R-Squared in the Real World

As I mentioned in my last post, the medical journal Haematalogica recently published results of a real-world study of R-Squared. The quick summary: R-Squared still works well for Relapsed/Refractory Follicular Lymphoma. The article is called "Rituximab and Lenalidomide for the Treatment of Relapsed or Refractory Indolent Non-Hodgkin Lymphoma: Real-Life Experience."

First some background on this (or a couple of reminders for those of you who have been following for a while). R-Squared is short for the tretament combination of Rituximab and Revlimid (also known as Lenalidomide). Those two R words are usually shortened to R-Squared. (Interestingly, this article uses R-Len to describe the combination, which I have seen elsewhere, too. Revlimid is the brand name for Lenalidomide, so they're trying to avoid using the brand, I guess. I'm sticking with R-Squared because that's what I have been using since I first wrote about it in 2012, and I'm getting too old to change now.)

This is what is known as a "real word" study. That's an actual medical term. Many articles in medical journals that describe the results of research are describing the results of clinical trials. Trials are necessary for a treatment to get approved, and the patients in the trials are restricted in many ways. For example, patients with previous heart problems might be excluded from a trial because the researchers need to know if the treatment will cause heart problems. So only patients with healthy hearts are allowed in the trial.

But those restrictions can also make it hard to know if a treatment is appropriate for people who have lots of comorbidities (that is, other health problems). So after trials are over and a treatment has been approved, and after the treatment has been given to many patients, with no restrictions, some researchers will conduct "real world" studies. These are studies of how a treatment affects all patients, not just the small group that was allowed into the trial. They can confirm that a treatment is as safe and effective as it first seemed to be. 

R-Squared is an important treatment for R/R FL because it was the first non-chemotherapy that proved to be just as effective as traditional chemotherapy. So getting real-world results is important.

The researchers did a fairly small (84 patients) retrospective study, meaning they looked back at the medical records of the patients who had received R-Squared between 2013 and 2023. About 82% of those patients had been diagnosed with Follicular Lymphoma, so those are the ones we'll focus on (the rest had Marginal Zone Lymphoma, another indolent, slow-growing blood cancer). The median age for the patients in the study was 65, with the range being 39 to 94. (I find that highest age kind of fascinating, and I think it says something about how much easier on the body R-Squared must be compared to traditional chemotherapy.) 

The results were in line with what the clinical trials from several years ago had suggested. The Overall Response Rate was 82%, with a 52% Complete Response Rate. (The CRR for FL patients was 55%, and 40% for the MZL patients.) The median follow-up for the patients was 22 months, and the median Progression-Free Survival was also 22 months (the disease hadn't gotten worse in that time). The Overall Survival at two years was 83%, and the median duration of that Complete Response was almost 4 years. Patients in the study who had bulky disease (larger lymph nodes) or who were refractory to Rituxan (that is, that treatment had stopped working for them) were more likely to have a shorter Progression-Free Survival. 

As for safety issues, the side effects were also in line with the earlier clinical trial results. The most common side effects were low blood  ell counts, fatigue and gastrointestinal problems like diarrhea and constipation. As for severe side effects, the most common were low white blood cell counts (making patients more susceptible to infection) and low platelet counts (making them more susceptible to risk of bleeding). There were no new side effects reported. 

The researchers in the study see all of this as very positive, and their main take away is that R-Squared should continue to be used as a comparison in clinical trials. That is, if a new treatment shows it is just as effective and safe as R-Squared, then it should be approved.

I see another important take away from this, for what it's worth. I think R-Squared isn't used as much as it should be. This isn't the first research that shows "real world" success for R-Squared. And yet, according to a survey from the Follicular Lymphoma Foundation from last year, only about 6% of respondents had been given Lenalidomide as a treatment. (About 10 times as many had been given traditional chemotherapy.)

A big reason for that is probably just habit. For Relapsed/Refractory disease, chemotherapy has always been the go-to option. It seems like a whole lot of treatment recommendations boil down to "that's how we've always done it," especially in a community clinical (rather than a research hospital). That's not to say chemo is a bad choice, and is probably an excellent choice for aggressive FL. But it doesn't necessarily have to be the first and only choice.

I wonder how much newer treatments like CAR-T and Bispecifics will cut further in the use of R-Squared. It could end up being one of those treatments like RadioImmunoTherapy that had great results but just kind of went away because of under-use. (Though RIT had its own set of problems that made it under-used.)  

The big lesson here? Understand all of your options, and make sure your oncologist is considering them all. Best to keep up with these things and have be able to have a conversation when the time comes, rather than having to make a decision under pressure.

Of course, that's why you're here, isn't it?

More soon. Take care. 

Rituxan, Watching and Waiting, and Reading Carefully

I was preparing to write a post this morning about some new research on R-Squared (you'll get that soon) when I got an alert about a  new piece in the ASCO Post about Watching and Waiting. As someone who spent two years watching and waiting, I'm always very interested in research on this subject. What I found was very interesting, but what was more interesting were the lessons and reminders I got about reading carefully. 

The ASCO Post is kind of daily newsletter for oncologists, and they often include stories about research. One of today's stories is titled "Benefit Suggested for Early Treatment of Advanced-Stage, Very Low–Tumor Burden Follicular Lymphoma," which describes a presentation at ASH (which I somehow missed). A group of oncologists from Japan wanted to know if their Follicular Lymphoma patients who were able to watch and wait were better off getting treatment with Rituxan right away instead of watching and waiting.

As I said, this always intrigues me, since I watched and waited for two years and then had 6 rounds of Rituxan. It seems like every few years, some researcher takes on this question, and finds one or the other approach is better. And then a couple of years later, someone presents data that says the opposite. For what it's worth, I am happy with the choice I made, and I think it's ultimately a personal choice. What this kind of research leaves out --always -- is the emotional factor. No matter what the data says, some people won't like the idea of knowing they have cancer and not treating it. That has to be a factor, no matter what the numbers say.

But back to the study from Japan. The researchers from the study say they usually recommend immediate treatment instead of watching and waiting, and so designed a study to test if their recommendation was a good one.

They designed a phase III clinical trial called the FLORA trial (it's phase III because the safety and effectiveness were already determined long ago -- this isn't a new treatment, so phase I and II aren't necessary). They studied 292 patients with low–tumor burden Follicular Lymphoma and divided them into two groups. The first had very low tumor burden, meaning the largest mass was less than 5 cm, the patient had two or fewer nodal sites, and no effusion (no fluid collecting in tissues). The second group had intermediate tumor burden, meaning the largest mass was more than 5 cm but less than 7 cm, had three nodal sites, and no serious effusion. Half of the patients were immediately given Rituxan, and the other half watched and waited until tumors grew enough to be classified as intermediate. The end point for the study was Event-Free Survival, which they defined as progression to high tumor burden, initiation of chemotherapy and/or radiotherapy, transformation to a more aggressive lymphoma, or death.

The results were interesting. After a median follow-up of 2.5 years for all patients, the ESF was much better for the patients who had been given Rituxan immediately.The events that caused the patients to no longer be "event free" were mostly transformation and having to begin chemotherapy. Twice as many patients in the W & W group transformed as in the Rituxan group (18 versus 9). The Progression-Free Survival rates were similar (50.6% in W & W versus 49.6% in the Rituxan group) and so were Overall Survival rates (98.4% versus 97.3%).

The researchers conclude that the difference in EFS is enough to justify giving patients Rituxan immediately rather than having them watch and wait.

Here's where the ASCO Post article gets interesting.

The editors asked a Lymphoma expert to take a look at the study. Dr. Andrew D. Zelenetz, who is the Medical Director of Quality Informatics at Memorial Sloan Kettering, "expressed some concerns" about the study. Among them were two things that I noticed with my non-expert eye -- there was no difference in Progression Free Survival or Overall Survival. In other words, taking Rituxan immediately won't make you live longer than watching and waiting, and it won't make the time until you need treatment again any longer. Those things have always been the criticisms of watching and waiting research -- no matter what the researchers do,there is never an OS benefit to one or the other. Patients end up living just as long no matter which option they choose.

Dr. Zelenetz also points out some other problems with the study. Their definition of "Even-Free Survival" is non-standard. In other words, when other studies talk about EFS, they do in a different way than this study does, so it's hard to compare them. In this study, an "event" only counts of it results in the patient being given chemotherapy or radiation. So taking more rounds of Rituxan, for example, doesn't count as an "event," and if that happened, it would stretch out the EFS time a little more. According to Dr. Zelenetz, the study is set up so the Rituxan group will come out ahead.

That doesn't mean the researchers were being dishonest. But it does mean that it's hard to compare this study with others, because they aren't using the same ways of measuring the data.

So what are the lessons here -- for me, anyway?

First, it seems like there is still no answer to the question "Is it better to treat immediately rather than watch and wait?" And that doesn't surprise me. I've been following that debate for 15 years, and here hasn't been anything new about Rituxan or about watching and waiting in that time, so it seems likely that any difference is just statistical.

Second, it's a reminder that Peer Review is essential with cancer research. A presentation at ASH or ASCO is not peer reviewed. That is, it's a presentation of data that hasn't been checked out first by other experts. When I write about ASH or ASCO, I always try to remind you (and myself) "this is a phase II trial, so it's still early in the process," or something like that. What Dr. Zelenetz has done here is what peer review is supposed to do -- ask questions, point out problems, make suggestions for improvement. If the researchers had tried to publish this in a medical journal, peer reviewers (others Lymphoma experts) would have pointed out those problems, and if the researchers couldn't fix them or explain them, the article wouldn't get published. ASH and ASCO presentations about new treatments are always exciting, but they also need the reminders that they have lots of time before they end up available to patients, and less than 10% of cancer treatments that start the clinical trial process actually end up getting approved.

Finally, for me, this is an excellent reminder to read carefully. I always read with hope. I want new treatments, exciting developments, and something to look forward to. But it's also very easy to be sucked in by a headline that's trying to catch a reader's attention. We all need hope -- it gets me out of bed in the morning. But we don't need false hope. And sometimes that means reading with a careful, critical eye, and deflating that hopeful balloon a little bit. 

I'll get back to work on that R-squared post. Look for it soon.

European Approval for CAR-T

A quick post today, because I'm visiting family and I like playing with my nieces and nephews more than I like writing about cancer. 

A few days ago, the European Commission gave approval for the CAR-T treatment Lisocabtagene maraleucel (also known as Liso-cel, also known as Breyanzi) for treatment of Relapsed or Refractory Follicular Lymphoma after two previous treatments.

This is, of course, excellent news. 

About six weeks ago, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the approval, so now it is official. Liso-cel should be avaioable for patients who meet these criteria in the European Union, as well as Iceland, Norway and Liechtenstein.

Liso-cel has already been approved in the EU for a few types of lymphoma, including R/R Diffuse Large B Cell Lymphoma , high grade B Cell Lymphoma, and Grade 3B Follicular Lymphoma. The FDA gave the same approval for Liso-cel last year in the U.S.

It will be very interesting to see how quickly CAR-T is approved for first-line treatment for FL. As far as I know, there has not been such an approval yet, anywhere. There are certainly clinical trials in place for this group of patients, with some good initial results. It will be interesting to see how popular CAR-T becomes once that is in place.

There are some fascinating politics and economics when it comes to getting a treatment approved. Most companies take the strategy of trying to get third-line approval with their initial application. It is the most likely to get approved, because there is the greatest need for new treatments among patients who have already had a couple that didn't work. Once that approval has been given, and some money is coming in, it's easier to work on trials to get first-line approval. (If you want to read a fascinating book about the development and approval process for Ibrutinib, check out For Blood and Money: Billionaires, Biotech, and the Quest for a Blockbuster Drug by Nathan Vardi. A great behind-the-scenes look at the process.)

That's all for now. I need to go see what my niece learned in her Scottish Country Dance class.

Real World Outcomes for Older Patients with FL

I'm way behind on my Follicular Lymphoma reading.

Almost a month ago, the medical journal Blood Neoplasia published an article called "Real-world treatment patterns and clinical outcomes in patients with follicular lymphoma: A SEER-Medicare analysis." It's very interesting, and I want to share some thoughts about it with you.

The article looks at "older" patients, meaning at least 65 years old. That's an interesting definition for "older," but we'll talk about that another time. 

The study looked at data from the SEER database. SEER (Surveillance, Epidemiology, and End Results)  is a massive database of information about cancer patients in the United States. When a patient is diagnosed, their oncologist enters information about their diagnosis, treatment, and outcomes, and researchers can use this database to do retrospective studies -- that is, looking back at patients from the past. I think those two things are important to keep in mind -- the information has to be entered by doctors (which might limit what is in there), and it looks at the past, which might not tell us much of anything about the future. A patient who was diagnosed 17 years ago (like me) had fewer options than one diagnosed a year ago (like many of you). The study covered patients who were diagnosed between 2000 and 2017. That's significant.

The study looked at two things -- the treatment pattern that the patients with FL received (what kind of treatment, how many treatments) and the outcomes (especially how long they lived). The 13,423 patients in the study were all at least 65 years old when they were diagnosed, with the median age being 76 (meaning half were older than 76 and half were younger). The median follow-up was 57 months (just under 5 years).

The researchers found that 38% of the patients in the study never needed treatment, watching and waiting for the entire time they were being studied. So 62% had at least one round of treatment.Of those, 23% had two or more treatments, 9% had three or more, and 4% had four or more. Chemoimmunotherapy (something like R-CHOP or R-Bendamustine) was the most common treatment. This is not surprising, given that non-chemo treatments became much more widely available after 2017 (things like CAR-T, bispecifics, R-squared, and even some inhibitors). 

Maybe most important (from my perspective as a patient) is this sentence: "Survival rates increased significantly over time."

For patients diagnosed between 2000 and 2005, the median Overall Survival was 65.4 months (about 5.5 years). For those diagnosed between 2006 and 2011, it was 83.9 months (just about 7 years). And for those diagnosed between 2012 and 2017, the median was not reached. That means that at least half of those patients were still alive when they did the study, since you need to find a half-way point to calculate a median. 

And keep in mind, too, that these were "older" patients, with a median age of 76. So if half of them were 76 or older, and were living for at least 7 years (or, to age 83), that puts them right in line with the median life span in the U.S. In fact, it's actually better than the current life span in the U.S. by about 5 years. 

That's all very good news.

It's important, too, to point out that the patients in the study who received more treatments had a lower OS than those who only received one treatment. That makes sense -- one treatment likely meant a less-aggressive version of FL. And patients who were POD24, meaning they had immunochemotherapy but had their disease return within 24 months, also had a lower OS. And patients who were diagnosed on the older end of the scale, or who had advanced FL stage, or who had a high comorbidity index at diagnosis (that is, had lots of other health problems) also had a lower median OS.

All of that said, this is an excellent reminder that numbers don't matter. Statistics tell the story of a large group of people, not of any individual patient. And statistics that are 25 years old (when this study began) don't tell us much about people who were diagnosed yesterday. The treatment options available today are so much better than they were back then -- more effective, more safe, just more of them. As someone who has been following all of this for 17 years, I can tell you -- the advances in cancer treatment are astounding.

So the lessons from all of this are clear to me, and it's the same lesson that I've known since I first started really thinking about statistics. The first lesson is -- don't pay attention to statistics. It's too easy to get into your head that numbers are destiny, and if you read that the Overall Survival for some group that you belong to is a certain number, then that must be your destiny. It isn't. It's the median number for a group from the past and has nothing to do with you. You're better off just not even thinking about statistics.

But I also know that patients are a certain way, myself included, and we're going to look at statistics. So if you are so inclined, then go back up to that statistic above. You know, the one that says older patients with FL have a median life span that is in line with the general population in the U.S. Pay attention to that one.

And if you are younger than 65, know that this kind of research keeps pointing out that same thing, no matter what the age of the patients is that are being studied. Taken as a whole, patients with Follicular Lymphoma have a life span that is close to the general population. That doesn't say anything about any individuals, but if you're going to go around reading statistics that don't have anything to do with you, then at least be wise enough to pay attention to the positive ones.  

Webinars for Follicular Lymphoma Patients

There are several free webinars coming up soon for patients with Lymphoma, from a couple of organizations that I have highlighted before.

First, the Lymphoma Research Foundation has three webinars coming up in their "Ask the Doctor" series. In these webinars, a Lymphoma expert gives an overview of the topic, and then answers questions from patients.

The first one is tomorrow, March 12 (sorry for the late notice -- I just found out about it).  The topic is "Information for Newly Diagnosed Patients." Even if you were diagnosed a while ago, this could be very helpful in giving you an overview. The presenter is Dr. Peter Riedell from the University of Chicago. This isn't about Follicular Lymphoma only, but will cover all Lymphomas (which is a lot), but my guess is, since FL is the most common indolent Lymphoma, it's going to come up a lot. You can find more info here and a link to register. 

Next up the LRF is "Information for Patients with Relapsed/Refractory Lymphoma," presented by Dr. Reid Merryman of the Dana-Farber Cancer Institute. This one is happening next week, March 18 from 2:00-4:00pm ET. Even if you haven't relapsed (you've had no treatments or just one treatment that has worked for you), this could be valuable. I'm always in favor of having information before you need it. Like the first webinar, this one will include time for Questions from Patients. You can find out more and register here.

Finally, the LRF is doing a webinar in Spanish on April 17, "Pregunte al Doctor Sobre el Linfoma." My Spanish isn't perfect, but from the description, it seems like this is a general webinar, rather than one aimed at specific populations like the other two are. Same format -- a presentation from an expert, Dr. Enrique Diaz of The University of Texas Health Science Center at San Antonio, and then time for questions to be answered. You can find out more and register here.

Finally, the Follicular Lymphoma Foundation is holding a webinar called "When FL Changes: Understanding Progression & Transformation." This webinar is being held because a whole bunch of FL patients asked for it. Certainly, this is thing that concerns most of us -- what happens when a slow-growing disease speeds up, or even changes into a whole different cancer. This webinar is being held on March 27 from 9:00-10:00am ET. It will also feature a presentation and time for questions. The presenters are Dr. Mitchell Smith, the Chief Medical Officer for the FLF; Dr. Carla Casulo Assistant Director of Cancer Research Training and Education at the Wilmot Cancer Institute in Rochester; and Fiona McMullen, a Follicular Lymphoma Patient who experienced transformation. Should be an excellent presentation. You can read more and register here.

Keep yourself informed. Consider registering.

Ibrutinib, Obinutuzumab, and Venetoclax for FL

Every now and then, someone writes a comment, and my response to it goes on so long that it ends up being as long as some of my posts. In that case, I decide it's easier to just write a response as a post in the main blog, rather than in the comments.

This post is one of those responses.

Reader Shelly wrote a comment last week, asking if I'd heard about the combination of Ibrutinib, Obinutuzumab, and Venetoclax for treating Follicular Lymphoma. Someone in the FL Facebook group had written about his experience in a clinical trial with this combination. He said the trial oncologist estimated that the combination had knocked out his FL in about 3 weeks, confirmed by a PET scan three months later, though he continued in the trial for almost two years. He said he had stage 3 FL, with 10 high burden tumors.

It sounds like an excellent trial. I'm very happy that it was successful for that patient.

The combination of Ibrutinib, Obinutuzumab, and Venetoclax has already been pretty successful for Chronic Lymphocytic Leukemia (CLL), another slow-growing blood cancer. That doesn't mean it will work in all blood cancers, of course. 

Obinutuzumab is a monoclonal antibody (like Rituxan) that has been approved for use on FL. Ibrutinib is a BTK inhibitor that has been very successful in treating several blood cancers, but it has never had a successful trial for treating FL. Venetoclax is similar, in that it has been successful in treating several blood cancers, but not FL.

If only one out of three has been successful in treating FL, is it worth trying them in combination?

Absolutely. Cancer is such a complex thing, it's hard to know what is going to work. Inhibiting or blocking one thing on its own might not work, but targeting and blocking several things at once might do the trick.

The Ibrutinib, Obinutuzumab, and Venetoclax combination for Follicular Lymphoma is in a phase 2 trial, which is probably the trial that the person from the Facebook group is a part of. I can only find one source discussing any results from the trial -- an article in the medical journal Blood from November 2022. In it, the authors discuss the early results of the trial. Eight patients were involved, with a 12 month follow-up. At that time, all 8 had shown a Complete Response, which is impressive. Side effects included fatigue, diarrhea, low white blood cell counts, rash, and low platelet counts. Two patients left the study by choice, and another had to leave because of side effects. The other 5 remained in the trial.

I'm not aware of any other published follow-up.

According to ClinicalTrials.gov, the trial is still ongoing, actively recruiting patients. The goal is to have a total of 40 patients in the trial, so if they are still recruiting, they probably haven't met that number yet, though the researchers estimated that they would finish recruiting in a few months.

It brings up an important question -- if a clinical trial had a 100% Complete Response Rate early on, why didn't it immediately get more patients?

I think one reason is purely practical. The trial is being conducted at four cancer centers in California. Many large trials are conducted in canters all over the country, and often in multiple countries. With lots of other options, I don't think many patients will travel to California. So the participants are likely limited to FL patients in that one state.

And another reason is one I just mentioned -- there are lots of other treatment options available. As I keep saying, CAR-T and bispecifics are what get lymphoma specialists excited these days. Treatment with a combination like this, especially if it requires travel, probably isn't something that oncologists will recommend. 

And there could be a third reason, having to do with the combination itself. It's possible that some oncologists would say "One out of three isn't good enough," despite the early success of the trial.

All of that is just speculation from me -- I have no insights into why specific oncologists would or would not recommend a trial.

This seems like an excellent time to remind everyone that I am not a medical doctor, or even a cancer researcher. I'm just a Cancer Nerd -- a patient who reads a lot. The best person to talk to about treatment options is always your own oncologist. 

So if the question is, would this trial be something to talk to my oncologist about?

The answer is, Absolutely, especially if you live in California. The published data from the trial is limited, and the lived experience of the person from the Facebook group is fantastic. But an oncologist would be the one to suggest whether or not it is worth looking into.

Shelly, I hope this answers your question. Thanks for the comment.

Treatment Approval News

There have been a few announcements in the last couple of weeks related to treatment approvals by the FDA and other regulatory bodies. I thought I'd give you a summary here. 

First, in my latest attempt to provide FL news from outside the United States: The Ministry of Health, Labour, and Welfare in Japan has approved Epcoritamab for Relapsed or Refractory Follicular Lymphoma. Epcoritamab is a bispecific, and the approval came from the results of the EPCORE NHL-1 clinical trial, which was conducted in 15 countries. Epcoritamab was approved in the U.S. last June. I don't hear a lot about Folllicular Lymphoma is Japan, which is too bad. My youngest child studied in Japan for four months, so I've learned about the country and culture. Looks like a great place to visit someday. It's always great to have another treatment available to people, no matter where they are. 

Second bit of news: The FDA has approved a generic version of Lenalidomide (Revlemid).  Lenalidomide is best known to patients with FL as half of the R-Squared combination (along with Rituxan). But it was first approved in the U.S. in 2005, and is now used to treat several different blood cancers. This approval is for capsules in different strengths, from 2.5 mg to 25 mg. (Studies on FL patients are usually at 20mg, though dosages can be different for different patients). In theory, a generic version of a treatment means the cost will come down, since the original developer has had time to recoup the costs of research and marketing and take some profit. We shall see. The new generic version should be available in January 2026.

Finally, The FDA has accepted the resubmission of the Biologics License Application (BLA) for  Odronextamab for Relapsed/Refractory FL. Odronextamab is another bispecific. It was approved by the European Commission in August 2024, but the FDA was more cautious. The makers of Odronextamab had submitted data from a phase 2 clinical trial, but the FDA wanted to see data from a larger phase 3 trial. It did not reject the Odronextamab application based on effectiveness or safety, but only because it wanted to see more data. So they now have that data. It will be interesting to see what comes of this. My guess is that it will be approved, but there were some concerns about side effects in the initial trials (about 16% of patients had to drop out of the trial because of severe side effects. This application will have more data on that, and the FDA can make a decision based on it all. 

I'll certainly keep an eye out for news about the Odronextamab application, and any other treatment approval news that affects us as FL patients.