Surviving (or Whatever You Call It)

Earlier this week, I read an interesting piece called "Surviving Blood Cancer: Lessons from a TV Show," by Ramae Hamrin, published on Blood-Cancer.com (a website that I still do some writing for). 

Ramae talks about the TV show "I Survived," where people tell stories about surviving something awful (like a bear attack or being trapped on a roller coaster). The people interviewed for the show talk about what they did to survive, usually involving finding some kind of inner strength. Ramae related this to her own experience with Myeloma, a blood cancer. We certainly need to find some kind of inner strength for our situation, even if it doesn't involve fighting a bear.

It all made m,e think of something else I read recently. It isn't something that has been published (at least not yet). It was a reflection on the word "survivor," written by a cancer patient who really doesn't like the word to describe herself. She gave lots of reasons. One is that she is still undergoing treatment, and she usually thinks of "surviving" as meaning that the ordeal is over. (The bear has walked away, if you want to think of it in terms of the TV show).

But she also felt like calling herself a "survivor" would make her complacent -- she would just forget about the cancer and stop ever worrying about it. (She's not a Follicular Lymphoma patient, but she does have a cancer that tends to come back.)

I'm not sure anyone with cancer -- especially one that comes back -- will ever forget that they have it. Side effects have a way of reminding us for a long time. But I get her point.

I also know that lots of organizations that help cancer survivors are careful to point out that "survivor" means anyone who has been diagnosed with cancer and is still alive, whether that diagnosis came 50 years ago or 5 minutes ago. I tend to agree with that one. I use the word a lot, and I tend to pay attention to National Cancer Survivors Day every June. 

At the same time, "survivor" isn't necessarily a word I use to describe myself. I usually go with "I'm a Follicular Lymphoma patient," because I still see my oncologist regularly, and if I'm still in his care, that makes me a patient. (That bear might turn around and walk back toward me, after all.) But it also leads to the question, if I stopped seeing him, that would mean I was no longer a "patient," so what would I be?

But there are times when I do call myself a "survivor," because I know that most people who have never had cancer will think of "survivor" in the "It's all over now and he's fine" sense. So I use that term sometimes because it's just easier for the people I'm talking to. They don't want to worry and I hep them up by using the non-worrying word. The bear is all gone. You can get back to your picnic.

But all of this makes me want to ask:

What do you think of the word "survivor"? Is it a term you use to describe yourself? Are there times you use and times you don't? 

I know there are lots of you from countries outside the U.S.A., and I'm especially interested in whether or not you use that word. Or is there another term in your country that people with cancer use to describe themselves? 

I'm fascinated by words, especially the words we use to talk about cancer, and I'd love to hear your thoughts. Add them to the Comments section. (And if you'd rather not, then send me an email. You can find the address in my profile.) 

I hope you're all doing well, surviving, or living in whatever way makes sense for you.

A Biomarker for Transformed FL?

Very, very interesting article published a few days ago in the medical journal Blood.

Some background first. As I'm sure you all know, one of the great fears of being a Follicular Lymphoma patient is that our relatively slow-growing cancer will transform, and turn into a fast-growing cancer (usually DLBCL, or Diffuse Large B Cell Lymphoma). Transformed FL has a lower Overall Survival rate, requires more aggressive treatment, and most importantly, is just about impossible to predict. And the statistics for how common it is for patients to transform are all over the place. Some say up to 50% of FL patients will transform, but most studies that actually look at large populations of FL patients put it at around 15%. All of that makes it a scary thing that kind of lurks in the background for many of us.

The lack of a way to predict to predict transformation is frustrating for lymphoma experts. And so far, there has been no biomarker to help predict this -- no feature of an FL cell or a gene that is different from other FL cells or genes. 

Maybe, just maybe, this research has an answer. 

The article is called "Genetic Subdivisions of Follicular Lymphoma Defined by Distinct Coding and non-coding Mutation Patterns." It features some pretty heavy science, and to be honest, I was greatly helped by a Twitter thread by Ryan Morin, whose lab did the work for this. Dr. Morin is not an oncologist or Medical Doctor, but a PhD Molecular Biologist at Simon Fraser University who studies DNA sequencing. His lab looks at full DNA sequences to study tumors by comparing the genetics of tumors with healthy cells. This is not so much about looking at tumor cells as it is about using computers to look at differences.

(See? Lots of heavy science.)

I'll try to make this simple for you (which is my nice way of saying that I have to keep it simple for myself).

The research looked at the whole genome sequences of 423 patients. This means that they looked at all of their genes, roughly 20,000 per person (this is why computers are involved here). Then using the computer, they were able to compare patients with FL, patients with transformed FL, and patients with DLBCL (that developed on its own, not DLBCL that came from transformed FL).

What they found was that there were enough genetic differences to put Follicular Lymphoma patients into two groups.

They call the first DLBCL-like Follicular Lymphoma, or dFL. 

The call the second group Constrained Follicular Lymphoma, or cFL.

Each of the two groups has different patterns for mutating or changing, and has some different biological characteristics, and also may different clinical characteristics (they seem different to a doctor). 

Most importantly, they found that the cFL group has a lower rate of transforming. 

How they did this was pretty interesting (and again, I have a basic sense of how this worked). Research has already shown that FL and DLBCL have a lot of the same features. So the research team looked instead at what features do not overall. They found that many of the differences occurred in places involving somatic hypermutation. Here's what that means -- FL and DLBCL are both cancers of B cell lymphocytes, which are immune cells. As B cells develop, they have to be flexible, so they can go after different types of invaders. During that period where they are flexible, where they can in change in lots of different ways, sometimes the changes go wrong, and cancer develops.

Specifically, they found that the dFL group (the one more likely to transform) had more problems with something called the CREBBP gene. This is a gene that helps control cell growth. So when there are problems, cells grow uncontrollably, which is what cancer is. The cFL (the one less likely to transform) had fewer problems with this gene, so cell growth was kept in check. In other words, it was "constrained" -- cFL = Constrained FL. 

When they tested this idea, they found that the dFL group (more likely to transform) had a median time to transformation of about 5 years. The cFL group (less likely to transform) had a median time to transformation of about 15 years.     

(A reminder about medians -- that means half of the group transformed sooner than that number, and half transformed later, or not at all. A 15 year median for time to transformation means a lot of them probably died of old age before they ever transformed).

The researchers are guessing that the CREBBP gene has a big affect on transformation.

So what does all of this mean for us as patients?

At the moment, it means nothing. This is a bunch of computer nerds, not a bunch of oncologists.

But they are pretty amazing computer nerds (and you all know how much I appreciate a nerd). But ti will take some time to test this out on a larger group of patients, and then begin to develop treatments that perhaps target the CREBBP gene in some way. Whether that happens before transformation or after, I have no idea. It will likely take a while to figure all of that out.

But for now, this seems to me like the most promising attempt at isolating a biomarker that I have read about. I do see articles like this a lot, and they often hedge ("It seems like this this might be important for lots of patients, but not all of them..."). The genetics of cancer is incredibly complex, and there's probably no one simple answer to transformation.  

But every new step toward an answer is exciting.

Bi-Specific CAR-T

I don't usually pay as much attention to what happens at the AACR (American Association for Cancer Research) when it happens in the spring, at least compared to ASCO. It's a busy time for me. But I do see news from the conference, and this one is worth sharing. 

The news article I saw is called "Bispecific CAR T-Cell Therapy Has “Robust” Activity in Non-Hodgkin Lymphoma." A bispecific and a CAR-T in one? The two hotest treatments in the Lymphoma world combined? Sounds good to me.

It's not exactly a combination of, say, the bispecific Mosunetuzumab and the CAR-T Kymriah. But it does combine the two ideas. The treatment described in the article is a CAR-T, so it involves changing a patient's T cells so they recognize lymphoma cells. The bi-specific part comes because they are changed to recognize two different proteins on those cells -- CD20 and CD19. Both are very common on B Lymphocytes (the type of white blood cell that turns cancerous in Follicular Lymphoma and many other Lymphomas).

This research involves a phase 1 clinical trial (you can see the details of the trial here), so its main purpose is to measure safety -- how much of the treatment can be given to remain safe while still being effective. The researchers hope to have 24 patients in the trial, and they report here on the first 11. Four of them have Follicular Lymphoma, and the rest have other types of lymphoma. All had already had at least 2 lines of treatment before this one.

Patients were first given traditional chemotherapy, and the bi-specific CAR-T, tryi ng two different doses. Results look good. Combing the results from the two different doses, the Overall Response Rate was 91% (10 out of the 11), and the Complete Response Rate was 73%. The patients who received the higher dose had a 100% CR and the lower dose had a 63% CR. After 21 months, the median PFS was 18 months.

The bigger issue is safety -- how are the side effects?

There were certainly some to be found. All patients reported anemia (low red blood cells). 10 of the 11 had neutropenia (low white blood cells), and thrombocytopenia (low platelets). There was one case of  grade 5 (very high) hypocellular marrow (fewer than normal bone marrow cells). There were no cases of damage. Six patients had low level Cytokine Release Syndrome (CRS), all of which were controlled by medication. 

That all seems promising to me.  I would have expected more problems with side effects, given the chemo at the beginning of the process. Of course, this is a very small number of patients, so a larger phase 2 trial might show more of them, or lower effectiveness.

But it's promising. I wrote a couple of months ago about the different directions that researchers were going with CAR-T treatments, and this is just another example of how that kind of treatment might change and improve over time.

As always, there's lots to be hopeful about.

 

A Potential New Inhibitor

I saw news recently about a potential new inhibitor. It's so new that I'm not even sure its being tested in Follicular Lymphoma. But it does say some interesting things about clinical trials and treatments anyway.

The news came from a press release with the title "Glenmark receives acceptance from U.S. FDA on its IND application for GRC 54276 to proceed with a Phase 1/2, first-in-human clinical study of the molecule for the treatment of patients with advanced solid tumors and lymphomas." 

A few important things here.

First, the treatment is called GRC 54276, and it is a Hematopoietic Progenitor Kinase 1 (HPK1) inhibitor. As you know if you've been reading for a while, in general, an inhibitor is a treatment that inhibits or stops something from happening. Many cancer begin, or continue, when there is a problem in a chain of events that keeps our bodies running well. So in order for a cell to grow normally, a gene controls an enzyme that signals to a protein that signals to another enzyme that signals to another protein to allow a cell to die. If something happens to that gene, then the whole chain gets thrown off, and the cell doesn't die. And that's what cancer is (to oversimplify) -- a bunch of cells that won't die.

When cancer researchers find one of these chains, they can figure out which part of it is broken. Then they can develop an Inhibitor that inhibits or stops that broken chain of events. In other words, it will tell the body to let the cells die like they're supposed to.  

Hematopoietic Progenitor Kinase 1 (HPK1) inhibitors like this one work by inhibiting a process that keeps T cells from going after cancer cells. As you might know, T cells are immune cells (they are the "T"in "CAR-T"). Inibiting HPK1 will let the T cells do their job and go after the cancer cells.  At least that's the theory right now.

The company that makes the inhibitor has been given permission to begin a phase 1/2 trial in the U.S. They will be able to test the treatment on patients with "advanced solid tumors and lymphomas." So that's why I'm not even sure if this will be a treatment for Follicular Lymphoma. Phase 1 trials are often kind of broad like this, and will test the treatment on patients with several lymphomas (the specific ones aren't mentioned in the press release). Interestingly, the original trial in India involved patients with Hodgkins Lymphoma, not Non-Hodgkins Lymphoma. 

The other interesting thing about this trial is that it involves both lymphomas and solid tumors. We're so used to thinking about cancer in terms of body parts. All breast cancers must be the same, right? Not at all true. More and more, researchers are finding that cancers are about these kinds of genetic processes -- those chains of events. And that same chain of events happens whether the cell is in the blood, or the stomach, or the lung. That's not true for every cancer, but we're probably moving to a place where we don't think of cancer in such local terms.

The final important thing to me is that there is still a lot of great research happening in inhibitors. With the problems that we saw with PI3K inhibitors, it's easy to lump them all together. But there is still lots of excellent research happening in finding those chains of events and figuring out how to inhibit the issues that come with them. Very cool, research.

All of this reminds me that ASCO is coming up soon -- the first week of June. The abstracts should be coming out soon. I'll start sharing once I get access.

Hope and Flowers

This is an annul thing for me now, but where I live in Connecticut, spring flowers are finally in bloom, and that means the daffodils I planted in my back yard are coming up:

This is a special flower, and I've written about it before, in a piece on The Mighty called "Finding Hope Among the Thorns of Cancer."

If you look closely at the picture, you can see that the daffodil is surrounded by thorny blackberry canes. I planted the daffodils many years ago, when that section of my yard was in shade for most of the year. Except for the spring, before the trees were covered with leaves -- then spring flowers like daffodils would bloom, when they still had some sun.

And then my neighbors had to cut down some of those trees, and suddenly that part of the yard got a lot more sun. Before I had a chance to plant something else, some wild blackberries started to grow there, probably because a squirrel buried some blackberries there. they are wild blackberries, so the canes are covered with thorns.

Now, every summer, we pick blackberries and make jam (or we share the berries with birds and hope we get some next year). But every spring, we wait for that daffodil to grow up among the blackberries.

It's a reminder that beautiful things can happen even in the worst circumstances. There can be good things happening in life even when we live with the thorns of cancer.  

That's hard to remember sometimes.

Being a native of New England, I have always loved autumn. I like the cooler air, and bright colors of the changing leaves. I can smell fall in the air when it starts to come around.

But as I get older, I've come to love spring even more. So much new life. So many reminders that there are new beginnings all around us.

Last fall, my wife and removed a section of our front lawn and planted a pollinator garden. (You might remember that my middle child is a wildlife biologist who has had a love of nature since he was a baby.) Our neighbors weren't necessarily happy with us -- they would prefer a that everyone had a perfect green lawn in front of their house.

But with our son's help, we found some native plants that will attract butterflies and bees and a few birds. It will be in full bloom probably around July. So we added a few spring bulbs so we could have some color a little earlier. Those bulbs are starting to show their colors now.

And the summer flowers are peeking through the soil and mulch.

And the flowering cherry tree in front of our house is just now popping open.

I hope the message for all of this is obvious.

Even without the drama of the thorns, it's nice to be able to look around and see signs of hope. Every day is new, with a chance for something wonderful.  Maybe it's something that might pay off in the future -- small green leaves that will bloom in September, or bare blackberry canes that will be filled with flowers, then berries, and then delicious jam.

Or maybe it's not something that pays off in the future. Maybe it's something to just enjoy for today. That's great, too.

I hope you all find something nice to look at that brings you some hope. Today and every day.

Take care of yourselves.

How to Treat High Risk Lymphoma [video]

Since people seemed to like the last video I posted, I'm going to post another.

This one is from Lymphoma Hub, a site aimed at doctors. Members of its steering committee got together for an online discussion called "How to Treat High-Risk Follicular Lymphoma."

The discussion is hosted by Dr. Giles Salles from Sloan-Kettering in New York. Dr. Salles says this discussion is a "global perpsective." Indeed Dr. Salles moved to New York from Lyon University in France just a few years ago, and the other guests represent other hospitals and research centers from around the world. I like that -- I have to remind myself that not everyone who reads this blog is from the U.S. Sometimes I talk about treatments that aren't available yet in other parts of the world. So the global perspective is nice.

One of the guests is Dr. Stefano Luminari from the University of Modena in Italy. He talks about how he defines "high risk" in a Follicular Lymphoma patient. He pays attention to diagnostic factors like FLIPI and staging to decide whether or not a patient needs to be treated immediately. He also discusses whether to give a high-risk patient R-CHOP or R-Bendamustine. There's no easy answer there -- it depends on the patient and their situation. 

Other guests include Dr. Martin Dreyling of Ludwig-Maximilians University in Munich, Germany and Dr. Grzegorz Nowakowski of the Mayo Clinic in Minnesota, who talk about some of the limitations of FLIPI scores. Better to find as much information as possible through biopsies and scans, which may reveal more information  about the level of risk (such as whether or not a patient has transformed). Liquid biopsies may be helpful in the future. They rely on their experience to come up with a plan. And they agree that coming up with a first treatment plan for FL patients is a challenge, because there are so many different factors to consider. It's hard to say for sure which patients are "high risk."

The group also talks about high-risk FL for relapsed/refractory patients (those whose last treatment stopped working, or didn't work at all). This group is a little easier to identify as "high risk" -- POD24 and transformed patients are much more clearly in this category. For some parts of the world, treatments like CAR-T and bi-specifics are not yet available, so the best options are more intensive chemotherapy. They agree that more data is necessary to determine which treatments are best, and to help get newer treatment options approved for use.

Another guest, Dr. Michael Dickinson of the Peter McCallum Cancer Centre in Australia, was asked about different strategies including Stem Cell Transplants, which Dr. Salles points out are used much less in the U.S. lately. Dr. Dickinson points out that they are still using SCT on transformed patients, but that patients don't like them, and that many experts think that other, newer options are better. But, again, in his country, some options are not available, so STC is the best option. He said his cancer center is being more aggressive about genetic testing, to help identify biomarkers that could help patients.

It's very interesting to me to hear directly from oncologists from other countries about which options are available and which are not. The U.S. has quite a few options, but there are some that are not used. PI3K Inhibitors, for example, are available in some countries, but no longer in the U.S. 

As I said, this is a good reminder for me to continue to pay attention to news from other countries and report on it when I can. 

And it's good reminder about how heterogeneous Follicular Lymphoma is. In other words, we all seem to have slightly different variations of the same disease, and our treatment paths will be different, based on our disease and on the options available to us. 

Still, even with all of that being true, I'll keep doing my best to share what I know. I hope it continues to help.

Stay well.

The Problems with Accelerated Approvals

I've been doing a lot of reading lately about the FDA approval process and some of the things that make it problematic. There have been a couple of really interesting books published in the last year that look at this process from a couple of different angles. I may try to write about them soon. But the big theme that I find in all of my reading is that the when new treatments are up for approval, there is a delicate balance that needs to be achieved -- the safety of the treatment and its effectiveness for patients, the desire for doctors to help their patients but also to keep them safe, the need for drug companies to make a profit to justify doing research, etc. It's a very complex process.

So it was interesting to see an article in JAMA Internal Medicine a couple of weeks ago that highlighted some of these issues in ways that are similar to the books I have been reading. 

The article is called "Clinical Trials Portfolio and Regulatory History of Idelalisib in Indolent Non-Hodgkin Lymphoma."

Now, I will admit to a small obsession with Idelalisib and other PI3K inhibitors. It was about a year ago that they were pulled from the market, or voluntarily withdrawn. I wrote about this a few weeks ago. The problems came because of safety issues (more serious side effects, including patient deaths, than were expected). There were also problems with recruiting enough patients into the trials, probably because of the Covid pandemic (but also, I think, because there were at least 4 PI3K inhibitors competing for the same patients).

PI3K inhibitors fascinate me because they held so much promise (and maybe still do?), and got oncologists very excited about their possibilities. Their trial results were very good, and they worked against cancer in new ways that targeted the cancer cells while sparing many healthy cells (unlike the way chemotherapy works). 

As I've written before, several PI3K inhibitors (including Idelalisib) were given accelerated approval by the FDA. This meant that the companies could start selling the treatments, and doctors could start prescribing it, based on the results of small phase 2 clinical trials. The stipulation was that a larger phase 3 trial would be conducted to confirm the small phase 2 trial. The term "accelerated approval" is probably not completely accurate. It's more like "temporary approval." It allows the manufacturer to start earning some money on the treatment earlier than usual.

Here's the problem, as the JAMA article points out -- the issues with serious side effects were already clear, up to 6 years before the withdrawal from the market. The researchers who wrote the article looked the clinical trials involving Idelalisib. There were 31 of them. 20 of those involved indolent lymphoma (including Follicular Lymphoma). During the period after the accelerated approval, the results of 6 of those trials were available. These 6 trials were Randomized Clinical Trials, meaning they allowed a direct comparison between Idelalisib and another treatment. And in those trials, it was clear that Idelalisib had higher rates of serious side effects and patient deaths than the treatment it was being compared to.

The big problem here? It was six years later that Idealisib was withdrawn from the market, and in those 6 years, the manufacturer had $842 million in sales (though they declined over time, as problems became evident).

It's a tricky thing. Patients need new and better treatments, and businesses need incentive to spend money to develop them. Accelerated Approval from the FDA seemed to solve both problems -- promising treatments get to patients sooner, and businesses begin to make money sooner.

But, as the article's authors point out, there needs to be greater oversight during the process. It's not enough to complete the phase 3 trial and then ask for approval; there need to be steps along to way to make sure things are doing well, particularly in terms of patient safety. There isn't much incentive for a company to make trial results public after Accelerated Approval. That needs to change.

I hear lots of patient opinions about drug companies, and the kind of gray area we are all in. We need them, but we don't trust them -- I think that sums up a lot of our attitudes. Problems like this doesn't make us trust them any more, but it certainly makes us need them more.

My biggest fear with a situation like this is that it damages patient trust in other ways -- in the clinical trial process itself. If we are being asked to be a part of a trial, but problems are being "hidden," will that make fewer people want to be a part of them?

I hope that's not the case. I hope that anyone interested in a trial places their trust in the oncologist who they are working with -- someone who can explain the potential risks as well as the benefits, and pay close attention to each individual patient to make sure they are staying safe. (In the books I read about this process, that was very clear -- the oncologists working directly with patients made it a priority to protect those patients. They were kind of the heroes of the stories, even if they were in the background sometimes.)

And I hope none of you are turned off from being a part of a trial. They're the only way we find new treatments, as risky as they are, by their nature. 

Cancer is a complex thing -- within our bodies and outside of them. But like knowing all I can about my disease, I'd still rather learn about the process and know what I'm dealing with than be in the dark.