Zevalin: Real-World Success for Follicular Lymphoma

First, a quick colonoscopy update: I had a biopsy during the procedure, and it came back benign. Right after the procedure, the doc said everything looked good, but now it's official.

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Now, back to Follicualr Lymphoma.

Nice article from about a month ago in Clinical Lymphoma, Myeloma, and Leukemia called "Real World Long-term Follow-up Experience with Yttrium-90 ibritumomab tiuxetan in Previously Untreated Patients with Low-Grade Follicular Lymphoma and Marginal Zone Lymphoma."  

Yttrium-90 ibritumomab tiuxetan is the scientific name for Zevalin, a type of RadioImmunoTherapy (RIT). The last time I wrote about RIT was in January. It doesn't get a lot of attention these days, except for Betalutin (which you can read about in the link). To remind you: Radiation is an effective treatment for lots of cancers, but not blood cancers, since blood cancer cells move around too much for radiation to work. So along came RIT. It basically works by taking a little bit of something like Rituxan, which can find and attach itself to a blood cancer cell, and adding a tiny bit of radiation to it. So when the Rituxan finds a cancer cell, it can deliver the radiation right to it. 

Zevalin was one of the first two types of RIT to be approved for Follicular Lymphoma. It was very successful in clinical trials, and I know two people who have had very long remissions after Zevalin. The problem has been, at least in the U.S., that Zevalin is complicated to deliver. Not because of the way the treatment works, but because there are rules in place for who is allowed to give the treatment, since working with radiation requires special training. So Zevalin has never been a popular treatment -- not as popular as something that is so effective.

Because it has been a fairly under-used treatment, there hasn't been much done in clinical trials, where records are kept to show how successful a treatment has been. This study is a "real world" study, that is, looking at patients outside of clinical trials. 

The results are great.

Because this isn't a trial, the researchers look at records of patients who had Zevalin as a first treatment, and determine how well they did on the treatment. The study looked at 51 patients, with 41 of them diagnosed with FL. The median follow-up was a little over 5 years. Of those patients, all 51 had a response to Zevalin, with 94% of them getting a Complete Response, which is pretty amazing. (Remember, about 70% of CAR-T patients had a response in early trials, though that number is going up.) After 2 years, about 59% of those patients continued to have a CR (it's about half that in CAR-T). And about 25% of them had a long-term CR of over 7 years.

Those are pretty great numbers for effectiveness. As for safety, again, the numbers are very good. More serious side effects (grade 3 or higher) for thrombocytopenia (low platelets) was 47%; neutropenia (low white blood cells) was 37%, and anemia (low red blood cells) was just 4% . Sometimes radiation treatments can cause other blood cancer likes myelodysplasia or acute myeloid leukemia, but none were found in this group. 

So, overall, Zevalin continues to be a really good treatment, with short-term and long-term effectiveness, and manageable side effects for most patients.

I'm not sure it will ever be a popular choice, but it's still there for us. And maybe Betalutin will turn out to be just as effective, but with some incentive to make it easier to administer. In the meantime, we still have some other choices, which is a good thing.

Colonoscopy

I had a colonoscopy this morning. Everything looks pretty good. I'll hear about biopsy results in a week or so, but the doctor isn't concerned.

I assume everyone knows what a colonoscopy is, and why it's important. In the U.S., it is recommended that we get a colonoscopy at age 40 (it used to be age 50 until fairly recently), and then every 10 years, unless there is an issue that makes it important to get one more frequently. 

I had my first colonoscopy 10 years ago. The lymphoma and some other issues put me at higher risk, so I went with the recommendation to have it done. So there were no real surprises this time, at least as far as what to expect with the procedure.

And if you have had one, or you know someone who has, then you know what that means. The preparation for a colonoscopy is not fun. Someone I spoke to about it a couple of days ago called it "character building." 

But I knew what to expect, like I said. Really, the prep is annoying, but for me, the worst part was the bad music that was playing in the operating room. It was awful. I was sure they were going to play a Nickelback song while I under anesthesia, and then it would be in my head all day and I would not know where it came from. 

As a I said, everything looked good. I did have a "benign-looking" polyp removed, which will be biopsied. Also, some mild diverticulosis. I need to eat more fiber.

I'm sharing those details becuase, as you know, I think it's important to talk about these things. Especially something like a colonoscopy, which some would consider "impolite." 

But people also used to think talking about things like breast cancer was "impolite," and that wasn't good. It meant people didn't get tested because it was too embarrassing. We can't let that happen anymore.

I assume anyone reading this shares the same attitude, and understands the importance of getting a colonoscopy. If not, please keep reading. And if you know someone else who might be reluctant to get one, please share this with them:

If you are eligible to get a colonoscopy, please get one. You've probably heard about the procedure, and how unpleasant the prep is. If that's what holding you back from getting the procedure, get over it. A few hours of discomfort and inconvenience is worth the peace of mind. As a cancer survivor, I know it's nothing compared to the physical and emotional pain of getting a diagnosis and treatment for you and your family. Just get it done.

Stay well, everyone.

 

How Patients Make The Treatment Decisions

The British medical journal BMJ Open has an interesting article this month called "Treatment Decision Making (TDM): A Qualitative Study Exploring the Perspectives of Patients with Chronic Haematological Cancers." It looks at a small number of patients with chronic blood cancers (35 patients in all, with 8 of them being Follicular Lymphoma patients), and what influenced the decisions they made about which treatments they decided on.

The results aren't all that surprising to me (the patients considered a lot of different factors), since I communicate with so many FL patients. But it is interesting to see the thought processes behind the way people make those important decisions. 

The patients in the study had a few different chronic blood cancers (FL, but also CLL, MZL, and Myeloma). By "chronic," the researchers mean a cancer that is likely to come back -- the kind we live with for a long time (I'm sure you all understand what that means). Because our cancers are likely going to need several different treatments over our lives, we probably have more things to consider when it's time to chose a treatment. (Thinking of people I know who have had aggressive cancers, they seem more likely to say to a doctor, "Yes, whatever you say, just make it happen!") But for us, we (and our doctor) are more likely to have to consider things like quality of life, and which treatments we've already had, and what might be available soon. It's a more complex process.

And that's basically what the research found.

The researchers ultimately found five themes in the interviews:

1) Preference for Clinician Recommendations. While most of the patients in the study wanted to have a discussion with their doctor (though a few had the "Yes, whatever you say!" approach), almost all wanted the doctor to make a recommendation. This makes a lot of sense to me. As much as I know (or like to think I know) about current treatments for FL, I still want my oncologist to tell me what he thinks. He's read the literature, but he's also seen hundreds of patients, and seen how the treatments worked for them. I want his input. I need his input. I don't want to make that decision on my own. That would be foolish. But I want to make sure he knows what is important to me.

2) Factors Implicated in Patient Involvement. This theme got into why certain patients wanted to be as involved as they were. Some patients do want a lot of input, and others don't. There are a lot of factors that influence this, including how complex the decision will be, how much support the patient has from others, and their emotional state. Again, this makes a lot sense to me. Even for someone who is highly informed, there are lots of things to consider. That could even change day to day.

3) Proactive and Non-Proactive Approaches. This was more about what kind of person the patient is, and what they have access to, that allows them to be proactive about treatment decisions. Some people have the time, the internet access, and the personality to do the kind of research that allows them to have a voice in the decision. Others don't, though they may wish that they did.

4) Experiences During the Disease Trajectory. Here, again, is a theme that make s a lot of sense. Patients might behave differently at different points in time. Someone who has just been diagnosed might be more likely to say "Yes, sure, whatever you say, doctor." But someone who has been living with the disease for years, and maybe has already had a few treatments, might be more willing to say, "OK, thanks for the recommendation, but can we talk about this other treatment, or this clinical trial, as another option?"  

5) Support from Others. The final theme is about the importance of having input from people other than the doctor. This might mean having someone at an appointment who is clear-headed enough to ask questions and take notes (a very good thing to have). It might also mean having someone at home, after an appointment, to talk through a decision with. As great as it is to have a doctor who can be trusted, it's also great to have a friend, or a family member, or a caregiver to talk things through with. I've been on both sides of this -- having a loving wife who I can talk things through with, but also getting emails from some readers asking for my opinion (which I'm happy to give). It helps to talk, whether it's about the treatment itself, or about other issues, like your fears and worries. It's just easier to agree to a treatment after you feel like you've considered it thoroughly.

These general themes give a good sense of how many different factors we have to consider before we make a treatment decision. They also give some good advice what you might want to think about when the time comes to make a decision.

But I would recommend you read the article (it should be available to everyone, since the journal is open-access). It includes lots of quotes from the patients who were interviewed for the study. It was interesting to me to see how they made the decisions they made. I'll bet many of you will see some of yourselves in those quotes.

I hope none of us need to make any treatment decisions anytime soon. Good luck to those of you who do. 

 

Bi-Specific Antibodies for Refractory Lymphoma

Just a short post today. I've been very busy for the last few weeks, and that will keep up for a few more days, but I wanted to post something, so here it is: an interview with Dr. Elizabeth Budde about bi-specific antibodies, published by MedPage Today.

As you might remember, Bispecifics are similar to monoclonal antibodies like Rituxan and Obinutuzumab, in that they can find and attach themselves to proteins on the surface of B cells that become cancerous in diseases like Follicular Lymphoma. But they are different in that they also attach to other cells at the same time -- usually T cells, another important immune cell (they're the T in "CAR-T"). So they work by bringing a cancer cell into close contact with an immune cell that might eliminate it. 

Bi-specifics are one of those newer treatments that get oncologists very excited. (I often ask my oncologist what gets him excited in the world of Lymphoma, and bi-specifics were one of the first things he told me about, just before they started to get talked about widely.)

In this interview, Dr. Budde talks specifically about the results of a phase 2 trial for Mosunetuzumab, one of several Bi-specifics being tested now for FL. This bi-specific caused a lot of excitement at the ASH conference in December, and you can see form the interview that Dr. Budde is excited about it as well. 

She compares the treatment to CAR-T, pointing out that CAR-T needs to be given in a very particular setting, but a bi-specific like Mosunetuzumab can be given in a regular treatment room, like Rituxan or chemotherapy. She also compares it to PI3K Inhibitors, and shows how much more durable (long-lasting) Mosunetuzumab compared to inhibitors. 

It's a short interview, but an interesting one, and confirms how likely it is that bi-specifics will be a part of our treatment options soon, and for a long time. 

More later, after things slow down for me.

Stay well.

 

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.)

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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.

 

POD24 in Follicular Lymphoma

Important research from the journal Blood. 

In the article called "Validation of POD24 as a Robust Early Clinical End Point of Poor Survival in FL from 5225 Patients on 13 Clinical Trials,"the authors confirm that POD24 is an important concept in Follicular Lymphoma.

POD24 stands for "Progression of Disease before 24 months." (It is sometimes called EFS24 -- Event-Free Survival before 24 months.) The idea is simple, but unfortunate -- for FL patients who have had immunochemotherapy (like Bendamustine + Rituxan, or R-CHOP), if the treatment is successful, but the disease returns within 24 months, their Overall Survival is much worse than for most FL patients. Specifically, the 5 year survival is about 50%, while the 5 year survival for other FL patients is about 90%. 

The concept of POD24 has been around for a few years. It first came out in the GALLIUM study (see the link for more). It's important to understand what POD24 means. There isn't necessarily something magical about 24 months. It's that, statistically, there seems to be a greater chance of lower survival at about that point. Like all statistics, the 24 month cut off is not a guarantee of anything. Patients who progress before that point might be just fine. (Remember the numbers are about medians -- half will do better and half will do worse.)

Also, the treatment -- immunochemotherapy -- doesn't necessarily affect whether or not a patient does well or poorly. Statistically, patients who have only Rituxan (like me) don't have POD24 problems the way immunochemo patients do. But this doesn't mean Rituxan is more effective than chemo. It means people who are given Rituxan are more likely to have a less aggressive disease than a patient whose doctor recommends chemo. 

My point is, this study confirms that POD24 is a real thing, and it looked at 5225 patients in 13 different clinical trials (not just the 1200 patients in the GALLIUM trial) to make sure. But my other point is this -- remember that statistics tell a story about a particular group of people at a particular point in the past. Everyone's situation is different.

The research didn't just confirm that POD24 is legitimate. It also tried to understand why it exists. The problem right now with POD24 is that, while it affects about 20% of FL patients, no one knows whether or not a patient will be POD24 until their disease progresses. What we need is something to tell us, as soon as diagnosis if possible, whether a patient is likely to progress before 24 months after immunochemotherapy.

And the researchers did find some possible clues. 

And remember -- think of these as trends, not guarantees. 

Patients who did not progress at 24 months were more likely to have "Patients without progression at 24 months at baseline had favorable performance status (PS), limited-stage (I/II) disease, low-risk FL International Prognostic Index (FLIPI) score, normal baseline hemoglobin, and normal baseline β₂ microglobulin (B2M) level."

Patients who did progress were more likely to be male, have a Performance status greater than or equal to 2, and have a high-risk FLIPI score (3-5).

Some of those things don't need an explanation like being male. But others probably do. I've written a lot about FLIPI before; you can read more about it here.  It's basically a measure of some particular traits in FL patients (like age and how many places in your body the lymphoma has shown up). A patient is given a score based on how many of the traits she possesses. A high score means higher risk. Performance Status is similar, in that it looks at certain traits in a cancer patient (not just an FL patient, but all cancer patients), and assigns a score. But PS looks at how well the patient can perform some every day activities. A PS of 0 (the best) means fully active with no restrictions, while a PS of 2 (the cut off for this study) means the patient is able to walk but usually not able to work. A 3 means confined to bed more than half of the time. (Read more about PS here.)

So, essentially, patients are more likely to do well after treatment when they are healthy, and less likely when they have health issues or have more advanced disease. That's an over-simplifiction (a big one), but it makes sense. 

And that's helpful, but it's not enough. The article I have been discussing was accompanied by another article, commenting on it. This one is called "POD24 in Follicular Lymphoma: Time to be 'Wise'," written by Dr. John Leonard. He makes a point that lots of expert commentators make -- we need to do a better job of predicting, right from diagnosis, which patients will likely be POD24, and take care of them right from the start. He talks briefly about a study being done that looks at some biomarkers that might help identify patients who are POD24. In other words, researchers are trying to specific features of the cancer cells, not just general traits about the patient, that could help show which patients are likely to progress before 24 months. That's what we need.

This is an important study, if only because it gets people talking about how important POD24 is for 20% of FL patients. I wish those researchers luck in finding some answers. There's a real lack of answers for most of us with FL. 

 

 

 

Biosimilars for Follicular Lymphoma

The journal JAMA Oncology recently published a review of 31 biosimilars for different cancers, including Follicular Lymphoma. The results were very positive. It has some good implications for FL patients.

Some background first.

When a cancer treatment is developed, it usually takes years before it is available to all patients who could benefit from it. It goes from the laboratory, to being tested on cancer cells in test tubes, to being tried out on animal models (like mice), to then being tried on humans in a stage 1 clinical trial, and then if that goes well, in stage 2 and 3 trials. The maker of the treatment spends a lot of time and money developing and testing the treatment -- millions of dollars. When the treatment is finally available (and less than 10% of treatments will make it through a phase 3 trial), the maker is given a patent, where no one else is allowed to profit from that treatment. In the U.S. and Europe, the patent lasts 20 years. The idea is that the maker of the treatment is allowed all of that time to make back the money that they spend on developing the treatment.

After 20 years, the patent expires, and other companies are allowed to make their own versions of the treatment. If the treatment is made up of chemicals (something like a traditional chemotherapy), the new version is called a "generic." They are relatively easy to make -- it's a matter of figuring out the chemical formula and putting the right chemicals together. It's like following a recipe.

But if the treatment being copied was developed from something that was alive --something like Rituxan, that is developed from mouse cells -- it's a little more complicated. Living things tend to want to be different from other living things. It's why kids aren't exactly like their parents (which is probably good a lot of times, and not so good other times). I like to think of it this way. Creating a generic, where you're copying a chemical formula, is like following a recipe to bake a cake. But creating a biosimilar is like baking a cake, but first you have to grow the wheat and get chickens to lay the eggs, and hope that growing conditions on the farm are all OK and there isn't too much rain to affect the wheat and the chickens don't eat something weird that affects the taste of the eggs. And if everything works out, you can harvest the wheat and eggs and then make your cake. It's just more complicated -- there are more factors that have to be dealt with when the treatment is a biosimilar because it involves living things.

Because it's more difficult to develop a biosimilar -- to copy something that was alive once -- it's a big deal when one is developed and then tested and shown to be as effective and as safe as the original. 

The JAMA Oncology article, called "Characteristics of Clinical Trials Evaluating Biosimilars in the Treatment of Cancer: A Systematic Review and Meta-analysis," looks at 31 different clinical trials, involving 12,310 patients, that tested biosimilars for 3 different cancer treatments. One of them was Rituxan, and the trials tested biosimilars for patients with FL and other blood cancers. 

(Just to be clear -- this study didn't test biosimilars; it looked at studies that were already conducted.)

In reviewing all of these trials, the researchers found that the biosimilars were as effective and as safe as the treatments that they were copied from. That's not a surprise -- they wouldn't have been approved if they weren't. But what the study found was even more impressive. Basically, the clinical trials for the biosimilars were even better than the trials for the originals. They involved more patients, and the designed was better (more of them involved direct comparisons between Rituxan and the biosimilars). So basically, the developers of the biosimilars made sure that the trials were as rigorous as possible, so there were no questions about whether or not the treatments were really safe and effective.

So why does al of this matter? What's so great about biosimilars?

The big reason for using a biosimilar is that it is less expensive than the original. The original treatment was developed over years, and cost millions of dollars. The biosimilar's makers didn't need to spend all of that money. They can afford to sell it for less money.

And that's good for individual patients who have to pay for treatments on their own, as is the case for some patients in the U.S. But it's good for people in other countries as well. Lower medical costs are good for everyone.

In the U.S., the question is, will doctors prescribe biosimilars instead of the original? Will insurance companies insist on the biosimilars? 

Whatever the case, it's likely that more of us will see Rituxan biosimilars in the future.