Heart Problems and CAR-T/Bispecifics

 MedPage Today has a really interesting piece this week, looking at a review article published in JCO Oncology Practice. The review article looks at research on how and why patients to take CAR-T or Bi-specifics develop heart issues, also known as cardiotoxicity.

(The MedPage Today article is in the form of an interview, but it's not really an interview, just kind of a Questions and Answers that they developed based on the review article.)

I won't go too deeply into the article (you can read it yourself -- its pretty clearly written). But it makes some important points that are worth bringing up. 

First, there are a wide range of heart problems that can be caused by CAR-T and Bi-Specifics. They include everything from myocardial dysfunction (poor heart pumping) and heart failure to coronary artery disease, and arrhythmias (irregular heart beat). What's more, they are unpredictable. Some can happen after one dose of treatment, and some show up years later.

Second, researchers are still trying to figure out why they happen. Something about the treatments affects the heart. When they figure that out, they can work on stopping it, perhaps.

Third, in the meantime, doctors have strategies for treating these side effects, and hopefully detecting them early. 

This is a really important issue for a few reasons. The first is that it's a common and serious set of side effects, of course, that can affect Quality of Life. 

But there are others, too. (And this seems like a good time to remind you all that I am not a doctor or a cancer researcher, just a Cancer Nerd -- a patient who reads a lot. So keep that in mind as you read on, and always remember that the best person to talk to about treatment is your oncologist.)

A large number of people (at least in the U.S.) have some form of cardiovascular disease, in that wide range that is listed above. And I'm included. For a patient with heart issues, that can be a reason to keep them out of a clinical trial. It makes it harder for researchers to know if the treatment being tested was the cause of the heart problem. 

Important: That is NOT usually a reason to keep someone from getting a treatment after t has been approved (like CAR-T and Bi-specifics). But it might cause an oncologist to think about alternative treatments instead of CAR-T or Bi-specifics, if there is enough of a concern that the cancer treatment might do more damage than the cancer.

So, here is my hope: First, that researchers continue to look at why these very popular treatments cause heart issues, and find ways to prevent them as newer versions of them are being developed. As I have said many times here, those two treatment types seem to be the ones that get most oncologists excited, and it seems like they are going to be a big part of Follicular Lymphoma  treatment plans in the future. We need to make sure they are as safe as possible. (Obviously, this is a goal for all cancer treatments. But with so many people having heart issues on top of cancer, it seems like it should be a priority.)

My second hope: that researchers continue to develop effective treatments that do not have heart-related side effects. That's asking a lot. Many available treatments for FL already do, with R-CHOP being the most prominent example. No treatment will ever be without side effects, but making sure Safety is treated as highly as Effectiveness should also be a priority.

As someone with heart issues, as I said, I'd love to know that CAR-T or Bi-specifics are an option for me, as long as they stay as safe as they are effective. And I'm sure many of you feel the same way.

I'm not sharing this to panic anyone. As I said, plenty of people with heart conditions do just fine on CAR-T and Bi-specifics. But it's a clear reminder to make sure to talk to your doc about any side effects and any pre-existing conditons before treatment, and make sure you are both comfortable with the possibilities, long-term and short-term.

New Bispecific for FL: TNB-486

I don't usually report much on the European Hematology Association Congress, the annual meeting for blood cancer specialists in Europe. That's only because it comes right around the same time as ASCO, in early June, and especially for the last few years, I have better access to ASCO information than any other big cancer conference.

But sometimes there is a presentation from EHA that is worth taking the time to look at. OncLive had an interview last month with Dr. Ryan Jacobs, who talks about one of the presentations at EHA. The focus is on a new bispecific called (for now) TNB-486. 

As a reminder -- a bispecific antibody is sort of like Rituxan, in that it finds and attaches itself to a protein on the surface of the cancerous B cell. Rituxan attaches itself to the protein CD20, but this one attaches itself to CD19. However, a bispecific also attaches itself to another cell (the "bi" means "two"), usually a T cell. T cells are immune cells that are very powerful, but don't recognize cancer cells as "bad," since they are just other cells from the same body. But because the bispecific attaches to a protein on the T cell (in this case, CD3), it puts the powerful immune cell right next to the cancer cell, allowing the T cell to destroy the cancer cell. 

So this bispecific is a little bit different than Mosunetuzumab, which has already been approved for Relapsed and Refractory Follicular Lymphoma. Mosunetuzumab attaches to CD20, not CD19, though both of them target CD3 on the T cells. It also attaches to the T cell with "less avidity" (to use Dr Jacobs' word) -- less "enthusiasm" -- which might lead to fewer dangerous side effects.

The EHA presentation reported on a phase 1 trial, which means it had relatively few patients in it (just 17), and focused mostly on dosage -- how much would result in the most effectiveness with the fewest side effects.   

The effectiveness was great -- 91% of the patients had a Complete Response. Because this trial focuses on R/R patients -- those whose last treatment stopped working, or never worked at all -- the researchers are especially interested in how this could benefit patients who are running out of options. So they looked at "heavily pre-treated patients" (those who already had at least 3 other treatments). All 12 of them had a Complete Response. Also the 2 patients who were CD20 negative (and so can't be treated with Rituxan or Obinutuzumab or Mosunetuzumab, for example) also had a CR. And so did the 5 patients who were POD24 (who had immuno-chemotherapy and had their disease return within 24 months). And the 6 month Progression Free Survival was 91%. Overall, some excellent numbers for effectiveness.

As for safety, the numbers were also good. Because bispecifics have been around for a little while, researchers knew what to expect. The most common side effect was Cytokine Re;ease Syndrome (11 of the 17 patients). No patients had to stop the trial because of side effects, though there was one death among the patients. This was because of Covid-19, rather than because of a reaction to the bispecific (in fact, the patient had already received a CR).

As I have said many times, it seems like most of the excitement in the lymphoma community these days comes from two types of treatments -- CAR-T and Bispecifics. Both have had variations been approved for use, and both have newer variations in the pipeline that (hopefully) are more ffective and safer.

Definitely something to keep an eye on.

Zanubrutinib Plus Obinutuzumab for FL?

The FDA has accepted a supplemental Biologics License for the combination of Zanubrutinib and Obinutuzumab for patients with Relapsed/Refractory Follicular Lymphoma.

Lots to explain here. (And thanks to reader Shelley for sending me the link to this news.)

Zanubrutinib is a BTK Inhibitor. BTK stands for Bruton's Tyrosine Kinase, a protein that is an important part of the pathway that controls B cells (the immune cell turns cancerous in Follicular Lymphoma). As I wrote a few weeks ago, BTK Inhibitors seem like they should be really successful for FL, since they target B cells. But there hasn't been a huge amount of success with them -- at least not what would seem logical. It has already been approved for certain patients with some other B Cell cancers -- Chronic Lymphocytic Leukemia, Waldenström Macroglobulinemia, Mantle Cell Lymphoma, and Marginal Zone Lymphoma. But this combo does seem to have some success, as I'll get into below.

Obinutuzumab, the other half of this combination, is a Monoclonal Antibody, like Rituxan. In fact, of al of the alternatives to Rituxan that have been developed in the last few years, Obinutuzumab has been the most successful.

The FDA will consider giving the combination a Supplemental Biologics License. A Biologics License is given to treatments that are created from living materials (unlike a chemotherapy, which is created from non-living chemicals). 

The application is based on results from the phase 2 ROSEWOOD clinical trial. This trial compared Zanubrutinib and Obinutuzumab to just Obinutuzumab. After a median follow-up of 12.5 months, the 102 patients taking the combination had an Overall Response Rate of 68.3% (with a Complete Response Rate of 37.2%), compared to the O group having an ORR of 45.8% (CRR of 19.4%). The Duration of Respose after 18 months was 70.9% (versus 54.6%). So adding Zanubrutinib clearly improved the results. 

In a follow up, after a median of 20.2 months, the combo ORR was 69% (CRR of 39.3%), versus the O group's ORR of 45.8% (CRR 19.4%). The median Duration was Not Estimable, meaning more than half of the patients were still getting a  response (so a median -- the halfway number -- couldn't be calculated).

(ORR is the primary end point for the clinical trial, which I find interesting. In other words, it's the main thing that they will measure to determine if the trial has been successful. They will also measure other things -- Duration of Response, Progression-Free Survival (PFS), Overall Survival (OS), Time to Next Treatment, and safety. All of them are important, maybe more important than ORR. Response is great, but if it doesn't last and doesn't keep someone alive, it's not that impressive. Just my Cancer Nerd opinion. The FDA will ultimately decide what kind of data it wants to see from them.)

Safety is important, so side effects matter. The most common side effects were diarrhea (combo, 18.2%; O only, 16.9%), fatigue (15.4% vs 14.1%), and fever (13.3% vs 9.7%).

The FDA will probably make a decision about this in early 2024.

Maybe we'll get some more updated data at ASH in December.

It would great to have a treatment that showed that BTK inhibitors might actually work well on Follicular Lymphoma. I'll be sure to share any more news. (And thanks again, Shelley.)

Artificial Intelligence and Cancer

 I just saw a really thought-provoking article fro ASCO Daily News called "AI in Cancer Research and Care: Setting the Stage for a Promising and Safe Future."

If you pay attention to the news, you've probably seen a lot in the last 6 months or so about Artificial Intelligence. While AI has been around in some form for many years, it was only last November that it became widely and easily available  when the program ChatGPT was introduced to the world. Maybe you've tried it out yourself. It has become popular because it allows a user to ask questions and get responses in plain language, so it seems like you're having a conversation.

ChatGPT runs on a predictive language model. That means when it gets asked a question, it looks at its large database (basically the entire internet) and makes a prediction about how to respond based on what it finds in the database. So if you ask it for a chocolate cake recipe, it will search for lots of chocolate cake recipes, and then predict what such a recipe would look like, and give it to you. (That's an over-simplification, but it's basically how it works.) 

That works really well sometimes. But when you have the internet as your source, you can run into a whole lot of misinformation, and ChatGPT can't evaluate what is true and what isn't. It also has a habit of making some things up when it doesn't know the answer. 

It's far from a perfect system. At least for now. Some experts think it will be much more refined in a few years.

Now, I should say up front, I have long been an advocate for technology. But I am also in a job that could potentially be threatened by AI in some ways. At the very least, it's going to be changed by AI quite a bit. We're not quite sure just yet if those changes will be good or bad. So I'm looking at all of this with a very skeptical eye. I tend to see the bad as much as (maybe more than) I see the good.

Back to the ASCO Daily News article. The authors (who are all cancer researchers at the National Cancer Institute, try to point out the good and bad about how AI is currently being used in cancer research. For example, a few researchers have published articles in medical journals that have used ChatGPT to help write the article. (Great researchers aren't always great writers, and I know as much as anyone that writing can be hard, so having a program that helps with writing can be a very good thing -- as long as the work is checked very carefully.)

Other research has shown how AI can go through a large database to find answers to questions. I sometimes write about research that looks back at thousands of patient records to find patterns about cancer. AI is perfect for that. It is built to go through a large database. 

It could also, in theory, be used to write up clinical notes -- that patient visit summary in your Electronic Records that describes what happened at your appointment. That could be a great thing, assuming the notes are checked to make sure they are accurate. (One of my previous oncologists retired because the Electronic Records were so overwhelming for him.)

But, of course, there are plenty of potential bad things that can happen, too. A patient who tries to find information on their disease by asking questions of ChatGPT is taking a huge chance. As much as there is good stuff online, there is loads and loads of crap. And remember, ChatGPT doesn't do a good job of evaluating the difference.

(If you are interested in a nightmare scenario of AI and Medicine, consider the novel The Algorithm Will See You Now by JL Lycette. The author is an oncologist who started writing to help with the burnout from her job. She's writes essays and fiction, and this novel is a medical thriller involving AI. Please remember it is SPECULATIVE FICTION, not real life. But as a doctor, she has some fears about technology and medicine, and this is her way of thinking about them.)

And I think that is ultimately the danger of Artificial Intelligence, in medicine and in other areas -- it takes out the human element. It's fun to play with ChatGPT, but when it becomes a replacement for the human element, then that's where the problems begin. Last month, I saw a news story about how some doctors are using ChatGPT to find "compassionate" ways to break bad news to patients.

That strikes me as problematic, if it's done poorly. I'm sure we all know doctors who are so robotic that a computer would show more compassion than them. Breaking bad news is definitely a skill that some have and some don't (I know this all too well). But if ChatGPT helps a doctor figure out the best way to do it, maybe that's not a bad thing?

The problem is, because it is predictive, the AI program will kind of see when is typically done in these situations, and offer that as a suggestion. But because delivering bad news isn't done very well, there's a chance that the advice that the doctor gets won't be very good either. It seems to me that the best way to use that is as a starting point. Advice about bad news is often to give it indirectly -- ease into it instead of coming right out and saying it. But a doctor hopefully knows a patient well enough to know whether that person wants the news broken gently, or wants it to be direct. ChatGPT can't tell a doctor that. Only spending some time with the patient can do that.

It's a complex topic. I suspect we're going to have to deal with AI as patients at some point, if we haven't already. My prediction about al of this is that the excitement will die down a little bit as problems emerge, and my hope is that we ultimately end up valuing the human element a little bit more. AI can't provide the kind of emotion that goes into great writing, great art -- and great medicine. And I hope we all insist that it never does.

I'd love to hear your thoughts about this -- and your experiences with AI, if you have any.

 

FLF Webinar

As I said last post, I'm still going through some posts that I had saved up for a while. This one is a video from the Follicular Lymphoma Foundation.

The FLF was founded a few years ago, after Nicola Mendelsohn was diagnosed with FL. Mendelsohn was a regional Vice President of Facebook at the time (she is now Head of the Global Business Group for Meta). She had a hard time finding information about the disease. Eventually, she had used her position and her connections to help create the foundation, which raises money for FL research.

They've had some new initiatives recently, including a "Support Hub" on their website, with resources, patient stories, and ways to connect with other patients.

Anther initiative is a series of webinars about Follicular Lymphoma. You can sign up to attend them live, or watch them later. This video I'm sharing is a recording of their first webinar, called "An Overview of Follicular Lymphoma."

Like all of the resources on the FLF web page, it's pretty good. As the title suggests, the webinar gives some basic information about FL. (The plan is to get into more specialized topics in future webinars.) It features Dr. Mitchell Smith, the Chief Medical Officer for the foundation, as well as Dr. Jessica Okosun and Dr. Brian Hill,both FL experts.

The webinar covers topics such as:

• What is follicular lymphoma?
• How does it affect your body?
• How is FL diagnosed?
• What happens next, after diagnosis?
• What are the treatment options?

One of the nice things about this webinar is that it is aimed at patients and caregivers. I know that a lot of the videos I post and link to are meant for doctors and other cancer professionals. So these use some simpler language to describe the concepts, treatments, etc.

The webinar also features some questions from patients, which is always interesting.

The webinar is about 44 minutes long. You can sign up to get on the FLF email list and get notified about other upcoming webinars and FL news.

I hope you enjoy the video. More to come soon.

Unsuccessful Trial: Ibrutinib + Chemo

I'm finished looking at ASCO presentations, so let's move on to all of the stuff I haven't been able to look at from the last month or so.

The first one is a failure! A clinical trial that wasn't successful. We don't see many of these, even though about 90% of cancer treatments that begin the clinical trial process never get approved. Most of the failures aren't presented at conferences or get published in journals. Which is too bad, because we can learn a lot from failures. (In fact, when I was younger, I kind of made a career out of messing up and then letting everyone know what I learned. It was really effective, and bought me some time until I knew what I was doing.)

The research I'm talking about here was presented last month at the 17th Annual International Conference on Malignant Lymphoma is Lugano, Switzerland, called "Ibrutinib plus BR or R-CHOP in previously treated patients with follicular or marginal zone lymphoma: the phase 3 SELENE study." (I'm getting my information from a write-up from OncLive).

The study looked at the results of a phase 3 trial that compared Ibrutinib plus chemotherapy (either B-R or R-CHOP) against the standard of care (chemo) in FL patients who had already had treatment. Ibrutinib is a BTK inhibitor. BTK is Bruton's Tyrosine Kinase, a protein that is an important part of the pathway that controls B cells (the immune cell that becomes problematic in Follicular Lymphoma and other B cell cancers). So by inhibiting, or stopping, BTK, Ibrutinib helps control the cancer. Ibrutinib has been approved for treatment for several B cell blood cancers, but it hasn't been successful in treating Follicualr Lymphoma.

So maybe it's not a surprise that this trial ultimately didn't work out. 

The phase 3 study came about because the phase 2 study of Ibrutinib alone was successful. In that study, the combo had a response rate of 21% and a median response that lasted 19.4 months for FL patients, with better numbers for MZL, another blood cancer. The numbers were good enough to move on to the phase 3 trial (especially for MZL patients).

For the phase 3 study, the researchers added chemotherapy to see if the FL numbers would approve. To do the direct comparison between Ibrutinib + chemo and chemo alone, 403 patients were put into two groups, each one receiving one of the regiments. 

The numbers were actually good for the Ibrutinib group -- just not good enough. For the Ibrutinib group, the response rate was 91.6%, including 55% Complete Response. In the chemo group, the rsponse rate was 90.5%, with 50.2% CR.

The problem came with Progession Free Survival. There was no statistically significant difference between the groups. 

Safety was also an issue. Whuile no new side effects popped up for the Ibrutinib group, there were a larger number of patients in that group than in the chemo group that had serious side effects, and more patients in the Ibrutinib group had to reduce their dose, or stop it all together, because of side effects.

This isn't surprising, either; combination treatments often have more side effects, since there are more different treatments being used at once. 

The researchers still think that this combination could be useful for certain populations within Follicular Lymphoma, and it sounds like they are going to explore that some more.

So what is the lesson learned? Well, the obvious one is that Ibrutinib still doesn't seem to be a viable treatment for FL, though there are still some trials being conducted that might prove that wrong. And there are also some other BTK inhibitors out there that are a little different from Ibrutinib, which has been a very successful treatment for CLL, Mantle Cell, and other lymphomas. 

We'll see how things go. More research soon.