EHA: BMS-986458 for Follicular Lymphoma

As I have mentioned before, late May and early June is typically a busy time for Follicular Lymphoma research, with presentations at ASCO. (Though this year was kind of a less busy year for FL). But soon after that, in mid-June, the European Hematalogical Association's conference on Lymphoma takes place in Lugano, Switzerland. I don't usually hear as much about that conference, so I don't write about it as much. But there have been some interesting results coming from it this year.

One presentation that I have seen several stories about was called "BMS-986458, A FIRST-IN-CLASS, BIFUNCTIONAL CEREBLON-DEPENDENT LIGAND-DIRECTED DEGRADER (LDD) OF B-CELL LYMPHOMA 6 (BCL6) IN PATIENTS WITH RELAPSED/REFRACTORY NON-HODGKIN LYMPHOMA: INITIAL PH 1 RESULTS."

The presentation describes the very early results of a phase 1 clinical trial, so there's certainly no guarantee that this research will ultimately be successful. (Remember that less than 10% of cancer treatments that enter clinical trials are eventually approved.) But it's a very different kind of treatment, and worth writing about and keeping an eye on.

The treatment is currently known as BMS-986458, though it will eventually have a name that's easier to remember if it keeps moving forward. BMS-986458 is "oral, highly selective bifunctional cereblon-dependent LDD of BCL6."

There's lots of unpack there.

First, let's look at the target for this treatment, BCL6. As the leader of this research says in an interview about the presentation, BCL6, short for B Cell Lymphoma 6, has been a target for Lymphoma researchers for a long time. It is a protein that is connected to the BCL6 gene. The main function of BCL6 is to make sure B Cells (the cells that are cancerous in FL) can change so they can recognize invaders like bacteria or viruses. The B Cells can recognize an invader, fight it off, and then die. But if something happens to BCL6, then the B Cells can grow without apoptosis -- the natural process that results in the cells dying. No dying means they continue to grow uncontrolled, and uncontrolled cells means cancer, in the case FL or Diffuse Large B Cell Lymphoma or some other kind of B Cell Lymphoma. 

So BMS-986458 is meant to find cancerous B Cells by focusing on the BCL6 protein. It "degrades" or breaks down that protein, and since that protein is necessary for cell growth, the result is apoptosis -- the cell dies the way it is supposed to.

In the small phase 1 study that is described in the EHA presentation, BMS-986458 was given to 22 patients, including 13 with DLBCL, 3 with high-grade B-cell lymphoma with MYC and BCL2 rearrangements, and 5 with Follicular Lymphoma. A total of 13 patients were evaluated after a median of 2.4 months. 7 of them had a Partial Response and 3 had a Complete Response to the treatment. 

The primary goal of a phase 1 treatment, however, is to evaluate safety -- to figure out the best dose of a treatment while causing the fewest side effects. Safety was good -- there were no grade 3 or greater Adverse Events, which is very encouraging. However, one patient had to leave the trial because it seemed to affect a different health issue and another had to have the dose reduced because of side effects. In all 4 of the patients who were not evaluated had to leave the study because of adverse events/side effects. 

The early results are very interesting. Definitely worth keeping track of. The lead researcher said in that interview that combining BMS-986458 with bispecifics or monoclonal antibodies seems like a logical next step, since the combination would work against the cancer cells in different, hopefully complimentary ways.

But they are very early results. Lots can happen as the trials move forward. But it's good to be hopeful.

FLF Webinar: Charting our Progress Towards a Cure

The Follicular Lymphoma Foundation held a webinar a couple of weeks ago called "Charting our Progress Towards a Cure." It's an excellent webinar -- lots of information and lots of things to think about. 

The webinar provides some updates on FL research from a symposium that the Foundation sponsored at the 18th International Conference of Malignant Lymphoma (ICML) in Lugano, Switzerland last month. The ICML is one of the most important Lymphoma conferences in the world, and for the last few years, the FLF has held an event like this that provides up-to-date information for doctors about Follicular Lymphoma. 

Among the topics that the Expert Speaker, Prof. Jessica Okosun of Barts Cancer Institute in the UK, discusses are CAR-T, Bispecifics, and combinations that use multiple treatments together to target the FL cells in lots of different ways. The goal is to give patients the longest Progression Free Survival possible.

Prof. Okosun gives a very optimistic overview of several newer treatments and treatments in trials now. There are enough newer treatments in the pipeline, she says, that in 5 to 10 years, we may not even be using traditional chemotherapy or Rituxan anymore. There may be enough advances that these "old" treatments have been surpassed by newer, more effective and safer treatments.

And that brings up an important topic, and really the focus of the webinar -- the idea of curing Follicular Lymphoma. It's a controversial topic, in some ways. FL is still considered by many to be incurable, which means there are lots of treatments that can put the disease into remission or partial remission or keep it stable, but not necessarily wipe it out permanently. Individuals might be "cured," but not enough patients are in that situation that the entire disease is considered curable. 

When I say the idea of a cure is controversial, I mean that there are disagreements about whether or not that's true. There are some experts that say patients can be cured outright. There are others that speak about a "functional cure," meaning that a patient might not be technically cured, but are living with the disease for many years (perhaps the rest of their lives) without needing treatment.  

Part of what makes this all so difficult is that we can't say for sure what the future holds. We don't know if the disease will come back for any individual. I'll give a very personal example -- me. I haven't needed treatment in 15 years. But I also haven't had a scan in many years, and the last time I had one, there was still some evidence of the disease being present. Am I cured? Was this a "functional cure," since I'm living for so long without treatment? 

Personally, I don't consider myself "cured." It's always in the back of my mind that it might come back. 

But I live my life in many ways as if I'm cured. I have long-term plans for my life. I don't act like it's going to come back, even if I acknowledge the possibility. I think it's a good way to live.

In addition to the Expert Speaker, the webinar also features a patient speaker, Paul Christopher Mollitt. He does an excellent job of talking about what a cure would mean to him, and also talks about how he has made treatment decisions since her was diagnosed in 2017. (And he let viewers know that he was recently declared in remission after Bendamustine and Rituxan!!!!)

There's a third speaker for the webinar, Dr. Mitchell Smith, the Chief Medical Officer for the Follicular Lymphoma Foundation. If you've attended or watched these webinars, you know what an excellent job he does of moderating the discussion, connecting ideas from the speakers, and answering questions. 

There's a lot more detail in this webinar, especially about some of the very interesting research that came out of the ICML conference. It's certainly worth spending the hour or so that it takes to watch the entire thing. Lots of good information, and lots of reasons to be hopeful. 

 

Two Upcoming Webinars

I like to highlight webinars or other educational events that I think will be useful to us, and the Lymphoma Research Foundation has a couple of events coming up that are worth highlighting.

The first one is happening next Tuesday (July 22) at 1:00pm Eastern. It's called "Understanding Immunotherapy for Lymphoma (CAR T-Cell Therapy, Bispecific Antibodies, & Antibody-Drug Conjugates)." The webinar will give an overview of Immunotherapies; discuss when Immunotherapies are appropriate; look at Clinical Trials; and give advice about managing side effects. There will be time for questions and answers.

The webinar will be run by two Lymphoma experts, Dr. Samuel Yamshon of Weill Cornell and Dr. Justin Kline of The University of Chicago.

You can register for the webinar here.  This isn't specific to Follicular Lymphoma, but it should give a good overview of some of the treatments that Follicular Lymphoma experts seem to be most excited about. 

A second LRF event is also not specifically about Follicular Lymphoma, but might also be useful to many of us.  It's called "Ask the Doctor About Lymphoma: Information for Relapsed/Refractory Patients," and it's happening Wednesday, July 30 from 4:00 to 6:00pm ET.

LRF's "Ask the Doctor" series is just what it sounds like. It begins with a presentation from a Lymphoma expert, giving information about a topic (in this case, Relapsed/Refractory Lymphoma, with a focus on symptoms, treatment options, and what to ask your health care team). But "Ask the Doctor" sessions are twice as long as the other webinars, and spend much more time on Questions and Answers. So this is an excellent opportunity to get specific information from an expert.

The expert who will presenting and answering questions is Dr. Boyu Hu of the University of Utah. You can register for the Ask the Doctor event here.

(And for those of you who have not yet had treatment, and feel like you're missing out, there's an Ask the Doctor event for you next month -- "Ask the Doctor About Lymphoma: Information for Newly Diagnosed Patients." Read more about it here.)

I hope you find this information useful. 

Keep learning and stay well.

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.

 

Does It Matter How You Were Diagnosed?

I have communicated with many patients with Follicular Lymphoma over the years, and read many more patients' stories. I'm always struck by how heterogeneous this disease is -- how differently it presents itself in different people.

I know I'm fortunate to have a version of this disease that started slow and has mostly remained that way. So many others I have spoken to have had a very different course for their disease.

One of the places where we have different experiences is in how we were diagnosed. Some of us had very obvious symptoms -- swollen nodes, night sweats, weight loss, for example. Others of us had no symptoms at all, and were diagnosed almost accidentally, maybe because a routine blood test turned up an issue, or an unrelated surgery or scan found some hidden swollen nodes. My experience is kind of in between -- I had a persistent swollen node near my hip, but I didn't have any other symptoms, and I was otherwise healthier than I had been in a long time.

Some of us might have asked a question related to this -- does it matter how I was diagnosed? Is an "accidental" diagnosis with no symptoms somehow better than a diagnosis that came because of some very obvious symptoms?

Some researchers from the Mayo Clinic had that same question, and published their results in the Blood Cancer Journal. The article is called "Incidental vs. symptomatic diagnosis of follicular lymphoma: implications of earlier detection." They essentially want to know if a patient is better off being diagnosed before there are obvious symptoms. The logic is that such a diagnosis must be early, and an early diagnosis must be better. 

The results are interesting, and depend on how you define "better." To me, as someone who has been reading about FL for a long time, they aren't really very surprising.

The researchers looked at the medical records of 908 patients who were newly diagnosed with FL between 2002 and 2015. They looked at how they were diagnosed -- because of obvious lymphoma symptoms, or "incidentally." They found that 259 (or 28,5% of their sample) had an incidental diagnosis. 

They looked at some of the characteristics of the two groups. The incidental group was more likely to be diagnosed with "early" disease -- stage I or II. This makes sense to me. They also found that this group had normal LDH levels. Most of you probably know what LDH (lactate dehydrogenase) is, or have at least heard of it. It's an enzyme found in tissues, and high LDH is often present when FL is advancing. I know it's one of those blood test components that my oncologists always point out ("LDH looks good."). So those in the "Incidental" group had normal LDH levels -- again, not surprising.  

Those are the differences. It's the similarities between the groups that are so interesting.

comparing the "incidental" and the "symptomatic" groups, there was no difference in Event Free Survival (EFS), Lymphoma-Specific Survival (LSS) or Overall Survival (OS).

In other words, whether the patients in the study were diagnosed early or later, they tended to go about the same amount of time before they needed treatment. There was no difference in how long they lived because of their lymphoma. In fact, there was no difference in how long they lived, period.

As I said, as someone who has been reading about FL for a very long time, this did not surprise me. It takes a lot to improve Overall Survival in Follicular Lymphoma. Watching and waiting versus immediate treatment? Not much difference in OS. Maintenance versus no maintenance? Not much difference in OS. Traditional chemotherapy versus nob-chemo treatment? Not much difference in OS.

And that matters.

It would be wonderful to have some breakthrough in FL that vastly improved our Overall Survival. In general, our OS has improved quite a bit since I was diagnoses 17 years ago. It was still unofficially 8-10 years back then. Now, it's closer to 15-20 years. No one knows for sure for a really great reason -- FL patients keep living so long that they can't measure the upper end of their survival. That's an excellent thing.

But all of this really matters most to me because it should ease our minds just a little.

The disease is heterogeneous -- we all experience it just a little bit differently. One implication of that is that there is no real "right answer" when it comes to treatment. If all FL was the same, we'd be able to say "start with treatment X. If you need treatment again, go with Y. And then Z." But we don't have that clear path. 

And that means lots of decisions to make, and lots of doubt that the decisions were the right ones.

Research like this should ease your mind. The decisions that you and your doctor make -- about when to start treatment, which treatment to try, and what to prioritize -- in the end, those decisions probably won't affect your survival. You don't need to say "Maybe I should have tried a different treatment" or, more to the point of this study, "Maybe I ignored that symptom too long and I would have been better off if I had been diagnosed earlier."

Forgive yourself. You made the right decision, no matter what it was. 

As I said, I'd love to see some research that tells us the right thing to do, with no doubts or questions.

But research like this is second best -- it tells us that whatever it was that we did, it was OK.

Take care, everyone.

Princess Catherine and Survivorship

Catherine, Princess of Wales, spoke a few days ago about her post-cancer life. It happened as she was visiting patients at a hospital. It seems like it was prompted by her dropping out of an event (the Royal Ascot, a horse racing event) that the Royal Family traditionally attends each year.

In the interview, she talked about the struggles she has had since finishing her cancer treatment. It is remarkable in the way she covers most of the issues that are related to survivorship.

I won't go through everything she said, but it amounts to this:

After successful treatment, everyone, including yourself, can think that everything is OK.  During treatment, she said, "you put on a sort of brave face." But when treatment is over, it can be "really difficult."

Part of the difficulty is physical -- your body is still recovering from the side effects of treatment. As she said, "You're not able to function normally at home as you perhaps once used to."

And part of the change is psychological. After treatment is over, "then it's like 'I can crack on, get back to normal'." But "the phase afterwards is really difficult, you're not necessarily under the clinical team any longer."And without that team that you were working with, there's some element of fear that comes with it. All of this lines up pretty much exactly with the recent survey results that I wrote about a few weeks ago.

One of the patients she talked with agreed: "It can be very discombobulating, in that time when you've finished active treatment."

I think all of this is a great reminder that survivorship isn't easy. As she said, "It's life-changing for anyone, through first diagnosis or post treatment and things like that, it is a life-changing experience both for the patient but also for the families as well....You have to find your new normal and that takes time... and it's a rollercoaster it's not one smooth plane, which you expect it to be. But the reality is it's not, you go through hard times."

And in a weird way, that should be comforting. If you're post-treatment and struggling, whether it's physical or emotional or spiritual -- you're not alone. I'm sure Catherine is getting the best treatment and post-treatment care possible, and she's struggling anyway. Cancer doesn't much care whether or not you have a crown on your head.

The lesson, of course, is to seek help if you feel like you need it. See if your cancer center has a survivorship program. If not, ask your oncologist of there are services available -- physical therapy, or a social worker or other mental health counselor, or a nutritionist, or something else (the Princess apparently found acupuncture very helpful).   

I appreciate Princess Catherine being willing to speak out about this. I remember when her diagnosis was first announced, there was little detail given, and I defended her right to keep things private. We all need to deal with our diagnosis and treatment in whatever way makes most sense to us and helps us. I would love it if every famous person was completely open about everything. But that's not their responsibility. They owe no one anything, except themselves and their loved ones.

So Catherine speaking out about survivorship is a wonderful thing. I hope it brings some comfort to a lot of patients and survivors.

Primary Extranodal Follicular Lymphoma

The journal Hematological Oncology just published an article called "Primary Extranodal Follicular Lymphoma: A Retrospective Survey of the International Extranodal Lymphoma Study Group (IELSG)." It actually doesn't affect most of us directly, but I think the bigger picture is probably important to us all.

The study described in the article looks at Primary Extranodal Follicular Lymphoma.

Extranodal FL means FL that exists outside the lymph nodes, and other organs related to the lymphatic system like the spleen and bone marrow. It's fairly common for FL to move out of the lymph nodes and into the spleen or bone marrow -- that's the very definition of stage 4 for FL, and about a quarter of FL patients are diagnosed with that stage. 

And if the lymphoma starts in the lymph nodes and then moves somewhere else, it's called secondary extranodal FL.

This article looks at primary extranodal FL -- it starts in some part of the body other than the lymph nodes.  

As I said, this doesn't apply to most of us, but I have communicated with a few readers over the last couple of years who have had their FL present in this way. Maybe some of you are still reading.

The research was conducted by the International Extranodal Lymphoma Study Group (IELSG), made up of Lymphoma experts who are specialists in these types of Lymphomas. Keep in mind that "Lymphoma" is a very broad term, and there are as many as 90 different types of Lymphoma, depending on who is doing the counting. About 30 of them are Extranodal types.

This research looked specifically at Primary Extranodal Follicular Lymphoma. This seems much less common than other types of Extranodal Lymphomas. I say "seems" because, as the authors note, extranodal FL "has not been extensively described." So they set out to find as much as they could by surveying specialists about cases that they had documented. They looked at "605 pathologically reviewed cases from 19 different countries" so they could compare the clinical features at diagnosis and their outcomes, and compare them to nodal FL.

What they found was that the two most common sites for Extranodal FL were the skin (334 of the 605 they looked at) and the gastrointestinal tract (72 of 605). More importantly, those two subsets were very different from nodal FL and had different Overall Survival patterns. After a median follow-up of 5.5 years, the cutaneous (skin) FL had an 89% 10 year OS, and the gastrointestinal FL had a median 10 year OS of 79%. For those gastrointestinal FL that presented in the duodenum (the first part of the small intestine), the OS was 95%. Other extranodal FL sites were similar to nodal FL. 

I think this is all good news for those of you with Primary Extranodal FL.

The bigger picture, though, is what interests me more. The researchers conclude by saying "These findings support the identification of specific primary FL localizations as distinct entities with particular clinical and biological characteristics." In other words, not all FLs are the same.

In some ways, that's really obvious. FL has a reputation for being heterogeneous -- it seems like we're all a little bit different. That was the conclusion of one of the ASCO presentations that I reviewed a couple of weeks ago. 

And yet, as obvious as it seems, we're still all kind of lumped in together as "Patients with Follicular Lymphoma." I think this goes back to not so many years ago, when diagnosis was done mostly by microscope. On the surface, all FL cells look very alike. As diagnostic tools, and our understanding of genetic features, becomes more sophisticated, it gets easier to see the differences. So some of us are probably still close enough to be a patient with FL, and to follow the same treatment recommendations as everyone else.

But that greater recognition that not every FL is the same will have significant implications in the future. We already know that, for example, grade 3B FL isn't really like other FLs. And POD24 FLs aren't really the same as others. But the more researchers can recognize specific features of different subtypes, the better off we will all be when it comes to diagnosis and treatment.

So that's my takeaway from all of this. It seems like very positive news for those of you for with Primary Extranodal FL. And for all of us, it's at least a small step toward making FL a little more manageable by identifying the things that make it heterogeneous. 

And those small steps are what move us forward.