R-Squared: A Systematic Review

The Blood Cancer Journal just published an article called "Lenalidomide and Rituximab for Relapsed/Refractory Follicular Lymphoma: A Systematic Review and Meta-Analysis." 

We're at a point now where R-squared (Lenalidomide/Revlimid + Rituxan) is pretty firmly a part of our lives as Follicular Lymphoma patients. It's a standard treatment, the first option approved that showed to be as effective as traditional chemotherapy (but with a different set of side effects). It has been with us for about 7 years now as an approved treatment.

So this article is a "systemic review" of what we know about R-squared. It looks at all of the research that has been done since 2015, when the first stage 2 clinical trial results were published, on R-squared in Relapsed/Refractory FL. The aim here is to see if all of the results show the same thing, especially when compared to the AUGMENT trial that led to the approval. 

The authors wanted to look at as wide a pool as possible, so in addition to looking at just R-squared, they also looked at Lenalidomide + Obinutuzumab, which like Rituxan is an anti-CD20 monoclonal antibody. They also looked at triplets -- R-squared + some other lymphoma treatment. Finally, they looked at not just published research, but also at research that was presented at ASH, the largest hematology conference in the U.S., and EHA, the largest conference in Europe. 

Looking at so many sources of data is great, in that it gives them much more to work with. But it also complicates things. Each study had its own criteria for inclusion, so the patients across the studies don't match up with each other exactly. Some studies, especially those from the conferences, did not include all of the data that the published studies did. And some studies used slightly different dosing, so patients didn't get the same amount of the treatment across all of the studies.

All that said, they were able to do some analysis that made it possible to compare the different studies.

The results of their analysis aren't surprising -- R-squared works.

The Overall Response Rate for all of the R-squared or Lenalidomide + Obinutuzumab studies was 75.9%, and the Complete Response Rate was 39.6%. For studies involving a triplet (R-squared + another lymphoma treatment), the ORR was 85.1% and the CRR was 53.9%. This makes sense -- a third treatment will, in theory, add another way for the cancer cells to be treated. But something else happened, too, that also makes sense -- the rates of serious side effects went up, too.

In case you are curious about what the third treatment was in those triplets, they were Idelalisib; Polatuzumab; Atezolizumab; Bendamustine; ViPOR [a combination of 5 treatments, not three -- Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid]; Tazemetostat; Acalabrutinib; Epcoritamab; Azacitidine; and Tafasitamab. Some of those names are probably familiar to you, and I have written about a bunch of these trials over the years. You can search for them at the top of the page.

The analysis also broke down the data in a few other ways, including prior lines of therapy. They wanted to see if R-squared was more or less effective if someone had already tried a number of other treatments. If a treatment works when others don't, that's an important piece of data.  In studies where patients had received a median of just one prior treatment, the ORR was 76.7% and the CRR was 41.9%. For patients who had received a median of two or more prior treatments, the ORR was 73.5% and the CRR was 40.5%. There was no significant difference between the two -- R-squared works well no matter how many prior treatments a patient had received. The same was true for the triplets.

As for safety, as mentioned above, there were greater numbers of serious side effects for the triplets. Serious low white blood cell counts occurred in 46.6% of triplet patients, and just 29.1% of R-squared patients. There was a trend toward serious respiratory infections in the triplet patients vs. the R=Squared patients. Low platelet counts were similar in the two groups. Patients who had to leave the study because of serious side effects were also similar -- 23.3% in the triplet group and 16.6% on the R-squared group. 

There are other data breakdowns that you can read about in the article. Click the link. 

Overall, the analysis shows the effectiveness of R-squared and begins to look at some of the effectiveness of triplets, though they are generally more recent and will need more time to see long-term results. If you've been reading for a while, you now I like those "Here's where we are" articles and videos where an expert gives us an update on things that have happened in the past. I see this as one of those articles. It's clear the R-squared is effective and safe for Refractory and Relapsed patients and provides and important option for those of us in that situation. 

The Problems with Accelerated Approvals

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

A Future for PI3K Inhibitors?

In my reading about cancer (which I do way more of than I would like), I've been seeing some articles about PI3K Inhibitors. Coincidentally, the journal Blood and Lymphatic Cancer: Targets and Therapy just published a review of PI3K inhibitors for CLL and Indolent Lymphomas. As a review article, it isn't offering any new research. It's more of a "here's where we are" article. But it's been a little under a year since the FDA pulled its support for PI3K Inhibitors for Follicular Lymphoma, so it's worth thinking about their possible future.

The article is called "PI3k Inhibitors in NHL and CLL: An Unfulfilled Promise," and I think that's a really great way of describing this class of treatments. One of the things that always struck me about this type of treatment was how excited oncologists got when they discussed it (at least in the videos I have seen, many of which I have posted). In theory, it's an excellent treatment. "Inhibitors" are things that inhibit, or stop something from happening. PI3K inhibitors stop an enzyme called Phosphatidylinositol 3-kinase. This is an important part of a chain of enzymes and proteins that turn switches on and off in a cell that allow the cell to grow and live. When something does wrong with the chain, the cell refuses to die. That's what cancer is, in its simplest form -- a bunch of cells that refuse to die. A PI3K Inhibitor stops that process. That's exciting -- especially since some of them were given as pill that a patient could take every day on their own.

The discovery of that chain of events, and the role of Phosphatidylinositol 3-kinase, was very important for Follicular Lymphoma research, since PI3K was especially important in B cells (the cells that become cancerous in FL). Several PI3K Inhibitors were developed, with slight but important differences between them.

Eventually, four of them were approved for Follicular Lymphoma patients. Because they showed promise in early trials, and were treating cancer in new ways than treatments that were already available, they were given accelerated approval by the FDA. This meant that they could be given to patients based on the results of a small phase 2 clinical trial. However, this approval came with the understanding that a larger phase 3 trial would be necessary for full approval.

And that's where the problems started showing up. You can go back and read what I wrote about the PI3K Inhibitors having problems and then having their temporary approvals taken away by the FDA -- Duvelisib in December 2021, Idelalisib in January 2022, Parsaclisib also in January 2022, and Umbralisib in February 2022.  then in March 2022, the FDA discouraged the makers of Zandelisib from seeking Accelerated Approval.

The reason for all of this? Some of the phase 3 trials, which were supposed to confirm the good results from the smaller phase 2 trials, did the opposite -- they showed some new problems with side effects, including an decreased Overall Survival. In other words, instead of keeping people alive longer, there were a greater number of people dying in the trial than had died in the trial that they were comparing themselves to.

The FDA's solution to this was to cancel its temporary approval and insist that full approval would only come with a phase 3 Randomized Control Trial. What does that mean? The trials that had been set up were single-arm trials. A number of patients were given the treatments, and the results were compared to a trial from another treatment (the trial probably took place years before). The makers of the Inhibitor could then say, "See? Our treatment is more effective and/or safer than that other one." A Randomized Control Trial has two arms -- instead of looking back at the trial for another treatment, it's set up so that half the people in the trial get that other treatment directly, and half get the PI3K Inhibitor. This way, there can be more control over which patients are in the trial, and a direct comparison can be made. 

But RCTs are expensive, time-consuming, and complicated. They are also the best way to know if a treatment is safe and effective.

However, one by one, the makers of the PI3K inhibitors announced that they were withdrawing their treatments. This was all happening at the height of the Covid-19 pandemic, and they were having trouble getting patients to enroll in their trials. Most decided that the extra expense and time wasn't going to be worth it. It seemed like they had planned on making money and recovering their research costs right away, and they weren't able to. Personally, I think there was too much competition as well, with too many PI3K Inhibitors on the market without enough to distinguish between them. 

Business decisions aside, there were still problems with the treatments that needed to be overcome. As this article says, there are still some possible changes to PI3K Inhibitors that could make them safer without being less effective.

One is to change dosage. When they were approved, most had a daily dosing schedule -- the patient took a pill every day. But that constant treatment meant that their immune system was always suppressed. This led to more infections, some of which were fatal. Zandelisib was designed to get around this, with a different dosing schedule, with the patient getting the treatment for a couple of weeks, and then stopping for a couple of weeks. This seemed like it was helping with side effects. But its makers decided that it would be too expensive to continue to develop the treatment, and stopped all of its research (except in Japan). 

So that's where we are -- an "unfulfilled promise."

It's too bad. From what I read, this does seem to be a business decision more than a medical decision -- the investment just isn't worth what it would cost to make the treatment safer and more effective (or at least, to find out if it can be made safer and more effective).

But the authors of the article still seem to cling to a small amount of hope that maybe something can come of it. My hope is that a small company will take this on, one that hasn't already spent millions of dollars, and will find ways to improve on this promising treatment. 

I also think that failed research is never a failure, and that even if these treatments are never resurrected, researchers will still have learned something that will make some other treatments better. 

We'll move forward, one way or another.

Infection Risk in FL Treatments

Interesting research published last week in the European Journal of Haematology. Not very happy, but important.

The article is called "High Risk of Infection in ‘Real-World’ Patients Receiving Ibrutinib, Idelalisib or Venetoclax for Mature B-cell Leukaemia/Lymphoma." 

The quick summary: what we know about a treatment's side effects comes from clinical trials. Once a treatment has been approved for a particular use, there seems to be less research on side effects, so what we know about them is what we learned from the trials. There might be more research on effectiveness that happens after the trials, but not a lot of side effects. 

And I understand that impulse. I have mentioned a bunch of times that I have to stop myself from focusing only on how effective a treatment is, and ignoring side effects. The numbers for effectiveness are more hopeful and happy. So I make sure to mention the side effects -- the "Adverse Events," as they are called in clinical trials. They're important. Effectiveness doesn't mean anything if a treatment does a lot of harm. As someone said to me once long ago, "You can put cancer cells in a test tube and add gasoline. The gasoline will kill the cancer cells, but do you really want to put gasoline into your body?" The point stuck with me.

So I find it very interesting when researchers go back and look at treatments after the clinical trials are all done. It's called "real world" research. A treatment might be approved based on the results of 500 patients in a phase 3 trial. And then maybe thousands more patients actually take the treatment, and the effectiveness and side effects don't match up exactly with what happened in the trial. Those 500 patients are an excellent sample, but not always completely accurate. 

And that's what this article is doing. It looks specifically at three treatments used for B Cell Lymphomas and Leukemias -- Ibrutinib, Idelalisib, and Venetoclax. And it found that patients had a greater risk of developing infections than the trial results suggested.

While these three particular treatments are used effectively for a bunch of different blood cancers, they have had mixed results for Follicular Lymphoma. Venetoclax and Ibrutinib have both been tried on their own for FL patients, and didn't do as good a job as they have done for other blood cancers like Chronic Lymphocytic Leukemia. But they do seem to work better as part of combinations (like the ViPOR combination of Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid). 

Idelalisib is a different matter. It was given accelerated approval for Follicular Lymphoma based on phase 2 trial results, and then problems came up during the phase 3 trial that would confirm the smaller trials results. The company that makes Idelalisib withdrew the treatment from the market. The official reason was that they were having a hard time recruiting patients for the phase 3 trial due to Covid, but unofficially, it wasn't selling well, and the FDA was finding problems with other similar inhibitors. So to me, it's not a surprise that researchers would find more problems than the clinical trial found.

What this research found was that patients who received these three treatments developed infections at a greater rate than patients in the trials. In the small study (67 patients), 48% developed a severe infection. The median time to first infection was 5.4 months. All of that makes sense -- these treatments work by going after cancerous immune cells, but also normal immune cells, so patients are more prone to infections. 

More importantly, the researchers found that patients had more problems when they had high scores in ECOG (Eastern Cooperative Oncology Group) performance status and high CCI (Charlson Comorbidity Index) scores. Both of these tests are very common and also make sense, since they are based on traits that would show that  patient is more likely to have health problems. (You can learn more about ECOG scores here, and  CCI Scores here.)

The major point for me in all of this is to remember that all treatments have side effects, and if you're in the habit of reading about Lymphoma research (and that's probably a reason that you're here), you need to look at all of the results of research -- the bad stuff as well as the good stuff. And when it does come time to need treatment, and you have options, it's important to as the doctor about things like side effects. Quality of life matters -- maybe a less aggressive treatment with a shorter PFS is more important to you than a more aggressive one with a longer PFS, if the less aggressive one means fewer potential side effects. More questions to ask makes for a better experience.

More fun Lymphoma research coming soon. Take care of yourselves.

Good News (for the EU) and Bad News (for PI3K Inhibitors)

I know I (sort of) promised to stop giving bad news about PI3K Inhibitors, but I can't help it if they keep giving me things to talk about. I'll try to balance it with some good news this time, though.

You really haven't needed to have been reading this blog for long to know that PI3K Inhibitors for Follicular Lymphoma have really been having troubles over the last few months. In December, Duvelisib was taken off the market (for FL) by the manufacturer for "business reasons." It was given accelerated approval by the FDA based on a phase 2 clinical trial, but a larger, longer phase 3 trial was basically seen as not worth it. Pretty much the same thing happened in January with Idelalisib. It was trying to conduct a phase 3 trial after getting accelerated approval, but was having trouble getting patients enrolled, which they blamed on Covid (though, given the troubles that other PI3K inhibitors are having, I think it was probably more than that).

Then later in January, the manufacturers of Parsaclisib withdrew from the FDA approval process. This one had not been given FDA approval (unlike the other two), but was in the process of getting accelaterated approval from the FDA when they also made a "business decision" to not go any further in the process.

Then in February, the FDA stopped all clinical trials involving Umbralisib because of a possible increased chance of death. Umbralisib had already been approved, and it looks like this was done out of an abundance of caution, but it just added more bad news to the treatment class.

And just to make sure we didn't break the streak of monthly bad news, this week FDA "discouraged" the maker of the PI3K inhibitor called Zandelisib from seeking accelerated approval. They had conducted what seemed like a successful phase 2 clinical trial (in face, I wrote about it a few weeks ago in an attempt to be positive about PI3K inhibitors). But the FDA told them that the limited data from that small study wouldn't be enough for approval, and suggested that a larger phase 3 trial would be necessary (something they had already begun doing). The FDA also suggested they look more into dosing (how much each patient is given during treatment). The company suggested that the size of the phase 2 trials isn't necessarily the problem. Instead, they are looking for randomized trials, rather than single arm trials. In other words, instead of giving the treatment to 50 patients and then comparing it to a study that was conducted a few years ago, the FDA wants a study with a direct comparison (100 patients in the study, with 50 getting Zandelisib and 50 getting some other treatment). Randomized trials are much more reliable than single-arm studies, since the researchers can control who is in the trial and make sure every patient is as alike as possible. But it takes more time and money to conduct that kind of trial.

For now, the plan is to go forward with the phase 3 trial. Zandelisib might very well end up being approved in the future. The phase 2 trail looks very promising. But they might also decide to stop, for "business reasons." 

When I wrote about Parsaclisib, I mentioned the problems with accelerated approvals by the FDA, and how that seemed to be a common issue with PI3K inhibitors. The comments from the maker of Zandelisib say that the FDA's thinking has "evolved" when it comes to accelerated approval for PI3K inhibitors. In other words, we're probably not going to see any more accelerated approvals. That's too bad, in some ways, since it meant getting access to new treatments much sooner. But good, too, in a way, if it means safety will be less of an issue.

I'll keep you updated on any other bad news that comes this way. 

(I'm still confused that there is so little discussion of this in the lymphoma research community. I'm waiting for the "What's the Future of PI3K Inhibitors for FL?" article in one of the medical journals. Nothing I've seen so far.)

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

I promised good news, too, and this is what I had planned to write about all along:

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has suggested that the the European Union approve the use of the CAR-T treatment Kymriah (also known as Tisagenlecleucel), for patients with Relapsed or Refractory (R/R) Follicular Lymphoma who have already received two lines of systemic therapy.

The approval is based on the results of the phase 2 ELARA trial, which involved 94 patients. In the trial, 86% of patients had a response, including 69% who had a Complete Response. The response was durable -- 87% of patients who experienced a CR still had a response after nine months.

The Safety profile was also very positive. While 49% of patients experienced cytokine release syndrome (CRS), none were very serious (grade 3 or higher), and only 3% of patients had grade 3 or 4 neurological side effect.

Results from this trail were reported at last year's ASCO conference, and caused a lot of excitement.  

It would be pretty wonderful if our friends in the EU had CAR-T as a treatment option. The European Commission plans to review the CHMP recommendation and make a final decision in about two months. Of they approve, CAR-T will be available to R/R FL patients in all 27 EU countries, plus Iceland, Norway and Liechtenstein.

I'll keep an eye out for news about this, too. I look forward to sharing some happy news when I can.

 

More Bad News for PI3K Inhibitors

I hate to keep writing with bad news, but this seems too important not to. Another PI3K inhibitor -- this time it's Umbralisib -- has run into problems. Clinical trials for the treatment have been suspended because of an increased risk of death in a phase trial.

Just to remind you of a few things: 

There are currently 4 different PI3K inhibitors approved for Follicular Lymphoma. In the last couple of months, two of them -- Idelalisib and Duvelisib -- have been withdrawn voluntarily because the makers decided it would be too difficult to get final approval by the FDA. Another one -- Parsaclisib -- was withdrawn before it went through the approval process, for similar reasons. All of them were, essentially, business decisions. For whatever reason, it would take more money and/or effort to get final approval and make enough money than was worth it.

The Umbralisib issue is a little different. While it hasn't been taken off the market, clinical trials have been stopped. The trial, called the UNITY-CLL trial, is actually for patients with a different type of blood cancer, Chronic Lymphocytic Leukemia. It's similar to other indolent, slow-growing blood cancers like FL. Similar enough that all FL and Marginal Zone Lymphoma trials for Umbralisib have been stopped, and the FDA is recommending that FL and MZL patients who are currently receiving it should talk to their doctors about risks.

The trial is actually four-armed, meaning patients were given one of four different treatments, including Umbralisib on its own. The results of the trial, in terms of effectiveness, showed some good news. But the increased risk of death was problematic (obviously).

You can look at the links above for some more of my thoughts about this situation and what it means for us as FL patients (keeping in mind that I'm not a cancer researcher or a doctor -- these are just the non-expert opinions of a patient who does a lot of reading. Talk to your own doctor about any concerns you have about any treatments -- that's always the best choice).

But I'll add one more thought to all of this. The three inhibitors that have already been approved went through some form of an accelerated approval by the FDA. The FDA began using accelerated approval a few years ago, in response to many in the cancer community (and other health communities) being frustrated with how long it was taking for new treatments to be approved. The program allows a treatment to be approved based on the results of a small phase 2 trial. But the understanding is that a larger phase 3 trial would need to be conducted and finished, and if the results hold up, then final, permanent approval would be granted. 

But there are also many in various healthcare communities who don't like the accelerated approval process. Sometimes the process relies on what are called "surrogate endpoints." This means that, instead of looking at something like Overall Survival after 5 years, the developers of the treatment can use a different statistic, like maybe 2 year Progression Free Survival, as a substitute. This is done when another study has shown that enough patients who made it to that 5 year OS (maybe the first ones enrolled in the trial) also made it to 2 year PFS. So the assumption is that the approval can be given based on that 2 year statistic, and then things will be checked again at 5 years to make sure that 5 year statistic really did match up. 

My guess is that there might be more attention paid to accelerated approvals. That might end up being an issue with Umbralisib, if it's shown that the increased risk of death came later on. But it could also end up being an issue with the other inhibitors. Idelalisib was withdrawn because there weren't enough people who signed up for the phase 3 trial. that doesn't necessarily mean anything related to how effective or safe the treatment is. But it does say something about how resources are used. Researchers might think more carefully about how much effort, time, and money to put into a treatment if there's little chance it will be used by doctors.

The whole treatment development process is huge, takes many years, and lots of money, and its far more complicated than I can fully understand. But it seems to me that having 3 of 4 approved treatment options run into big problems says something about the process, even more than it does about the treatments themselves.

And what's especially frustrating is that I really haven't seen a lot of discussion about all of this online. Maybe that will come soon. I'll keep an eye out for those kinds of commentaries (maybe one of those video series that I come across pretty frequently), and if any of you see a Lymphoma expert with an opinion on all of this, please let me know.

I'll try to find something more positive to say next time. But, gosh, they're making it hard.

A Third Inhibitor is Withdrawn

Well, this is getting silly now.

The maker of the PI3K inhibitor Parsaclisib has withdrawn its New Drug Application with the FDA. This comes a little more than a week after Idilalisib was withdrawn from the market for Follicular Lymphoma, and about six weeks after Duvelisib was withdrawn.  

Unlike the other two PI3K inhibitors, Parsaclisib was not yet approved by the FDA. It had applied for accelerated approval, but after discussions with the FDA, it decided not to go through with the application. They were not confident that they would be able to meet the requirements. Like the other two, this was called a "business decision." The application would have covered relapsed/refractort Follicular Lymphoma, and MZL and MCL, two other lymphomas.

I haven't seen a whole lot of analysis or commentary about any of these withdrawals. On Twitter this morning, I saw someone comment that there would probably be more of this happening with NHL treatments, as the large number of treatments (especially PI3K treatments) would mean more competition, and so more data to show that this version of the treatment would be better than others -- either more effective or safer. Another commentor said everyone is afraid of bi-specifics.

As I said in my post about Idelalisib, it does seem we've reached a point where we (patients, doctors, the FDA) will need to start focusing on quality over quantity. It's great to have so many options for treatment, but if the differences between those treatments are minimal, then someone is going to win that competition. 

And as good as PI3K inhibitors seem to be (they seem especially popular as a third-line treatment, after two other treatments have failed), the treatments that have gotten the Lymphoma community so excited in the last few years have been R-Squared (Rituxan + Revlimid), CAR-T treatments, and more recently, bi-specifics. What do they al have in common? They are as good as, or better than, traditional chemotherapy. And by "better than," I mean they are either more effective (they work on as many patients as chemo does, for as long) or they are safer (with fewer or less severe side effects).

But really, the biggest thing that the "exciting" treatments has going for them is durability. They have shown that they can work for a long time before a patient needs another treatment. And that matters. 

When I was first diagnosed in 2008, the assumption about Follicular Lymphoma was that patients could expect a lifetime of treatment. The disease would become more aggressive over time, and treatments would need to become more aggressive as well, with less and less time between them. Maybe the first treatment would last 5 years, and then the next 2 years, etc.

That's certainly still the case for some patients. But if newer treatments are also providing durable responses, then we would have less need for a wide range of choices. In other words, there's less need (and maybe desire) for 10 treatments that will each last 2 years when we could have 4 treatments that each last 5 years. Fewer treatments means fewer side effects to deal with, and better quality of life.

At least that's what seems to be happening. Remember, I'm not a doctor or a cancer researcher. Just a Cancer Nerd -- a patient who reads a lot.

Whatever the case, I think we don't need to be worried about treatments being withdrawn from use or from the approval process. There are lots of options still available and lots more being developed. We can afford to be picky (and patient). 

I hope to give you some good news next time.

Idelalisib No Longer Available for Follicular Lymphoma (in the U.S.)

The maker of Idelalisib (also known as Zydelig) has announced that it will no longer offer the treatment in the U.S. for Follicular Lymphoma (and for Small Lymphocytic Leukemia).

According to the press release, the FDA's approval had been based on a phase 2 clinical trial. It was expected that a phase 3 trial (with a larger number of patients) would be conducted, and if the trial showed similar results (a 54% response for FL), then final approval would be given. Partly because of Covid, the company had problems recruiting patients for the trial. They decided that it was better to withdraw the treatment from the market for FL and SLL. 

Idelalisib has also been approved for Chronic Lymphocytic Leukemia (CLL) in the U.S, and it will remain available for patients with CLL. It will also remain available for FL patients in the E.U, the U.K., Canada, Australia, New Zealand, and Switzerland.

I say Covid is "partly" to blame because, from what I could tell, Idelalisib wasn't a very popular treatment. The sales for the first quarter of 2021 (January to March) was about $16 million. That's a lot of money, but not compared to Yescarta, the CAR-T treatment made by the same company, which had 1st quarter sales of $160 million. 

I don't think that's a coincidence. Certain treatments seem more and more to be the future of Follicular Lymphoma, and based on the excitement that I hear when I listen to Lymphoma experts, CAR-T (and lately, bi-specifics) are going to be the choice of doctors, especially for relapsed/refractory FL.

If all of this sounds familiar, it's because just over a month ago, the maker of Duvelisib also announced that it would be pulling its treatment from the U.S. market. Duvelisib and Idelalisib are both PI3K inhibitors. There were 4 available, and now there are two.

I have to say, I'm not entirely surprised. Last June, I wrote a post where I asked, are there too many inhibitors available for FL patients? All four (and another being featured at ASCO) did slightly different things. But it seems like there wasn't going to be room for all of them.

And that seems to be the case. Losing two options like this doesn't mean that they are bad treatments. If anything, it might mean that they are good treatments -- good enough that 5 different companies want to get in on the action. If an oncologist suggests one, either alone or in combination, it's probably still worth having that conversation.

It probably says more about the state of treatments overall for Follicular Lymphoma, rather than any one individual treatment.

I know I always get excited about approvals for new treatments -- or even about applications for new treatments. When one gets approved, I usually say it's "another arrow in our quiver" -- another option for treating our disease. (That's the phrase that the Lymphoma specialist used when I saw him about a week after I was diagnosed. It's stuck with me for 14 years.)

And I'll continue to get excited about new treatments being approved. But maybe we're at a point in Follicular Lymphoma research where the bar is being raised -- where the newer options (R-Squared, CAR-T, bi-specifics) are going to be so good that we'll see fewer new treatments being approved. Instead, we'll see better treatments being approved -- treatments with greater effectiveness, or fewer side effects, than what we have available now. 

If that's the case, then you won't hear me complain. I'll gladly write less if it means we have better options available to us. 

(I'll probably still write just as much.)

Something tells me this is going to be a very interesting year for FL patients. 

Managing Relapsed/Refractory Follicular Lymphoma

As I mentioned in my last post, the journal Haematalogica published a nice piece recently called "Prospects in the Management of Patients with Follicular Lymphoma Beyond First-Line Therapy." It's a nice summary of where we are and where we might be going. (And by "we," I mean those of us who have already had some kind of treatment.)

The article basically goes through the options that are available for patients who have already had a treatment, and whose FL has come back, or whose treatment failed. In the last 10 years or so, we've seen new treatments types become available -- PI3K inhibitors (Idelalisib, Copanlisib, and Umbralisib) , Immunomodulators (Lenalidomide), Epigenetic Therapies (tazemetostat), and CAR-T. Add these to the ones that were already available -- traditional chemotherapy (CHOP, Bendamustine, and CVP), Rituxan, radiation (for some stage 1 and 2 patients), RadioImmunoTherapy, and Stem Cell Transplants -- and you have a pretty good bunch of choices for FL patients.

One of the main points that the authors make is, despite all of these choices, there is still no clear Best Choice for R/R Follicular Lymphoma. It seems like all of our situations are just a little bit different from one another, and with so many choices, and so much incomplete data from clinical trials, it's impossible to handle it any way than to consider each patient's individual situation. and make a choice from the list.

(This is worth mentioning -- the authors say that "the flood of data derived from phase II studies, and the lack of randomized studies comparing treatment strategies" are part of the problem. There are so many new types of treatments that the FDA gives special consideration to many of them, allowing them to be used on patients even though they have only gone through a smaller phase 2 trial. The good thing is that they get to patients sooner; the bad thing is they don't come with the large amount of data that a phase 3 trial would bring. Same with the lack of "randomized studies." Clinical trials can be run in two basic ways -- give a bunch of patients the new treatment, or "randomize" the trial and give half the patients the new treatment and half an old treatment, and compare the two groups directly. Randomized trials are a little harder and more expensive to run, so they aren't used as often. Same deal as relying on phase 2 trials -- less information to use later on. So we have more treatments available to use in the last 10 years, since they got to us faster, but not as much information as we'd have if we'd spent 15 years on them. Nothing is easy with this disease.)

It's probably not worth going through every one of the available options. (I've pretty much been doing that for 14 years.) But there is a really cool-looking image in the article with many of the different treatments going after an FL cell, of you want to take a look.

I think it's more important to think about some of the other points the authors make about treatments for R/R FL patients.

One important point they make has to do with sequencing therapies. (It's important to remember that this is written by Lymphoma experts for other doctors.) For many of us, that first treatment won't be the last treatment, and neither will the second treatment. If that's the case -- we might live a long time, but those years will involve a bunch of treatments -- doctors need to think carefully about how side effects might build on the side effects of treatments that have come before. They might also need to consider things like "location and socioeconomics." Not every treatment is available at every cancer center, and even the expense of traveling for a couple of hours once a week might need to be considered. Not everyone can travel easily, and not everyone can afford to take a day off of work once a week, let alone being able to afford an expensive treatment itself. I like to think that doctors keep those things in mind, but it's good for them to be reminded of factors like that. 

And just as important, an treatment recommendations should "incorporate the patient’s goals." Some of us might be OK with taking a pill every day for a year or two (like with some inhibitors). Others might want to just "get it over with" and do all of the treatment at once (like with RIT). As patients, we have goals for how our lives will be lived. Doctors need to consider those goals. The "best" treatment isn't always the best treatment.

Which is related to the next point that the authors make -- Quality of Life matters, and needs to be preserved. If an FL patient has the potential to live for years with the disease, the treatment shouldn't cause such severe side effects that those many years are difficult. A treatment might offer the possibility of a cure, but with long-term side effects that case nerve damage of make the patients more vulnerable to infection. There needs to be an honest and careful conversation about that before a treatment is decided on.

Finally, the authors look to the future. Even as we have lots of good options available to us, there are still more on the way. (They mention bispecifics as an example.) There are also lots of combinations being studied. Sometimes, two treatments work together in ways that are better than the two individual treatments -- R-Squared is a good example.

The hope is that the newer treatments will mean fewer or less severe side effects, and longer times between treatments. We're learning more about the biology of FL, too -- more potential biomarkers, and more about the pathways that cancer cells take to live and grow. All of that knowledge may lead to better treatments.

There's a lot here to be hopeful about. The treatment options really have changed a lot in a pretty short amount of time -- even in the almost 14 years since I was diagnosed. The article isn't written to us patients in particular, but that lesson is definitely worth learning.

The other lesson here for patients is also important -- with so many options, it's important that we know what they are, and what the implications are for each of them. I don't think we need to know all of the science behind every treatment -- we're not doctors or researchers. But we should know which questions to ask, and we should insist that our doctors take the time to answer them and explain what we need to know. A very good place to start is to think about your goals -- what kind of life you hope to live after the treatment is successful. That's a good place to start, and a good doctor should be able to start a conversation from that point.

I'm looking forward to exploring more of this with you all this year.

ASCO: Too Many Inhibitors?

There are still a few things to talk about from the ASCO conference, but I saw an article this morning that I found really interesting. It basically says something that I have been wondering about for a couple of years -- are there too many inhibitors out there? Do we really need any more?

The article is called "Post-ASCO News Alert: Mei Pharma’s Phase II zandelisib in r/r follicular lymphoma draws expert pause on clinical value; side-effect edge doubtful," and it was posted today in Clinical Trial Arena. It isn't really reporting on research so much as questioning why the research is happening.

The article features some lymphoma experts discussing the results of clinical trials for Zandelisib. There were three presentations at ASCO this year that discussed results of Zandelisib. The results were good. But the question is, according to the article, are the better -- more effective or safer than the four other PI3K inhibitors that have already been approved for use on Relapsed or Refractory Follicular Lymphoma. Those are Idelalisib, approved by the FDA in 2014, Copanlisib in 2017, Duvelisib in 2018, and Umbralisib in February 2021.

The reason that four of the same kind of treatment have already been approved is because they are all slightly different. While they all inhibit the same process that is necessary for a cancer cell to survive, there are actually a few different variations of that process, because there are a few different variations of one of the proteins involved. They are the same in many ways, but different in some ways, too. 

So far, from what I can tell, the differences don't seem to make all that much of a difference. In other words, there isn't one inhibitor that whose difference makes it stand out all that much from the others. I'm sure the makers of the different inhibitors would disagree, but I don't see any consensus on one being "the best."

And that's the issue with Zandelisib. Is there enough evidence from trials to show that it will be more effective, or safer, than the other options already available? Those experts in the article don't seem to think so.

It's a tough situation for a pharma company, I'm sure. If they've already spent millions developing a treatment, they'll probably want to see it approved so they can make some sales and make back some of that money. Or maybe they think their treatment can help some people that otherwise wouldn't be helped. (If you're cynical, you might not believe that last one, but the people I have met who work for pharma companies do seem genuinely interested in helping others.)

The problem, though, with having so many treatments that do the same thing, without being hugely different from one another, is that it creates confusion for patients, who have too many choices (and maybe for some doctors, too). Worse, in my opinion, is that all of the money that went into developing a treatment that duplicates other treatments could have gone to developing some new approach.

But that's hard to know from the start. I've been a grant reader for cancer research (more on that soon!), and seeing a scientist describe early research is exciting. There's lots of hope and promise that this research project might be The One. And maybe it isn't until much later in the process when it becomes clear that The One is really just Another One. Still helpful to some people. Just not what everyone was hoping for. 

So I found the article interesting at first because it expressed my frustration -- there seems to be a lot of duplication in cancer treatment. Lots of inhibitors, lots of Rituxan biosimilars, etc. But then, as I thought more about it, it reminded me of how difficult it must be to try to create a new treatment, especially when you know that a bunch of other people are working on a similar project, and might do it faster than you. But it also makes me appreciate that we do have choices, and in the end, that's a good thing.

Looking at all of the presentations at ASCO on Follicular Lymphoma, it's still exciting to think that one of them might be The One some day. Here's hoping that some new treatment still in development gets to patients soon, and dies the job better and safer (and maybe longer) than everyone else.

ASCO: Copanlisib and Rituxan

There was a lot of CAR-T news coming out of ASCO -- much more than I have shared. And most of what I have shared is related to CAR-T in some way.

But one of the other big trends that I saw had to do with inhibitors -- treatments that inhibit cancer cells from growing and staying alive. For any cell to stay alive, there is a long path of reactions that need to take place -- genes telling enzymes and proteins to tell other enzymes and proteins to do certain tings, or stop doing certain things. Cancer happens when some part of that path goes wrong, and things that were supposed to stop don't stop, or things that were supposed to happen don't happen. Inhibitors are designed to stop something form happening, so the pathway gets blocked, and the cancer cell dies.

There are four inhibitors approved for use with Follicualr Lymphoma: Umbralisib (approved earlier this year), Idelalisib, Duvalisib, and Copanlisib (which I wrote about January). All are PI3K inhibitors (meaning they try to stop the same path, though by targeting slightly different things in that path), and all have been approved for different FL populations. 

A lot of the research on PI3K inhibitors has looked at their usefulness as part of combination therapies -- mixing the inhibitor with something else. Combinations of all kinds are important treatment options for FL, and they recognize how complex a disease it is -- cancer cells are tricky, and probably need more than one to get at them in order to be successful. Combinations are often more effective than the individual parts.

The problem, of course, is safety. Two different treatments might get at cancer cells in different ways (making them potentially twice as effective), but they also each come with their own side effects (making them potentially twice as dangerous). Like any treatment, the PI3K inhibitor combinations have to show that their improved effectiveness is balanced by their safety.

The ASCO presentation called "Copanlisib + rituximab versus rituximab + placebo in patients with relapsed follicular (FL) or marginal zone lymphoma (MZL): Subset analysis from the phase III CHRONOS-3 trial" seems to show just that. 

The presentation reports on results from a phase 3 clinical trial called CHRONOS-3 that looks at Copanlisib and Rituxan by comparing them to Rituxan and a placebo (in other words, comparing them to just Rituxan on its own). 

The title calls this a "subset analysis." That means the research are reporting on a smaller group within the larger group of patients who are in the trial. In this case, the smaller group includes patients with indolent NHL, including Follicular Lymphoma patients, as well as Marginal Zone Lymphoma patients. (In case you're curious, the others not included in this presentation were patients with small lymphocytic lymphoma and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.)

The effectiveness was very good.  The Overall Response Rate for the C + R group was 82.4% (including a 37.6% Complete Response), and for the Rituxan group it was 50.8% (with an 18.3% CR). The median Progression Free Survival was 22.2 months for C + R and 15.4 months for R.

More importantly, safety was also good, though (maybe not suprisingly) the C + R group had more side effects, with the most common grade 3 or worse (that is, serious) being hyperglycemia (56.4%), hypertension (39.7%), and diarrhea (4.9%). The C + R group had more serious side effects (47.2%) than the R group (18.5%). And 2% of C + R patients had a grade 5 side effects (the most serious) versus 0.7% in the R group.

Given the way things are described in this presentation, it seems like the Copanlisib + Rituxan combination is probably going to be marketed as a treatment for patients who have already tried at least a couple of other more aggressive treatments, especially those who might not physically be able to handle something more aggressive and harder on the body. The makers of Copanlisib filed for FDA approval for relapsed indolent NHL (including FL), so if it is approved, it would cover a wider range than the one I mention. But that seems to be what it's being aimed at. (They are also seeking approval from the European Medicines Agency, but only for Marginal Zone Lymphoma, not FL -- not sure why.)

As I said, this was one of many presentations on inhibitors. I'm sure we'll see more approval applications for them in the months and years to come.

Follicular Lymphoma Case Study

Targeted Oncology has a short video series (8 videos, each no more than 5 minutes) featuring an oncologist discussing a particular patient with Follicular Lymphoma and how she has treated him (and would treat him in other situations).

I like video series like this. It gives me a sense of how an oncologist would treat FL in the "real world." Sometimes I read so much about possible treatments and early clinical trials that I forget about what is actually available right now. So it's nice to hear an expert talk about how she handles things.

That expert is Dr. Kami Maddocks from Ohio State University. The patient she is discussing is a 74 year old man who had complained of fatigue and weight loss for 6 months. A scan showed some swollen nodes and a biopsy showed stage 4/grade 2 Follicular Lymphoma. The first video in the series talks about his case and his initial treatment -- R-CHOP followed by Rituxan maintenance. He had a Complete Response, but then a recurrence 24 months later. He was given Rituxan and Bendamustine for his second treatment, with more maintenance. 

Then 12 months later, he complained of more symptoms. He was re-staged and found to have grade 2 FL, and was given Idelalisib, an inhibitor. 

From there, the videos talk in more general terms, with this patient being used as an example -- how oncologists can use things like FLIPI to help guide them. 

The second video talks more about first-line treatment options, straight Rituxan to Immunochemotherapy (like R-CHOP or R-B, or Obinutuzumab in place of R). [No mention of R-squared as a first-line option, which is interesting.]

The third video looks at Maintenance, and when it is (or isn't) a good idea.

The fourth video looks at how Dr. Maddocks monitors patients to make sure the FL hasn't come back -- how often to meet with the patient, when to do blood work, and how often to order a CT scan. 

Finally, the fifth video discusses options for second-line treatment, generally an Immunochemotherapy, and why she usually likes to hold off on using R-CHOP (because it's useful if a patient transforms, but can only be used once, because it can cause heart damage).

The sixth, seventh, and eighth videos get into how she handles treatment if the second-line treatment failed (usually with an inhibitor), and what factors she considers (such as the health of the patient), and then some discussion of where research is headed for FL (including CAR-T and bispecifics).

And hey -- here's a nice quote: "Lastly, as I mentioned that the median OS of FL is over 20 years, so when we’re considering different therapies, it’s also important to think about the toxicities of these therapies in the quality of life for a patient."

I'll repeat the good part: "The median Overall Survival of Follicular Lymphoma is over 20 years." 

I think this is a pretty good summary for anyone at any stage of the disease experience, to give a sense of what the next steps might look like. For me, I feel less stressed if I know what my possible path might be. That possible path changes all the time, with new research and new treatments. That's another reason I like videos like these -- they help me keep up with what's going on.

Also -- each video has a transcript below it, in case translation is a concern.

I hope you enjoy this series. I did.

 

Umbralisib Approved by FDA

More good news for Follicular Lymphoma patients:

A few days ago, the FDA approved Umbralisib (also known as Ukoniq) for FL patients who have tried at least three other treatments. 

Umbralisib is a PI3K inhibitor. It is the fourth PI3K inhibitor approved for Follicular Lymphoma -- the others are Idelalisib, Duvalisib, and Copanlisib, which I just wrote about last month). They all work by blocking, or inhibiting, an enyzme called PI3K, which is part of a chain of enzymes and proteins that tell a cancer cell that it's OK to keep growing. By inhibiting it, Umbralisib (like the other inhibitors) turns off that switch and allows the cell to die like a normal cell.

The four inhibitors work the same way in general, but PI3K takes a few different forms in the body, and the different inhibitors work on one or more of those different forms. So there isn't necessarily a lot of overlap between them. They all do a slightly different job.

(Which one is best for you and your Follicular Lymphoma, should you come to a place where a PI3K inhibitor might be an option? No idea. Talk to your oncologist. She or he will know.)

The approval was granted based on a phase 2 trial that included 117 FL patients. (It was also approved for a different type of blood cancer with patients also included in the trial.) The Overall Response Rate for the FL patients was 43%, with 3% of patients getting a Complete Response. The median duration of response was just over 11 months.

Those aren't spectacular numbers compared to some other treatments. One big difference, though, is that is might be safer than other PI3K inhibitors. While it does have similar side effects, it will not come with a "black box" label, which indicates very serious side effects. That said, it still has side effects, including diarrhea, fatigue, nausea, and increased risk of infection, among others. And 18% of patients reported in the trial had serious side effects, especially diarrhea and infection.

My guess (and this is, of course, not coming from a doctor or cancer biologist) is that Umbralisib will end up being used in combination with some other treatment, and those numbers for effectiveness will increase.

The good news, though, is that there is another arrow in the quiver -- another treatment option -- for lots of Follicular Lymphoma patients. And another reason for hope.

ASCO Part 2: Non-Chemo Treatments for Follicular Lymphoma.

This weekend, ASCO continues its virtual conference, with the 2020 ASCO Virtual Education Program. I'm calling this ASCO Part 2.

(I really wanted to call it ASCO Part 2: Electric Bugaloo, but I don't know how many of you would get that reference, so never mind.)

As I'm sure you remember, the ASCO conference (from the American Society of Clinical Oncology) takes place every year in early June. This year, the conference was split in two, since it is al taking place online -- the Scientific Program happened in late May, and focused on clinical trial results and other scientific research. ASCO was very generous this year and allowed patient advocates to "attend" for free. I was able to look in on sessions for the first time (since I can't ever afford to attend the conference in person).

And since I was registered for the Scientific Program, I am able to the Virtual education Program, which takes place this weekend. While the Scientific Program focuses more on giving results of research, the Education Program is more about how oncologists can use all of that research to be better doctors. So while it has sessions that focus on things like how Bispecifics might change the way Non-Hodgkin's Lymphoma patients are treated, it also has sessions on the specific cultural needs of cancer patients who serve in the military, or how COVID-19 is changing cancer care practices, or how to better care for LGBTQ cancer patients and survivors, or how financial toxicity can affect patient choices.

So while the sessions are focused on helping oncologists become better doctors, I can already see a bunch of sessions that look fascinating to me, even if they don't affect me directly. I'll try to share the ones that you might like, too, over the next few weeks.

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I'll start out with the only presentation that specifically addresses Follicular Lymphoma. (There are only 90 sessions for the whole program, and a bunch of those are speeches or award presentations, so it's no surprise that there is only one for FL.)

(Also, since this conference isn't presenting the results of new research, this presentation is more of a summary of previous research. Remember, the idea here is to educate oncologists, probably non-specialists who need a summary of research.)

The presentation is called "Chemotherapy-Free Approaches in Follicular Lymphoma and Mantle Cell Lymphoma." I'm including a link, though I don't know if you can access it without being registered for the conference.

The idea of the presentation is probably familiar to many of you (being patients who like to be well-informed). Traditionally, lymphomas have been treated with chemotherapy. And chemo still plays a big role in our treatment choices, with Bendamustine, CHOP, and CVP being very common. 

But more and more, researchers are focusing on non-chemotherapy treatments. Since traditional chemo kills some healthy cells as well as cancer cells, leading to a range of side effects, there is a preference for many newer treatments, which do a better job of targeting cancer cells and leaving healthy cells alone. There are still some side effects, but they are different from those that we might experience with chemotherapy. (Less hair loss, more nerve damage, for example.) We are likely at "maximum impact" from chemo -- what we have now is as good as it's going to get. Non-chemo treatments are the future.

And we do have several options.

For patients who are "treatment naive" (that is, who will be getting their first treatment), the options include Rituxin (which I received 10 years ago). But there are several others with a lot of promise, including R-Squared (Rituxan + Revlimid/Lenalidomide). Just a few weeks ago, updated research on R-Squared showed that it is effective for untreated FL patients. Other research on Lenalidomide + Obinutuzumab (a cousin of Rituxan) also shows promise.

There are a few more options for patients who have Relapsed/Refractory disease (they already had treatment, and it stopped working, or didn't work at all).  R-Squared is the one that seems to excite most oncologists. It's already been approved by the FDA. There's also the trio of inhibitors (Idelalisib, Copanlisib, and Duvelisib). Another, Umbralisib, is undergoing FDA review. And ME-401 is another inhibitor under review. While the inhibitors have had some success as individual agents, they tend to do better when they are combined with other things. Of course, that also means the chances are higher for more side effects. 

And finally, there's Tazemetostat, which was approved for Refractory/Relapsed FL patients with EZH2 mutations.  

The take-away from the session is that there are now chemo-free options for all Follicular Lymphoma patients, no matter where they are in their treatment life. 

One thing I noticed as I was creating the links is just how many of them have been in the news in the last few months. We are definitely in the middle of a real change in the way FL gets treated.

I can see an important issue for oncologists, though maybe it matters less in reality -- for many (most?) cancer patients, any treatment they get is "chemo." I don't know if it matters to them that Rituxan isn't technically chemotherapy, but maybe knowing the difference might also ease their anxiety a bit, if they see "chemo" as something scary. Understanding the distinction might also lead more patients to consider clinical trials.

As I said, I'll comment on some more of these ASCO 2 sessions in the next few weeks (I'm looking at a presentation on diet and another on CBD oil). There are some other Follicualr Lymphoma news items from the last week that could use commentary, too.

Stay tuned.

Accelerated Approval for ME-401

I'm certainly paying attention to COVID-19 (and still working through my own anxieties about it), but I'm not sure I have a whole lot more to say about it than I've already said. Thinking and reading about kind of puts me in a holding pattern. I'm focusing on the present, trying to take things day by day.

But, at the same time, I need to look ahead. Hope is all about looking ahead, isn't it? Recognizing that things aren't necessarily great right now, and wishing that the future will be better?

With that in mind, it's time to get back to some Follicular Lymphoma news.

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The FDA has designated ME-401 for Fast Track consideration. I've seen a few notices for this online, but not really any details beyond what you'll see here.

The application is for patients with Relapsed or Refractory Follicular Lymphoma (their last treatment stopped working, or didn't work at all) who have received at least 2 prior systemic therapies (chemo, immunotherapy, etc.)

Fast Track designation by the FDA means the treatment is "serious" (likely to result in death if not treated), and the treatments "meets an unmet need" (it is shown to either be more effective or safer than what is available).  Fast Tracking might mean more frequent communication between the FDA and the company making the treatment, so that approval (if it comes) can come sooner.

There's no guarantee, of course, that approval will come at all.

ME-401 is a PI3K, or Phosphoinositide 3-Kinase, inhibitor. As you know from reading, inhibitors work by inhibiting, or stopping, processes that go on in a cell that make it cancerous. Inhibiting Phosphoinositide 3-Kinase means the treatment will stop one of the PI3K enzymes that tell cells to grow. When cells grow without knowing when to stop, they become cancer cells. PI3K inhibitors tell them to stop growing.

ME-401 is, in particular, a PI3K Delta inhibitor. There are four different PI3K enyzmes (alpha, beta, gamma, and delta), and a few different inhibitors that try to target one or more of those different enzymes. They are kind of a common treatment in the Follicular Lymphoma pipeline these days, with some familiar names -- Idelalisib, Duvelisib, and Copanlisib.

The Fast Track designation seems to be based on the results of a phase 1b trial, announced last fall. It's a small trial, with 55 Follicular Lymphoma patients (as of last fall, anyway). But the results were very promising, with 78% of patients in the trial responding. That seems more effective than other PI3K inhibitors.

It will be interesting to see hoe the FDA responds. A phase 1b trial is pretty small, so they may ask for more updated results (it has moved on to a phase II trial now, with 120 participants). I haven't seen a breakdown of how many of the responses were Complete and how many were Partial, which makes me think there were a lot more Partial Responses than Complete Responses. So maybe this ends up being one of those treatments that is taken every day for a year or two to help hold off the need for additional, more aggressive treatment? Certainly patients who would be interested in that.

The good news is, there is another treatment being considered for us. Not the best news, but good news. We'll wait for additional trial results, and more from the FDA, before we start getting especially positive about it.

But we can be hopeful.

ASCO: PI3K Inhibitors

More from ASCO.

PI3K Inhibitors have been an area of excitement in blood cancers for a few years. Like all inhibitors, PI3K inhibitors stop something from happening. Cancer cells go through a series of paths or steps to grow and live. Researchers have been able to identify what those paths are, and then how to interrupt or inhibit those paths.

PI3K stands for Phosphoinositide 3-kinase, which is a group of enzymes that are necessary for cancer cells to live and grow.

There are actually three PI3K inhibitors that have been approved (by the FDA) for Follicular Lymphoma.  Duvelisib was approved in 2018 for relapsed/refractory FL, and Copanlisib was approved about a year before that for relapsed FL. Idelalisib was approved in 2014 for relapsed FL.

There were a couple of nice presentations at ASCO this year that dealt with PI3K inhibitors.

One was about Copanlisib: "Long-Term Follow-Up of Patients (pts) with Relapsed or Refractory (R/R) Follicular Lymphoma (FL) Treated with Copanlisib." Interestingly, the reserach deals with both relapsed (a treatment worked for w while, then stopped working) and refractory (a treatment didn't work at all) patients.

This research looked at the patients who were in the trial that resulted in the FDA approval. 104 patents in the trial were given Copanlisib. In the current analysis, 59% had a response, with 20% having a Complete Response. The median for how long the response lasted was a little over a year. The CR numbers are higher than they were for the first analysis -- it was under 15% at that point. That included patients with "higher grade disease." Side effects were manageable, with no new long-term effects popping up after two additional years of study.


It's nice to see long-term results, even after approval.

Another presentation focused on a PI3K inhibitor called ME-401. This one is so new that it doesn't even have a cool name yet. The presentation gave the results of a phase 1b clinical trial. As part of the trial, 48 Follicular Lymphoma patients were given ME-401, by itself or with Rituxan. After a  median follow-up of about 9 months, 28 of the patients remained in the study. Responses were good, with 79% of patients of patients who had ME-401 getting a response, and 78% of patients getting the Rituxan combo getting a response. Patients were either given treatment every day, or for one out of four weeks. Those on the one week out of four had fewer side effects.

This is a very early study, with not many patients in it -- that's how stage 1 trials work. But they are good results, even if they're early, and we may see more of this treatment in the next couple of years, if they are able to move onto phase 2 trials.

It's all a nice reminder that, even if a first treatment doesn't work as well as we'd hoped, we have a lot of options for second and third treatments.

Intermediate Risk FL: One Patient's Treatment

Targeted Oncology has another short video series featuring an oncologist discussing one patient's treatment history. Like the one they did a couple of weeks ago about a patient with high risk Follicular Lymphoma, this one highlights a single patient's story. It's not supposed to be a description for how everyone in her condition should be treated, but it is interesting to see how an oncologist makes decisions.

This one features a patient with intermediate-risk FL, and the oncologist doing the describing is Dr. Peter Martin from Weill Cornell in New York City. The link will take you to the first video in the series; the others are linked to the right of the video box.

The patient is a 57 year old woman. A scan showed activity in lymph nodes near her collar bone and groin (stage 3), and a biopsy showed grade 2 FL. She also had low hemoglobin (which carries oxygen in red blood cells), making her intermediate risk.

Dr. Martin points out that the PET scan at diagnosis is valuable as a base line in case there is a suspicion of transformation later on. [That's one of those things that I like about the Targeted Oncology series -- the oncologists who do them are very good about explaining their reasoning, something our own doctors don't always do.]

The patient was treated with Bendamustine and Rituxan initially. Again Dr. Martin discusses soem of the reasoning; he considers GELF criteria, which inolves looking at "organomegalies [enlarged organs], cytopenias [low blood counts], elevated LDH [Lactic Acid Dehydrogenase, which shows possible tissue damage], and the size and number of lymph nodes [pretty sure we all know what that means]." In this patient's case, the cytopenias and fatigue were enough to say she needed to be treated early (low red blood cell count).

Dr. Martin also discusses the uses and limitations of FLIPI scores.

They might be useful in giving a  general idea of "where a patient is headed," but it doesn't say anything about an individual patient's survival or how they might react to treatment.

Again, Dr. Martin provides some reasoning behind the decision to go with B + R. Another option might be straight Rituxan. Interestingly, he says the patient's age and the fact that is probablly still working would be a factor in using Rituxan only -- minimal disruption to her Quality of Life. He also discusses other possibilities, like R-CHOP, as well as the possibility of using either Rituxan or Obinutuzumab maintenance.

Four years later, Dr. Martin saw the patient again. She was experiencing fatigue again, and a scan showed that the nodes near he groin were large again. There were no other signs of transformation, so he didn't do a biopsy. They tried R-Squared (Rituxan and Revlimid/Lenalidomide), which worked well.

Again, Dr. Martin discussed the reasoning for the decision. The patient wanted something that would put her in remission for a while, but without too intensive a treatment (again, seems like a Quality of Life issue). One thing to consider for R-squared is how long to keep it up. Dr. Martin's preference is to not use it any longer than necessary.

Two years later, the patient again needed treatment. There was more activity throughout her body, though the scan didn't show evidence of transformation. She was given Idelalisib, a PI3-kinase inhibitor. Once again, Dr. Martin discusses his reasoning for the choice -- one consideration was that the inhibitor works in ways that are different from the first two treatments, which makes sense, given that the other two types stopped working. The decision also had, again, Quality of Life considerations -- as Dr. Martin says, "Idelalisib is an oral therapy, so it’s easy to do. It requires some blood monitoring and some clinical monitoring after that. But it doesn’t require a lot of intravenous infusions, doesn’t cause hair loss, is relatively easy to administer, and is easy to take, and as long as we’re cognizant of the potential side effects and looking for them and being ready to act on them, it’s something that can be done relatively easily."


So, once again, an interesting description of one person's treatment, with a nice description of the reasoning behind all of the decisions. It won't be the same for everyone, since everyone's disease will act a little differently. But it does give us a lot to think about.


I'm hoping they do a series now on low-risk FL, and it's basically 25 minutes of the oncologist talking about how boring the office visits are since the patient is watching and waiting and they just talk about baseball instead (which is what mine were like).


No, really, there are plenty of decisions to be made even for low-grade FL -- whether to treat or watch and wait, which treatment to try, and certainly what kinds of Quality of Life factors are important to the patient.


I'm looking forward to that one.

High Risk Follicular Lymphoma: One Patient's Treatment

Targeted Oncology just did a really nice series highlighting how one oncologist treated one patient with high risk Follicular Lymphoma.

Now, of course, every one of us is different, and one patient's story doesn't tell us anything about our own disease and treatment. each of us will have to work that out with our own doctor. But I thought it was pretty interesting to see how this oncologist made decisions for this patient.

If you want to watch and read for yourself, the article/series is called "Approach to High Risk Follicular Lymphoma," and the link is here. There is a video near the top of the page, and clicking the boxes to the right of the video will let you see the next videos in the series. The transcript of the video appears below.

The doctor is Ajay Gopal from the Seattle Cancer Care Alliance, and the patient he is discussing is a 62 year old man with left axillary adenopathy (swollen nodes in his left underarm). Bloodwork was normal, and a biopsy of the nodes showed stage 2 FL. A PET scan showed FL in other areas, plus 30% bone marrow involvement.

Here's where the cancer nerd in me think it gets interesting -- if I were this patient, what kind of treatment would I want?

As Dr. Gopal points out, there are some choices here. Watch and Wait? Since he has symptoms, this was ruled out. Rituxan or other innumotherapy? Maybe, but that's more likely for a patient with low tumor burden. They went with Rituxan + Bendamustine. Interestingly, Dr. Gopal pointed out that R-squared (Rituxan + Revlimid) could also be appropriate for this patient, but it is not yet approved by the FDA for FL, so cost would be a factor -- insurance won't pay for it. It's nice to hear that patient cost is something that doctors think about.

B + R seemed to work well, but 18 months later, the patient came back with new symptoms -- weight loss and fatigue. Another scan showed that the FL had gotten worse. Dr. Gopal also points out that a short remission of 18 months should mean a new biopsy as well, to make sure the FL has not transformed. An 18 month remission puts this patient in the high risk category -- that PFS24 group that does not achieve 24 months of Progression Free Survival (about 20% of FL patients).

They decided to go with R-CHOP, but the patient did not tolerate it well. After only 2 cycles, he developed anemia (low red blood cell count) and the fatigue that goes with it. He had a Partial Response after the 2 rounds of CHOP.

Unfortunately, after only 5 months, he developed new symptoms again -- a feeling of fullness in his abdomen. An exam showed a swollen spleen and low platelet counts. This time, a new biopsy showed the FL had progressed to grade 3, with bone marrow involvement at 90%. As Dr. Gopal points out, the biopsy did not specify if it was grade 3A or 3B, which is an important distinction, since grade 3B is basically considered Diffuse Large B Cell Lymphoma, and would require much more aggressive treatment.

The question now is, which treatment to try next? Since he had trouble with reactions to chemo, a more aggressive chemo (such as RICE) was ruled out. An Autologous Stem Cell Transplant was also a possibility. Because the patient had several bone marrow-related problems, they needed to consider whether there was some kind of marrow disorder, too.

In the end, the choice was Idelalisib, a PI3-kinase inhibitor. More targeted and less harsh than traditional chemotherapy, it could do the job. Other choices were Copanlisib, another PI3-kinase inhibitor, and Zevalin, the RadioImmunTherapy.

The patient went on Idelalisib, had some side effects that were dealt with, and remains on it after about 5 months.

Dr. Gopal ends with the reminder that there are other treatments on the horizen that might be available in the future, including Revlimid and CAR-T.


Again, as I said, one patient's story really doesn't tell us much about out own. Mine has certainly been very different from this patient's -- my age, my health concerns, my stage and grade, my reactiosn to treatment. His path wouldn't work for me.

But I think it's really interesting to see what kinds of factors his oncologist considered with each step -- which health issues mattered, which treatment options were on the table, and which choices were made. It's good for each of us to consider what kind of map we might need to follow when the time comes.

And it emphasizes how important it is to have a doctor who is open to conversations about those choices. As patients, we certainly should have a voice.

Treatments for Relapsed and Refractory FL

Every now and then, someone will publish an article that lists the treatments available for Follicular lymphoma patients. It's nice to read. Even if there's nothing new on the list, I always feel better having it all laid out in front me, knowing what's out there if (when) I need it.

Best Practice and Research: Clinical Oncology has gathered some recent articles on indolent lymphomas into its March 2018 issue. A few of them look at Follicular Lymphoma, including one of those articles that lays out treatment options.

It's called "Novel Agents for Relapsed and Refractory Lymphoma," written by Dr. Chan Yoon Cheah and Dr. Nathan Fowler. As the title says, the focus is on treatments for patients who have already been treated at least once, and either did not have a response to the treatment, or who had a response and then had the FL come back.

(Since I've already had treatment, I'm especially interested in all of this.)

The article starts out with a description of indolent lymphomas like FL -- slow-growing, often manageable, usually incurable. Ideally treatment will result in remission that lasts a long time and allows for a good quality of life.

The authors recommend that, if a relapse is suspected, a new biopsy be taken, to make sure the FL has not transformed into a more aggressive form. If it has, then there's a whole different set of considerations (and a whole different article to look at in this issue of the journal).

If there is no transformation, then there are a bunch of options: if no organs are threatened and there are no problems, then watching and waiting is OK. If treatment is necessary, they recommend that patients go into a clinical trial "whenever possible."

That's worth repeating. Patients should consider clinical trials whenever possible. If the symptoms are not life-threatening, then a trial may end up giving a response. If not, there's probably time to try something else (again, the relapsed FL isn't aggressive). And at the very least, the patient has helped us all by trying out something that might be approved for the rest of us (or might not -- that's valuable, too).

From there, the authors list some options:

• Anti-CD20 Monoclonal Antibodies. Rituxan is the biggie here, but Obinutuzumab has been recently approved. They work on their own (I had straight Rituxan), or in lots and lots of combinations with other treatments.
• Lenalidomide. Also known as Revimid, and R-squared when combined with Rituxan. Lenalidomide worked just OK on its own, but it has been great in that R-squared combination. I think it's one of the treatment that gets lymphoma specialists most excited. 
• PI3K Inhibitors. Idelalisib is the one they focus on most, though they also mention Copanlisib and Duvelisib. While these inhibitors have been successful, the authors also point out some serious side effects.
• BTK Inhibitors. Like other inhibitors, these stop (or inhibit) processes that cells go through in order to grow and survive. Ibrutinib is their main example, though there are some others in development. BTK inhibitors are another treatment type that seems to work better when it is combined with something else. (That's a big theme these days.)
• Bcl-2 Inhibitors. Again, these treatments stop cancer cells from doing the things that the immune system can't. Venetoclax is their main example here.
• Antibody Drug Conjugates. Monoclonal antibodies like Rituxan work by seeking out a protein on a lymphoma cell and attaching to it. A conjugate takes advantage of that -- while the antibody is attached, it delivers something else to the cell to kill it. 
• Epigenetic Therapies. This is another group of inhibitors, thugh it targets something different than the ones above. Vorinostat is an example (though it is one that seems to work well on its onw, instead of in combination with something like Rituxan). Abexinostat and Tazemetostat are two others.
• Immune Checkpoint Inhibitors. Nivolumab and Pembrolizumab are two examples. Another type of inhibitor, this one stops something that stops something else. The result is that the immune system is able to find and attack lymphoma cells.
• Chimeric Antigen Receptor T Cell therapy. Also known as CAR-T, which has been in the news quite a bit lately. T cells, part of the immune system, are removed from the patients and changed so that the T cells recognize the lymphoma cells as something that doesn't belong. A very promising treatment. Read more about it at CAR-T and Follicular Non-Hodgkin's Lymphoma, the blog run by our friends Ben and Will.

Note that these are novel agents -- new ones. You may have noticed that they don't even inlcude chemotherapy, RIT, and some other treatments that have been around for a while.

A couple of trends -- lots of these treatments seem to work better when they are combined with others. And lots of newer treatments are kind of anti-chemotherapy -- instead of trying to kill the cancer cells directly, they try to to stop (inhibit) other things from happening that the cancer cells need in order to survive.

The good news with this list is that there are a lot of options being tested for us. Some of them will end up working, though not all of them will.

And it's important to remember that all of these treatments come with side effects. They might be anti-chemo, in a way, and more targeted, but that doesn't mean they won't cause some problems. Ideally, researchers are finding ways to make sure the problems aren't as bad as the solutions -- the success of the treatment is worth the side effects.

Lists like this are valuable because they give you something to talk about with your doctor, if and when the time comes to treat.

And it's worth repeating -- none of this stuff becomes available to patients until it goes through a few clinical trials and then gets approved. "Whenever possible," we should think about participating in clinical trials, and helping to make it all happen.

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.