Oncologist Appointment

I had a six month appointment with my oncologist today. Things look good (with some complications).

*******

As usual, I have had mixed feelings about my appointment. I feel fine, but it's still never fun to go t the cancer center.

For all of my appointments, I have a blood draw about 30 minutes before I meet with my oncologist. At the end of one appointment, I schedule the next one, and the blood draw, too. For some reason, I didn't do that last time. I booked my oncologist appointment, but not my blood draw. I'm not sure what I was thinking. I have a blood draw clinic near me that is run by the cancer center's network, so maybe I was thinking that I could save time by doing it a day before? I don't know -- that was six months ago. 

So when I got the reminder email a week ago, and the offer to pre-check-in on my Electronic Records portal, I saw that my blood draw wasn't scheduled. So I spend a week trying to figure out how to book the blood draw at the cancer center. It all worked out, but it seems like there is always something to add extra stress to the appointment. 

For this appointment, I asked my wife if she wanted to come with me. It's actually the first time in many years that she's come to an appointment. I almost always did appointments on Tuesdays, which was convenient for my work schedule, but not convenient for my wife's schedule. The after a while, she thought it might be bad luck to come, since my appointments had been going so well. It had been so long, she hadn't ever even met Dr. H, who has been my oncologist for a while. But she agreed to come with me.

It was nice to have her with me. I don't feel like I need the direct emotional support that I used to need, but it's still nice to have someone by your side. Plus, she sees and hears things that I don't because I'm so focused. And I don't mean things like the doctor's instructions. I mean things like overhearing someone else walking down the hall saying "I hate this place" ("You and me both, lady," was my wife's comment). Or noticing that the July 4th/World Cup decorations in the blood draw office looked like it was set up so people could take fun selfies with it, and then offering to take my picture, which she did:

 

For some reason, no one else at the cancer center blood draw office seemed interested in taking a fun holiday-themed photo. Go figure.

Anyway, my blood looked mostly good (more on that in a minute), and the physical exam was fine. No problems with the Follicular Lymphoma. 

But then there are the other problems.

For my last visit, Dr. H asked for some additional analysis for my blood because my total protein was too high. The analysis broke down the various proteins in the blood to see which one was causing problems. It turned out to be IgG, signalling a condition called MGUS -- Monoclonal Gammopathy of Unknown Significance. It's a benign condition that usually stays benign, though it can have some health consequences, the  most serious being the possibility of it leading to Multiple Myeloma, another blood cancer. For now, he says that there is maybe a 20% chance of that happening in the next 20 years. But the good news is, we are aware of it, and we can test it every 6 months to stay on top of it, so if it does turn into something else, we should be able to catch it early and deal with it. It was actually my General Practitioner who first noticed it, so my regular blood tests with her are also being analyzed for the same issue on top of the lipids, blood sugar, and everything else that she tests for. 

I don't particularly want to have to deal with Multiple Myeloma, if only because I would feel compelled to write about it. And then what am I supposed to do, start a new blog? "Myelo Bob"? I don't like it. Doesn't roll off the tongue the way "Lympho Bob" does. So I'm just not going to deal with it.

Dr. H says that it's unlikely that the MGUS is related to the FL, so if you're worried that this is something you or a loved one needs to pay attention to, you probably don't need to worry. I'm just special.

I hope all of you are getting good news at your own oncologist appointments, and that you are staying well. Take care of yourselves.

 

Donate to the Pan Mass Challenge

Hello everyone. I'm going to do something I very rarely do -- ask you for money.

It's not for me. It's for all of us, really. 

My brother is once again riding in the Pan-Mass Challenge -- a bike ride across Massachusetts to raise money for cancer research at the Dana Farber Cancer Institute in Boston.  

He's been doing this ride for 18 years, and he has raised over $88,000. Occasionally, he says "This year will be my last." It's a lot of work to train and ride on the day. Last year, he couldn't ride because he was injured, and it seemed like he was done. But here he is again. He just can't help himself. He knows how important this is. 

This is the email he sent out this year:

 

I hope you had a great July 4th Holiday weekend!  We're only 4 weeks out to this year's Pan Mass Challenge , and I'll be riding again for my 18th year.  

The PMC raises more money for charity than any other single event in the country, $1.125 billion since 1980 and $78 million in 2025 alone! This success is the result of a lot of people riding for, and caring about, a cure. And because every penny matters, 100 percent of your donation goes to Dana-Farber Cancer Institute. I've made a personal commitment to ride PMC 2026 and raise $4,000.00. I hope you can help me achieve this significant goal. To give online, you can use the following link to go to my personal fundraising site: http://www.pmc.org/profile/MM0386 Every donation brings us closer by the mile. Many thanks, Mike

PMC donations are tax deductible and 100% will go to Dana-Farber Cancer Institute. The PMC's tax ID / EIN is 04-2746912. The Pan-Mass Challenge only uses your personal information to thank you and will not share it with any other organizations.

 

I know not everyone is able to donate, and that's OK. But if you're inclined, please consider clicking the link and giving a little something. It doesn't need to be a lot. And it helps us all.

Thanks for considering the request.

 

Electronic Records, Data Sharing, and Identity

I have an oncologist appointment next week. I have one every six months, and I like it that way. My oncologist says I  an see him once a year, but I feel better seeing him more often, even if I'm feeling fine and I'm not having any problems. I'll be sure to give you all a report next week after the appointment.

As usual, I received an email a few days ago, asking me to go to my Electronic Health Records and make sure everything was correct. The list of medications and the list of diagnoses get longer every time I look at them. I guess it happens with age. Everything was fine. 

About the same time, I needed to have a blood test done for another doctor and another condition. This doctor's office has its own Electronic Health Record. I think I deal with 4 different EHR systems. 

One thing surprised me, however -- my Follicular Lymphoma diagnosis. It says I have grade 3 FL with extranodal activity. That's not correct. I have grade 1/2 disease, and no extranodal activity. 

My immediate thought was panic. It didn't last long, but I thought, "Did my last blood test show something and no one told me?" But that thought didn't last long. A blood test wouldn't show any of that, and I know for sure that I haven't had a biopsy recently. So the panic came and went pretty quickly.

But I thought about it some more, and decided it shouldn't be dismissed. It wasn't in my oncologist's EHR. It was in my general practitioner's record, which matters less, since she doesn't treat me for cancer. My guess is that someone entered the information in my record after looking at old notes, and mistook stage 3 (which I am) and grade 3 (which I am not). As you probably know, stage is determined by location of disease, usually determined by a scan. Grade is a measure of how aggressive the disease is, usually determined by a biopsy and looking directly as the cancer cells.

So why is this important? Well, accuracy is always important in medical records. And I've had a bunch of inaccuracies over the last few years that I can't explain easily. If someone is looking at a "conditions" page because they're trying to determine something like which treatment or medication to recommend, they may base it on comorbidities. In other words, if there's something inaccurate about a kidney condition, they may recommend a more aggressive treatment for another condition -- or maybe a less aggressive one. So accuracy just matters in general, even if it's about a condition that isn't being treated by a particular doctor.

Another reason accuracy is important is because of potential voluntary data sharing. There are more studies happening that rely on data sharing. In other words, researchers can learn a lot by looking at large numbers of patients' records. The Follicular Lymphoma Foundation did a webinar on this a few months ago. It's a really interesting way to contribute to research without being a part of a more traditional clinical trial. But for this to be valuable, the data has to be accurate.  

But there was something else that bothered me about the mistake. It's less about medical accuracy, and more about identity. I've spent 18 years as a stage 3, grade 1/2 Follicular Lymphoma patient. It's who I am. Obviously, that changes over time for many of us. We have successful treatment. Or treatment unfortunately stops working, and we need a new biopsy and a re-staging. FL is a notoriously unstable disease. I'm sure over 18 years I have gone up and down in stage.

But that's never been official. No biopsy, no scan in about 8 years. So the stage 3, grade 1/2 is who I am. And I don't like someone else telling me who I am.  And that's what that mistake was doing. 

It's a little strange. As much as I have enjoyed being a cancer advocate, I would have preferred to have not had the cancer diagnosis. I'm sure I would have been able to find something else fulfilling to do. So taking that diagnosis off of my Conditions page would have been just fine. But it's there. And I own it. And I don't want anyone else messing with it.

So I suppose the lesson here is to take some time to make sure everything is accurate on your Electronic Health Records -- all of them. I don't always pay attention to all of the details on them. They're like Terms and Conditions when you download an app -- just scroll through them and say Yes at the end so you can get to that doctor's visit that much faster. But the details matter, for now and for later.

 

CAR-T and Cures

The big news this week in the Lymphoma World is an article that was published in the New England Journal of Medicine yesterday. It describes long-term follow-up of patients with B Cell Lymphoma, including some with Follicular Lymphoma, who received CAR-T. The results were very encouraging, and that "C word" ("cure") is being used again. More on that after I describe the article. 

The article is called "Ten-Year Outcomes after CAR T-Cell Therapy for B-Cell Lymphomas." It presents results from 38 patients -- 24 who were diagnosed with Diffuse Large B Cell Lymphoma and 14 with Follicular Lymphoma, all of whom had refractory/relapsed disease (so they'd had at least one previous treatment).  They received just one infusion of the CAR-T treatment Tisagenlecleucel (also known as Tisa-cel or Kymriah) a median of 10 years ago. It's a pretty small study, but it has some important results.

I'll stick to the FL patients' results, since that's what most of us are here for. Almost half of the FL patients in the study had gone 10 years without a relapse. And for patients who had gone 5.4 years without a relapse, they continued to be Lymphoma-free after that. Most relapses occurred within the first year after treatment. 

I'll put this into a little bit more context. Early research on CAR-T treatments had kind of a 33/33/33 breakdown. For about 33% of patients, the treatment didn't work at all. For another 33%, it worked for about a year or less. And for the final 33%, it worked for more than a year. Those numbers aren't exact, but they're roughly accurate, and it's how I often think of CAR-T's effectiveness early on. Those numbers have also gotten better over time. So now, in this study, we're at 50% rather than 33% for long-term effectiveness. I can't see a breakdown for the other 33/33 groups, but they have to be smaller. 

Of course, CAR-T isn't perfect; half of the patients in the study did not have good long-term results. And there were side effects, too, to deal with. Two of the 38 patents had long-term low white blood cell counts, but there were no cases of long-term low red blood cells or ongoing anemia or low platelet levels. But perhaps more importantly, 9 patients developed a second cancer (including 3 with Acute Myeloid Leukemia, 2 with prostate cancer, 2 with lung-cancer (possible smoking-related), one with melanoma, and one with a T-cell lymphoma that affects the skin. All together, that is a higher incidence of cancer than the general population, though it is similar to the incidence for Lymphoma patients who received traditional chemotherapy.

What's most interesting about this to me is a press release from University of Pennsylvania Medicine, where the research occurred. Here's where the "C word" comes in:

Most relapses occurred within the first year after CAR T cell infusion, supporting the hypothesis that patients who experience a long-term response to CAR T cell therapy may be cured. "As oncologists, we use the word ‘cure’ with great care, but I am increasingly confident that CAR T cell therapy has the potential to cure a meaningful number of patients with B-cell lymphomas,” said senior author Stephen J. Schuster, MD, the Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research and director of Penn’s Lymphoma Program. “At the same time, our work is far from done. This therapy does not yet work for everyone, and we are committed to understanding why so we can continue to improve the next generation of CAR Ts."

It's interesting to see both of things happening here -- that the word "cure" is used, and that the researcher is cautious about using it.

It certainly brings to mind the research that was published a few months ago that suggested a 15 year follow-up after R-CHOP might show that some patients were cured. I was hesitant to use the word "cure" then and I'm still hesitant to use it now. 

That's not to say it isn't possible, but it's still hard for me to wrap my brain around, 18 years after I was told it was incurable.

Last month, the Follicular Lymphoma Foundation published a blog post called "Could Some People with Follicular Lymphoma Be Cured? New Evidence Sparks Careful Optimism." It reports on an interview that the FLF's Chief Medical Officer, Dr. Mitchell Smith, conducted with the lead researcher on that study, Dr. Jonathan Friedberg. (They are both Lymphoma Rock Stars, by the way. I'm going to start using that label again, I think.)

I'm actually quoted in the blog post. And since I love to quote myself, here's part of what I said: "It opens up a whole new way for patients to think about FL: that some of us might be cured. I was diagnosed over 18 years ago… and I haven’t needed treatment since. I might fall into that category of patients who are cured, and yet I still have that small little bit of doubt and fear in my head."

I think that explains my feelings pretty well. Here's another quote from me: "It's going to take some courage from both doctors and patients to change our way of thinking...but what an exciting future it will be."

I think that explains things pretty well, too. I suspect we're going to see more long-term studies of FL treatments very soon. They are a lot easier to conduct than clinical trials -- all of the data is already collected. And I suspect we'll see a lot more doctors using the word "cure" as a result.

What an exciting future it will be, indeed. We have lots to look forward to. 

 

Jamie Reno

I want to take a quick break from ASCO and EHA to write about Jamie Reno, who died in April. 

I used to write about some people as Lymphoma Rock Stars -- people who did great things for the Lymphoma community, whether they were doctors, researchers, patients, or something else. Jamie was a Lymphoma Rock Star.

I didn't find out he had died until a couple of days ago. Jamie was a long-time journalist, and his most recent job was as editor of Breaking Cancer News, which I wrote about a couple of years ago.  The folks at BCN sent out an email to their mailing list, with a really nice tribute to him, two months after he had died. From what I can tell, his family wanted to keep things kind of quiet, and there wasn't much about it online. I looked at the Living with Follicular Lymphoma Facebook page to see if there was any news there, but there wasn't. There was nothing on the discussion board/support group that helped me so much 18 years ago. I thought maybe some old-timers there might have heard something. But there wasn't anything.

I'm not criticizing the family's decision in any way. As patients, we deal with our cancer in the way that makes most sense to us. And as family's, we mourn our loved ones in the way that makes most sense. I've been in the unfortunate position to have to decide how to mourn both of my parents' deaths from cancer. 

But at the same time, Jamie Reno really was a Lymphoma Rock Star, and I feel like there should be something said about that. I never met him, didn't know him, but he was definitely a presence in my life as a Follicular Lymphoma patient.

In 2008, when I was diagnosed, if you googled Follicular Lymphoma, one of the first things that came up was Jamie Reno's book Hope Begins in the Dark. It's a collection of 50 stories from Lymphoma patients and survivors. He was a life-long journalist, writing for Newsweek for 23 years, and winning a National Magazine Award as part of the Newsweek team that wrote about 9-11. He was a cancer survivor himself. He was diagnosed with an aggressive form of FL when he was 34, and went through CHOP. He was in remission for over 2 years, and when it came back, he tried Bexxar, a RadioImmunoTherapy. It gave him 28 years of remission. At some point, he left Newsweek and devoted himself to writing about cancer. In addition to Hope Begins in the Dark, he also wrote a book called Snowman on the Pitcher's Mound, about a 10 year old boy whose mom is diagnosed with cancer. The mom character's experience with cancer kind of parallels Jamie Reno's experience with relapsing and receiving RIT.

He was a musician, too, managed to get some great musicians to play on a CD that he put out.  

With all of the stories he helped to tell about cancer, it seems like his needs to be told to the people who haven't heard it before.

Death is always hard. Even the death of someone we never met can break of a small piece of us.

But maybe that little piece that is gone can be replaced by hope. That was certainly a message that Jamie Reno seemed to want to pass along. The email that I got from Breaking Cancer News talked about how much he emphasized the "good news" about cancer -- breakthroughs in treatment, positive stories about survival and courage, and the importance of hope.

The title of his book, "hope begins in the dark," echoes a quote from the writer Anne Lamott. I honestly don't know if she said it first, or if it came from somewhere else, but here's what she said: "Hope begins in the dark, the stubborn hope that if you just show up and try to do the right thing, the dawn will come. You wait and watch and work: you don't give up."

That's a fitting message for cancer patients, and especially for those of us living with Follicular Lymphoma, who do plenty of watching and waiting and working and not giving up.

Our stories matter. As I said, much of my FL experience had Jamie Reno's story lingering over it, in very good ways. It always helps to have a model, someone who has been there and has done OK, someone who has been in the dark and found a way out.

I try to be that for other FL patients. Now you know why.   

 

EHA: Epcoritamab and R-Squared

A reader asked me a couple of weeks ago if I reviewed presentations from the EHA Congress, the annual meeting of the European Hematology Association. It's the European equivalent of the ASH meeting in the United States. It happens soon after the ASCO conference. I have written about some EHA presentations in the past, but as I told him, I sometimes have trouble accessing their abstracts. So it hasn't been something I have done on a consistent basis. EHA has some excellent research. But it's always been a matter of access.

This year, I figured out how to look at EHA abstracts. And I had some incentive -- I got many notices about a particular presentation, "CLINICALLY RELEVANT SUBGROUP ANALYSIS FROM THE RANDOMIZED PHASE 3 EPCORE FL-1 TRIAL: TREATMENT (TX) EFFECT OF EPCORITAMAB WITH LENALIDOMIDE AND RITUXIMAB (R²) IN R/R FOLLICULAR LYMPHOMA (FL)." 

The presentation is an update on the EPCORE FL -1 clinical trial. I wrote about this a few months ago. 

First, some background. Epcoritamab is a bispecific, 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 EPCORE FL-1 trial is a phase 3 trial involving 488 patients with relapsed or refractory Follicular Lymphoma. Half of the patients received R-Squared (Lenalidomide + Rituxan) and the other half received R-Squared + Epcoritamab. The earlier results from late last year, with a median follow-up of 14.8 months, showed an Overall Response rate for the Epcoritamab group of 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. 

The updated results break down the comparison into some sub-groups to determine if the Epcoritamab combination holds up better for certain populations. What the researchers found was that Epcoritamab + R-Squared seems to work better than R-Squared alone no matter how they divided things up. 

The results were better for the Epcoritamab group regardless of the age of the patients. For patients under 70 years old, The ORR was 96% versus 78% for the R-Squared group, and the Complete Response was 84% versus 50%. In patients 70 or older, the ORR was 91% versus 81% and the CR was 79% versus 50%. 

When patients were divided into low versus intermediate/high comorbidity (with the NHL-5 scale, a measure of how other health issues like heart, lung, or kidney disease might affect survival), the Eporitamab group again did better. Those with low NHL-5 comorbidity in the Epcoritamab group had an ORR of 94% versus 76% for the R-Squared group, and a CRR of 81% versus 50%. In the NHL-5 High/intermediate group, the ORRs were 97% versus 84% and CRRs were 86% and 49%.

The same held up for patients who received one previous treatment (ORRs were 96% vs 80%, the CRRs were 87% vs 53%,) as well as two or more previous treatments (ORRs were 94% vs 78%, the CRRs were 77% vs 45%). 

All of that matters, of course, because it shows that the Epcoritamab combination will work no matter the population. One big concern for a "triplet" like this  -- a combination of three different treatments -- is that there is the potential for three times the side effects. Patients who are older, or who have other health problems, or have been weakened by multiple treatments may have more problems with a triplet. But that wasn't the case here.

One more breakdown of the data in this presentation had to do with Lenalidomide, which has the potential for dangerous side effects. As part of the study, the researchers tried different levels of Lenalidomide -- at full strength, at 70%, and at 50%. But even with less Lenalidomide, the Epcoritamab triplet did better than the R-Squared. 

So, to sum up, Epcoritamab on its own is very good. R-Squared is very good. Combined, they are all even better, without sacrificing safety. 

I still have a few more ASCO presentations that I'm sifting through. I'll try to do the same with EHA presentations as well. More to come soon.

 

ASCO: Bispecifics in the Real World

Another ASCO review. This one is for the presentation called "Real-world outcomes of bispecific antibodies in relapsed/refractory (R/R) follicular lymphoma (FL)."

A little background first. Bispecific antibodies are one of the two general types of treatments for FL that (in my opinion) Lymphma specialists are most excited about in the last few years, with the other being CAR-T. My own oncologist brings up bispecifics as a possiblity if I need treatment again.

Bispecifics work similarly to monoclonal antibodies like Rituxan or Obinutuzumab. Those treatments are able to seek out specific cancer cells by finding a protein on the surface of the cancer cell (CD20) and then destroying the cell. Most of us who have treatment have probably been given one or the other of those monoclonal antibodies. A bispecific also finds and attaches itself to a protein on the surface of an FL cell. But it has another side to it -- one that attaches itself to a T cell, an immune cell. This brings the T cell next to the cancer cell, and the T cell is able to eliminate the cancer cell.

Mosunetuzumab and Epcoritamab are currently the two bispecifics that are approved in the U.S. (and elsewhere). In this presentation, the researchers are interested in how well they work in the real world.

That phrase "real world" means something very specific in cancer research. It refers to how a treatment works after it has gone through clinical trials and been approved. Clinical trials are very limited in many ways. They are designed to put as much focus on the treatment being tested as possible. So clinical trials participants are limited in different ways, maybe by the number or types of treatments they have already received, or by comorbidities -- pre-existing health problems. If the trial designers are concerned that a treatment might cause kidney problems, for example, they won't let anyone with kidney disease into the trial, so if participants develop kidney problems, they know it was the treatment that probably did it.

"Real world" research doesn't have those restrictions. If a clinical trial uses an "ideal patient," a real world study includes everyone, even those who aren't ideal. A great treatment isn't so great if only a limited number of patients can actually use it.

This is a retroactive study, meaning the researchers didn't ask patients to use bispecifics. Instead, they looked back at records of patients who did use them to see how safe and effective they were, especially compared to the clinical trials. A total of 99 patients with Relapsed/Refractory FL were studies. 92 of them had received Mosunetuzumab and 8 received Epcoritamab (Mosunetuzumabhas been available longer). It was a diverse group by age (raging from 33 to 101 years old) and treatment history (ranging from 1 to 14 prior treatments), including 15 who had received CAR-T.

The results were very positive. They were able to collect data from 96 patients. The Overall Response Rate to a bispecific was 87%, including a Complete Response Rate of 72%.  The responses were not significantly associated with other factors like which bispecific they received, their FLIPI score, or whether or not they had received CAR-T. All of them were successful.

The Progression Free Survival rate at 12 months was 72%, and at 18 months was 56%. Overall Survival rate were 94% and 92%. PFS was not influenced by those factors like FLIPI score or CAR-T use. 

As for safety, 34% of patients had CRS (Cytokine Release Syndrome), though none were grade 3 or higher, which is the most serious levels. Only 3% of patients had ICANS (Immune Effector Cell-Associated Neurotoxicity Syndrome). Again, side effects were not assocaited with the other factors mentioned above. 

I'm leaving out some details, which you can see yourself in the abstract. But the conclusion remains the same. This retrospective study included a diverse group of patients who had received lots of previous treatments, and the two bispecifics were effective and safe for most of them, including patients who were very elderly (did you catch that one of them was 101 years old?). They held up well in the real world.

It's important confirmation for a popular and exciting treatment.

A few more ASCO reviews to come soon.

 

ASCO: PET Scans vs Bone Marrow Biopsies

Looking at another ASCO presentation. This one looks into whether a PET scan can do a better job of detecting disease after treatment has been given to see if there was a complete response.

The presentation is called "Effect of FDG-PET–based bone marrow assessment on prognostic accuracy compared to conventional histologic evaluation in patients with follicular lymphoma: A subanalysis of the FIL FOLL12 trial."

The research comes from the phase 3 FIL FOLL 12 clinical trial. In the trial, 189 patients received a PET scan and then either Bendamustine + Rituxan or R-CHOP. After 6 rounds of treatment, patients received another PET scan as well as a Bone Marrow Biopsy. Patients who received a negative scan (no evidence of disease) were given Rituxan maintenance. Those who had a positive scan (some disease showed up), were given a second treatment, decided on by their oncologist. 

I think it's important to point out all of those details. It's a good reminder that, no matter what a clinical trial is trying to prove, patients are taken care of. There's a plan in place whether a patient's treatment is successful or not.

This particular ASCO presentation focused on those PET scans and whether or nor they could replace a Bone Marrow Biopsy (BMB).

My guess is that most of us have had a BMB. If you're lucky enough to not know what it is, a BMB is part of the standard bunch of tests that are given at diagnosis. A BMB involves having  sample of bone marrow removed from the patient's hip. If cancer cells are present in the bone marrow, it affects staging -- FL cells in the bone marrow mean the disease is at stage 4. That often (but not always) affects treatment timing and type. But it also depends on some other factors. Bone marrow is in the center of the bone, so it takes a little work to get it out. I won't get into details. It's not a fun procedure. 

So anything that keeps a patient from getting a BMB is a good thing.  

Researchers found, in compari g the results of the post-treatment PETs and BMBs, that not only did the PET scans do as good a job in identifying disease, it actually did a better job -- 8 patients who had no evidence of disease in the BMBs did have evidence of disease on their scans.   

Perhaps more importantly, the positive PET scan had longer-term implications. Patients with a positive BMB had a 33% Five Year Progression-Free Survival (PFS). That is, about a third of them went 5 years without seeing their disease progress. However, the patients with a positive PET scan and a negative BMB had a 74% Five Year PFS, and those with a negative BMB and negative PET had a 66% 5Year PFS. In other words, patients who had disease show up on their PET scans had their disease identified earlier, and were able to get it treated earlier.

My initial reaction to this was to be happy that patients might be able to avoid a Bone Marrow Biopsy. But then I was a little skeptical -- I'm not a fan of BMBs, but I'm ever less of a fan if PET scans, given how much radiation they result in. But I thought about it some more, and I'm OK with this. The research is looking at a very specific situation -- a PET scan before and after treatment along with a BMB after treatment. Patients are going to receive a PET scan before and after treatment anyway -- there's really no better way to measure if a treatment has been successful. I'd be a little more skeptical if they were suggesting that PET scans could be used for surveillance, maybe giving a patient a scan once year or something like that. That would be a bad idea. But in this context, measuring treatment success, it makes sense. 

This is another small study, in the sense that it isn't moving us forward in terms of treatment. But it might improve the Quality if Life for some patients, and that's a great thing, too.

More ASCO reviews to come.

 

ASCO Review: Off-the-Shelf CAR-T

 As I had assumed, now that the ASCO meeting is happening, I'm seeing more press releases and articles (and soon, some videos, I'm sure) about some of the presentations. I'll look at several over the next few weeks, but I thought this one was really interesting. Keep in mind, though, that it is a very small study and only one Follicular Lymphoma patient was included.

The title is "Safety and efficacy of Azer-cel, an allogeneic CD19 CAR T for the treatment of patients with relapsed/refractory non-Hodgkin lymphoma and chronic lymphocytic leukemia not previously exposed to autologous CAR T therapy."

If you've been following FL research for even a short time, you know about CAR-T. In this treatment, a patient had T cells removed from their blood and brought to a special laboratory. T cells are a type of immune cell. The immune system can't recognize cancer cells as something that doesn't belong there, so the T cells are changed in the lab so they do recognize the cancer cells. It can be a very effective treatment for many patients. (I wrote about the whole behind-the-scenes process last month.) 

One big problem with CAR-T is that it can be very expensive. I haven't seen any recent figures, but a few years ago, the cost was close to a half million US dollars. Which really isn't surprising, since each patient is basically getting a treatment made just for them. 

So one of the problems that newer versions of CAR-T are being created are trying to solve is how to bring the cost down. And one way of doing that is to create an "allogeneic" version -- one that uses someone else's T cells, so that one sample of cells can be grown and grown and used for many patients. It would create an "off-the-self" version of CAR-T.

This presentation discusses research that is attempting to do that. The specific CAR-T is called Azercabtagene Zapreleucel, or Azer-cel. The study is a phase 1b dose escalation clinical trial. Phase 1 studies are usually small, and the focus is on safety -- figuring out how much of a treatment will be effective before it starts to do more harm than good. That's what "dose escalation" means -- they increase the dose until they find out how much is too much.

This study involves only 19 patients with many different subtypes of Lymphoma. Five had Diffuse Large B-cell Lymphoma, five had Marginal Zone Lymphoma (MZL), four had CLL/Small  Lymphocytic Lymphoma, three had Primary Central Nervous System Lymphoma (PCNSL), one had Waldenstrom Macroglobulinemia (WM), and one had Follicular Lymphoma. All of them had Relapsed/Refractory disease, so they had received at least one prior treatment. 

The results were good, with 81% (13 of 16 who were evaluated) of the patients having a response, including  31% (5 of 16) achieving a Complete Response. The FL patient was one of the 5 who had a CR.

Phase 1 trials are usually focused on safety, though the abstract didn't give too much information about safety. ICANS occurred in 7 patients (37%), with 3 Grade 1-2 events, 3 Grade 3 events, and 1 Grade 4 event.  ICANS stands for Immune Effector Cell-Associated Neurotoxicity Syndrome, where immune cells can cross into the brain. Higher grade ICANS can be very serious. Another common side effect of CAR-T, Cytokine Release Syndrome, occurred in 79% of the patients (15 of them), though there were no grade 3 or grade 4 events.

The researchers conclusion is that Azer-cel is worth studying further, given that it was effective in multiple sub-types of Lymphoma, and the side effects were manageable. 

An off-the-shelf CAR-T would indeed be a very exciting new treatment. It's very early -- years from Azer-cel making it to the doctor's office -- and only 1 FL patient has been involved so far in the study. But this isn't the only off-the-shelf CAR-T being developed, and we might very well be moving closer to this being a reality.

More ASCO stuff soon.

 

ASCO: Barriers to Treatment in R/R FL

I'm continuing with my look at ASCO abstracts. In my last post, I mentioned that that you can sort the abstract search results by "Top Rated," so I looked at the "lowest rated" abstract then. I'm going about halfway down the list this time. I could look at the top of the list, but I'm guessing those will be discussed after the meeting is over, since they are likely to be about research that someone wants to brag about.

Is it just a coincidence that "top rated" abstracts tend to look at clinical trial results and other research on things like CAR-T and bispecifics, while the lower-rated abstracts tend to be about things like survivorship? Probably just a coincidence.

This abstract is called "Bridging gaps in relapsed/refractory follicular lymphoma care: Perceived barriers to treatment and clinical trial access." It looks at the special circumstances of patients who have Relapsed or Refractory disease -- that is, their last treatment stopped working after a while, or never worked at all.

It reports the results of a focus group of 25 people. A few words about what that means. If someone wanted to get the opinions abut Follicular Lymphoma from a group of people, they could do a survey (like this one from last year). The survey was answered by 337 patients from 25 countries. It's very valuable information -- all of them answered the same questions, which makes it easy to compare answers. You get a wide range of opinions.

A focus group involves a lot fewer people. Instead of filling in an online survey, a focus group is usually in person (or maybe by Zoom). The format allows the person leading the group to ask follow-up questions. And since the participants are listening to one another's answers, it often results in conversation. Both types of gathering information -- surveys and focus groups -- are valuable. But they do different things. Surveys result in breadth, focus groups result in depth.

So this group of 25 people provides some good information. They were actually divided into two focus groups included patients with Relapsed or Refractory Follicular Lymphoma, caregivers, and patient advocacy representatives. The other was made up of " multidisciplinary healthcare professionals (HCP) involved in R/R FL care in the U.S." Six HCPs and twp patients also had interviews to go into further depth about the subjects that came up in the larger groups.

Not surprisingly, there was some overlap in the outcomes from the two groups. Also not surprisingly, there were some places where they didn't agree.

The Health Care Professionals thought a few things were very important for R/R FL patients. The first was Individualized Treatment Sequencing. FL is a heterogeneous disease -- it acts a little differently for each of us, so each of us needs an individual plan for treatment. They also valued assessment for transformation, making sure patients were following closely for any signs of transformation to a more aggressive lymphoma. They also valued newer treatments when they seemed appropriate, and the need for clinical trials. They also emphasized SDM -- Shared Decision Making, where patients have some input into which treatments they would receive. 

Patients also valued many of those things. However, patients said there were varying degrees of Shard Decision Making -- some felt empowered to make decisions, while others were given limited options. The patients also said that emotional support was inconsistent, and often they only received it when the patient or the caregiver made an effort to find it. (I assume this emotional support is something formal, like access to a therapist.) Patients also valued clinical trials, but noted "limited information for refractory disease" and unequal access to trials, though some (again) were able to gain access when they made the effort to get it. Patients also pointed to how they could have a better experience with Shared Decisions Making -- by trusting relationships with HCPs, getting better access to accurate information, and engaging with patient organizations for peer support.

The researchers conclude that while Shared Decision Making is a priority for both groups, there is a need for more intentional strategies to make it happen -- better communication, patient education, and structural support.

The good thing from research like this is that is encourages more of the work to be done by the HCPs, the hospitals and cancer centers, and other people and organizations from that end of the spectrum. In other words, the people who have knowledge need to find better ways to share that knowledge with patients. They think they are, and most are doing their best. But "intentional strategies" are important -- creating formal processes to make it happen all the time, not just when a patient or caregiver asks for it. 

That said, "intentional strategies" take time to create. And oncology tends to be habit forming -- even if a new way of supporting patients is available, sometimes doctors need a push to make it part of their routine. 

So it's still going to be important for us as patients to educate ourselves, be proactive, and make sure we are getting what we need.  

The ASCO conference starts in a coupe of days, so I expect some nice press releases and video analyses to start showing up soon. I'll be sure to share the good stuff with you when I find it.

 

ASCO Abstracts Are Here! (plus, Survivorship!)

Huzzah!

ASCO has published their abstracts! It's like Cancer Nerd Christmas!

If you have no idea what I'm talking about, ASCO is the American Society of Clinical Oncology. It's the largest professional group for oncologists in the United States. Every year in late May or early June, they have their annual meeting. It's the largest gathering of oncologists in the U.S., and it's where many researchers present their work -- results from phase 1, 2, and 3 clinical trials, theoretical work, research on cancer biology that might lead to clinical trials. This year, the meeting is taking place May 29 to June 2. 

About a week or two before the meeting, ASCO releases the abstracts -- the summaries for all of the presentations.  The people who go to the meetings use the abstracts to decide which presentations they want to hear and see, so they can more details. I have never been to an ASCO meeting -- it always comes at the worst time of year for my job. (The other major meeting for blood cancer research, ASH, comes in December, at the second worst time of year for my job. When I retire, I'm going to go to all of these cool meetings.)

The ASCO Abstracts were released yesterday, so I can finally see all of the cool new research that is being presented. Like I said -- it's Cancer Nerd Christmas.

I did a quick search on the Abstracts page for Follicular Lymphoma, and 29 presentations came up. That's a little less than in the past, and a few more may show up, but there are definitely a few that are worth paying attention to.

Over the next few weeks, I'll write about some of the abstracts tat look particularly interesting. And while the conference is happening, and in the days after it is finished, there will be lots of press releases and video commentary about the presentations that are most significant, so I'll write about those, too. It's usually about a month or so of ASCO news from here. It's all very exciting.

So I might as well start with an abstract right now: "e24130: Living after lymphoma: A retrospective study of survivorship outcomes from a tertiary cancer centre in rural India."

On the abstracts page, you can sort the results in a few different ways, but the default for me was "Top Rated." I don't know who is rating the abstracts or how they are rated, but I thought it would be interesting to go down the very bottom and see which one was apparently rated last (whatever that means).

And so we have "Living after lymphoma: A retrospective study of survivorship outcomes from a tertiary cancer centre in rural India."

If you've been reading for a while, you've picked up that the idea of "survivorship" is becoming much more important to me lately. Many cancer patients complain that they get excellent care when they are diagnosed and in treatment, but after all of that is over, when they are "finished," nobody seems to care. So there are many cancer centers that have Survivorship Clinics that help cancer survivors deal with the long-term physical, emotional, and mental challenges that come when cancer is "finished."

So this particular title, with "survivorship" as part of it, certainly caught my eye.

It looks at 100 Lymphoma patients in a cancer center in rural India who were diagnosed between 2012 and 2022. They were diagnosed with several different Lymphomas, including Diffuse Large B-cell Lymphoma (45%), Follicular Lymphoma (17%), Hodgkin Lymphoma (20%), and others (18%). Almost all were treated with some kind of chemotherapy (97%). Other treatments included radiotherapy (20%) and autologous Stem Cell Transplant (9%). The researchers collected information about the patients, including "demographics, disease characteristics, treatment exposures, metabolic parameters, endocrine function, bone health, cardiovascular events, secondary malignancies, and psychosocial outcomes."

They found a wide range of long-term issues that the patients had to deal with: Metabolic complications like obesity (40.4%), hypertension (31%), high cholesterol or triglycerides (56%), diabetes (31.1%),  hypothyroidism (8.4%) and vitamin D insufficiency or deficiency (76.5%).

Other health issues included osteopenia (37%) and osteoporosis (23%). In addition, "Two patients developed new-onset left ventricular dysfunction, three experienced cerebrovascular events, and two developed premature cataracts before the age of 50. Two patients developed tuberculosis post-treatment. Second primary malignancies occurred in two patients." Finally, "Psychosocial impact was notable, with five patients remaining unmarried and one experiencing marital disruption attributed to fear of recurrence and social stigma."

The researchers conclude that greater survivorship care is needed for patients in rural India.

I'd say that is probably true no matter where we live.

I look at that list of issues, and almost half of them apply to me as well. So I'm not sure it's a problem confined to rural India. One difference might be that I may have better access to treatment of those long-term health issues. My heart-related issues are under control because I take a handful of pills every day. 

But I have to say, I see very little research on the long-term side effects of cancer treatment. Or maybe I should label them "very long-term side effects." After that 5 year mark, there isn't much attention being paid.

I guess the attitude is "Hey, you're alive after 5 years. Of course you'll have some health issues from treatment. And there is only so much time and money available for research, so we need to put our focus elsewhere." That's true, but if nothing else, more attention paid to very long-term side effects might mean more attention is paid to Survivorship and to the resources that are already available and under-used. (Read about research on survivorship services from a couple of years ago.)

I think I'd feel better if this presenttaion wasn't at the bottom of the "Top Rated" list." 

Wasn't that a good one to start with? Lympho Bob is feeling a little salty, as the kids say. 

I'll be sure to look at the top of the "Top Rated" list soon. I'm sure it will be much more exciting, and I'll have more positive things to say.

It's still a great Cancer Nerd Christmas, and I'm ready to open some more presents. 

Tazemetostat: Official FDA Alert

The big news in my inbox this week was the official FDA Alert for Tazemetostat. 

Tazemetostat had been voluntarily pulled from the market a couple of months ago by its manufacturer after results from a trial showed that there were concerns about patients developing new cancers. The news from the FDA gives more detail about that.

Tazemetostat had been given accelerated approval by the FDA, based on results from a phase 2 trial. It is an EZH2 Inhibitor, meaning it stops or inhibits an enzyme called EZH2, controlled by the EZH2 gene, which is part of process in calls that keeps them from dying as they normally would. About 20% of Follicular Lymphoma patients are effected by this issue with EZH2, and Tazemetostat was the first treatment that specifically targeted EZH2. That was enough to have the FDA give accelerated approval, which means patients could start taking Tazemetostat outside of a trial while the larger phase 3 trial went on to confirm the results of the phase 2 trial. 

But even  when they grated accelerated approval, the FDA was aware of potential issues with secondary cancers. About 1.7% of patients in the trial had developed a new cancer.

The FDA's alert gets into more detail about this. During the phase 3 trial, the rate of new cancers went much higher, with 18 of 318 patients (about 5.7%) developing new cancers, some as soon as 7.5 months after they began treatment, though most developed them 1-3 years after beginning treatment. 

Most of the new cancwrs were Myelodysplastic Syndrome and Acute Myeloid Leukemia, though there were some other blood cancers as well. 

The phase 3 trial isn't taking new patients, but it will remain open so doctors can follow up on long-term side effects of the patients in the trial.

Obviously, there is lots of bad news all around, but most especially for the patients in the trial who developed new cancers. The rest of the patients in the trial will also have to deal with the uncertainty of long-term side effects. And the rest of us have one less treatment to rely on.

The good news, if we can still see good news, is that things were handled as well as they could be, with the trial sponsors shutting it down as soon as they could, and then making sure they are following up with the patients in the trial and making sure they are taken care of. Let's all hope they are doing OK.

I think it's very important to state, though, that this doesn't mean we shouldn't take part in clinical trials. 

It's a natural reaction to read something like this and get nervous about serious side effects. But that's going to be the case no matter what treatment we end up taking. It's worth a conversation with your oncologist about whether or not a trial is right for your situation. I talk about trials with my oncologist at least every other visit, so I know what 's available.

Trials are the only way new treatments can become available. There is no other way. I remember very early on, soon after I had been diagnosed, someone in the online support group that I belonged to said that patients who agreed to be a part of a clinical trial are "heroes." I agree. 

If you are still concerned about clinical trials, or even if you just have questions about them, the Follicular Lymphoma Foundation has a webinar coming up on Tuesday, May 26, called "What No-one tells you about clinical trials and why it matters for your care."  It's going to be an excellent webinar. Click on the link to read more about it and register. 

More coming soon. Those ASCO abstracts must be just about ripe. 

 

R-Squared: 10 Year Follow-Up

The medical journal Blood published the results of a 10 year follow-up of R-Squared. The results aren't surprising (they are positive), but it's the larger content that it more interesting to me.

The article is called "Lenalidomide plus rituximab for previously untreated advanced follicular lymphoma: the 10-year RELEVANCE trial analysis."  As a reminder: R-squared is the shirt name for the combination of Rituxan and Revlimid (also known as Lenalidomide). R-squared was the first non-chemotherapy treatment that was shown to be as effective as traditional immunochemotherapy (like R-CHOP or R-Bendamustine), though it had a different set of side effects that were just as serious. The AUGMENT trial and the MAGNIFY trial led to R-Squared being approved for FL patients who had already received treatment. 

The RELEVANCE trial involved patients who had yet not received any treatment.  The original trial was large -- 1030 patients. More importantly, it is a two-arm study, so it shows a direct comparison between patient receiving R-Squared and those receiving immunochemotherapy. In 2022, I wrote about a 6 year follow-up study.  As I said then, "The results of the study showed that R-Squared remained just as effective after 6 years as it had been up to that point. The Progression-Free Survival (showing that the disease didn't get worse after 6 years) was 60% for R-Squared and 59% for R-chemo. Overall Survival was 89% for both groups. The transformation rate (the slow-growing FL turned into a fast-growing cancer) per year was 0.68% for R-Squared and 0.45% for R-chemo, and secondary primary malignancies (patients developed a new, different cancer) was 11% for R-Squared and 13% for R-chemo. There are some other statistical comparisons as well, but they all say the same thing -- R-Squared is as effective as R-chemo, and as safe."

So would R-Squared hold up as well after 10 years? Yes it does.

The median Progression Free Survival after 10 years was 110.6 months for the R-Squared group and 102.8 months for the Immunochemotherapy group.  The rate of patients with a 10 year PFS was 46.4% for R-Squared and 46.6% for chemo. Almost identical. The median Overall Survival and the median Time to Next Treatment were not yet reached in either group. (Remember that the "median" means the middle of a group, so if the median wasn't reached, it means that more than half of the group has survived and has not yet needed treatment after 10 years). The 10 year Overall Survival rate was 82.4% for the R-Squared group and 81.1% for the chemo group. The 10 year Time to Next Treatment rates were 62.2% and 66.3%. Only 9 cases of transformation occurred (3 with R-Squared and 6 with chemo). 

Comparing the 6 year follow and the 10 year follow up, it's not surprising that numbers went down after 4 more years, but more importantly, the numbers comparing the two treatments were very similar. As the researchers say, R-Squared continues to be an alternative to immunochemotherapy for untreated FL patients.  

The researchers also said this was 10 year follow-up was always part of the plan for the study, and that it would be their final analysis.

Here's what I mean when I say it's interesting in a larger context.

A few months ago, researchers published a 15 year follow-up of R-CHOP and used some statistical analysis to show that about 40% of patients in the study were probably cured. One of the big outcomes of that article was the idea that we now have a new benchmark -- other long-term studies are going to be challenged to do the same kind of statistical analysis to determine what their cure rate was. In other words, the RELEVANCE study shows that after 10 years, there isn't a whole lot of difference between R-Squared and immunochemotherapy, in terms of effectiveness. But can R-Squared match the 40% cure?

We're not getting that information here (or in the 15 year follow-up of R-Squared in the MDACC trial that was published in February) because that wasn't part of their plan. I don't know enough about statistical analysis of clinical trials to know if a biostatistician can come in later on and look at the data for a trial and make that same kind of call. But it will be really interesting to see if that kind of analysis starts showing up at conferences like ASCO and ASH and in medical journals. I'm certainly all in favor of it. I have a complicated relationship with the word "cure" after 18 years, but more studies that use that analysis and use that word might change my mind.

In the meantime, though, it's great to see long-term data of any kind to show that we have some choices. Given our own individual circumstances, there's more than one treatment available for us that will give us a chance at a good, long Overall Survival. That's some very happy news.

Odronextamab Versus the Real World

The medical journal Leukemia and Lymphoma recently published an article about the bispecific Odronextamab called "Comparative effectiveness of odronextamab monotherapy versus real-world systemic therapies in R/R follicular lymphoma." It says good things about Odronextamab, though it's the methods for the research that I find most interesting.

Odronextamab is a bispecific. If you need a reminder, bispecifics are kind of like monoclonal antibodies like Rituxan, in that they seek out a protein (CD20) on a cancer cell. But a bispecific also seeks out a protein (CD3 for Odronextamab) on a T cell (an immune cell). So it attaches to the cancer cell on ne end, and on the immune cell that can eliminate it on the other end. Bispecifics are one of those newer treatments that oncologists get very excited about (including my own oncologist). 

Odronextamab was approved for use in Europe in 2024, though it has not yet been approved for use in the United States. 

The study described in this article is interesting because of its methodology - the way it gathers and analyzes data.  

Some more background: Clinical trials are considered most effective when they are randomized, two-arm studies. What this means is, the people running the trial will decide on criteria for the trial (which previous treatments the trial participants have received, or maybe certain health conditions). The idea is to make sure that everyone in the trial is as alike as possible, so they can be compared to one another easily. As patients sign up for the trial, they are randomly placed into two groups (the two "arms" of the study). One group receives the new treatment that is being tested. The other group receives the "standard of care" -- the treatment that they would have probably received if there was no trial, a treatment that is accepted as being the most effective available. (In Follicular Lymphoma, that's complicated, because there a whole bunch of treatments that are effective for different patients.) But the idea is, you have two groups of very similar patients, receiving two different treatments, so they can be compared easily. It's the best way to argue that one treatment is better than another.

But randomized, two-arm studies are large and expensive and take lots of time. So some clinical trials are one-arm studies instead -- everyone gets the new treatment.But then when it comes time to argue that this new treatment is better than the others, it's harder to do so, because there isn't a group already set to compare it to. So the researchers have to find a study that is kind of close, that was done sometime in the past, and compare it to that study. The problem is, it won't be an exact comparison, because unlike a two-arm study, that older study might have had different criteria. One-arm studies like this aren't considered as reliable (though there are plenty of approvals of new treatments based on one-arm studies, especially accelerated approvals).

The study in this article did something a little bit different. Instead of comparing the results of an Odronextamab trial (ELM-2, which looked at 128 patients with Relapsed/Refractory FL), it kind of created its own second arm.  The researchers looked through electronic records to find patients who were treated at cancer centers similar to those in the ELM-2 study, who were R/R, and who were "real world," meaning they weren't part of another clinical trial. "Real world" research like this is less restrictive -- no criteria that exclude certain patients. 

A small digression to help explain things. Are any of you baseball fans who love statistics?  There's a baseball statistic called WAR, or Wins Above Replacement. It looks at a whole lot of statistics for an individual player, and then compares them to the average statistics for a player who would replace them if they had to leave the team. So WAR says "This player is valuable, because if he wasn't on the team and someone else was, the team would have lost 5 more games per year." It's all very theoretical, based on statistics. But it tries to show how things would be different under different circumstances.

This study seems to do the same thing. It's saying "Odronextamab is valuable because if it was available instead of these other treatments, this is how many more patients would have been successfully treated."

The "real world" patients' records were put together in something called the FLORA study. There were 88 patients who had received a total of 100 lines of treatment. Remember, these patients weren't part of a two-arm study, they were just regular FL patients whose records were examined years after they received treatment, which they received between 2015 and 2020. They received a wide range of treatments, mostly chemotherapy and immuno-chemotherapy, but also monoclonal antibodies, BCL-2 inhibitors, Stemm Cell Transplants, radiation, and some others. 

The researchers found that, compared to the real world group, patients in the Odronextamab study did better. The Overall Response Rate was 80.5% for Odronextamab vs 52.7% for the real world group. The Complete Response Rate was 73.4% vs 33.6%. Median Progression Free Survival was 20.7 months vs 11.5 months. Time to Next Treatment was 40.4 months vs. 9.7 months. 

The researchers recognzie that there are limitations with this research. For one thing, because it looks at patients from 2015 to 2020, it doesn't include any patients who received newer treatments like CAR-T or the other bispecifics that are now available. That might make things turn out differently. And, of course, because they are "real world" patients, they may have had health issues that would have made them ineligible for the ELM-2 trial. It's not really a fair comparison.

But the main ideas are still there. Odronextamab is an effective treatment for many patients, and safe enough to have already received European approval. And just like the theoretical statistical "Wins Above Replacement" in baseball, it's possible that some of the patients in the FLORA study would have had better outcomes with Odronextamab.

It's a very interesting study. I don't think it would hold up as a way to win FDA approval, but it does illustrate how effective Odronextamab is, and how great a need there is for more effective treatments for R/R FL.

I'm still looking out for news about Odronextamab being approved by the FDA. Maybe we'll get some updated news at ASCO in a few weeks.

 

CAR-T: Behind the Scenes

Fierce Pharma published a story a few days ago about Kite Pharma, the makers of the CAR-T treatment Yescarta, also known as Axicabtagene ciloleucel or Axi-cel. It's one of the three different types of CAR-T treatments that are approved for use on Follicular Lymphoma patients. (The others are Liso-cel or Breyanzi, and Tisa-cel or Kymriah). I know I often write about CAR-T as if it was just one thing, but it's a class of treatments, with a bunch of different options, not just one treatment. It's like referring to "chemotherapy" when there are a bunch of different specific types of chemo. 

The story reports on an interview with Kite's Senior Vice President in charge of technical operations. I'm not suggesting Yescarta is a better version of CAR-T than the others (I have no idea which is best, and it probably depends a lot on each patient's situation). But I thought some of the behind-the-scenes information was really interesting, and gives some hope for CAR-T maybe being more widely available. 

If you're new to the world of FL, or in case you just need a reminder, CAR-T stands for Chimeric Antigen Receptor T-Cells. If you know your Greek Mythology, you know a Chimera is a monster made of parts of different animals (a lion, a goat, a snake, and a dragon). A Chimeric Antigen Receptor T-Cell is also made up of different parts.  

The Kite website has a cool short video on the process. Basically, T cells are removed from the patient. T cells are immune cells, so their job is to find and eliminate invaders like viruses. They can't find and eliminate cancer cells, though, because cancer cells are not "invaders" -- they are our own cells that won't die like they are supposed to. So the T cells that were removed from the patient are taken to a laboratory where they are changed by adding a CAR gene. The CAR gene helps the cells create a receptor -- a little spike on the surface of the immune cell. Normally, T cells have receptors that allow them to attach to antigens on the surface of the invader. The CAR gene creates a receptor that lets them do the same thing to a cancer cell. They find the antigen on the cancer cell and attach to it and eliminate it.

So after the T cells are changed in this way, they are grown in the lab so they multiply. They are then shipped back to the hospital and infused back into the patient. This whole process can take 3 to 4 weeks. Once they are back in the patient, hopefully they will work as intended. And the great thing about T cells is their memory. Months or years after they encounter a virus (or a cancer cell), they will remember the antigen and send a signal to the body to create more T cells with that receptor. So when CAR-T works, it can work for a long time from just that one dose.

CAR-T treatments are exciting, but they have some downsides. For one thing, they don't always work, either in the short term or the long term. When they were first approved, they were described as being unsuccessful about 33% of patients, successful for about a year for 33% of patients, and successful long term for about 33% of patients.  Those numbers have gotten better as CAR-T treatments have been developed, but they still certainly are not perfect. 

Another issue is the potential side effects, like Cytokine Release Syndrome, or CRS. Cytokines are basically those proteins that signal the body to make more T cells when an invader is discovered. But too aggressive a response from the immune system all at once can create unintended problems, even death. This was more of an issue when CAR-T was first introduced, but doctors have done a much better job of recognizing it and managing early on. (And CRS is an issue with lots of immunotherapies, including bispecifics.) 

One of the biggest issues, though, is the cost. Because this is a bespoke treatment -- the T cells can only be used for one patient -- CAR-T can cost up to $500,000 per dose. It's a one-time cost, and some studies have shown that a successful CAR-T treatment can actually end up being less expensive than three or four unsuccessful courses of other treatments like chemotherapy. But it's still a lot more than most health insurers or health systems are willing to pay when cheaper options are available. That seems to limit its use.  

Back to the behind-the-scenes article. Another issue with CAR-T has been in the manufacturing process. It's a tricky thing. The T cells have to be stored properly and then shipped to a specialized facility. Ideally, there would be lots of those facilities so the cells wouldn't have to travel too far, and there could be lots of patients helped all at once. But that takes some time and money, and without a large group of patients paying for it, the building was slow (for all of the companies that have a CAR-T treatment). 

Apart from buildings for laboratories, the CAR-T companies also dealt with the supply of viral vectors. These are viruses that are used to carry the genetic material to the T cells. Viruses survive by getting int healthy cells and then multiplying. Viral vectors are viruses that have been changed so they won't do harm, but will carry the new gene material to the cells. But they needed to be produced, too. The CAR-T manufacturers have been improving all of those processes. 

These are some of these behind-the-scenes issues that are described in the article. I think we forget everything that needs to happen to actually make a treatment. We see it in a bag on an IV stand, but it went through a lot to get there. 

The last issue that is discussed in the article is to me the most exciting. CAR-T manufacturers are working on "in vivo" versions of CAR-T. Right now, CAR-T treatments are "ex vivo," meaning "outside the living body." T cells are removed from the body and shipped somewhere else to be changed into a form that can treat cancer. And this all adds to the cost.

But an "in vivo" version -- "in the living body" -- is one where the CAR genes are put into the patient, where they can find the T cells and change them. This is a whole lot harder. "Ex vivo" T cells are isolated in a container, all by themselves. "In vivo" T cells are floating around in the bloodstream with lots of other cells, so the "in vivo" process needs to find them first, and then go through everything that happens now in a laboratory.  That's a big challenge.

But if they can overcome that challenge, it might change the game in big ways. The process would be much less expensive -- the patient is the laboratory. 

That's not going to happen anytime soon -- the interview mentions this process happening "over the next decade." But it would be a huge change to FL treatment. 

It's fascinating to me to look a little deeper into a process that we don't think much about. And I love to see how excited people are about possibilities. It's a constant moving forward.

There's so much to be hopeful about.  

 

Cancer-Sniffing Dogs

 New from the Journal of Clinical Oncology: "Canine Olfaction Combined With Bayesian Modeling for Multicancer Detection From Breath Samples: A Phase II Study in India."

Of all the ways to detect cancer, the best has to be dogs who can somehow smell it.

(I know, I know -- the "best" is the cancer detection test that works the best at detecting cancer. But a colonoscopy doesn't love you unconditionally. That would make a great slogan on my Lympho Bob t-shirts, if I actually had any for sale.)

I'm fascinated by cancer-sniffing dogs. This study took place in India. The idea is that training dogs to sniff cancer might be especially helpful in what the authors call "low and medium income countries."  Cancer detection can be very expensive. Dogs will work for very little -- a couple of biscuits and a pat on the head.

Seriously, though -- as the authors point out, dogs have been trained to sniff cancer for 30 years. The first known cancer-sniffing dog was standard schnauzer named George, who was able to detect skin cancer. Studies that looked at cancer-sniffing dogs have mostly been small, and have taken place in higher-income countries. 

For this phase 2 clinical trial, 3275 patients were enrolled. 1773 were used in training the dogs, and 1502 in the actual testing. For the tests, patients breathed into cotton surgical masks, which were then stored at -20 degrees Celsius. 283 of the patients actually had cancer -- one of seven types (head and neck, breast, lung, gynecologic, upper and lower GI, and genitourinary cancers -- there were no blood cancers among them). Each mask was sniffed by three different dogs, and the collective results were combined.  The dogs correctly detected about 90% of the samples with cancer, and about 91% of those without cancer. They were just as accurate with stage I and II cancers as with later stage cancers -- important for those cancers where early detection can increase survival.

You might not have access to the JCO article, so you can read more about it here. The company that did the testing is called Dognosis. They are working on a system that will use AI to help pick up the signals that the dog is giving. (If you've ever trained a dog to do any kind of scent work, you know it can be hard to pick up their signals on your own.)

And if you're wondering what breeds of dogs were involved, they were four Beagles, one Labrador, one Labrador-Indie mix, and one Dutch Shepherd-Belgian Malinois mix. There was less than 2% variation between the dogs, meaning it really didn't matter which dog was doing the sniffing. They all did equally well in detecting the cancers. 

The reason I find all of this so fascinating is because I have owned two standard schnauzers -- like George, the first cancer sniffing dog. Our first, Strudel, was about a year old when I got my cancer diagnosis. If she noticed anything, she didn't let me know. Our current dog is Katara, who is 5. She didn't say anything about either of my skin cancers. Maybe I just haven't been listening very well.

 

We've actually done some scent work training with Katara, just for fun. And we've learned a lot about how sensitive dogs' noses are -- about 10,000 times more sensitive than a human's nose. Out trainer explained it to us this way: when we humans smell a chocolate cake, we smell a chocolate cake. But a dog can smell the flour, the eggs, the sugar, the cocoa, etc.  Their noses are really amazing instruments.

So if you have a dog, give them an extra hug today on behalf of all the work that other dogs are doing for us.

 

 

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.  

Laughter Yoga

We're in that slow period now, as far as Lymphoma news goes. It's about six weeks until the ASCO conference, and I think researchers are holding on to all of their "good stuff" now, hoping they will make a big splash at that conference. But it's also too early for ASCO abstracts to come out, so there's nothing to read there.

What's a Cancer Nerd to do?

Go out and find something interesting, I guess.

I came across an article today about Laughter Yoga. It was emailed to me by a Public Relations group. I get lots of press releases about health issues from PR groups, and most of them have nothing to do with what I write about. I guess technically, this didn't have anything to do with it either -- not cancer or lymphoma. But I do take a yoga class once I week, and I certainly like to laugh, so I thought it was at least worth reading.

The email describes an article from the journal BMC Pediatrics called "Healing with laughter: the therapeutic power of laughter yoga in pediatric health – a systematic review."

The article describes research laughter yoga and its benefits for children. It's a review of several studies involving a total of 305 children who were taught laughter yoga.

So what is "laughter yoga"? It's a practice that combines laughter and playfulness with breathing exercises and mindfulness. It's not necessarily what many of us think of as yoga -- no downward facing dogs or warrior poses.  But it does focus on other things that are familiar to yoga practitioners, like mindfulness and breathing. 

I you would like to see Laughter Yoga in practice, here is a nice video from the Mayo Clinic. And this one from Celeste Greene reminds us to be playful for 5 minutes. No jokes -- just deliberate laughter. They made me laugh just watching them. But, honestly, I'm a very easy laugh. Ask my wife. 

The article collected data from studies about children, and it found some positive results. The children who practiced laughter yoga had a reduction in anxiety and stress levels. It did not seem to have an effect on clinical depression or self-esteem. But it did show an increase in Salivary Immunoglobulin A (SIgA), a measure of immunity. 

So there is definitely some good that comes from laughter yoga, at least for children.

I haven't looked into whether laughter yoga helps adults in the same way, but I can guess that it does. Laughter is a known stress relief, as is some deep breathing. It all kind of makes sense. 

So this is your reminder to stop every now and then and take a deep breath. And if you can, find something that makes you laugh. It might not help, but it certainly couldn't hurt.

In the meantime, I'll keep looking for any little gold nuggets of Follicular Lymphoma news that might be hiding out there.  

Take care of yourselves. 

 

Biomarkers for FL Relapse

The American Journal of Clinical Oncology published a very interesting article a couple of weeks ago that described research on biomarkers in Follicular Lymphoma. The article is called "Surveillance Strategies in Follicular Non-Hodgkin’s Lymphoma’s Using Molecular and Genetic Markers Improve Cost-efficiencies Over Routine Imaging Studies."

The idea behind the research is that we have a difficult time identifying patients who may transform or have POD24 (Progression of Disease within 24 months). Right now, about 80% of FL patients have good responses to treatment and then experience long survivals. But about 20% either transform or relapse after treatment within two years, and this 20% tends to have a shorter Overall Survival. 

The tools we now have to identify these folks are not very effective. They include things like FLIPI,the Follicular Lymphoma International Prognostic Index.  The FLIPI was never intended to be used as a tool to guess the likelihood of an individual patient's survival. If you take this little quiz, you'll see that it includes things like age, which is kind of useless -- thousands of people live long long lives with FL no matter what their age at diagnosis. The FLIPI index was developed many years ago, and has not been very effective in identifying that 20% of patients.

Over time, other prognostic models have been developed that look at factors that are a little bit more personal. For examples, the m7-FLIP which took the original FLIPI and added some possible biomarkers. This was an improvement, but still didn't completely identify that 20% as well as it was hoped. Too many of those high-risk FL patients were only identified after they transformed or relapsed within 24 months.

Other newer prognostic tools were developed in the years after that, like POD24-PI, PRIMA23, and ICA13. The authors of the article look at how effective they have been. Like m7-FLIPI, they do a good job, but not a perfect job, being anywhere from 43% to 86% effective.

The researchers looked at all of these models and essentially tried to find the best parts of them. Each prognostic model was developed from research tat looked for biomarkers, and those studies were all looking for (and finding) slightly different things. So looking at all of the data together might find some places that they overlap or that they do things that the others don't do.    

In the end, they came up with a model that they say is more comprehensive than the other models, and may do a better job of identifying high-risk patients as early as diagnosis. At this point, patients need to transform or relapse before they know for sure that they were in the high-risk group.  Identifying them early will allow doctors to possibly treat them more aggressively, and may in the future help to point researchers toward new targets for new treatments. 

The research team identified 10 biomarkers that seemed to only be present in high-risk FL patients. They did this by looking at data from patients who relapsed over a 14 year period. The biomarkers usually involve genetic mutations, which make them easier to identify.  

Of course, research like this is based on past results, so it's hard to know how effective it will be in actual patients at diagnosis. That's how these things often work -- it seems like it will be effective, but then they discover something else that their model hadn't picked up. And if that happens, that's OK -- that's how science works, and any step forward is great. But it does seem like this could be a step forward for a group that needs some help. 

I find it interesting that this study is being framed in financial terms. As the title says, a more effective model might "Improve Cost-efficiencies Over Routine Imaging Studies." In other words, a fairly simple genetic test that identifies a high-risk patient early on will mean fewer blood tests and scans and biopsies, and all the cost that goes with it. 

Lower costs are certainly important, and goodness knows that financial toxicity is a major problem for cancer patients. But all of the other benefits that come with improved prognostics matter even more  -- better Quality of Life, better mental health, and most importantly, improved Overall Survival. 

I'm hoping we see more data from this research in the next year or two as it gets applied to patients who are diagnosed now in the future.  I'll certainly be keeping an eye out.