications published an article a couple of months ago (I know, I'm behind on things) called "Frontline acalabrutinib, lenalidomide and rituximab for advanced stage follicular lymphoma with high tumor burden: phase II trial." 

It's a follow-up on some research that was presented at the ASH conference in 2023.  

In this study, researchers added Alcalabrutinib (also known as Calquence) to R-Squared. Alcalabrutinib is a BTK inhibitor. Just like other inhibitors, its job is to inhibit, or stop, something from happening -- in this case, Bruton's Tyrosine Kinase, an enzyme that is necessary for B cells to develop. B cells are, of course, the type of immune cell that includes the cells that can lead to Follicular Lymphoma. And that's what happens with a BTK inhibitor. The BTK enzyme does its job too well and won't die off, meaning the B cell won't die, leading to cancer. A BTK inhibitor stops that process and lets the cell die the way it is supposed to. 

Alcalabrutinib is already approved for some other blood cancers -- Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), and Waldenström's macroglobulinaemia.  So it makes sense that researchers are trying it with FL. However, there have also been several other BTK inhibitors that are effective with other blood cancers, but not FL.

The presentation at ASH in 2023 showed that this combination of Alcalabrutinib was very promising. The research is from a phase 2 clinical trial with 24 patients (a pretty small number). The patients had not received any treatment yet. The Overall Response Rate was 100%, and the Complete Response was 92%. After 26 months, 6 patients had their disease progress. The most common serious side effects (grade 3-4) were low neutraphils, a type of white blood cell, 58%, liver function test elevation (17%), infection (12.5%; 2 out of 3 related to COVID19), anemia (8%) and skin rash (8%). 

The Nature article was meant as a follow-up, looking at some longer-term data. The researchers were especially interested in what they call CR30 -- how many patients were able to maintain their Complete Response after 30 months. For them the CR30 rate was 65%. I'm not sure how that compares to some other treatments, but it seems positive. (This is a single-arm study, meaning they didn't split the patients into two groups so they could compare two treatments directly).   

After a median follow-up of 43 months, the median PFS (Progression-Free  Survival) was not reached, meaning more than half of the patients had not progressed. The PFS rate after 2 years was 79%, and for 3 years it was 62%. The POD24 rate was 17%, meaning 17% of patients who had a response had their disease return within 24 months. About 20% of FL patients are POD24, so this seems roughly in line with that number. 

Overall, the numbers look very promising. It will be interesting to see how this goes in a larger phase 3 trial.

I think what's really interesting, though, is the number of articles I've seen recently that look at R-squared triplets -- combinations if Rituxan, Revlimid (Lenalidomide), and something else. It makes sense. R-Squared has been shown to be as effective as traditional chemotherapy, but with a different set of side effects. SO instead of combining a single agent with chemo, researchers are hoping a combination with R-squared will increase effectiveness, hopefully without increasing side effects. That seems to be the case with this triplet, making a BTK inhibitor more effective than it has been on its own.

 Time will tell. 

FLF's Midyear Research Update

The Follicular Lymphoma Foundation just published their mid-year update on Follicular Lymphoma Research. It's a fairly short document, and fairly easy to read (it's written by Dr. Mitchell Smith, the FLF's Chief Medical Officer, who always does a  good job of explaining things well).

Most importantly, it's very hopeful, pointing out the progress that's being made in FL research. 

I want to point out a few things that I found interesting, though I encourage you to read the report yourself.

First, I liked this line near the beginning: referring to the name of their symposium at the ICML conference in Switzerland this year, "Charting Our Progress Towards a Cure in FL," Dr. Smith says the title "reflects how the research community is increasingly convinced that FL will be curable -- the question is how and in what time frame."

That's a very hopeful thing to say!

I personally don't like to talk about cures for FL, because I've been dealing with it for over 17 years and I don't like to get my hopes up. The whole idea of a cure is complicated, given how hard it can be to measure a cure. But I do believe it will be considered curable one day, as the FLF report says, and it's very encouraging to hear that the Lymphoma community is feeling that same way. 

The report looks at three different types of research: from clinical trials that test out treatments; from translational developments that looks at biomarkers that might predict how a patient will react to treatment; and from biological research that identifies new information about how cancer cells stay alive and grow, which may open up new targets for treatments.

The clinical trials that Dr. Smith mentions are things like CAR-T and bispecifics. CAR-T is "maturing," meaning it's been around for a while so we're getting more information about how it works long-term. For example, about 50% of patients who were given one type of CAR-T remained progression free after 4 years, including about 45% who were POD24. That's great. I remember early research that had about 33% of CAR-T patients having a long-lasting response. It's improving.

Dr. Smith also points out that bispecifics don't have as much long-term data to look at, but what is there is encouraging, especially when they are combined with R-Squared. In general, there are more and more attempts at chemotherapy-free combinations, and more success with them.

One very interesting thing that he mentioned was the approval of Tafasitamab combined with R-Squared. The effectiveness is greater than most treatments currently available. However, he says, it might not be used quite as much as it could be because it requires "frequent hospital visits" and could be less effective than newer bispecifics like Epcotamab + R-squared. (As you may know, I've been thinking lately about how often Tafasitamab will be used and what might complicate that use.)

The clinical trial results are always the most interesting, because they are the easiest to understand and also the research that is closest to showing up in the doctor's office. But the more biology-based research is just as important, because they are the first steps in that clinical trial research. He mentions the research that has proposed three different subtypes of FL as well as research on the Tumor Microenvironment in FL (the stuff that surrounds the cancer cells, not just the cells themselves). 

He ends with another very hopeful quote about the state of FL research and the search for a cure:

 "It is clear the FL research community is moving from cautious optimism to genune confidence that cure is an attainable goal. By uniting scientific innovation, collaborative trials, and patient advocacy, we can accelerate the shift from managing FL as a chronic disease to eliminating it altogether. We are advancing faster than ever -- and with ongoing collaboration, the horizen for those living with FL grows ever more hopeful." 

Some excellent words to hang on to.

I encourage you to read the full report. You can find it here.

Stay hopeful, everyone.

 

Three Factors to Consider in Choosing R/R Treatment

The website Oncology News Central posted an interview a few days ago with Dr. Ahmit Mehta, a Lymphoma specialist at the University of Alabama at Birmingham. It's called "Three Factors to Consider in Relapsed/Refractory Follicular Lymphoma Care." It runs a s a video, but there is also a transcript if you'd rather read, or you need to translate. The website is mostly aimed at oncologists and other health professionals, but I have to say, Dr. Mehta does a fantastic job of explaining things very clearly. I don't know if anyone out there is a patient of his, but I'd bet he's just as good at explaining things in person. 

I thought it was an interesting interview for two reasons. 

First, it focuses a lot on Tafasitamab, which I talked about in my last post. So it's kind of a timely video that way.

Second, he discusses the factors that he considers when he needs to help a patient make a decision about treating Relapsed or Refractory Follicular Lymphoma. Let's look at that first, since it's the title of the video.

When he was asked how he makes decisions about treating R/R FL, he said, "When the patient relapses, at that time, there are multiple factors we consider for second-line treatment. Usually, the way I think in my mind, is: Patient-related factors are number one, disease-related factors are number two, and number three (that I’ve added recently) is center-related factors."

I find this really interesting. I've seen lots of general descriptions about the kinds of factors that go into those decisions, but never in quite this way.   

First, the patient-related factors. (It's nice that he puts patients first, and not surprising if you watch the whole video). These factors include things like comorbidities -- the other health problems that a patient might have. Certain problems will mean that particular treatments are not a good idea, since their side effects can be aggressive and create even more new health problems. Second are the disease-related factors. Is the patient POD24 or showing B symptoms? An aggressive relapse might mean a more aggressive treatment recommendation.

And third is "center-related" factors. I thought it was really interesting that he added this consideration recently. Not all treatment centers offer every treatment, and something like a bispecific or CAR-T are only offered at a limited number of centers. If a patient will have a hard time getting to a treatment center, or staying at the center for a couple of weeks to be evaluated, then a different treatment might be considered instead.

Now, any decent doctor would consider all of those factors as well, and I don't think Dr. Mehta came up with all of that on his own. But I do appreciate the way he breaks it down, and how he shows the things that he prioritizes. As we consider our own treatment choices, those same factors are what we should be thinking about, or at least be prepared to ask questions about. 

The second interesting thing that Dr. Mehta talked about was Tafasitamab. As I wrote about in my last post, there are lots of Lymphoma specialists who are very excited about the newly-approved combination of Tafasitamab and R-Squared (Rituxan + Revlimid). Dr. Mehta is one of those specialists. He sees very real possibilities for Tafa-R-squared, as he calls it, becoming a very popular choice for R/R FL.

One thing I thought was interesting was that he said R-Squared was currently the most popular second-line treatment for FL. I haven't seen evidence of that, though I'm also not someone whose job it is to know such a thing. But anecdotally, it seems to me that lots of FL patients are receiving R-CHOP or B-R, especially if they didn't receive chemo as a first line treatment, as well as CAR-T or bispecifics. I wonder sometimes if doctors who work in academic medical centers, where cutting-edge treatments are developed and tested, have a different perspective on things than doctors in community clinics, where old habits tend to rule. 

Or maybe Dr. Mehta is correct, and more and more doctors are using R-squared as a second treatment for R/R FL. And if that's true, then the jump to Tafasitamab shouldn't be hard. (But, as I said last time, I have my doubts, still.) 

Overall, it's a very good video, and those of us who have already had treatment would find it very interesting. The video is about 15 minutes long, and as I said, there's a transcript available as well.

I hope you get a chance to watch or read.

Tafasitamab: New Standard for R/R FL?

I've been seeing some discussion online lately about Tafasitamab, and its promise for treating Follicular Lymphoma. There are a few people who think it could become the standard treatment for Relapsed/Refractory FL, given the success of the clinical trial that led to is approval a couple of months ago.

But all of the positive talk got me thinking more about how certain treatments get to be so popular, and why others never really seem to catch on.

Part of my thinking this ways comes from a conversation I had recently with someone about RIT (RadioImmunoTherapy). This type of treatment involves taking a monoclonal antibody (something like Rituxan) and adding a tiny amount of radiation to it. Because the antibody seeks out a protein on the lymphoma cell, the radiation gets delivered right where it is needed, so there is less damage to cells that don't need the treatment. It was all the rage when I was first diagnosed, and I know a few people who received it many years ago and who a very long remission because of it.

However, it never really caught on the United States. The rules for a treatment like this required that an expert in nuclear medicine administer it, rather than a regular clinical oncologist. To be able administer it, the doctor would need 400 hours of training (if I am remembering this correctly). So very few people received RIT, even though trials showed it was very effective and there were a few different options available.

It's an example of a good treatment not getting to patients who would benefit from it.

So when I see the headlines about Tafasitamab -- that it might be a "game changer," or a "new horizon," or a "new standard," I have to wonder if it's really going to happen. (The "game changer" headline comes from a website that uses that phrase once a week about some new cancer treatment. The articles are generated by Artificial Intelligence. That's a whole different blog post.)

The reasons for excitement over Tafasitamab are pretty clear. In the InMIND trial, the phase 3 trial that led to its approval, 548 patients were either given R-Squared (Rituxan + Revlimid/Lenolidomide) or R-Squared plus Tafasitamab. The results were great. The Tafasitamab group had an 83.5% Overall Response Rate (versus 72.4% for the R-squared group) including a 49.4% Complete Response (versus 39.8%) and a median Progression Free Survival of 22.4 months (versus 13.9 months for R-Squared). Safety was comparable to R-Squared alone. You can find a good summary of all of the side effects here.

But here's why I'm a little skeptical about Tafasitamab becoming a new standard. One of the very enthusiastic pieces I saw about this said that this new combo would be a potential replacement for patients who would be eligible for R-Squared. This makes sense, given that it was shown to be more effective than R-squared. But how many patients would be given R-Squared in the first place?

About a year ago, the Follicular Lymphoma Foundation conducted a survey of FL patients from 49 different countries. One question asked which treatments the patient had received. In that survey, only 6.2% of respondents had received R-Squared. That's not a huge number. But if that's the ceiling -- if the Tafasitamab combination is going to replace it for some patients -- I'm not sure how much of a "game changer" it's going to be for patients in general.

I want to be clear about a couple of things. 

First, and most importantly, I'm not a doctor. I remind you all of that every now and then because it's really important for you to remember. I have not formal medical training. I'm not an oncologist or a cancer biologist (or a scientist of any kind). I'm a Cancer Nerd -- a patient who reads a lot, and then thinks and rights about what I read. So why listen to me? Good question. The most important person to listen to is your own doctor. 

Second, I want to be clear that I'm not anti-Tafasitamab in any way. Just the opposite. I hope it gets to the patients who would benefit from it. I still have a lot of frustration over RIT. I think it could have helped a lot of people 15 years ago, and it was frustrating t see it not being used. (Search for "RadioImmunoTherapy" on this blog and you can see my long history of frustrated posts.)

But take another look at the FLF survey. The treatment type that most patients have had? Chemotherapy, with 60%.  

And that's not necessarily bad (it can be very effective) and it's also explainable in some ways (FL patients can live for a very long time and treatment types were limited 15-20 years ago).

But I also think it's true that FL patients can be over-treated, given more aggressive treatments than necessary. (I'm getting this from a couple of conversations with oncologists.) People get chemo who don't need chemo, and maybe could do just as well with something like Rituxan.

So why so much chemo? I  read a comment from an oncologist once that doctors are creatures of habit. If they have always recommended chemotherapy, and it has worked well, there's not much reason to change to something else. It's hard to argue with that logic. As a patient, if my doctor said "My previous patients have done really well with Bendamustine," I probably wouldn't argue.

But I think that's ultimately what this is all about. Very few of us patients argue.

And I don't really mean "argue," as in getting mad at the doctor. I mean, few of us know enough to have a conversation with a doctor that might lead to a different option. Why chemo? What are the other alternatives? Why not them? Can you recommend someone else I can talk to for a second opinion? 

It's not really about arguing so much as asking questions. And that can be hard to do when you've just been told you have cancer. 

But it's what I hope you will do, especially with Relapsed/Refractory FL, when we've had some time to think and learn and perhaps plan. We don't all have the opportunity to get a second opinion, or to question the decisions that a doctor or a health plan make for us. But if we can? That's how change comes, and how good treatments get to people who need them.

Stay informed, and stay well.

 

Epcoritamab + R-Squared: Interim Results

The makers of the bispecific Epcoritamab just issued a press releasewith some interim results from the phase 3 clinical trial for Epcoritamab and R-Squared (Revilid + Rituxan) for Relapsed/Refractory patients with Follicular Lymphoma. The press release points out some very good news. The combination has an Overall Respose Rate of 95.7%, an improvement over R-Squared alone (which has an ORR of 89%). It also had a higher Progression Free Survival; it "reduced the risk of disease progression or death by 79%."

The plan is to present the results at the ASH conference in December, where they will present all of the data. The FDA agreed to a priority review of the combination last month, meaning they should issue a ruling by November 30 (which would be before the ASH conference).

All of this sounds great, but I have some questions. And, to be clear, I'm not suggesting anybody is doing anything wrong.

Te press release gives very little detail. And there's a good reason for this -- they're holding off on releasing any details until the ASH conference, which makes sense. This is a "scheduled interim analysis," meaning they had planned to look at the results they had so far at this point in the trial. Because they haven't competed the trial, they don't want to give too much detail yet.

The other side to all of this is that they need to keep investors happy. A little good news will do that, and a fairly general statement with some plans for the future won't hurt either.

But for me, it all raises more questions than it provides answers. Last year, there were some safety concerns about Epcoritamab, though they were explained by the trial taking place during the Covid pandemic, when some trial participants had lower immunity which caused some side effects. The press release here says that there were no new safety issues with this combination -- only the side effects that were already known for the three different elements. But if there were already some concerns, saying this doesn't really answer the initial questions about safety.

Again, I'm not saying anybody is doing anything wrong. For me, this isn't really an issue with Epcoritamab or its makers. It's more about frustration with the larger system for approving treatments, and the place of the patient in it all.

I'm looking forward to the ASH conference, so we can see more of the data that this FDA application is based on. I have little doubt that the data presented will be positive and encouraging for patients. I hope my questions and concerns are answered. I just wish that I didn't have to have so many of them along the way.

Some Analysis on Tafasitamab (Monjuvi)

CURE magazine has a nice interview with Dr. Christina Poh of the Fred Hutch Cancer Center about Tafasitamab. 

As you might remember, Tafasitamab was recently approved by the FDA, in combination with R-Squared (Rituxan and Revlimid/Lenalidomide), for Follicular Lymphoma. I wrote about this recently, looking at the the announcement from the FDA. 

But Dr. Poh offers some more insight into why this approval is so significant. Some of it came out in the FDA announcement, but hearing it from a hematologist/oncologist at a prestigious cancer center is even better.

For example, Dr. Poh points out how great the design of the clinical trial was. It's a double-blind study, meaning half of the patients in the trial receive one treatment, and the other half receives a different treatment. This allows for a direct comparison between the two. But more importantly, as a "double blind" study, it means that neither group knew for sure which of the treatments they were receiving. Knowing the treatment (which happens in lots of trials) can influence how a participant feels. If they know a treatment may cause a certain side effect, the patient may "feel" that symptom and ask to pull out of the trial. That's not a criticism of the patient -- any trial participant has the right to pull out of the trial for any reason at any time. But it's one example of how a double-blind study can be more significant. 

Another element that Dr. Poh points out is that the population more accurately mirrored a "real world" population. Many trials for newer treatments have strict limitation on who can participate in the trial. It's for a good reason. If a new treatment might affect a patient's heart, for example, then patients with heart issues are kept out of the trial. If they did participate and then had heart issues, it would be hard to know if the new treatment caused the issue or if it was a pre-existing heart issue. Once a treatment is approved, researchers might do a "real world" study without those restrictions, to get a better idea of how the treatment will really affect all patients. Because all of the elements in this trial (Tafasitamab, Rituxan, and Revlimid) had already been approved, there was already plenty of "real world" data on side effects. So the trial could include a wide range of FL patients -- those who were asymptomatic, those with POD24, etc. So there is more certainty that the combination will be helpful for many patients.

Finally, Dr. Poh talks about the significance of this being a non-chemotherapy treatment. When R-squared was approved, it was a very big deal.  It was the first time a non-chemotherapy treatment was shown to be as effective as traditional chemo like R-CHOP or B-R. And now, this combination is perhaps even more effective than R-Squared. Because treatments like this are more targeted, affecting fewer non-cancer cells than chemotherapy, they have a different set of side effects. (One of the big takeaways from R-Squared being approved was just that -- different side effects, not necessarily fewer or less harsh side effects.) But the feeling is, according to Dr. Poh, that it will not result in long-term side effects like bone marrow damage that can come from chemo. So it may result in greater use by oncologists.

It will be interesting to see if that is true -- that this non-chemo treatment becomes a replacement for chemo, or if it becomes just another option for second and third line situations. I haven't seen too much of this kind of analysis, but it's speculation, anyway. "Real world" data will tell us for sure in the years to come.

Dr. Poh was on the team that conducted the trial, so she has seen the effects of the treatment in patients. If any of you has a conversation with your oncologist about this as a treatment option, please do share what you learned.

 

FDA approval for Tafasitamab-cxix for R/R FL

The FDA has approved Tafasitamab-cxix (also known as Monjuvi) in combination with Lenalidomide (also known as Revlimid) and Rituxan for Relapsed/Refractory Follicular Lymphoma.

I wrote about this combination in November, just before the ASH conference. The results of a phase III clinical trial were being presented at ASH, and the website Fierce Pharma called the early results a "triumph." The makers of Tafasitamab had said immediately afterwards that they were going to seek FDA approval. And it came.

Tafasitamab had already been approved by both the FDA and the EU for use on R/R Diffuse Large B Cell Lymphoma, in combination with Lenalidomide.

Tafasitamab is a monoclonal antibody, like Rituxan. But Tafasitamab targets a different protein, CD19, on the surface of B cells (Rituxan targets CD20). The idea was that combining the two (along with Lenalidomide) would increase the chances that the treatment could find the cancer cells. That seems to have been the case.

The trial involved a direct comparison between Tafasitamab + Lenalidomide + Rituxan and a placebo + Lenalidomide + Rituxan. In other words, patients in the trial were going to receive either this new combination or just R-squared (Lenalidomide/Revlimid + Rituxan). Patients in the trial had already received at least one treatment for their FL already.

As Fierce Pharma said, the results were triumphant. After a median follow up of 14.1 months, the Progression Free Survival for the Tafasitamab combination was 22.4 months and 13.9 months in the other group. The Complete Response Rate was 49.9% for Tafasitamab and 39.8% for the other group, and the Overall Response Rate was 83.5% vs 72.4%.

The question with the combination was going to be about safety. Monoclonal antibodies like Tafasitamab and Rituxan work by eliminating B Lymphocytes, a kind of immune cell. They target both healthy B cells and cancerous B cells. So while having two antibodies targeting the same cells might mean it's more effective, it also means you're running the risk f having too many immune cells being disabled all at once, opening up the possibility of greater risk of infections.

And that did happen. In their announcement, the FDA points out that "serious adverse reactions occurred in 33% of patients" in the Tafasitamab group, including serious infections in 24% of participants.The announcement doesn't give a direct comparison to the other group in the trial, though the ASH presentation did -- 36% of the Tafasitamab group vs 32% for the other group (the FDA numbers are a little different because they were updated 6 months later). Also in the ASH presentation, it was noted that during the study, 15 patients in the Tafasitamab group died, 5 because of disease progression and 6 because of side effects, versus 23 in the other group (17 due to disease progression and 6 from side effects). 

It will be interesting to see how popular this combination becomes with oncologists. Will this become a substitute for R-Squared? Similar way of working, but more effective? Or will some patients still be given R-squared instead because it seems slightly less aggressive on the immune system? (Remember, I'm not a medical doctor -- these are just questions that are coming to me immediately after reading this). I look forward to reading more commentaries in the coming weeks and months.

ASCO: Amulirafusp alfa

 As I have been saying, there really weren't a lot of presentations on Follicular Lymphoma at ASCO this year, and most of them have been focused on treatments that are already established.

But there is at least one presentation on a newer treatment. It's one that I haven't written about before. (To be clear, I'm not saying that I manage to write about everything FL-related. But this is definitely one that I haven't mentioned before.)

The presentation is Abstract #7051: "Phase II safety and preliminary efficacy of amulirafusp alfa (IMM0306) in combination with lenalidomide in patients with relapsed or refractory CD20-positive follicular lymphoma." I actually remember reading about this when I looked at abstracts from ASH in November and December, but for whatever reason, I decided not to write about it. The ASH presentation looked at phase 1 trial results. This one looks at phase 2 results.

In this research, a treatment called Amulirafusp Alfa is given in combination with Lenalidomide (also known as Revlimid, one of the Rs in R-Squared). Amulirafusp Alfa is a very interesting treatment. It worls in ways that are similar to a bispecific, but it isn't a bispecific (which attaches to a protein on a lymphoma cell, and to a protein on a T cell, a kind of immune cell, bringing them together so the T cell can elimiate the cancer cell).

Amulirafusp Alfa works by targeting two proteins on the lymphoma cell. One of them is CD20, the same protein that is targeted by Rituxan and by some bispecifics. But it also targets CD47, another protein on the cell. By attaching to CD47, it blocks something called SIRPα (Signal Regulatory Protein a). When CD47 and SIRPα interact, they send a "Don't Eat Me" signal to the immune system. When that interaction is blocked, the immune system can eliminate the lymphoma cell.

And just as a bispecific is an immunotherapy -- it allows the body's T cells to work against cancer cells -- Amulirafusp Alfa allows other (even more powerful) immune cells to work against the cancer cells, in this case Macrophages and NK/Natural Killer cells.

This phase 2 trial involves 34 patients with Relapsed/Refractory FL. All of them had a previous treatment with anti-CD20. In the study, 22 patients were evaluated; 10 of them had a Complete Response (45%), 8 had a Partial Response, making the Overall Response Rate 82%; 2 more had Stable Disease. As for safety, the side effects were considered "well-tolerated," with most pateints having descreased blood cell counts of different types, another 35% having an infusion-related reaction. About 65% of patients had a more serious (grade 3 or higher) side effect. 

It certainly seems like a promising treatment, one that works in ways that are different from what we have seen so far.  It will be interesting to see updated figures (only 22 of the 34 patients in the phase 2 trial were evaluated), and to see how this treatment goes in a larger phase 3 trial.

Definitely one to keep an eye on.