Trouble for R Squared?

The big Follicular Lymphoma news from the past week or so has been the report from the phase III RELEVANCE trial, which looked at R-squared (Rituxan + Revlimid/Lenalidomide), plus R-squared maintenance) and compared it to Rituxan + chemo (CHOP, CVP, or Bendamustine) plus Rituxan Maintenance. The patients in this trial did not have any previous treatments for FL.

This is the first trial to do a direct comparison between FL patients who are getting traditional chemotherapy and patients who are getting a treatment that does not include chemo.

The first reports find that the R-squared was not superior to the chemo. There was no difference in Progression Free Survival -- the R-Squared did not extend the time that it took for patients' FL to get worse. There was also no difference in the percentage of patients who had a response.

The reactions to this have been kind of mixed -- and kind of fascinating.

A lot of the reports that I had seen about this are from business websites (like this one). The company that  makes Revlimid/Lenalidomide is one of the sponsors of the RELEVANCE trial, and made the announcement. Their stock price fell and their outlook was downgraded. Basically, investors think they aren't going to make as much money off of Lenalidomide as they had hoped.

But the medical and oncology websites are more hopeful (like this one -- OncLive is always great about exploring things from lots of different sides). So while there is some disappointment about the results, there is a lot of positive that is coming from it, too.

The lead researcher for the trial, Dr. Gilles Salles, said "This is the first phase III trial to evaluate a chemotherapy-free regimen to the established standard of care in patients with previously untreated follicular lymphoma and represents a landmark study in this disease setting. We look forward to further analyzing and presenting these important data at a future medical congress."


So that's the first positive here. For all of the talk of the future of treatment being chemo-free, this is the first trial that has actually done a direct comparison. Half of the patients got R-squared and half got R + chemo.  Other trials look at non-chemo treatments, but they compare them to previous trials that are already finished. This one took the same group of patients, making sure they are easier to compare, and divided them up. That's important. Direct comparisons are the best way of testing treatments.

But the other important thing that Dr. Salles said was that they will continue to analyze the data and will present it at future conferences. This was just the initial look at the numbers.

What else will they look for? Dr. John Leonard is quoted in the OncLive article: “Follicular lymphoma patients frequently choose less effective treatments—like rituximab alone versus rituximab/chemo—based on perceived quality of life advantage. R2 might be a choice made by some patients, even if less effective. The details of efficacy, toxicity, and qualify of life are key here.”

In other words, maybe the R-squared won't be as effective as the chemo, but it has fewer or less harsh side effects, making it possible to live a more normal life. Quality of Life is a big issue for Dr. Leonard, who recognizes that many of us could be living with FL for a very long time. What makes a treatment "effective" isn't just that it has met an endpoint like OS or PFS or CR, but that it helps us live our lives -- on our own terms, whatever they may be.

And so, I added the question mark to the title of this post. Is there trouble for R-Squared? Yes, in some ways, since it didn't do what it was hoping to do. But that doesn't necessarily mean it's a failure, and it doesn't necessarily mean it won't be approved.

It's also important to keep in mind that the RELEVANCE trial is for R-squared in untreated patients. Another trial, the MAGNIFY trial, is looking at R-squared in FL patients who have already had at least one treatment. They received R-Squared, and then maintenance with either R-Squared or just Rituxan. Unlike the RELEVANCE trial, the MAGNIFY trial did not do a direct comparison with another treatment.

And then there's the AUGMENT trial, which does do a direct comparison -- R-Squared versus Rituxan alone -- for patients who have had at least one treatment.

Both of those other trials seem to be doing well. So R-Squared isn't going away completely.

But it will be interesting to see how the RELEVANCE trial is analyzed, and what the reaction to it will be when the results are presented (maybe at ASCO or Lugano next spring/summer?). Just how important will Quality of Life end up being in the analysis?

Stay tuned.

Merry Christmas

I want to wish a Merry Christmas to all of you who celebrate the holiday.

And if you don't, I wish you a joyful day all the same.

Two years ago, I sent a wish for some inner peace for all of us. We could all use it -- not just at this time of year, but all the time.

Last year, I wished us some outer peace. We lived in a world way back then (a whole year ago) where there was so much that divided us. I'm not sure it's much better a year later. So I hope we can all do just a little bit this year to try to understand others, especially the ones that we disagree with.

I was trying to think of a Christmas wish for this year. It feels like I should be wishing for more of the same. We could all still use some peace.

On Saturday, I heard some good news. Someone I love will get the opportunity for a new beginning. And I started to think about some other people I know who could use a new beginning, too. It turns out there are lots of them.

So while I hope everyone finds some peace, I also know that finding peace sometimes means accepting the situation you find yourself in. And that's important.

But a new beginning is different. It means changing your situation.

For those of us with Follicular Lymphoma, acceptance is a big deal. Inner peace means we have wrapped our heads around the idea that we might be in this situation for a while.

But sometimes that can also mean that we wait for the next thing to happen.  Usually the next bad thing to happen. It's hard to start over when you're just waiting.

I can remember, early on after my diagnosis, having an opportunity come up at work, and turning it down, thinking "If I'm in the middle of this thing, and I need to get treatment, I'll have to give it up and that will ruin it all." I did that a couple of times. And then one day I thought about it. Don't bother with the special project at work, because you might not be able to finish it. But then, maybe don't bother with some of the regular work stuff, because you might not be able to finish that, either. And then I started thinking about all of the stuff that I shouldn't bother doing because I might not be able to finish them. In the end, I found that I shouldn't bother getting out of bed, because I might not finish the day.

And I saw how ridiculous that was.

Peace can mean acceptance. But acceptance can mean giving up, and being at peace with that decision. And that isn't always a good thing.

So this is my wish this year, whether or not you celebrate Christmas. When you are ready, I hope you find a way to make a new beginning. However big or small.

Enjoy the day, everyone. And thanks, as always, for reading.

The Importance of Exercise for Lymphoma Patients

I'm still cleaning out my files of links from ASH, and getting around to the things I saved before ASH. I'm backed up a lot.

I found one item from October on how exercise helps cancer patients, and then another from ASH on how exercise helps Lymphoma patients specifically.

The general cancer article from October discussed how good exercise is for cancer survivors. It reduces fatigue and improves physical function -- and "lean body mass to fat mass ratio," so we look better, too. They recommend "150 minutes of moderate or 75 minutes of vigorous aerobic activity per week, and 2 days per week of resistance training (e.g., with exercise bands or light weights)."

That shouldn't be too tough, right? Take a 30 minute walk 5 times a week. You even get to skip two days.

The Lymphoma research describes a session at ASH. It found that physical exercise may actually contribute to longer survival for lymphoma patients. Lymphoma survivors who increased their physical activity had a higher Overall Survival than those who decreased activity.  The researchers believe there should be more active attempts to encourage exercise in Lymphoma patients.

I recently looked back at some of my very early blog posts, and I saw how many of them involved running. I used to be a runner. Not so much any more. My knees aren't happy with me when I try. But I do try to get to the gym 3 days a week to work up a sweat, and I've tried to walk more (my phone helps me measure how many steps I have taken for the day, and I aim for 10,000, but I'm happy if I hit 8,000 on days when I can't be as active as I'd like).

I'm not going to claim that my being active has kept me alive this long. But I will say that I feel better and happier when I am being active. And I also think it's important to stress that it's really not too tough to get to that 150 minutes of moderate exercise each week.

But I also know that, for some of us, it's hard to be as active as we would like. It's worth talking to your doctor about what you can do to be active and get moving. If generally feeling better wasn't reason enough, then maybe the chance at a higher Overall Survival rate might be the incentive.

(One more thing -- one of the researchers for this study was Dr. Carrie Thompson. She was also the lead researcher on the Quality of Life study I wrote about a couple weeks ago. I'm happy that research like this is taking place. As much as I crave research reports that look at new treatments, I also know that we actually have to live our lives, day to day. I appreciate solid research that gives us some direction on how to extend our lives while we enjoy the time that we have. Dr. Thompson is quickly becoming one of those Lymphoma Rock Stars that I like to follow.)

Since we're coming so close to the beginning of a new year, when we traditionally resolve to make changes for the better, I hope you'll all think about small ways that you can be more active. Start slow -- no one is suggesting that you plan on running a marathon. But a 10 minute walk around the block after dinner would be a good place to start.

Atezolizumab Combo for Follicular Lymphoma

As I have said, now that ASH is over, I've been looking at the ASH follow-ups out there -- either commentaries on some of the FL research that was presented, or descriptions of some of the interesting research that I missed the first time around.

Here's another one that I missed -- a presentation on the combination of Atezolizumab (also known as Tecentriq), Obinutuzumab (also known as Gazyva), and Bendamustine (also known as Treanda).

Bendamustine has been well-known in the FL community for a while. It's a traditional chemotherapy that has been shown to be effective and well-tolerated. Obinutuzumab is a little newer. It's a monoclonal antibody that targets B cells (like Rituxan, which has been around much longer).

Atezolizumab is less well-known to people with FL, but it's better known to the wider cancer community. It was approved by the FDA in the last couple of years for certain types of kidney and lung cancer. Like Rituxan and Obinutuzumab, it is a monoclonal antibody. It works by targeting PD-L1, or Programmed Death Ligand 1. Just as Rituxan targets the CD20 protein on a cell's surface, Atezolizumab targets the PD-L1 protein. By blocking PD-L1, the immune system is able to send signals that the cancer cells are invaders and should be attacked.

According to the presentation at ASH, 42 FL patients were given the combination. 35 of those patients then had maintenance with Atezolizumab and Obinutuzumab. Most of the patients had not received treatment before.

The results were pretty good -- 85% Overall Response Rate, with 75% Complete and 10% partial. (The Response rates were calculated a few different ways; these numbers are the most conservative of them.)

There were, of course, side effects, with all 42 patients experience Adverse Effects of some kind (and over half of them experiencing grade 3 or 4, the highest AEs).

This combination  makes sense. There have been some attempts at using Atezolizumab on its own in Lymphoma, but they haven't been very successful. The three different treatments mean the cancer cells are being targeted in 3 different ways. An approach like that makes sense.

However, as we have seen in combination treatments, sometimes different treatments interact in ways that create problems that aren't there when they are used on their own. It seems like this combination has that potential. The lead researcher, Dr. Anas Younes, noted that long-term follow-up will be necessary to see if the risks of the combination is worth the results.

Dr. Younes describes the study in a video for OncLive. Definitely early, but something worth keeping an eye on.

CAR-T Follow-Up

Well, ASH is over, and that means it's time for the press releases from researchers and analyses from experts about what mattered most. I'll keep an eye on it and report back on the good stuff.

One of the outcomes from ASH that has gotten some attention was the updated numbers on CAR-T therapy.

If you've been reading the blog for a while, you are familiar with CAR-T, or Chimeric Antigen Receptor T cell therapy. It's a very recent, very promising treatment that involves removing T cells (a kind of immune cell that usually attacks invaders) from a patient, changing them in a way that makes them recognize cancer cells as invaders, putting them back into the patient, and allowing them to do their job. CAR-T has shown some real promise for Follicular Lymphoma.

You can read more about CAR-T from two readers, Ben and Bill, who run the CAR-T and Follicular Non-Hodgkin's Lymphoma blog. Bill sent me a couple of emails with links (thanks, Bill) -- for a presentation at ASH, and a publication in the New England Journal of Medicine, with updated data on CAR-T treatments in lymphoma, including Follicular Lymphoma. (Ben is a CAR-T patient, as is Bill's wife.)

The NEJM article looks at 111 patients with "refractory large B-cell lymphoma after the failure of conventional therapy." Basically, they haven't been able to get a response with the things they have tried. And that group of large B-cell Lymphoma patients includes patients with Transformed Follicular Lymphoma.

Of the 111 patients, 110 were able to have T cells changed, and 101 of them were able to have them administered.

The Overall Response Rate was 82%, with a Complete Response of 54%. With a Median Follow-Up of 15.4 months, 42% of patients who had a response continued to have one, and 40% of patients who had a Complete Response continued to have one.


Out of this larger group, 16 patients had Transformed Follicular Lymphoma. They were analyzed as part of a slightly larger group of 24 patients (the rest had another type of Lymphoma). In that group of 24, 20 of them had a Response (17 had a Complete Response), and 2 more had Stable Disease.

One of the concerns about CAR-T treatments are the side effects, which can be especially harsh. In the NEJM study, every patient had at least one adverse event. These included neurologic problems and Cytokine Release Syndrome, though they seemed to be controlled, and the treatments to control the symptoms did not seem to have an impact on the treatment. (I get the sense that CAR-T researchers are better prepared for these problems, though I don't want to downplay how serious they are.)

The most important thing to come out of the study is the treatment's durability -- it lasts a while. People who had a response right away continue to have a response.

It seems like CAR-T treatments remain as promising as we had hoped (so far). It will be interesting to see the next long-term follow-up to see if the responses remain as durable as they have been.

ASH Preview: Quality of Life

The ASH conference is going on this weekend, but I have one more preview. It's a presentation scheduled for tomorrow (Monday, Dec 11): "Changes in Quality of Life in Indolent Non-Hodgkin Lymphoma 3 Years after Diagnosis." Since it hasn't happened yet, it's still technically a preview.

I am indebted to Dr. John Leonard for pointing this one out to me. When I searched for ASH abstracts for FL, this one didn't show up, since it covers "indolent lymphomas," which, of course, includes Follicular.

Dr. Leonard is active on Twitter, and in the days leading up to ASH, he tweets "Leonard's List" -- the 10 presentations he is most excited about. This one is #1 on The List. His comment on Twitter when he named this one as his #1 was this (I'm translating a little bit from Twitter-ese -- I know many FL patients are on the older side, and this kind of this is difficult for you to understand):

Since a large percentage/most indolent NHL patients will live a normal lifespan, here Quality of Life is a key issue/goal in long-term management. The study has important insights for Quality of Life course, reassures patients that Quality of Life likely won't deteriorate despite diagnosis, and patients seem to have psycho-social adaptation.

(Actually, I know most of you could have figured it out, even at your age. I was more concerned with how it would translate for my non-English-speaking friends.)

I appreciate his giving the top spot on his influential list to something that focuses on Quality of Life. As much as we all appreciate research that moves toward a cure (or at least a longer Overall Survival), we need to live with the disease, and the quality of that life can be an afterthought.

So QOL becomes an important factor. There are two approaches to FL research these days. One school of thought says we should go for a cure. But the other approach is to treat FL like a chronic disease, something that will always be with us, but can be managed through medication. I personally am open to either approach. But if I am going to treat FL like a chronic disease, then whatever treatment I receive must take Quality of Life into account.. There's no point in staying alive as long as the general population if I'm going to be miserable doing it.

For this presentation, the researchers acknowledge that Quality of Life can be affected by the disease itself, by side effects from treatments, and from the "psychosocial effects of living with an incurable cancer." (I'll say it again -- Follicular Lymphoma is an emotional disease as much as a physical one.)

Patients with Indolent (slow-growing) Non-Hodgkins Lymphoma (including Follicular) were included in the study. Their QOL was measured at Baseline (from what I can tell, within 9 months of diagnosis) and then 3 years later. QOL was measured using a survey called Functional Assessment of Cancer Therapy-General scale (FACT-G). You can see the survey here. It asks patients to measure their responses to fairly simple statements in 4 areas: physical, social/family, emotional, and functional well-being. So statements for "emotional well-being," for example, include things like "I feel sad" and "I am losing hope in the fight against my illness." Patients respond with how they have felt in the last 7 days.They were also asked to complete a "a single item Linear Analogue Self-Assessment (LASA) for measuring overall QOL."

1050 patients were included in the research (32% of them had grade 1 or 2 FL). At the 3 year follow-up, 577 patients (55%) had received treatment, 42 (4%) transformed, and 53 had an event (progression of disease, re-treatment, or death).

Interesting results:
Emotional Well-being significantly improved over 3 years.
Social/family Well-being  significantly decreased.
Functional Well-being, physical Well-being, and overall Quality of Life were not significantly different. 
The results were similar whether patients got treatment, or they watched-and-waited. 

In patients with an event during the 3 years, emotional Well-being had a significant improvement, but overall QOL decreased.

In patients without an event, improvements were reported in functional Well-being, physical Well-being, emotional Well-being, and overall QOL, but social/family Well-being went down.  

In their conclusion, the researchers say that the increase in emotional Well-being is a sign of "psychosocial adaptation by the patient." In other words, we learn how to deal with it.

I think that's probably true. We don't have much choice to adapt, so we adapt. We are, on the whole, very strong people. Sure, we have our bad days, but we get out of bed and get stuff done. That's just the way it is.  

It's hard to think back to where I was 3 years after I was diagnosed. I was a year past Rituxan treatments. I think I felt pretty good. It always helps to get a pretty clean scan. I was still running, so my physical Well-being was great.  I had support from family and friends. My day-to-day life was OK -- I was still working and playing with my kids. It all matches up for me.

What I found kind of surprising (though as I think about it, it shouldn't be surprising) is that the Social/family Well-being went down. 

As I think about it, this, sadly, makes sense. I hear lots of stories from people whose relationships were changed by cancer. family and friends stopped calling, probably because they didn't know what to say. That happens a lot, no matter what kind of cancer.

But people with FL and other indolent blood cancers face a different set of challenges, I think. 

When we get a diagnosis, lots of people come to our side. They want to help. And then -- nothing happens. Many of us watch and wait. The heat from the diagnosis starts to die down. Some people might feel a little betrayed. That cancer diagnosis had everyone worried, and now you don't even need treatment? Even worse than the people who don't know what to say are the ones who went on the emotional roller coaster ride with you, and got off before the ride started up again.

Are think there are two big lessons here.

The first is for patients. For many of us, we learn how to deal with the emotions that come with the diagnosis. We are, as I said, a strong group of people. We find ways to deal with it, and we do our best. For some us, though, we don't get the social help that we'd like. The lesson is that it's really important to find a social outlet. If family and friends can't help, then some group that understands what you are going through is crucial. Maybe that's a support group at the hospital you are being treated at. Or an online group (which is what worked for me). A Facebook group. Some bunch of people who can hear what you have to say and respond with "Yeah, I felt that way, too." 

The second lesson is for doctors. The physical check-up should be easy. The emotional check-up doesn't always come with the office visit, but it's just as important. And maybe doctors aren't comfortable with that, or aren't trained in that. But having some kind of resources available at hand would be helpful. Just a quick, "How are you feeling, emotionally?" might bring great results. Sometimes just being asked is a wonderful thing.

But the biggest take-away here is that researchers are paying attention to Quality of Life. That's a great thing. Certainly worthy of being #1 on any list.

More on Rituxan Maintenance

I had planned on writing about something else today, but Mylegacy left a comment with questions last night on my last post. I put the comment off to the side and got back to writing, but the Cancer Nerd got the best of me and I started doing some research, and I found the whole thing fascinating, so I'm just going to answer it here.

At least, I'm going to try to answer it. This is a good time to remind everyone that I am not an oncologist or a cancer researcher or a biologist. I'm just a patient who reads a lot.

**********************

Here is Mylegacy's comment:

What follows is/are a/several convoluted question(s). I do not know enough to say what follows as a statement of fact. IF I've missed the boat - PLEASE give me the smack down I'll deserve!

I understand that most of us who die with our "incurable" guest will do so from "infection." Most likely pneumonia or other respiratory illnesses. We will not succumb to FL, as such, but to the failure of our - by the time we're near dying - badly damaged white B cells being unable to guide the T cells to the pneumonia in great enough numbers, and in a short enough time frame, for our immune system to save us. Is what I have just written there correct(ish)?

IF SO: Then that is why I'm opposed to R maintenance. R is an indiscriminate killer of white B cells (is it not?). Cancer, or no cancer, R kills them. The ONLY reason it is safe(ish) is because it DOES NOT kill white B STEM cells. These "Baby B cell factories" continue to produce new B cells in our bone marrow.

However - over time IF you use R maintenance - who are reducing B cells and you end up with mostly new(ish) immature B cells. Our immune systems suffer - those of us who will die, will do so from the infections our mostly "baby/immature" B cells can not destroy. Our adult, mature, effective B cells have been decimated over time.

I've only had one 6 month R/B dance so far but just now (6 months after my final 2 day adventure) I'm in the 19th day of a cold. I'm 71, had a few colds in my time, but NEVER have I had one last this long. I'm beginning to think I understand what my future might look like. To make this journey even more interesting - I've already had pneumonia once about 15 years ago.

Intuitively, why wouldn't B maintenance (just killing Cancer cells) make more sense than reducing generations of adult B cells and diminish our bodies immune system being able to find and identify the bad guys for or T cells to kill? 

*****************

OK, lots to respond to. (And it's just a response. I don't think I've given anyone a "smack down" since I was on the wrestling team in high school....)

We'll start with how we die -- that's the thing that caught my eye first.

I'm not a big fan of talking about death (I'm sure not too many of us are), though it's certainly in the back of our minds as cancer patients (and maybe the front).

I think the description of FL patients dying of infection is accurate for some patients, but I'm not sure I'd commit to "most" patients.

And before we go any farther, I want to remind everyone about what I wrote a couple of weeks ago about Overall Survival. Death is always part of the equation for cancer, but the median OS for FL patients is close to 20 years, and statistics don't say anything about individuals. Keep reminding yourself of that.

There has actually not been a lot of research on how FL patients die, though earlier in the year, there was a presentation at the Lugano Conference called "Cause of Death in Follicular Lymphoma in the Rituximab Era: A Pooled Analysis of French and US Cohorts." There were 1643 patients in the study, who were diagnosed from 2001 onward. The median OS for the patients was about 80% at 10 years.

The median follow-up for the patients was about 85 months, or about 7 years. In that time, the OS was about 83% -- 283 of 1643 patients had died.

(Let's repeat that, since we're talking about death here -- 83% of the FL patients in this study lived.)

Of those 283 patients, 49% of them died of Lymphoma. Another 15% died of treatment-related causes, including infection, heart problems, and Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) -- basically side effects of the treatment, whatever the treatment was. Another 12% developed and died from a different cancer, and a final 12% didn't have a cause of death listed for the study.

Of that 49% (about 140 of the 1643 patients) who died of Lymphoma, about 55% of them died from Transformed FL.

Now, even though "infection" is listed as part of that 15% treatment-related cause, Mylegacy's comment seems to be including "infection" in a broader way, one that would make it part of the "Lymphoma" cause. It certainly is the case that for some cancer patients, a weakened immune system leads to infection, including pneumonia. But that's not the case for everyone.

I think the important thing here is to understand that 1) Follicular Lymphoma doesn't kill everyone who has it -- it's a fairly small percentage, and 2) the cause of death varies.

That's important to make clear, given the second part of the comment.

Rituxan Maintenance does indeed kill mature B cells. But I don't think the immune system works in such a way that we end up with only immature B cells as our only defense. For one thing, not all B cells express CD20. And for those that do, not all of them are killed by Rituxan.

Stepping back a little -- Follicular Lymphoma is a B cell lymphoma. It affects a particular type of white blood cell called a B cell. B cells go through a a series of steps before they are "mature" -- able to do their job of finding invaders in the blood. If you want an explanation of how B cells develop, this video does a decent job of explaining. B cells start out in the bone marrow, and over time become differentiated -- the body sends signals that let the stem cell know which type of blood cells they need to develop into. So they develop into a form of B cell that is able to accept an antigen -- the thing that lets them fight a specific type of invader.

In the scenario described in the comment, Rituxan would wipe out all of those later-stage B cells that are able to accept an antigen, leaving only B cells that can't fight off invaders.

I don't think it works that way. Bone marrow produces new stem cells all the time. (I read somewhere that it is several million every day, but I can't find that source again.) Some of those cells will move on down the chain that eventually leads them to develop into mature B cells. The point is, the body has a supply of them ready to go when signals come that an invader needs to be fought. It's an ongoing process.

Rituxan goes after those B cells -- they have a protein on their surface called CD20 that Rituxan attaches to. It goes after them whether they are cancerous or not. That is certainly true. And while people are taking Rituxan, they are, for that reason, more susceptible to infection.Their B cell counts are lowered. But it's important to note that Rituxan doesn't wipe out the entire immune system. Some B cells remain in the blood, and stem cells go untouched, and they keep differentiating into B cells. 

The next question is, how long is the patient affected by this?

Well, Rituxan works slowly. It can take a couple of months for it to really start to bring the size of tumors down. And then Rituxan's effects can go for up to 6 months. It could be a full year before the immune system is back to "normal" again.

(By the way, I'm getting a  lot of what I'm giving here from the Lymphomation.org page on Rituxan. They're my go-to for all things Lymphoma-related.)

With Rituxan Maintenance, that period could extend for up to a year after the maintenance is finished (so if we're talking about the standard 2 year maintenance, then you'd have a good 3 years before the Rituxan's effects were finished.)

Next important question: are there any long-term negative effects from Rituxan?

Yes, for some patients. Again, Lymphomation.org helps us here, citing some studies that show that "Late Onset Neutropenia" is a side effect for 5% to 27% of patients who received Rituxan. For as much as a year after treatment, patients can have abnormally low levels of neutraphils, a type of white blood cell. I haven't seen anything to suggest that it's a chronic condition brought on by Rituxan. My understanding is that it is treatable.

So, again, the important point here is, Rituxan does a good job of taking out cancerous B cells, and does result in some side effects, including making patients more prone to infection. But those don't seem to be long-term. The idea that Rituxan Maintenance might have a negative effect on our immune systems over the long term just doesn't seem to be the case.

And further evidence about a lack of long-term side effects comes from the study that Mylegacy was commenting on. Both the maintenance group and the non-maintenance group in that study had about the same median Overall Survival rate -- about 80% after 10 years. If there was a negative long-term result from Ritiuxan Maintenance, I assume we would see a difference there, with a lower OS for the maintenance group.

****************************

So let's sum all of this up.

Rituxan Maintenance is controversial. Given how it works -- finding and killing off B cells, whether they are cancerous or not, and lasting for up to a year -- it makes sense that it prolongs Progression Free Survival, when compared to patients who had a similar initial treatment but no Maintenance. 

However, while it does increase the risk for infection (given that it weakens the immune system), there does not seem to be a long-term negative affect. Patients who had maintenance after immunochemotherapy had the same Overall Survival rate as those who didn't have maintenance. The controversy comes when you ask whether the short-term risks are worth it, given the same long-term result in OS. Lots of different answers to that question.

Now, as far as causes of death, there's no question that infection (in some form) is a cause of death for some FL patients (as it is for other cancers). Many different treatments affect our immune systems -- including Rituxan.

But long term? The evidence that I found does not suggest that Rituxan or Rituxan Maintenance plays a role in long-term infections. If anything, experts agree that Rituxan has extended Overall Survival. Since the beginning of the "Rituxan Era" in the late 1990's, OS for Follicular Lymphoma has about doubled. 

And as for the last question in the comment -- why wouldn't Bendamustine Maintenance work better? Well, Bendamustine is a chemotherapy, and its side effects would probably cause much more damage through repeated use over the long term than Rituxan would. But the point is well-taken -- treatments that target the cancer cells, and not healthy cells as well, make a lot more sense.

And that's exactly what more recently-developed treatments are trying to do. We know so much more about the genetics of cancer cells now than we ever did, enough to know how to find particular biomarkers -- clues that let us know which cells need to be killed and which can be left alone, and which treatments can find distinguish between them. 

That's the future. And partly the present. Lots of treatments in different stages of development that will find cancer cells and get rid of them as needed. Researchers are still working on those.

But until that's all perfected, we could do a lot worse than Rituxan.

Thanks for the comment, Mylegacy. I hope that answered your questions. And I'll close out by saying, once again, that I'm not an oncologist or other expert in this area. I'm confident in the numbers I give, and what they have to say, but I know I oversimplified the biology. If anyone has a better explanation for all of this, please let us know.

ASH Preview: Rituxan Maintenance

Another ASH preview: This one is for "Long Term Follow-up of the PRIMA Study: Half of Patients Receiving Rituximab Maintenance Remain Progression Free at 10 Years."

The PRIMA Study has been looking at the long-term effects of Rituxan Maintenance on Follicular Lymphoma for a while now, and this presentation will look at how patients have been doing after 10 years.

Rituxan Maintenance has been fairly controversial in the Follicular Lymphoma community. It's one of those topics where enthusiasm kind of flip-flops with every new study. One study will find a benefit to it, and then another will show that the benefit wasn't as great as it seemed, or that there were new drawbacks. But neither side has shown enough evidence to make everyone agree on a definite Yes or No to Maintenance.

The PRIMA study looked at FL patients who were given Rituxan + chemo (mostly CHOP, but some CVP or Fludarabine) as an initial treatment, between 2004 and 2007. This was followed by half of the patients (505 of them) being given Rituxan Maintenance (every 8 weeks for 2 years), and the rest (513) getting no Maintenance. There have been follow-up studies of the patients at 3 years and 6 years, and now at 10 years.

The results certainly back up a benefit for R-Maintenance. Those who received it had a median Progression Free Survival of over 10 years. For those who didn't get it, the median PFS was just over 4 years. At the 10 year follow-up mark, 51% of the Maintenance patients had not had their disease progress, while only 35% of the non-Maintenance patients had no progression. The median time to a new treatment was just over 6 years for the non-Maintenance group (that is, it took that long for half of them to need treatment), while the Maintenance group hadn't yet reached the median.

One of the arguments against R-Maintenance is that it means patients are being treated for a long time when they haven't necessarily shown a need to be treated. They might have a clean scan, but continue to get Rituxan anyway. Some argue that this could result in over-treatment, with unnecessary side effects and potential long-term problems. 

The argument that the researchers make here for the value of R-Maintenance is that, because Follicular Lymphoma patients are living longer, it's worth the risk of giving Rituxan for two extra years. If it means patients will then not need treatment for another 8 years (at least), it frees them from the side effects (including developing secondary cancers) that might come if they had to go through another round of chemotherapy or other treatment. It's a compelling argument.

On the other hand, despite the longer PFS, there is no Overall Survival benefit to Maintenance. Both groups had a median OS of about 80% at 10 years. There is a group of people in the FL community that says, while extended PFS is nice, Maintenance doesn't make anybody live longer, and that's really the ultimate goal. So maybe the extra cost, time, and potential side effects of the Maintenance aren't worth it.

I'm still on the fence about it, for what it's worth. I do think that OS is ultimately what we are all aiming for. But as someone who has managed, with just Rituxan, to go almost 8 years without further treatment, I can say that it's pretty nice to not have to stress out about going to the treatment room. There's certainly a Quality of Life argument to be made here. Patients who can go for years without further treatment? That's a worthy goal, too.

The ASH conference is always followed up with commentary from experts, and I'll be very interested to see what the experts have to say about this. Will some of those anti-Maintenance folks come around and change their minds? Will they point out something in the data that we can't see right now by just looking at the abstract? I have a feeling this is going to be one those presentations that gets lots of attention.

ASH is coming up very soon -- it starts next week. We won't have to wait for long to hear from real experts (and not just Cancer Nerds).

ASH Preview: Progression of Disease in 24 Months for FL

A few posts ago, I looked briefly at an upcoming ASH session called "Early Disease Progression Predicts Poorer Survival in Patients with Follicular Lymphoma (FL) in the GALLIUM Study."


The presentation looked at 1202 patients in the GALLIUM clinical trial, which compared two immunochemoptherapy regimens.  In one, patients had Obinutuzumab + chemo, followed by Obinutuzumab maintenance. In the other, patients had Rituxan + chemo, followed by Rituxan maintenance. As I said in the post last week, the results from this trial helped get the Obinutuzumab regimen approved for untreated Follicular Lymphoma.

Because the study dealt with untreated patients who were getting immunochemotherapy (the chemo was CHOP, CVP, or Bendamustine), it was a convenient place to also look at POD24.

POD24 stands for Progression of Disease at 24 months -- for patients who had received  immunochemotherapy and then had their disease get worse, their Overall Survival was lower than those who did not have Progression of Disease in that time.

I know some of you are in this group, or have had immunochemotherapy and haven't made it to 24 months yet, and the numbers worry you. I'm not going to tell you not to worry. I've been in your shoes -- the diagnosis is still raw, and it might not matter what anyone tells you. The worry is going to be there.

But it might be helpful to look more closely at the numbers.

Of the 1202 patients in the trial, after 24 months, 155 were POD24, and 916 did not progress.  So, first off, if you've had immunochemo and you haven't gotten to 24 months yet, the numbers show that the treatment worked well for a whole bunch of people -- about 87% of them. Of the 155 patients who were POD24, 56 died. Of those 56, only 40 died due to Proogression of Disease; the other 16 died of other causes (remember, Overall Survival measures death by any cause).

So 40 of 1202 patients who received immunochemotherapy died from their disease -- that's about 3%. As for those who were POD24, that's about 26%.

It's easy to focus on words like "lower Overall Survival," and it's easy to get caught up in numbers. But it's also important to remember that those numbers look at trends, not at individual patients. What happened to 40 people in a large trial doesn't say anything about you individually. And if you want to look at numbers, look at this: 40 of 155 POD24 patients died, but 115 of 155 didn't. That's a 74% survival rate. Pretty good odds, really.

To me, you can look at POD24 as being bad or good. Most who are in the situation will think of it as bad, and that's an understandable reaction. While the idea of POD24 is only a few years old, POD24 patients have been around for as long as Follicular Lymphoma -- we just hadn't identified that group yet. So being able to identify POD24 patients is a good thing. Researchers know they exist, and can start finding ways to help them.

There are a few other POD24-related presentations at ASH.

Like the GALLIUM presentation, another one confirms that POD24 is a valid thing: "Validation of POD24 As a Robust Early Clinical Endpoint of Poor Survival in Follicular Lymphoma: Results from the Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) Investigation Using Individual Data from 5,453 Patients on 13 Clinical Trials"

The good thing about this one is, besides confirming that there are POD24 patients, they also found some other factors that could help build a prognostic model. In other words, they might be able to identify trends that could allow oncologists to identify patients as being at higher risk for POD24, and find other ways to treat them.

Another presentation, "The Tumor Microenvironment Is Independently Prognostic of Conventional and Clinicogenetic Risk Models in Follicular Lymphoma," also confirms that POD24 is real, and goes a step farther by identifying some Tumor Microenvironment markers that could help researchers figure out who is at higher risk.

Yet another presentation, "Impact of PET Staging of Follicular Lymphoma on Treatment Outcomes and Prognosis," looked at the effect of CT and PET scans on EFS24 (Event-Free Survival at 24 months, similar to POD24). Researchers found that patients who had PET scans had a higher OS than those who had CT scans, indicating that PET might be useful in predicting EFS24.

All of this research points to the same thing. While there isn't yet a way to predict POD24 patients, or a way to treat them that is guaranteed to work, a bunch of teams of researchers are working on it. In the last couple of years, I've seen many Follicular Lymphoma experts give summaries of where they think research is headed, and almost all of them said that it was important to work on the POD24 issue -- finding ways to identify them, and finding ways to treat them. Clearly, that work is happening.

In the meantime, the best thing we can do is what we've always done -- pay attention to you body, stay informed, and insist on honest and open communication so you can get the best care possible.

Being Thankful

Today is Thanksgiving in the United States (I know some of you are from other countries). It's a day we're supposed to stop and think about what we are thankful for.

I say "supposed to" because I think the "being thankful" part of the day is kind of automatic for a lot of people. Many families have a tradition of going around the table and having everyone say something they are thankful for. It's a nice tradition, though I think it's easy for people to joke about, or say something obvious.

It's harder to really think about, and answer to honestly.

Harder still when you're a cancer patient.

And maybe even harder than that when you have a cancer that is considered incurable.

It kind of takes one of those automatic answers off the list -- "I'm thankful for my health."

But I really am thankful for my health.

I'm healthy enough to be able to spend the day with my family. I'm healthy enough to wrap my arms around my wife and tell her I love her. My kids are all home, together under one roof, for the first time in months. I spent yesterday afternoon making pies, and today I'm going to eat way more than I should. I can do that. Not everyone can.

I'm healthy enough to continue working. I like my job -- a lot -- and even on bad days, I can get things done and look back at the end of the day and see what I accomplished. Maybe not everything I'd hoped, but something. Not everyone can.

I'm healthy enough to help others. As many of you know, since last spring, I've tried to expand my advocacy work, writing more than just the blog, and sharing all those years of experience with others. I'm healthy enough to do that. Most nights, I have enough energy left to do some reading and writing. Not everyone can.

Like most people, I can look back at my life and think of the people who haven't been able to do the things that I'm healthy enough to do.

I know people who haven't been healthy enough for receive the hugs I wanted to give them. I can remember a Thanksgiving dinner in a hospital room, visiting a loved one. I know folks who really want to help with the dishes, but who just need to lie down, and not because the big meal made them sleepy.

I'm not trying to make Thanksgiving about guilt. It should be a joyful time, focusing on the blessings we have.

But I also know how easy it is to focus on the things are not so joyful. So maybe focusing on what we are not -- completely healthy -- can be a way of helping us see what we are -- healthy enough.

That's what I'm focusing on today.

I hope you all enjoy the day, wherever you are, and that you're healthy enough to do something special, that makes you feel good, whatever it is.

FDA Approval for Obinutuzumab (plus more ASH stuff)

The FDA announced on Friday that it had approved an Obinutuzumab combination for untreated Follicular Lymphoma.

Specifically, the approval is for Obinutuzumab plus chemotherapy (CHOP, CVP, or Bendamustine), followed by Obinutuzumab Maintenance. A similar combination with maintenance was already approved for FL patients who could no longer take a Rituxan-based treatment.

The approval came because of results from the GALLIUM trial, which compared the Obinutuzumab + chemo + maintenance to Rituxan + chemo + maintenance. In the trial, Obinutuzumab showed better Progression Free Survival than Rituxan. Overall Response rate was slightly better as well.

Given the results, it seems appropriate that Obinutuzumab gained FDA approval. The numbers do show that, in the circumstances tested, Obinutuzumab outperformed Rituxan. It's another option for us.

At the same time, though, when the results of the trial were published about a month ago, some experts questioned whether or not Obinutuzumab really was superior. The doses of the two treatments weren't same (Obinutuzumab's was higher), and the adverse events (bad side effects) were higher for Obinutuzumab as well. Lots of experts thought this meant there was not as clear a reason to switch from Obinutuzumab to Rituxan as it might seem at first.

But the approval is there now. Time will tell if oncologists make the switch.

*********************

Updated results from the GALLIUM trial will be presented at ASH next month.

It looks like there are several presentations about data from the GALLIUM trial.

One that really stands out to me is called "Early Disease Progression Predicts Poorer Survival in Patients with Follicular Lymphoma (FL) in the GALLIUM Study."As part of the analysis of the GALLIUM data, researchers looked at POD24 -- patients who had Progression of Disease within 24 months after receiving immunochemotherapy (which would include patients in both the Obinutuzumab and Rituxan arms of the GALLIUM trial). It's been known for a few years now that this particular group of patients (about 20% of those with FL) has a lower Overall Survival that other Follicular Lymphoma patients.

The researchers found that the Obinutuzumab patients had a better chance of not being in the POD24 group (about a 33% better chance). However, overall, the study confirmed the idea that POD24 was an issue -- patients who have had immunochemotherapy whose disease returns or gets worse within 24 months have a lower Overall Survival rate.

While the whole idea of POD24 concerned FL experts, it also gave them some hope. Identifying this group of patients meant that they could start working on identifying them early and finding treatments that would be effective.

I'm working my way through those abstracts and trying to find a way to make sense of them all.

If you're in that group, stay hopeful -- a greater chance of something doesn't mean it's guaranteed. And some of the ASH research of POD24 seems to provide more reasons to be hopeful. That problem isn't solved, but it's clear that there are a lot of smart people who are looking into it.

More ASH stuff soon.

Some Thoughts About Overall Survival in FL

This is sort-of related to ASH, though it isn't looking at one of the abstracts, like I usually do this time of year.

I've been reading the ASH abstracts (over 200 of them) looking for the ones that I find interesting or worth talking about in some way. And I came across a few that mention OS, or Overall Survival for Follicular Lymphoma. It's worth talking again about OS and what it means.

************************

The ASH abstracts are basically summaries of what the presentation is going to be about. They mostly start off with an Introduction -- some description of the general topic of the presentation. The rest of the abstract gets into the specifics. Some of the Intros start off really general, describing what Follicular Lymphoma is, and, if it's appropriate, giving some statistics about things like OS.

As I was reading, one of the things that I found really interesting was the different ways that various researchers talked about FL and OS. For example, these are from 4 different Introductions:

• "Most patients experience an indolent disease course, with median survival of over 15 years."
• "Follicular lymphoma (FL) is the most common indolent lymphoma with a median survival approaching 20 years."
• "Follicular lymphoma (FL) is usually an indolent malignant B-cell lymphoma with median survival now approaching 20 years in the rituximab treatment era."
• "Despite an indolent course, it remains an incurable disease and the overall survival (OS) is 70-80% at 8 years in the rituximab era."
• "The clinical course of follicular lymphoma (FL) is characterized by recurrent relapses and progressively shorter remissions, with many patients surviving beyond one decade from initial diagnosis."

Now, to be clear, these are written for other oncologists and hematologists -- experts in blood cancer. And, to be clear, they have reasons for presenting these numbers the way they do. It helps set up the point they want to make about the research they did and why it's important. And those numbers all mean basically the same thing, if you look at them closely enough. But it's strange that they are all presented differently.

And I'm looking at these numbers as a patient. Patients read numbers differently than doctors do.

I did a quick Google search, and it showed me various sites (all up-to-date and reputable) that give the median OS for FL as 19 years; 14 years; over 20 years; "historically 8-10 years" but longer recently; and "Around 10 years," but ranging from 1 year to 20 years.

It's all very confusing, isn't it?

And what makes it worse is that, especially for someone newly diagnosed, survival numbers are really, really important. It's one of the first questions we ask -- "Cancer? Oh no! How long do I have?!"

Unfortunately, the media OS isn't going to give you an answer.

********************

So what's the deal with Overall Survival?

First of all, the reason the ASH abstracts are kind of fuzzy is that there isn't really agreement on what the median OS is for Follicular Lymphoma. I have read that it's because many patients live for a long time. It's hard to calculate a median survival (a measure of when people die) when people are staying alive. So that's a good thing.

The numbers are also kind of fuzzy because different studies have come up with different figures. There are a lot of factors that can mess with that number -- the age of the patients, the treatments they have had, how long ago they were diagnosed, and how treatments have improved recently. So it's easier to say "approaching 20 years" or "over 15 years" or (to be especially vague) "beyond one decade" than it is to give a definite number.

But, as patients, none of that really eases our minds. There's a big difference for us between 10 years and 20 years.

So here are some things to keep in mind about Overall Survival, especially if you're one of those folks who was recently diagnosed, or who obsesses over numbers. I hope it eases your mind just a little.

First, OS is usually expressed as "Median Overall Survival." And "median" matters. It doesn't mean "average." In statistics, the median is the middle of a group of numbers. So if the median OS for Follicular Lymphoma is 20 years, and they came to that number by looking at 1000 patients, that means that 500 of them will live for less than 20 years, and 500 will live for more than 20 years. On the "more" side, that could go on for a long, long time -- 21 years, 25 years, 50 years. There is no upper limit. A median OS of 20 years does not mean you have only 20 years to live. It meas you have a 50% chance of living longer than that -- maybe much longer.

Second, "Overall Survival" is just that -- the number of patients who have survived overall. It measures death by any cause. That includes lymphoma-related deaths, but also death by heart attack, or by snake bite, or by getting hit by a double-decker bus. It's easy to think of that number as being just about lymphoma, and that makes lymphoma seem so much scarier. But OS includes any reason for not surviving.

Third, keep in mind that the average age at diagnosis for Follicular Lymphoma is somewhere in the 60s. That puts the OS number in a different light, especially for those of us who were diagnosed at a younger age (like me, diagnosed at 40). Right now, in the United States, a male who is 60 years old has a life expectancy of 83.3 years. He will live, on average, another 23 years. Compare that to the OS for a patients diagnosed at 60 with FL: about 80 years. Not a huge difference. In fact, you will sometimes see discussions of FL survival point out that it is "approaching the general population."

And keep in mind that the numbers are different for different age groups. People under 60 (I have read) have a higher OS than the overall median. We can expect, statistically, to be on the part of the scale that goes way beyond 20 years.

One more thing: this OS number changes. All the time. It has risen steadily in the almost 10 years that I have been a patient. I remember a loved one emailing me and my wife in a panic because he'd looked up Follicular Lymphoma and Wikipedia said the median OS was 8 to 10 years. So it has about doubled since then, thanks to better treatments and better ways of measuring. I expect it to go up some more in the next 10 years (and I expect to be around to watch it).

********************

Here's the point I want to make:

Try not to obsess about numbers.

I know it's hard. Numbers seem so sure, and so final, and so unchanging. 2 + 2 always equals 4. In our emotionally-charged brains, it's easy to go from that to thinking "and therefore, I have only 20 years to live" (or 14, or 8 to 10).

Numbers aren't as sure as they seem to be. The huge range of OS statistics out there should prove that. And if experts are only willing to give fuzzy numbers, that should make it even more likely.

A median or an average says nothing about each of us as individuals.

The best we can do is live a good life, enjoy every day, be kind to one another, make the world a better place, learn as much as we can about our disease, and be active in the decisions that get made about our healthcare.

And have dessert.

So go do all of those things.

ASH Preview: Surveillance Scans for Follicular Lymphoma

Surveillance Imaging is common in Follicular Lymphoma -- CT or PET scans after treatment that are meant to find out whether or not the FL has returned.

They are common, but controversial. With every scan, you get radiation. In fact, a CT scan exposes a patient to about 200 times the radiation of a chest x-ray. The question is, is it worth it? Will the scan catch the cancer before the doctor or patient can? I have read (and I cannot find or remember the source) that about 80% of recurrences of FL come from the patient reporting symptoms, not from routine scans. Is that true?

The ASH presentation "Surveillance Imaging during First-Remission in Follicular Lymphoma Does Not Impact Overall Survival" adds some data to answer that question.

The research involved 148 FL patients who had responded to a first treatment. The were observed for a median period of just under 5 years. Of that group, 55patients then had a relapse, discovered either by a surveillance scan or by clinical examination (the presence of symptoms, an abnormal exam, or by lab findings).

Of those 55 relapses, 35 of them (64%) were detected clinically, and 18 of them (33%) were asymptomatic but were found during a routine scan. There was no difference in Overall Survival between the two groups.

Breaking things down even more, the researchers looked at all of the scans for the 130 FL patients who had routine scans at their cancer center (including those who didn't relapse). 584 of the scans were part of routine surveillance for patients without any symptoms, with 68 of them for patients who were thought to have relapsed (even though they were asymptomatic). Just 22 of those "concerning" scans showed that there was FL. So only 3.8% (22 out of 584) of the scans for patients who didn't have symptoms resulted in a positive diagnosis.

Their conclusion: Only 1 in 25 scans results in a confirmed diagnosis for Follicular Lymphoma. With no Overall Survival benefit from doing the scans, there has to be some question about whether it's worth it. They recommend a larger study to see if the results can be confirmed.

As a patient, I have a mixed history with scans, but I now firmly believe that if there's no reason to do a scan, they shouldn't be done.

After I finished my Rituxan, I had a PET to confirm the results (this is common and NOT controversial). My dear Dr. R put off doing another scan. At every visit, he'd say, "We could do one, but there's no reason to, so let's hold off. Maybe next time." After about four years, I asked for one. I wanted to satisfy my own curiosity, mainly. It's hard writing about cancer so much and not knowing what exactly is going on inside your own body.

So I had the scan. It confirmed the presence of some FL, but not much. I was satisfied.

A couple of years later, Dr. R moved out of state, and I was switched to Dr. K.

Dr. K had a bad habit of not listening to me. He kind of had a set speech for every visit, and any time I tried to break in ("Yes, I do know what white blood cells are...."), he would steamroll over me. Very frustrating. I don't like it when I'm not being listened to.

So after a couple of visits, he said he wanted to do a PET scan. I asked if there was a concern.

"No, no concern. Just for a baseline. I don't think we'll find anything, to be honest."

"Then why do it?" I asked.

"Just so we can see what's there. I don't think we'll find anything."

"Then why do it?"

We did this a couple more times, and then the visit was over. His assistant noted that Dr. K wanted to schedule a scan.

"I'll get back to you on that."

Dr. K retired before my next appointment. I still haven't gotten the scan he wanted. It made no sense to me to get one when even the doctor didn't think it would find anything, Why take on all of that radiation for no reason?

The evidence from this research certainly seems to show that I was right.

(Oh my gosh, do I love being right!)

I understand the need to want to confirm that things are still OK, and want a clear picture (literally) that they are. It's the same as any kind of watching and waiting -- we're relying on our own understanding of our bodies to make sure everything is, and sometimes it's helpful, emotionally, to have science confirm that understanding. I get it. And I would never judge any Follicular Lymphoma patient for wanting a scan because it makes her feel better. that matters, too.

But, looking at things long-term, we also need to trust that clinical exams will find bad things, and that includes our own self-examination of symptoms.

Don't be bullied into a scan. Get it if it's your choice, and you understand the risks.

ASH Preview: Follicular Lymphoma: The Good, The Bad, and The Grade 3

OK -- time to start looking at some ASH abstracts.

In the comments in my last post, Dan suggested I look at the abstract for a session called "Effect of Histologic Grade on Clinical Outcomes of Follicular Lymphoma: Prolonged Progression Free Survival of Grade 3 Follicular Lymphoma in the Rituximab Era."  I had my eye on this one because a few people were discussing it in the support group I've been in for years. ( I rarely post anymore, but I check in every day. the link is on the right under "Sites I Like.")

There's a lot going on in this abstract.

The researchers are interested in Grade 3 Follicular Lymphoma, and how it compares to grades 1 and 2 in terms of outcomes. (I was diagnosed as grade 1, with some grade 2.) In general, a higher grade means the cells are expected to behave more aggressively. The grade is determined by how many large, aggressive cells are visible by a pathologist in a particular area. (See Lymphomation.org for more on this.)

The important thing is, higher grade = more aggressive type of FL. It's more complicated than that for lots of reasons; the Lymphomation link gets into some of that.)

Grades 1 and 2 are usually considered less aggressive. Grade 3 used to be just one grade, but now it is usually broken into grade 3A (which behaves like grade 1 and 2) and grade 3B (which behaves more like Diffuse Large B Cell Lymphoma, a more aggressive type).

I'm going to assume that anyone reading this knows their (or their loved one's) grade.

The researchers wanted to know the difference in outcomes for the different grades. It seems reasonable to think that grade 3 would probably have worse outcomes, right? We've all been told about Transformation, and we're scared of it. Our slow-growing lymphoma becomes fast-growing, and that's bad. Aggressive must be bad. right?

Turns out that's not the case.

The researchers looked back at 227 patients who were diagnosed with FL between 2002 and 2014. 27% of the patients has grade 3 FL (either 3A or 3B) and the rest had grade 1 or 2.

The results: patients with grade 3 FL had a higher rate of Transformation (30%) than grade 1 and 2 (12%).

But there was no real difference in Overall Survival between the groups.
Grade 3 had a higher Progression Free Survival (61% after 5 years, versus 41% for grades 1 and 2).
The grade 3 group had a higher PFS when they limited it only to those who had immunochemotherapy with anthracycline (like R-CHOP). And when they isolated out the grade 3A patients, they had a higher PFS, too.

Here's their conclusion: "In this retrospective study of outcomes of follicular lymphoma in the rituximab era, we observed that patients diagnosed with grade 3 FL have better PFS than patients diagnosed with lower grade FL. This improved outcome appears to be independent of the choice of initial therapy, with an apparent plateau in the risk of relapse of patients diagnosed with grade 3A FL, suggesting a subgroup of these subjects can receive front line treatment with curative intent."

In other words, their data suggests that initial treatments for some patients with grade 3A might last long enough that it could be considered a cure.

Wow.

I'm guessing there's going to be some commentary from experts on this one in the next few weeks, as we get closer to ASH. It's surprising, but it makes sense.

DLBCL is an aggressive cancer, but it's curable, unlike most Follicular Lymphoma. So a grade that has more aggressive cells, and that behaves like an aggressive lymphoma, would more likely to be curable.

From a patient perspective, though, it brings up an interesting issue (one that was touched on the the support group discussion).

When it comes to Lymphoma, what's "good" and what's "bad"?

I remember, years ago, in that same support group, a discussion broke out about indolent and aggressive lymphomas. A lot of us have had people say to us, "Follicular Lymphoma? Well, at least you got the good one," or "If you're going to get one, this is the one to have."

Is it?

The folks in the support group had a debate over which was "better" -- the aggressive one that is potentially curable, or the indolent one that you might live for years with.

The aggressive one is scary. It grows quickly. You see the numbers getting larger by the week.

But R-CHOP or B-R or a stem cell transplant might cure it. That's good.

But it might not. That's bad.

An indolent lymphoma like Follicular might go years without needing treatment. That's good.

But those years aren't always happy years. Every bump or lump or lingering cold or tingling foot or swollen ankle or pulled side muscle means panic for a few days until it gets better or the oncologist will see you and check it out. That's not so great either. It takes a toll, emotionally and physically.

(As you know, I think FL is as much an emotional disease as a physical one.)

If I could go back 10 years and choose one over the other, which would I choose?

I honestly can't say.

The lesson, I guess, is that as patients, we can't assume a diagnosis, whatever it is, is better or worse than another. Our job is to understand what we have, educate ourselves enough to be clear about our options, and insist on an honest and open conversation with our doctor in which our voice is respected.

More ASH previews to come. I hope they aren't all this emotionally exhausting.....

ASH Abstracts Are Here!

Last night, I saw my first ASH abstract linked on Twitter. You know what that means -- ASH is coming!

It's the Cancer Nerd Christmas!

If you're new to this, ASH is the American Society of Hematology, a large professional group for blood cancer specialists (and specialists of other blood disorders). Their annual meeting takes place around the first week of December every year. This year, it's in Atlanta, Georgia (lovely city) from December 9 to 12, and it is often the place where researchers will talk about the work they are doing, sometimes releasing or updating results from clinical trials.

A few weeks before the meeting, the chatter starts. Last night, I saw an abstract on Twitter. This morning, I had a couple of emails in my inbox from publicists who were hinting that good things were going to be announced at the meeting.

It really is like Christmas, with moms and dads telling kids that Santa Claus will be coming soon. Only it's researchers and public relations offices, and instead of getting me excited about video games and dolls, they're talking about immunotherapy combinations and cell-signaling pathways.

Tome, that's just as much fun. And even better, I don't need to behave myself for the next 6 weeks because Santa might be watching.

I have only taken a very quick look at the abstracts for Follicular Lymphoma (you can see them here if you're curious), but it looks like a lot of updates to data from recent clinical trials. I see a lot of Rituxan-focused abstracts, too, and Bendamustine keeps coming up. There will be more updated data for Copanlisib, and more results for trials involving Obinutuzumab, and for Lenalidomide. And it looks like a few abstracts on Transformation.

There's going to be a lot to go through.

My plan, as usual, is to sift through abstracts and write about things that I find interesting. It's pretty subjective -- some of the things I find interesting aren't necessarily that ones that the actual experts are excited about.

It's also important to remind you that I'm not going to be at the meeting. I'm just looking at the abstracts -- the summaries of what's going to be talked about. Sometimes what actually gets said is more important than what gets sent in weeks before the meeting.

I'll also keep an eye out on Twitter and elsewhere for what some of my favorite blood cancer specialists are saying about the meeting, and what has them excited.

And I'll keep an eye out for press releases and articles that come out during the meeting and soon after, bragging about the success of their presentations. (And many of them will be worth bragging about.)

So look for lots of stuff about current research over the next few weeks.

I'll post as often as I can. Looking forward to it. Merry Cancer Nerd Christmas!

What Breast Cancer Awareness Month Can Teach Us

October is coming to a close, and that means Breast Cancer Awareness Month is ending.

I've always had a funny relationship with Breast Cancer Awareness Month, or "Pinktober" as it is sometimes called. On the one hand, I really hate all of the pink that comes with it. My kids' old school did a "Pink Day,"and my town painted one of its police cars pink. Plus there are all of the pink-wrapped products at the grocery store.

Part of it is jealousy. I'd love it people cared about Lymphoma as much as they seem to care about Breast Cancer.

But I also recognize that there is some good that comes with "awareness."

I wrote about this is a piece I had published on The Mighty a few days ago. It's called "What the Rest of Us (Cancer Patients and Survivors) Can Learn from Pinktober." I invite you to take a few minutes to read it.

Ultimately, the lesson for all of us is that if we want others to be "aware" of our cancer, then we have to be the ones to make it happen. And that means being open about what we experience, encouraging people to do things to prevent cancer, to get themselves tested (and to do self-exams), and, if they are unfortunate enough to get a cancer diagnosis, to educate themselves about their disease.

So if you are like me, and you got a little frustrated at all of the pink from the last month, try to see some good in it. There are absolutely people who exploit Pinktober for their own gain, and that's a shame. But -- big picture -- talking about cancer is better than not talking about it.

I'm looking forward to another month of learning and writing.

Follicular Lymphoma: Changes in the Treatment Landscape

Thanks to William, who sent me the link to an hour-long video from OncLive. I thought it was a compilation of some shorter videos, and I was going to ignore it, but I'm glad William alerted me to it. It features some great Lymphoma specialists, and is worth watching.

The video is aimed at oncologists, to give them a sense of the state of the art when it comes to treating Follicular Lymphoma. It's called "Follicular Lymphoma: Changes in the Treatment Landscape," and it features Dr. Bruce Cheson of the Georgetown Lombardi Comprehensive Cancer Center, Dr. Nathan Fowler of MD Anderson Cancer Center, and Dr. Anas Younes of Memorial Sloan Kettering Cancer Center.

That's some serious Lymphoma Rock Star stuff.

[I might go back to my idea from a few years ago of creating trading cards with Lymphoma Rock Stars on them. You'll get a free pack with every Rituxan infusion. Trade with your friends!]

The Rock Star Doctors cover a lot. From my perspective as a Cancer Nerd, it's all fascinating to me. Their subject is how treatments are changing, so they go into a lot about specific treatments, and the clinical trials that they were involved in, so it can kind of technical. But I'm OK with that.

Aside from being Cancer Nerd, though, I'm also a cancer patient, and that's different. It's one thing to gaze lovingly at a video, and another to think about how it all affects my actual life as someone with Follicular Lymphoma.

So these are the things that stood out for me as a patient:

First, they open the discussion by talking about some of the "scoring systems" that are used to measure prognosis. these are things like FLIPI and FLIPI-m7. The problem with these scoring systems, as they point out, is that they tell us a lot about groups of patients (they were created by looking at data from large groups), but don't say anything about individual patients.

Sometimes, as patients, we look at "scores" like FLIPI, and the numbers seem so definite, that we assume they will predict our futures. They won't. They can't. It's just not what they are meant to do. I'm happy that these three make that point -- and I hope that message gets through to oncologists who may use those numbers without explaining their significance to patients.

Another topic that thrilled me as a patient was their discussion of Subcutaneous Rituxan. All of them were thrilled with the amount of time that subcutaneous Rituxan cuts out from the patient's visit. It can go from about 6 hours (roughly how long my first Rituxan infusion took) to about 10 minutes. That's a huge improvement on Quality of Life. Dr. Cheson asked an important question -- how accepted will this be? He hinted that some doctors might stick with the IV version if Rituxan, because it might generate more revenue. That would be pretty horrible, putting profits ahead of patients. It's great that this discussion was being aimed at working oncologists. I think some of them can use the reminder that our Quality of Life matters, especially if some of us will be living with FL for years and years.

I'm happy that the good doctors made that point to lots of other doctors who might watch.

Another interesting exchange: the possibility of a cure. Dr. Fowler first brings this up, and Dr. Cheson asks if he "used the 'C' word" (and then makes it clear that it was he who has encouraged Dr. Fowler to think in those terms). The two are clearly more open to the idea of an eventual cure for FL than Dr. Younes, as least at this point.

But I like that, too -- that mix of optimism from Fowler and Cheson, balanced with a little skepticism from Younes. I think that's about the right mix -- 2/3 optimism about our future and all the great stuff that is happening in the FL treatment landscape, with 1/3 reminind ourselves that there's a long way to go.

Which isn't to say that Fowler and Cheson are blindly optimistic, or that Younes isn't also enthusiastic about things. Because there is plenty enthusiasm and plenty of realism from all three of them.

In fact, one of the really great things about the video (I'm speaking as a Cancer Nerd again) is the way they consider the many clinical trials and treatments that they look at -- with enthusiasm and realism. They're all hopeful about the future, but they know there's a way to go. These treatments are going to help a lot of people, but we're not there yet.

Another Cancer Nerd thrill for me: at the end of the discussion, they discuss how the community can try to prioritize certain treatments or combinations of treatments. there are, for example, a fairly large number of BTK inhibitors. It's an excellent target, but maybe putting resources into other targets would be good, too. There's certainly a patient aspect to this as well -- there are only so many patients who are willing to participate in trials, so a better focus would be more more efficient. Also, doing more to consider the safety of some combinations would also be good. And for that matter, maybe greater incentives for patients to participate in trials would help a lot.

[And for my CAR-T friends, going back to a discussion we had a few weeks ago in the comments -- certainly seems like CAR-T is going to be focused on patients who have had 4 or 5 previous treatments already. Cost and toxicity are the issues for now, though maybe that will change.]

So, once again, this is really great video, with some Rock Star panelists. (I'm too much of a Fanboy, I know, but this was like watching Glengarry Glen Ross or Doubt -- a bunch of Oscar winners and nominees doing their thing.)

Awesome Video on the Importance of Educating Yourself

I want to recommend another great Lymphoma video for you. This one is great because of the star -- me!

WEGO Health asked me to make a video about the importance of doing research and educating yourself -- definitely something that I'm in favor of. The video is being used to introduce a WebMD slide show about a side effect of Hodgkin's Lymphoma treatment. (Yes, it's not the same as Follicular Lymphoma, but that's OK -- as I say in the video, doing research is important no matter what lymphoma subtype you might be living with.)

You might remember that WEGO Health are the folks that sponsor awards for online health advocates, and I was nominated for a couple of them (best blog and best kept secret). Alas, I didn't win, or even make the final five for either category. But that's fine -- it was nice to be nominated, and be listed among all of those great online health advocates. Thanks to those of you who voted for me.

I know some of you voted for me just so you could go to the page and see my picture. Well, here's your chance to hear my voice, too.

If you've been reading the blog for a while, my message in the video will be familiar.

There were 3 things I wanted to make sure I said: 1) There is a lot of information online, and it's important to find good information that is evidence-based, backed up by science; 2) Cancer is an emotional disease as well as a physical one, and doing research can help with that, too; and 3) doing research gives me a feeling of control over things that seem uncontrollable. I'm happy I was able to get all three of those messages in.

And I think I seem waaaaay more serious in this video than I usually am in real life. But that's because I did this in about 30 takes (I went too long, or the dog would make noise, or I'd forget what I was going to say, etc, etc. There are lots of frustrated bad words in the blooper reel). So by the end, I was focusing really really hard on just getting it right. That's not me being serious so much as just really focused.

The video is on the WEGO Health Facebook page. You can watch it even if you don't have Facebook.
The full video is here:
https://www.facebook.com/36556179253/posts/2000787863501222

The short version (just the invitation to click the link to the slide show) is here:
https://www.facebook.com/36556179253/posts/2000790436834298

(For some reason, the shorter version is way more popular. I guess people get sick of listening to me. I'm used to it -- I have three kids.)

It was fun making the video. I might do more of it soon. Thanks, WEGO Health, for the opportunity.

CAR-T Approved for Lymphoma

More good news for us -- the FDA has approved a CAR-T treatment for some Follicular Lymphoma patients.

(As usual, when it comes to CAR-T news, Ben beat me to the news. I just learned that he is a fan of the New York Yankees -- rivals to my beloved Boston Red Sox. I still like him anyway, and I'll keep sending you to his blog for everything you want to know about CAR-T and Lymphoma.)

The treatment is called axicabtagene ciloleucel, or axi-cel, though it will probably known to patients as Yescarta (to help you remember: Yes! CAR-T! Ahhhhhh!). The approval came from the results of the ZUMA-1 clinical trial, which involved patients with refractory aggressive B cell lymphomas.

That's important to remember. For now, anyway, the approval is for a very specific group of Follicular Lymphoma patients -- those with Transformed FL. There are other types of aggressive B cell lymphomas, too, who meet the approval criteria. But it's a big step for all lymphomas.

As a reminder, CAR-T stands for Chimeric Antigen Receptor T cell therapy. In the procedure, a patient has T cells removed from her blood. T cells are a type of white blood cell, part of the immune system, whose job is to attack invaders like viruses and bacteria. But they don't attack cancer cells. With CAR-T, after the T cells are removed, they are genetically engineered so that, when they are put back into the patient, they do recognize the cancer cells as invaders, and they attack. T cells have a memory, so if the cancer cells come back, they should be able to find them and attack again.

The ZUMA-1 trial involved 101 patients with several types of aggressive B cells lymphomas, including Transformed FL. The results were great -- 82% had a Response, including 54% who had a Complete Response. Six months after treatment, 36% were still in remission.

There are some side effects, of course, though researchers are looking into ways to recognize the most dangerous ones early and control them.

But there may be some other problems with this treatment (which I have seen coming up since the approval news).

The first will be the cost. This is an expensive treatment -- about $373,000. Granted, it's a personalized treatment -- each patient will have her own cells removed, manipulated, and put back, so it's not like it can be manufactured in large quantities. But it's still a lot of money.

The second will be the limited number of patients who have conditions that it has been approved for. It's pretty clear that only certain patients are approved for this (as is the case with any FDA approval). But Dr. John Leonard had a good point on Twitter last night. He said "I expect MDs to spend much more time explaining to lymphoma patients why they are not CAR-T candidates than managing the very few who are." This is likely to get a lot of attention (which it deserves), but won't be able to help a lot of patients -- yet. The manufacturer is developing CAR-T treatments for other types of solid cancer. The ZUMA-2 trial is looking at this treatment in Mantle Cell Lymphoma patients. ZUMA-3 is for Acute Lymphoblastic Leukemia patients.

It keeps going. ZUMA-5 is the trial for indolent (slow-growing) lymphoma patients, like those who have Follicular Lymphoma. It will look at 50 patients with indolent lymphoma whose disease has relapsed within two years of initial treatment, or had a second (or greater) treatment stop working, or who relapsed after a transplant. The first patient to get treatment in that trial got it in August.

We have a lot to look forward to.

(And I don't just mean next spring, when baseball starts up again for some of us.)

EJM: New Paradigms for FL

Let's keep this theme going. The European Medical Journal published an edition that looked back at the European Hematology Association conference from last June.  In all of my reading about Follicular Lymphoma, it seems like the kinds of research that gets done in the U.S. is the same as in other parts of the world, more or less, but I enjoy getting a different perspective on things.

One section of the journal is called "Shifting Treatment Paradigms in Non-Hodgkin Lymphomas," and in that section is a piece called "Follicular Lymphoma: Strategies in the Era of New Targeted Therapies." [The link should take you right to the article on FL, but if it doesn't, scroll to page 36.]

The FL article is written by Professor Dolores Caballero from University Hospital Salamanca in Spain. She gives a sense of the current state of treatment and its results. In a nutshell:

The median Overall Survival for FL is about 15 years. [Remember "median" means half of patients will survive less than that, and half will survive more. Also remember that most FL patients are diagnosed in their 60's; the media OS for younger patients is much longer than 15 years.] Common options are watching and waiting, straight Rituxan, and immunochemotherapy (usually Rituxan + CHOP, CVP, or Bendamustine.)  Patients with no symptoms often get W & W or Rituxan; patients with a higher tumor burden often get R + chemo. Some benefit from Rituxan Maintenance. Some more aggressive approaches seem to improve Progression Free Survival (how long it takes until the disease starts to get worse), but don't improve Overall Survival.

That about sums it up, right?

Prof. Caballero continues: While something like R-CHOP might increase PFS, it also comes with side effects that affect Quality of Life. Traditional chemotherapy attacks healthy cells as well as cancer cells. What we need (and what we have) are treatments that focus on the cancer cells and leave everything else alone. This should result in fewer side effects. And since FL is a heterogeneous disease -- it's a little bit different for everyone -- it would be good to have a bunch of options.

And that's what we have. Prof. Caballero gives a brief discussion of some of the targeted options available, and how well they have performed in trials. These include Obinutuzumab (combined with chemo, it had a higher 3 year PFS  than Rituxan + chemo), Idelalisib (a PI3K inhibitor, which seems to work best with patients who are high risk and have had several prior treatments), Ibrutinib (a BTK inhibitor with high response rates), and Lenalidomide.

Lenalidomide gets the most discussion here (it's not a long article, but it gets about 4 paragraphs). An immunomodulatory agent, it has been combined with Rituxan to create "R-squared" (Lenalidomide also goes by the name Revlimid). It's a combination that has had lymphoma specialists very excited for a few years.

Dr. Caballero finishes by pointing out that next generation treatments will combine biologic and targeted agents, in ways that are based on individual patient needs. But we need to learn more about biomarkers -- those clues that help predict which patients will respond to which treatments even before they try them.

So, looking at the trends here, and comparing what a European expert is excited about to what American experts seem excited about, I'd say Lenalidomide is near the top of everyone's list. More targeted treatments like inhibitors are also up there. And there's plenty of buzz about CAR-T.

The big lesson I'm taking away is that we have a lot of options, and more on the way. And if you think about some of the combinations that are being tested, that's even more still.

The future looks bright, on both sides of the world.