ASH Review: Mosunetuzumab (Bi-Specific) for FL

As I have said a couple of times, there weren't really any game-changing presentations at ASH for Follicular Lymphoma. But the one that I am seeing the most commentary on is for research on the Bispecific treatment called Mosunetuzumab. 

The specific session is "127 Mosunetuzumab Monotherapy Is an Effective and Well-Tolerated Treatment Option for Patients with Relapsed/Refractory (R/R) Follicular Lymphoma (FL) Who Have Received ≥2 Prior Lines of Therapy: Pivotal Results from a Phase I/II Study."

To remind you: A bispecific is kind of like a monoclonal antibody (such as Ritixan). It can recognize and attach to a protein on the surface of a cancer cell (like the way Rituxan attaches to CD20). But the bispecific has something extra. The other end also attaches to something -- a T cell, a powerful immune cell (that's the "T" in "CAR-T"). So a bispecific ("bi" means "two) can bring two things together -- a cancer cell and the immune cell that can kill it. 

It's one of those treatments that oncologists get excited about. My own oncologist, Dr. H, has mentioned bispecifics to me a few times. Some say they might be a cheaper alternative to CAR-T treatments, since they use the same immune cells, but don't have to be created specifically for each individual patient. 

The ASH study is fairly small (a phase 1 and 2 trial), but seems to provide some important data about how effective the treatment might be. The patients in the study had relapsed or refractory disease (their last treatment didn't work, or stopped working after a while), and had already tried at least two other treatments.

90 Follicular Lymphoma patients were in the trial, and had already received a wide range of treatments, including chemo, inhibitors, stem cell transplants, and CAR-T.  In total, the Overall Response Rate was 78.9%, with 57.8% getting a Complete Response. Pretty good numbers. Some groups did particularly well, with POD24 (patients whose FL returned within 24 months of getting chemo) having an ORR of 83% and a CR of 55%. The median Progression Free Survival was 17.9 months.

Again, this is a relatively small study, but the numbers for effectiveness look very good. 

Of course, the second part of an early trial is looking at safety -- how bad were the side effects?

The most common Adverse Event was Cytokine Release Syndrome (also very common in CAR-T), though the researchers say most of those reactions were low grade (Adverse Events, or side effects, are grades from 1 to 5, with 1 and two considered low grade, and 3 to 5 being high grade, ore more dangerous. About 42% of patients had grade 1 or 2 CRS, while one patient had grade 3, one had grade 4, and none had grade 5.  Other common side effects included fatigue (36.7%), headache (31.1%), and some low blood counts. Two patients died during the study of causes that were not related to the treatment. Four patients needed to stop treatment due to side effects. The full list of AEs is available on the link to the ASH session.

I'm mentioning all of the AEs/side effects for a couple of reasons. First, I know I tend to not get into as much detail as I should (one of the problems with being a "look on the bright side" kind of person). But also because reader Shelley commented on my last post:

Bob, Have you seen this video, Q&A style, from: Noah Merin, MD, PhD, from the Blood and Marrow Transplantation Program and assistant professor of medicine at Cedars-Sinai Medical Center. I thought bi-specifics might be the next best thing compared to CAR-t, but from what he says about reactions to it, turns me off. I'm sure you've watched/read other specialists view on bio-specifics vs. CAR-T - what's your opinion?
Shelly  

I haven't seen the video, Shelley, and if you can put a link in the comments, I'd appreciate it.

The researcher who presented the data at ASH called the side effects "manageable," using a C1 inhibitor to manage the CRS. (The C1 inhibitor is a treatment that can help slow down CRS and keep the reaction from becoming harmful to the patient). 

I can't say for sure whether the side effects are risky enough to choose another treatment over this one. The commentaries I have read seem to agree with the researcher, and don' think they are serious enough to discount Mosunetuzumab. We need to keep in mind that this is a phase 1 and 2 study, so it's still fairly small, and a larger study might show that the side effects are better (or worse) than for this group of patients. The FDA and other regulators will ultimately decide whether or not the benefits outweigh the risks. 

There will be lots of post-ASH comments in the next few months; I'll be interested to hear what experts have to say about this (if anything). 

In the meantime, Shelley, please send a link to the video. Thanks.

 

No More Duvelisib for Follicular Lymphoma

Taking a quick break from ASH reports to talk about some news from earlier in the week: The maker of the PI3K Inhibitor Duvelisib has taken it off the market as a Follicular Lymphoma treatment. 

In their statement about the decision, they said this was a business decision, and didn't have anything to do with its safety or effectiveness.

A little background, as a reminder: Duvelisib is a PI3K (Phosphoinositide 3-kinase) Inhibitor. It works by stopping, or inhibiting, some signals that cancer cells receive that allow them to live and grow instead of dying when they are supposed to. 

There are currently four different PI3K inhibitors approved for Follicular Lymphoma. They all work in the same basic way, but there are different variations of PI3K in the body, and they each work on a different variation (or two). They have been fairly effective when given on their own, though they seem to do better in trials when they are combined with another treatment. 

Duvelisib was was approved by the FDA in 2018 for Relapsed or Refractory FL. The approval was based on a phase 2 clinical trial, and the FDA gave Accelerated Approval for the treatment. However, because it was based on a phase 2 trial (which is usually smaller than a phase 3 trial, which typically provides the data for FDA approval), the makers of Duvelisib were required to continue with a larger trial before the FDA would give final, permanent approval. 

And that's where things got a little difficult. The statement said that the "current treatment landscape for FL patients in the U.S. and the logistics, cost and timing of the post-marketing requirements (PMR) for COPIKTRA [another name for Duvelisib] in FL was no longer merited." In other words, the costs of getting the approval probably wouldn't be worth the effort. They will continue to study Duvelisib as a treatment for T-Cell Lymphomas.From what I know, there is a lack of non-chemotherapy treatments for some types of T-Cell Lymphoma, so maybe it will help some folks over there.

It's unfortunate that we're losing a treatment option, but there are plenty still available, and more to come. 

This is a good time to remind everyone that I'm not a doctor or a cancer researcher, just a patient who reads a lot . But in my Cancer Nerd opinion, it seems like we're in a middle place right now. There are still some chemotherapy treatments available, and they're still very commonly used, and lots of doctors are used to them. But there are more and more non-chemo options becoming available -- inhibitors and monoclonal antibodies and bispecifics and CAR-Ts and combinations of all of them. Maybe too many of them to meet the demand that's here now, though there may be more demand in the future if they hang on? That's one possibility, anyway.

As I said, there are more new treatments on the horizon. The ASH Conference ends tomorrow, and we'll start to see commentaries soon about what the experts thought was exciting at ASH. I'll pass that along as I find it.

ASH Preview: R-Squared (Lenalidomide + Rituximab)

As I said a few weeks ago, I was surprised at how many ASH presentations this ear are focusing on Lenalidomide (also known as Revlimid), either in combination with Rituxan (to make R-Squared) or combined with other treatments. I probably shouldn't be surprised. When R-Squared was shown to be as effective as Rituxan + chemo, it opened up a lot of possibilities. The idea of effective treatments that don't involve traditional chemotherapy (like CHOP or Bendamustine) is very attractive to patients and to doctors.

I may review a few more of those presentations at some point, but the two that have caught my attention most are these:  

2417 Six-Year Results from the Phase 3 Randomized Study Relevance Show Similar Outcomes for Previously Untreated Follicular Lymphoma Patients Receiving Lenalidomide Plus Rituximab (R²) Versus Rituximab-Chemotherapy Followed By Rituximab Maintenance 

3532 Ten Year Follow up of the MD Anderson Cancer Center Phase 2 Study of Rituximab in Combination with Lenalidomide (R2) for Patients with Low Tumor Burden Follicular Lymphoma 

The studies are a little different from one another, but similar in that they are fairly long-term studies of R-Squared, and both show very good long-term results for Follicular Lymphoma patients.

The 6 year study (number 2417) is part of the RELEVANCE trial, which looks at R-Squared in previously untreated FL patients (that is, the R-Squared would be their first treatment). Patients are either given R-Squared and then Rituxan Maintenance, or are give immunochemotherapy followed by maintenance. Importantly, all of the 1030 patients had high tumor burden -- lots of FL in their bodies. The results in the abstract might be a little confusing, because they do the analysis two different ways (one by the researchers themselves, and the other a little more objectively). Either way, the results are good, and after 6 year follow-up, the R-Squared patients are very close to the Chemo patients, in terms of effectiveness and safety. The Progression-Free Survival after 6 years was 60% for R2 and 59% for chemo, and the Overall Survival was 89% for both groups, and there were no new side effects issues reported. The data confirms that R-Squared is a good alternative to traditional chemo for high tumor burden FL patients who have not received treatment. that's pretty great news.

The 10 year study (number 3532 above) looks at a different population -- FL patients with LOW tumor burden, though they also had not received any other treatment. This is also a much smaller study -- only 40 patients. But the results are similar. The Overall Response Rate was 98%, with 39 patients getting a Complete response and 1 getting a Partial Response. (One patient dropped out of the study before finishing, which is why the ORR is 98% and not 100%). After 10 year follow-up, the Progression-Free Survival rate (the lymphoma came back) was 59%, the Time to Treatment Failure (starting a second treatment) was 82%, and the Overall Survival was 95%. This study did not have two arms  -- that is, unlike the 6 year study, it didn't have half of patients taking R2 and half taking chemo. They all took R2 for this one. But the numbers are pretty similar to the 6 year study, and even add a few years on to the median follow-up.

Taken together, the lesson seems to be that we can expect more doctors to consider R-Squared as a first-line treatment for Follicular Lymphoma. There will still be lots of options (R-CHOP, R-B, straight Rituxan, watch-and-wait, plus lots of clinical trials), but my guess is that more oncologists will consider the option. Chemo is generally more effective than Rituxan or W and W, but with more side effects. R2 gives similar effectiveness, but with different (maybe less harsh) side effects than chemo.

It would be nice to have easy answers for which treatments will be most effective for individual patients (see my last post), but for now, I guess we can be glad that there are options available for us.

More to come soon.

ASH: Why Do Some FL Patients Do Well with Only Rituxan?

We're on to another ASH preview. This one is for the presentation called "3500 Follicular Lymphoma Microenvironment Signatures Define Patients Subsets Obtaining Long Term Clinical Benefit after Single-Agent First-Line Anti-CD20 Immunotherapy." 

Two things to remind you of. First, I have been fortunate that, when I was diagnosed almost 14 years ago with Follicular Lymphoma, my disease was slow-growing enough that I was able to watch and wait (hold off on treatment) for two years. After that, I had six rounds of Rituxan. I haven't needed treatment since. 

Second, when I look at and write about presentations from ASH, I focus on the things that I find most interesting. For me, "interesting" might mean something that affects many of us. In this case, "interesting" means it affects me personally.

At my recent oncologist appointment, Dr. H said he was very pleased with how things were going (and why wouldn't he be?). And he said something that he has said before -- it was great that Dr. R had tried Rituxan, rather than something like CHOP, all those years ago. And that my experience might have us questioning the field's wisdom in first-line treatment. Maybe we don't need to rush to R-CHOP, or B-R, or R-squared. maybe trying just Rituxan will help a lot of people without a lot of the side effects. He also pointed out that we don't really know why just Rituxan on its own works for some people but not others.

And that's why this presentation is so interesting to me -- it's about research that tries to answer that question. It's personal for me.

As the researchers point out, Rituxan on its own does a better job of bringing on Progression Free Survival than just watching and waiting. But not as good as immunochemotherapy (like R-CHOP or B-R), though Rituxan by itself results in far fewer side effects. The question is, how does a doctor know which patients might benefit from just Rituxan, the way I have?

To try to answer that question, the researchers looked back at the records of 81 FL patients who who had received only Rituxan as their first treatment, and also looked biopsy samples to look for biomarkers in their microenvironment (that is, anything that they had in common like gene mutations that might explain why the Rituxan was successful for them). They followed up for a median of 9.5 years, and found that Overall Survival was 82%, and PFS was 35% (they lived a long time, but most had their FL return).

The analysis that they did for the microenvironment is pretty dense, and probably not something you want to know the details of (though if you do, the link to the presentation will give you those details). But they did indeed find some biomarkers. Genes involved in "chemokine-cytokine signaling, T-regulatory cells, natural-killer cell activity and interleukin-17 signaling" were present in patients who achieved a Complete Response. (These are all related to the immune system responses.) Also, another set of genes was associated with worse PFS, with one group (IL22RA2, CCL22, TNFRSF4, IL17RB, CCL19) having too much activity, and another gene (CD209) having not enough activity. At the same time, GELF criteria and FLIPI score were not associated with PFS.

(I've written about this before, including in my last post -- things like FLIPI are too general to really say anything about an individual patient.)

The conclusion is that relatively simple genetic test could help doctors figure out if just Rituxan would be effective for a certain patient as a first treatment. It could potentially save money and improve quality of life, if Rituxan on its own results in a long stretch of time before another treatment is needed.

The bigger lesson here is that biomarkers may help to determine which treatments could help FL patients, for all the same reasons. Ideally, a genetic test at diagnosis could help a doctor say "Given the biomarkers that we have, the patient should have treatment X, which will give the best chance of success."

But, as I said, ideally that's what would happen. There has been plenty of research on biomarkers in Follicular Lymphoma, some moderately successful, some less so. Even this research shows some promise, but it doesn't say "Yes! We found the answer!" It shows that there is an increased chance that Rituxan will work better for certain patients, but there's still no guarantee. Cancer is too complex for guarantees -- especially a cancer like Follicular Lymphoma.

But it's step in the right direction.

ASH Preview: Rituxan Maintenance

Here we go -- time to start looking at some of the Follicular Lymphoma abstracts from this year's ASH conference.

Before I get into the first one, a couple of important reminders.

First, I don't think there's anything really ground-breaking at ASH this year, in terms of Follicular Lymphoma. Occasionally, there's some big news that everyone is talking about before the conference begins (on December 11), I'm just not seeing anything online. Maybe something will show up on this year's Leonard's List, but so far, I'm not hearing about anything major. And that's OK. It means there will be lots of interesting articles about existing treatments and other FL-related topics that help us better understand our disease and our options for treatment. That's usually how science works, anyway -- baby steps.

Second, even the presentations that I do excited about are not necessarily all that exciting. A lot of what I see are results from phase 1 and phase 2 clinical studies. That means they are still pretty early in the process, and there is plenty of time for things to go wrong (the treatments being studied are not as effective or as safe as they seemed). Looking back at my old ASH and ASCO previews, there are lots of things that got me excited that never made it to the clinic. Remember that. My excitement is about hope for the future, not reality in the present. It's kind of like looking through the Sears Wish Book as a kid -- I knew I was never going to get most of the stuff that got me excited, but it was fun anyway. 

(And if you don't understand that reference, sorry. If you do understand it, you'll know why I still have happy memories of a purple Chuck Foreman #44 Minnesota Vikings jersey from Christmas 1976.)  

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So which one are we looking at first?

Let's go with "3544 Rituximab Maintenance Benefits Less for Follicular Lymphoma Patients with Low Risk of the Follicular Lymphoma International Index."

Some background for this one: As many of you know, Rituxan Maintenance (RM) is a common practice. After receiving immunochemotherapy (like R-B or R-CHOP), some FL patients are then given Rituxan every 3 months for 2 years. (There are other possibilities for how often and how long the patient might get RM, but every 3 months for 2 years is most common.) Research has shown that RM can increase Progression-Free Survival (PFS) is many patients. 

The other important part of this study has to do with the Follicular Lymphoma International Prognostic Index, or FLIPI. The FLIPI is kind of a misunderstood thing. It uses information about a patient like age, disease stage, and how many places in the body the disease is found. Using that information, the index classifies a patient as low, intermediate, or high risk. It was created to help classify patients in clinical trials, not to tell an individual patient what their future is, which is now many use it. 

All of that said, the study has some interesting things to say about Maintenance.

The study involved 203 patients who were diagnosed with FL between 2003 and 2020. Of those patients, 192 received immunochemotherapy and had either a Complete Response or Partial Response. 96 of those patients then had RM (every 3 months for 2 years). The other 96 received no Maintenance, or had fewer than 4 rounds of Maintenance (less than a year). Follow up was a little over 3 years. The 5 Year Overall Survival rate for the whole study was 95%, and the PFS was 83%. Both excellent numbers. But FL patients who received RM, the numbers were even better for the PFS -- 92%, instead of the 70% for patients who did not have RM. Clearly, the study confirms what we've known -- Maintenance helps prolong PFS. It keeps the disease from coming back, at least for a while.

However, when the patients were looked at again according to their FLIPI score, the PFS was a little different, when compared to those who didn't have RM. Patients classified as low-risk had a 95% PFS, intermediate had an 84% PFS, and high risk had a 67% PFS. The conclusion here? Maintenance works well for intermediate and high risk patients, but there is no difference for low-risk patients between those who had RM and those who didn't.

It's a small study that involves a small percentage of FL patients (not all of us have immunochemotherapy, and not every oncologist recommends RM). But I think it brings up the bigger issue of just how much treatment we need. RM is clearly an effective strategy for a lot of patients. But as with any treatment option, it has risks. Rituxan destroys B cells, and those are an important part of the immune system (as we're all being reminded of lately). Lots of patients put off RM because of the effects it has on the immune system during the pandemic. I think those patients, especially those who were low-risk, can feel better about that decision.

The study also highlights some important issues related to our treatment choices. At my oncologist appointment this week, Dr. H again pointed out how pleased he was that Rituxan did such a good job for me. He said maybe 10-20% of FL patients get the long-term results I got with Rituxan, and he kind of imagined how different things would have been if I had been given R-CHOP instead. Probably the same result, but with much more toxicity and the possibility of more long-term side effects. I was fortunate to have an oncologist back then who was willing to try something less aggressive as a first treatment.

So that's the larger lesson for me, though it might not be obvious. No one is lucky to get cancer, and no cancer is "the good kind," even though you may have heard someone use that language. But one upside to having FL is that we usually have a little more time than people with a more aggressive cancer have, and we can use that time to get a second opinion from a Lymphoma specialist who can hep us think through our options. Even small bits of research like this might be something that a specialist can use to say "Maybe RM isn't the best choice. It will bring side effects without adding much effectiveness. Let's skip it and see how you do." That's the value of a lot of the research at ASH, I think.

I'll keep reading and reporting, and keeping an eye out for other commentaries from experts. More to come soon. 

Oncologist Appointment

I had a six month oncologist appointment today. Everything continues to look good. 

As usual, I went to the hospital early to get my blood taken. Phlebotomists tell me that I have good veins, and it seems to be true. I almost never have any problems getting a blood sample taken from my arm, or getting an IV line put in. Of course, today was different. The oncologist's office never sent my paperwork over to the blood draw office, so I had to wait a while for that. And then the phlebotomist completely missed my very large, inviting vein. She apologized a lot, but it was fine. We got it done, and I went to the oncologist's office for my exam.

Before I saw Dr. H, I saw another doctor, one who is receiving specialized training in blood cancer. He did the initial exam, asking all of the questions and feeling around. He seemed nice enough. It's not the first time I've had one of these trainees, and I always ask them the same question before they leave: Why oncology? Of all the specializations in medicine, why focus on cancer?

He said he had received some training already to be an internist -- a general practitioner or family medicine specialist. He thought he'd like to specialize in something, though, and he liked the idea of being able to possibly cure someone. A good answer. But he added a little more information. More on that below.

Dr. H came in next. As usual, we chatted away while he did his physical exam. He asked me questions about work. Asked about some other health issues I've been dealing with. Asked about any movies I've seen lately. I haven't been to a movie theater in 2 years. He hasn't been to one in 6 years. (His kids are small.) He said he's asking about movies because there really isn't much more for us to talk about. Everything looks good for me.

I always ask him what he's excited about in the world of Follicular Lymphoma. He's excited about CAR-T, which he thinks will ultimately cure FL, at least for a lot of patients. And he's excited about bispecifics, which he thinks will be approved for FL within the next year. (I'm still looking for any sessions at ASH this year that look at bispecifics -- if he thinks they are that close to approval, there will likely be some reports at ASH.)

And then he told me I was doing great, and that I should enjoy life. I told him that HE should enjoy life -- get a babysitter and go see a movie sometime. 

I go back in six months.

Now, back to that doctor who is training in oncology. He reflected a little bit on his choice of specialty, and said something that I've been thinking about since then: "I was concerned that I wouldn't be able to disassociate myself. But I think I'm able to."

What he meant was, he wasn't sure if he'd be able to not let his emotions get the best of him. I completely understand -- it's why I ask the question. Why would anyone go into oncology when there's so much possibility of things not going well for your patients?

But it also made me think -- how much do I really want an oncologist that is able to disassociate himself? How much do I want an oncologist that can cut off his emotions? And when does that process start? Is it only after the patient gets bad news? Is that when a doctor starts to distance himself? Because it seems like that's when I would need him most. So is it sooner, when things are going well? Does that mean no more discussions about movies, or how work is going, or where to get the best hot dog in the area (a discussion I have also had with Dr. H)? No sense in making connections like that if you ust need to cut them off later, right?

It can't be an easy job, and I don't know I there's an easy answer to that that question -- how much of an emotional connection to patients should an oncologist have?  I'm curious about how all of you feel about this, and how much of a connection you have with your oncologist.

The bottom line, though -- things look good. It's happy news as we are just a few days from Thanksgiving.

ASH Abstracts are Here!

It's that time of year again -- the ASH conference is coming up soon, and the abstracts are now online.

ASH is the American Society of Hematology, the organization for doctors and other healthcare professionals who deal with blood diseases, including Follicular Lymphoma. Every December, they hold their annual meeting (this year, it runs December 11-14), where researchers present the results of their work. Along with the ASCO conference in the spring, it's a conference I pay close attention to -- it's often where researchers choose to reveal their biggest, happiest results. 

Unlike ASCO, ASH doesn't allow for free registration for independent cancer advocates like me. So I won't get access to a lot of the data that would be most interesting. But that's OK -- I'll do as I always do, and look at some of the abstracts (the summaries of the presentations that the researchers will make at the conference) and share some thoughts about the ones that seem most interesting. Because the abstracts are already available, I'll do some "ASH preview" posts over the next few weeks, and keep an eye out during and after the conference for any news in the Lymphoma World with some expert opinions about the conference. (Expert opinions are good. Better than Cancer Nerd opinions, which is what you'll get from me.)

I've taken a quick look at the abstracts, and there are 269 presentations related to Follicular Lymphoma. From what I can tell, none of them are the kind of "blockbuster" presentations that we sometimes get, the kind that will change the way people think about FL. Most seem to about research that helps us better understand what we already know about FL and its treatments -- and those are certainly valuable.

One thing I did notice, though (and again, this is just on my quick scanning of the abstracts), is that there are a lot of presentations involving Lenalidomide (also known as Revlimid). This makes a lot of sense. Lenalidomide is half of the treatment combination known as R-squared (Revlimid + Rituxin). The combination was the first non-chemotherapy treatment to be shown to be as effective as chemo like R-CHOP and R-Bendamustine. Researchers are going to want to build on that, and find new combinations that are even more effective. I plan to report on some of that.

There is some research on CAR-T as well, though not as much as I expected. It seems like CAR-T research doesn't wait for conferences to be announced. There's plenty of good stuff out there on CAR-T, even without ASH. I'll share some of that, too.

I'm also seeing some of the broader "Here's Where We Are" type of research. By this I mean, every year some researchers look at our assumptions about Follicular Lymphoma (who gets it, why they get it, how it is commonly treated), and does some research that shows whether or not those assumptions still hold up. For example, for many years (including when I was first diagnosed), the assumption was that the Overall Survival for FL was 8-10 years. Researchers keep challenging that by looking at different sets of data, so now we know that the OS for FL is closer to 18-20 years. So I've seen a few of those "here's Where We Are" studies, and I'll share those, too.

I'm looking forward to presenting some good news to you all. If there's bad news, I'll present that, too. But here's hoping there's much more good news than bad.

More soon.