Sunday, October 15, 2017

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.

Tuesday, October 10, 2017

NCCN Congress on Hematologic Malignancies

A few days ago, the NCCN Congress on Hematologic Malignancies took place in San Francisco. The NCCN is the National Comprehensive Cancer Network, a group of cancer research centers best known for their guidelines for cancer treatment. They have a number of meetings every year for different cancer specialists, to give updates on different sub-types. Of course, Follicular Lymphoma was one of the topics of discussion.

I wasn't at the Congress, but OncLive has a couple of articles (one with a video) describing the FL session. (OncLive has a whole series of pieces on the sessions for different blood cancer subtypes, and they posted them almost immediately. OncLive has always been good, but they are just nailing it lately. My thanks to them.)

(While I'm at it, I just want to say that I would love to actually be at all of these meetings, like ASH and ASCO and NCCN and the rest. I wish I had the time and money to go. Maybe some day after i retire.)

(And yes, even though I'm 15 or 20 years from retiring, I do plan to be around until then -- and longer after that.)

Anyway, both articles focus on Dr. Jane Winter from Northwestern University in Chicago. (I believe she was the expert who presented on Follicular Lymphoma.)

The first OncLive article gives an overview of the session. Some of the issues she covered:
  •  Stage 1 FL can sometimes be treated with radiotherapy -- traditional radiation. A PET scan can help identify if this approach will be helpful. Up to half of stage 1 patients can possibly be cured with radiotherapy. Unfortunately, fewer than 1/3 of patients who could benefit from this treatment actually get it. (Don't know why, but I suspect that the difficulty of diagnosing at stage 1 might be part of it -- for most of us, we don't actually notice symptoms until stage 3 or 4.)
  • For many patients with stage 3 or 4 disease, watch and wait is still an option. The signals that it is time to treat? Symptoms start to show up, threats to organs [that's what happened with me -- swollen inguinal nodes started pushing on things], cytopenia or low blood counts, bulky disease, and steady disease progression. Right now, there is no evidence that watching and waiting results in a lower Overall Survival than treating right away.
  • Maintenance Rituxan after a treatment does not offer a better Quality of Life than treating and then waiting for a reason to treat.
  • Long-term follow up of patients who received R + Chemo shows that there is no one treatment that prolongs Overall Survival better than others.
  • R-squared (Rituxan + Revlimid/Lenalidomide) continues to impress experts, enough that the results of a phase 3 clinical trial might be enough to recommend that the combination replace chemotherapy as the standard choice.
  • Patients who receive R-CHOP and then have progressive disease within 24 months have a lower survival rate than other patients. This group accounts for about 20% of Follicular Lymphoma patients. One of the big challenges for FL researchers is figuring out how to identify these patients early, and how to treat them.
The second OncLive article features a short video of Dr. Winter, and a lot of the video focuses on that last item -- the 20% of patients who progress within 24 months. It's good that researchers have been able to identify that group of patients, and it's great that lots of energy is going into identifying and treating them early.

So these articles aren't presenting anything brand new. And that makes sense -- they are reporting on a session that was meant to get oncologists up to date on a bunch of things. But it's always interesting to see what FL experts think is important enough to want to make sure all of their peers know about it. I hope we see more in the near future about that 20% of patients.

(And I'm serious about wanting to go to one of these conferences. If any of you is a kindly billionaire who grants wishes, my email is in the profile on the right.)

Friday, October 6, 2017

Obinutuzumab vs Rituxan

The New England Journal of Medicine published an article yesterday on the results of the GALLIUM study that compared Obinutuzumab and Rituxan as part of an initial treatment for Follicular Lymphoma. Obinutuzumab came out ahead.

Or did it?

Obinutuzumab was in the news at the end of August, when it was given priority review by the FDA. The review will also be based on the GALLIUM trial results. Obinutuzumab is similar to Rituxan, in that they are both monoclonal antibodies that target the CD20 protein on B cells. But Obinutuzumab  is considered a possible improvement over Rituxan, because it was created differently, to target B cells better, and to cut down on some of the side effects that come with Rituxan's being made from mouse cells (instead of Obinutuzumab's human cells).

The NEJM actually provides a really helpful video that explains the results of the trial. As shown in the video and the article, the GALLIUM study looked at how effective and how safe Obinutuzumab was when compared to Rituxan in FL patients who had not yet received any treatment. The trial involved 1202 patients. Half of them (601) were given chemotherapy + Obinutuzumab, while the other half was given chemo + Rituxan. The chemo could have been Bendamustine, CHOP, or CVP. Patients who had a Complete Response or Partial Response were then given maintenance treatment for up to 2 years (361 for Obinutuzumab and 341 for Rituxan, or an 88.5% Response Rate for Obinutuzumab and 86.9% for Rituxan).

As you can see, there were slightly more patients who had a Response from Obinutuzumab + chemo than Rituxan + chemo. The study was stopped after almost 3 years when it was clear that Obinutuzumab had a better Progression Free Survival rate for 3 years -- 80%, vs. 73.3% for Rituxan. That number is considered significant enough to say that Obinutuzumab is more effective that Rituxan.

This is one of those stories that's getting lots of play in the oncology community. Rituxan has been around for 20 years, and there have been a bunch of attempts to find something that does the same job, but in a better way. Lots of stories online are suggesting that Obinutuzumab has done that.

But then, there are a few more stories that are looking at a second piece in the NEJM, an editorial called "Which Anti-CD20 Antibody is Better in Follicular Lymphoma?" In it, the authors raise some questions that should be raised, and that should make the "Obinutuzumab is better than Rituxan!" article writers slow down a bit. Not many of them did. Medscape was one -- their article reporting on the research is called "Obinutuzumab vs Rituximab in FL: 'Too Close to Call'."

The Medscape article points out some problems with the study that might make the results a little less simple than it might seem. The PFS is significant -- about 7% better for Obinutuzumab.

But there are some problems, too, as the editorial (and the Medscape article) point out.

For example, there is a dosage difference. Patients who received Obinutuzumab had a dose almost 3 times higher than the Rituxan dose. Those are both standard doses for the two, but it raises the question, if the two treatments are generally the same thing, would a higher dose for Rituxan have given better results?

Also, the Obinutuzumab had a higher incidence of adverse events -- things like low blood cell counts, nerve issues, infections, and infusion-related reactions. All of them were more frequent (for some adverse events, twice as frequent) in Obinutuzumab as in Rituxan. That raises the question -- if there is a higher Progression Free Survival, is it enough to make it worth the higher risk of adverse events?

Finally, the editorial authors point out that, while PFS is higher, there is no Overall Survival benefit. So people might go longer before they need another treatment, but they don't live longer as a result of taking Obinutuzumab instead of Rituxan. (I think, though, that's it's too early to measure that statistic.)

The Medscape article also looks back at the ASH session last year that first reported these results of the GALLIUM trial, that showed problems with Bendamustine and Obinutuzumab (and Bendamustine alone).

The Medscape article ends with some interviews with oncologists about whether or not Obinutuzumab will replace Rituxan. The responses were mixed. I can see why -- the study does raise some questions. And, as one doctor points out, the potential FDA approval will be for this very specific course of treatment -- Obinutuzumab plus chemo, followed by Obinutuzumab maintenance. That might not be the best choice for everyone.

My sense is, human nature being what it is, many doctors will continue to stick with what they know, and that means using Rituxan. And my guess (and it's only a guess) is that it will remain that way until there is a really big improvement in the numbers.

And finally, there is a lesson here for us as patients -- a reminder, really. Online stories about cancer are meant to be read, and that means sometimes making them sound better than they are. Most stories about this study didn't bother with the editorial, and the questions it raised. We need to all be careful (me included) to think carefully about what we see, and to make sure we're getting the full story.

Staying informed is the best way to have a voice in our treatment.

Saturday, September 30, 2017

The Future of Follicular Lymphoma Treatment

About a month ago, I posted a link to a video series from OncLive called "The Evolving Landscape of Therapy for Follicular Lymphoma," which features interviews with two of my favorite Lymphoma Rock Stars -- Dr. Bruce Cheson and Dr. Anas Younes. OncLive does a lot of these video series -- they post a new video every four five days, so the series takes about a month to complete.

It looks like they're getting to the end of this one. It's been a really good series.

The last video is called "The Future of Treatment in Follicular Lymphoma." The good doctors discuss some particular treatments, and how they represent paths that the field might take. Dr. Cheson discusses some kinase inhibitors, for example.

But both doctors also focus on some different issues that are just as important. We would expect them to focus on different treatments and how they work and what we can expect from them. But both doctors also mention a critical part of the future of treatment -- the patient.

Dr. Younes describes the long-term nature of the disease, one that is slow-growing and will probably require multiple treatments over a lifetime. "It's an irritating disease...the anxiety and the inconvenience of coming back and forth for multiple treatments in a lifespan is not ideal."

First of all, I love that he calls Follicular Lymphoma "irritating." I think he's right. It's not that way at first. When we're diagnosed, it's terrifying. But for many of us, as we learn to live with it over time, it becomes....irritating. It's frustrating to not have any symptoms, but to have all the anxiety that comes with waiting for symptoms. I really like that word.

But more important, I love that Dr. Younes recognizes how important Quality of Life is for patients. His solution is a hope that we can eventually have initial treatments that will give us 15 years before we need a second treatment. That's a good, long stretch of time, where maybe we can put this irritating disease out of our heads for a while.

Dr. Cheson also recognizes the need to pay attention to patients' needs. He mentions a new treatment that might be better than one that is currently available, but is less toxic. But is it "better"?  Well, he says, "I think the major issue is the schedule of administration, which is 3 weeks in a row and then a week off. To do this indefinitely, you’re going to have problems with patient compliance."

Very interesting. Sometimes I hear researchers describe Follicular Lymphoma as a "chronic" disease (actually, Dr. Younes uses that word in this video). But if it's "chronic," that means it's going to keep coming back, like, say diabetes. And that means it will need to be treated constantly. And, as Dr. Cheson says, patients are going to have to be willing to keep up the treatment schedule that comes with a chronic disease.

Follicular Lymphoma is different from other cancers. I know all cancers are different, and even FL has a bunch of different sub-types that make the experience really different for all of us. But I really do believe that FL is different on an emotional and Quality of Life level. For a lot of us, we learn to live with this in ways that lots of other cancer patients don't have to deal with.

And so, "the future of treatment" needs to take that into account, as Dr. Younes and Dr. Cheson very helpfully point out.

Whether or not that is actually happening is a different story.

But the important thing is that we patients need to remember that we have a voice, and we need to remember to use it. That might mean being active in working with an individual doctor to come up with a treatment plan that meets our lifestyle goals, and not just one that has a the longest median Overall Survival.

But it also means being active in the lymphoma community when we can, making sure that patients' voices are heard in larger ways, so we have a role in shaping research plans. That's harder, of course, but those opportunities do exist.

Fo now, though, I'm thankful that influential voices like these two Rock Stars are reminding the lymphoma community that patient needs do matter.

Wednesday, September 27, 2017

Managing CAR-T Side Effects

I don't think my friends at the CAR-T and Follicular Non-Hodgkin's Lymphoma blog have gotten to this one yet, but they'll forgive me if I look at it first.

Some folks at MD Anderson, along with colleagues at some other institutions, have published "Chimeric Antigen Receptor T-cell Therapy — Assessment and Management of Toxicities" -- a plan for watching and responding to the potentially fatal side effects that can come with CAR-T therapy.

CAR-T has been in the news in the last few weeks because the FDA approved the treatment for some Leukemia patients. CAR-T thrapy involves removing a patient's T Cells (part of the immune system that attacks invaders) and changing them so they can recognize cancer cells as invaders and take care of them. The results in clinical trials have been excellent -- good enough to justify FDA approval, with more approvals possible in the future (including one, potentially, for some Follicular Lymphoma patients).

The problem with CAR-T is some of the side effects. In a way, CAR-T can work too well.

The potential side effect that causes the biggest problem is Cytokine-Release Syndrome, or CRS. CAR-T has been called a "living cancer treatment," because unlike something like  chemical treatment, T Cells do their job by not just attacking invaders, but by overwhelming them -- when they sense an invader, they signal to other T Cells to attack. So an effective response means a whole army going against the invaders.

Those T Cells are activated by Cytokines, which are proteins whose job is to signal cells. The problem is, the Cytokines signal the T Cells, which then produce more Cytokines. Which signal more T Cells. Which produce more Cytokines.

The body can usually keep this cycle in check, so it doesn't cause too many problems. But sometimes it can't do that. And this results in CRS. The body is overwhelmed by Cytokines and T Cells. At best, it can make the patient feel really horrible (like having the flu, I have read). At worst, it can be fatal, and there has been at least one patient in a CAR-T trial who has died as a result.

Another side effect is neurotoxicity, or toxicity that affects the nervous system. CAR-T treatment can cause a specific type of neurotoxicity called CAR-T-cell-Related Encephalopathy Syndrome, or CRES. This affects the brain in particular.

These very nasty side effects have been dealt with since CAR-T treatments (and other Immunotherapies) have been in trials.

The folks at MD Anderson and their colleagues looked at published studies and about 100 patients to develop a system for identifying CAR-T side effects early, and dealing with them quickly before too much damage occurs. Cytokine release Syndrome does not have to be fatal, but it does have to be treated quickly to keep the worst from happening.

The system involves monitoring the patient for symptoms, grading the symptoms (determining how severe they are), and treating immediately. The treatment could involve "aggressive supportive care, anti-IL-6 therapy, and/or corticosteroids for severe cases." Anti-IL-6 are antibodies that target the Interleukin-6 Cytokine. Corticosteroids are commonly used to stop allergic reactions. Basically, the treatments are used to slow down the immune system response.

Interestingly, one researcher who was not part of this team pointed out that other approaches are also being used in other places, and that the ways to deal with CAR-T side effects are still evolving.

So while there is no guarantee that the system will stop a CRS reaction, but I find it comforting that there is a system being recommended. Lots of very good minds worked together for this, and it sounds like even more good minds will keep working to make it better.

Saturday, September 23, 2017

Taking a Break from Follicular Lymphoma

An anonymous reader posted a comment yesterday on my last post (about Immunotherapies), and I started to respond to it as a comment, but I decided it would be better to put it here, where it might be seen more easily.

The comment said this:

All excellent news! Thank you for keeping us informed! I am approaching my one year diagnosis anniversary, and had a complete response to B&R seven months ago. I'm on the fence about staying informed. On one hand I'd like to put all of this in the rear view. But on the other hand, it's the kind of baggage that keeps hanging on... At any rate, thank you for your efforts! 

First of all, congratulations on the Complete Response! That's awesome, and even more awesome that it is a durable response, and continues to last. I hope it goes on for a long time.

Second, and just as important -- if you need a break, then take it.

This blog is a funny thing (from the perspective of the person who writes it).

I've been doing this for almost 10 years now, and I noticed a distinct pattern a long time ago.

There are people who discover the blog, usually soon after they were diagnosed. And based on what they say in their comments and private emails to me, they spent a few (or more than a few) hours reading the blog, going back a few years, learning new things, and getting into Follicular Lymphoma through my eyes, as someone who lived it. (Some of you might recognize yourselves in there.....)

Very often, those people will continue to read -- eager for every new post. And they'll comment on every one, or send me another email. And I love to hear from them. And then they'll let me know that a treatment worked, and I'll celebrate with them. And then they'll comment some more.

And then, after a while -- 6 months, a year -- the comments and emails will become more infrequent. And then they'll stop, and I'll never hear from them again. Over 10 years, that's happened a whole lot of times.

And I'm fine with that.

The blog is run through Blogger, which is owned by Google. I really like the platform. One of the nice features is its analytics -- the statistics that Google provides to me about readers. Google doesn't tell me anything about individual readers, but I do know things like how many people have visited each day or week, and what countries readers are from (there are a lot -- I've had readers from over 70 different countries in the last year. As I'm writing this, there are people reading the blog from the U.S., Brazil, and France. How cool is that?!).

And I can see patterns in the analytics, too. I will go from a large number of readers, to a slow decline over a few months, so that I have about half as many monthly readers as I once had.

I can put things together. Readership goes up and down, because that mirrors the way Follicular Lymphoma works. People get diagnosed, and they get hungry for information. They get a Complete Response, and they take a break. That's how it works.

And I'm fine with that.

One of the reasons I've never had advertising on the site is that I don't want to be tempted to have a few dollars be the motivation for doing this. If I relied on making money from the blog, I would never say what I'm about to say:

If you need to stop reading, then stop reading. My great hope is that I can give people something that they need. If you don't need it any more -- or if getting it is making you feel worse -- then stop reading.

That makes me a lousy social media manager. But that's not what I am. I'm a patient, like most of you, and I'd want someone to tell me the same thing -- do what you need to do to make yourself happy.

I say it a lot, and I'll say it yet again -- Follicular Lymphoma is an emotional disease as much as it is a physical one. Take a break and heal that part of yourself.

Anonymous reader -- Stop reading if you need to.

When you're ready, come back. I'll still be here.

I promise.

Good luck with the remission. I sincerely hope you never need to be informed about Follicular Lymphoma ever again.

Thursday, September 21, 2017

Immunotherapies for Blood Cancers

The Journal of  Community and Supportive Oncology has a really nice article in their last issue called "Immunotherapies Shape the Treatment Landscape for Hematologic Malignancies."

The journal describes itself as "Research and reviews for the practicing oncologist," so the article itself is a little technical. However, for a not-a-medical-doctor-but-still-a-cancer-nerd like me, it's a fun thing to read.

As the title of the article suggests, the focus is on looking at how Immunotherapies are playing a big role in blood cancer treatment these days. Immunotherapies are treatments that use the body's own immune system to fight off cancer. That's the problem with cancer cells -- they don't belong in the body, but they also have lots of ways of fooling the body into letting them stay. And then they grow  and do bad things.

(They're like your roommate's friend who is going just sleep on the couch for a few days "until he finds something else," and the next thing you know, it's six months later, all of his stuff has taken over the living room, and there's never any milk for your cereal because the "guest" watched The Big Lebowski one night and now he drinks White Russians all day instead of looking for his own place.

That's basically what cancer is. If you don't understand the comparison, just skip to the next paragraph.)

As the article points out, blood cancers are especially good for Immunotherapy, since the immune cells that should be attacking the cancer cells are swimming right beside them in the blood.

The author breaks down some of the Immunotherapies that have been approved or are in clinical trials.

T Cells. The first general way of using Immunotherapy is by "exploiting T cells." T cells are immune cells that work in a bunch of different ways to battle invaders in the body. One common way of using T cells is in Stem Cell Transplants. In an Allo Stem Cell Transplant, someone else's T cells are put into the cancer patient's body. The big danger is Graft Versus Host Disease, where the new T cells attack the patient's healthy cells, thinking they are invaders.

CAR-T. A more sophisticated use of T cells is through CAR-T therapies. They have been getting lots of attention lately, and for good reason. In CAR-T therapies, T cells are removed from the body, changed into something that can recognize cancer cells as the invaders that they are, and attack them. (If you want more news about CAR-T treatments and Follicular Lymphoma, go to the CAR-T and Follicular Non-Hodgkin's Lymphoma blog. They have some nice updates today.)

Monoclonal Antibodies. These are the oldest of the Immunotherapies, and Rituxan is the king. It first appeared in 1997, and it has played a huge role in increasing Survival rates in Follicular Lymphoma. There have been a lot of attempts to create a MAB that is as good as Rituxan, with little success. But that could change. For FL, an Obinutuzumab combination seems a little  better than Rituxan, and some other MABs that target different things are also being tested (like Keytruda, targeting PD-1).

Innovative Design. This group, according to the author, takes Monoclonal Antibodies "to the next level." It includes treatments like "Antibody-Drug Conjugates." Basically, you use a MAB that targets cancer cells, and add a little bit of a chemotherapy (or something like it) so the chemo gets delievered right to the cancer cell. In theory, that should mean the effectiveness of chemo but with the limited side effects that come with a targeted treatment. It also inlcudes BiTEs, or Bi-specific T-cell Engagers. These treatments involve fusing together two antibodies. there are ADCs and BiTEs that are being developed for Follicular Lymphoma, but none are very far along the trial process just yet.

B-Cell Receptors. Finally, there are B-Cell targeting treatments. These aren't really Immunotherapy treatments, but they are kind of hot right now. The target the B-Cell Receptor pathway, the chain of events that keep B-Cells alive and (if they are malignant) doing damage. of course, Follicular Lymphoma is a B-Cell lymphoma, so these treatments are especially important for us. there are some familiar names here, including Ibrutinib and Idelalisib.


So the article provides a nice review of some of the promising developments in blood cancers, including Follicular Lymphoma. Even if you don't read the actual article, click on it and take a look at the charts, just to see how many treatments have been approved recently or are in development. It's impressive.

Of course, not all of them will work for Follicular Lymphoma, but that's OK. It's still hopeful to see how many treatments are in the works -- and this isn't even all of them.

Lots to look forward to.