Follicular Lymphoma Year in Review

Looks like this is going to be my last blog post of the year. 

I'll save any words of wisdom for a couple of weeks from now, when I do my diagnosiversary post (though I'm not promising anything to wise). But I did think it might be nice to look back at the year.

I'm going to let an article from Medpage Today do some of the work for me. "Year in Review: Follicular Lymphoma" was published December 1, but it covers some of the good some of what happened this year for FL.

The subtitle for the article is "A Promising Year for Bispecific Antibodies," and that is indeed the focus of the article. Though the article says that the year began with the FDA approval for Mosunetuzumab, that actually happened in late December 2022. But since the article was published a month before the end of the year, we'll forgive them for getting their dates mixed up.

The important thing is, the bispecific was improved, and the numbers from the clinical trial were great -- an Overall Response Rate of 80%, with Complete Responses of 60%, and a median duration of almost 2 years. Those are very good numbers, and follow-ups and expanded studies of Mosunetuzumab just confirm this (I'll try to write about one of the follow-up studies soon).

In addition to the approval, bispecifics as a class got more good news from the FDA, with Glofitimab getting accelerated approval in July for Diffuse Large B-Cell Lymphoma, including patients whose FL had transformed (I didn't write about this in the blog), and Odronextamab getting priority review in October from the FDA based on its phase 2 trial. Great numbers here, too -- ORR of 82% and CRR of 75%, with the CRs lasting a median of 20.5 months. 

And finally, the FDA gave breakthrough designation for Epcoritamab, yet another bispecific antibody.

The other bit of news that the article gives is the PI3K inhibitor Copanlisib being pulled from the market in November. I've written enough about that already -- no more comment.

In terms of FDA approvals, that about covers what happened for the year. But I think there were lots of other good things, too. Progress happens in small steps -- sometimes smaller than we'd like. But those small steps are worth celebrating, too.

So I would add a few more things to the year in review.

• Phase 2 trial results for Liso-cel were very positive. An eventual approval would give us a third option for CAR-T treatments.
• The FDA has accepted a supplemental Biologics License for the combination of Zanubrutinib (a BTK inhibitor) and Obinutuzumab (a monoclonal antibody) for patients with R/R Follicular Lymphoma. A decision should be made in the next couple of months.
• Subcutaneous Rituxan performed very well in a phase 3 trial. Approval could mean less time and lower costs for those receiving the treatment.
• Rituxan celebrated its 25th birthday.

These are all excellent things. Looking at the headlines from conferences like ASH and ASCO, it seems like DLBCL and Multiple Myeloma had excellent years compared to FL. Lots of bigger steps forward for them.

But I'm OK with our little steps forward. Good things are continuing to happen for FL patients, and many more good things are to come. 

I hope you all have a very happy new year. I look forward to sharing more with you in 2024.

Peace

Sometimes I write a message on this day, Christmas Day. I know many of you celebrate and many don't. I do. But the message I like to send on this day is one that, I hope, is appropriate no matter what faith one follows, if any.  

As I've said in the past, there are lots of phrases and greetings associated with Christmas. You see them on gift tags and bags, on cards, on posters in stores. Of all of them, my favorite has always been "Peace on Earth." It's usually a wish, a desire, rather than an observation. This year is no different. Maybe even worse than usual -- there's so much division in the world. Some people can't even agree on which greeting to use for Christmas. And that's not even considering the war and violence going on in the world, and the division that happens as a result, thousands of miles away from it. 

This is a tough time to find peace.

And my message on this day usually connects that desire for peace on earth with a need for peace inside ourselves. That hasn't changed. In fact, with so much going on outside of us, there's probably a greater need for peace inside of us. Stress takes its toll on a cancer patient. We all need a break. Now more than ever.

After almost 16 years of living with Follicular Lymphoma, I wish I had some better words of wisdom than I do. But it seems like the wiser I get, the harder the problems around me seem to get. 

I just re-read that last paragraph, and I corrected a word I had misspelled -- I had said "After almost 16 years of loving with Follicular Lymphoma." And I suppose that's true, too. I've been doing my best to spread some love for all of that time. It's strange how writing a blog post about radioimmunotherapy or tazemetostat can be an act of love, but here we are.

And I suppose that's the message, in the end. When it comes to living with Lymphoma, we need to find our own path to inner peace. I've always believed that we each need to live our lives as cancer patients in the way that makes most sense to us. Our path to inner peace has to be our own path. It needs to make sense to us.

So on this day, my biggest wish for you is that you find your path to peace, whatever it might be. 

And maybe, if enough of us find our own peace, it makes the world just a little more peaceful. Not entirely peaceful -- I'm nothing if not a realist. Just a little more peaceful. I'll be happy with that.

Merry Christmas to those of you who celebrate it. Happy holidays to those of you who celebrate other days, weeks, and months this time of year. 

And peace to all of you.

 

ASH Review: Mosunetuzumab for Untreated FL

 Another ASH presentation that has some lymphoma experts excited:

604: Subcutaneous Mosunetuzumab As First-Line Therapy for Patients with High Tumor-Burden Follicular Lymphoma (FL): First Results of a Multicenter Phase 2 Study.

 As you probably know, Mosunetuzumab is a bi-specific antibody. It's a lot like Rituxan, in that it attaches to the same CD20 protein on the surface of a cancer cell. But it also attaches itself to a protein on a T cell, an immune cell that can eliminate the cancer cell when it gets close to it. Bi-secifics are one of those newer treatments that get lymphoma specialists very excited. Mosunetuzumab is already approved by the FDA for FL patients with Relapsed/Refractory disease (just about a year ago). 

This research looks at a different population -- untreated patients, though those with high tumor burden (about 72% had stage 4 disease). There was also a different delivery method -- subcutaneous, an injection, rather than intravenous. 

The study looked at 43 patients. The title says "First Results," and these are indeed very early results -- some patients in the study haven't even been evaluated yet for how effective the treatment has been for them.

Of the 26 patients that have been evaluated so far, the Overall Response Rate has been 96%, with the Complete Response Rate at 81% ( that's 22 out of 26, and all 22 were seen at the first response assessment, meaning the treatment worked very quickly). Responses were also durable. At 6 months, 2 patients had disease that progressed (one of them transformed to DLBCL), but the rest of the group had remained stable or in remission.

A larger group were able to be evaluated for safety -- 39 patients. In this group, the most common side effects were problems at the injection site (72%), Cytokine Release Syndrome (51%), fatigue (33%), dry skin (33%), and skin rash (26%). More serious neutropenia (low white blood cells count) occurred in 10% and infections occurred in 26%. One patient died of cardiac arrhythmia while being treated for COVID19-associated pneumonia. Only 2 patients needed to be hospitalized with CRS. 

So overall, this is really great data to make the case for Mosunetuzumab for untreated FL. One of the researchers pointed out that more data is needed to show that it is effective over the long term. 

An article in Healio called it "remarkable" and  "highly encouraging" (though it doesn't say who exactly is being quoted). 

Lots of good news lately in the world of bi-specifics. I'm sure we'll be seeing even more in the near future.

 

ASH: Acalabrutinib and R-Squared

Many thanks to longtime reader William, who learned about a promising Follicular Lymphoma treatment from an email from MD Anderson. This one was discussed at ASH, and it's worth highlighting. 

The ASH presentation is "#983: Addition of Acalabrutinib to Lenalidomide and Rituximab Induces High Complete Response Rates in Patients with Previously Untreated Follicular Lymphoma: Results of a Phase II Study." 

To break down the title a little bit -- if you've been reading for a while, you are familiar with R-Squared, or the combination of Rituxan and Revlimid (or Lenalidomide). It was shown to be a viable alternative to traditional chemotherapy. It's very good, but could be better (like every other FL treatment). This research looks at adding Acalabrutinib.

The logic makes sense. Alcalabrutinib (also known as Calquence) is a BTK inhibitor. Like all inhibitors, its job is to inhibit, or stop, something from happening. In this case, the target is Bruton's Tyrosine Kinase, an enzyme that is necessary for B cells to develop. As you probably know, B cells are immune cells that can cause a number of B cell lymphomas (including Follicular Lymphoma) when things go wrong. Alcalabrutinib stops one of the processes that allows B cells to grow unchecked. 

BTK inhibitors should make sense for B cell lymphomas like FL. Indeed, Alcalabrutinib has been approved in the USA and in Europe for other B cell lymphomas like CLL and Mantle Cell, both indolent like FL. But for some reason, BTK inhibitors just haven't been as effective on FL as it has with those other lymphomas. (Ibrutinib, also known as Imbruvica, was the first major BTK inhibitor, and has also been very successful for some other lymphomas, but not for FL.)

So maybe the trick is to use it in combination with another successful treatment?

This ASH presentation does present some good evidence for that. 

As the researchers point out in the abstract, they have already had some success with this combination with FL patients with Relapsed/Refractory disease. For this research, they tried the combination on untreated FL patients. It's a phase 2 trial, so there is a relatively small group of patients involved (just 24 of them).  As the researchers explain, one possible reason that R-squared might not be effective is because of "pro-tumoral macrophages." A macrophage is a kind of heavy-duty immune cell -- when B cells and T cells don't work, macrophages take over. But cancer is all about things not working the way they are supposed to, and macrophages can become "pro-tumoral" -- working to protect cancer cells, not eliminate them. BTK inhibitors like Alcalabrutinib can help keep macrophages from protecting tumors.

The small phase 2 study was pretty successful. The Overall Response Rate was 100%, and the Complete Response was 92%, with a median time of 3 months to the CR. As for durability, after a median follow-up of 26.8 months, 6 patients had their disease progress, including two whose disease transformed. After 2 years, Progression Free Survival was 79.2%, and Overall Survival was 91.7% (two patients dies, one from Covid).  The most common serious side effects (grade 3-4) were neutropenia (low neutraphils, a type of white blood cell, 58%), liver function test elevation (17%), infection (12.5%; 2 out of 3 related to COVID19), anemia (8%) and skin rash (8%).

The researchers also point out that some blood cells had changed in ways that indicate that BTK was being inhibited.

So overall, it seems like a promising treatment. The researchers think so, too -- they are expanding the trial from 24 patients to 50. I hope we'll see updated results next year.

Thank you again to William for pointing this one out. We're getting to the point where people will be looking back at the conference and writing and talking about what excited them. I'll keep sharing.

ASH: Leonard's List/Quality of Life

The ASH conference is happening this weekend, so I can't really call these "previews" now. I'm far behind in my attempts to write about what's happening there.

For this post, I'm looking at "Leonard's List." This is the annual list of the Top 10 presentations at ASH, in the opinion of Dr. John Leonard, a blood cancer specialist at Weill-Cornell in New York. I like Dr. Leonard a lot. He is as good as it gets when it comes to expertise, and he explains things very clearly for a non-expert audience. 

So every year, in the 10 days before ASH begins, he releases the next entry on his Top 10 List on Twitter/X. Then he does a podcast episode on the Weill-Cornell CancerCast where he goes into a little more depth on the whole list. 

He does mention a couple of Follicular Lymphoma-related presentations on the List, but I was surprised to see that an FL presentation was one of the ones that tied for his top spot. 

The presentation is called 3761 Frontline Management Strategy and Quality of Life in Follicular Lymphoma: A Multi-Institutional Prospective Cohort Study.It came in as co-number 1 with a similar study of Quality of Life for patients with CLL, another indolent, slow-growing, incurable blood cancer. 

The presentation looks at 1544 FL patients who have Quality of Life data available (along with information on disease status, health behaviors, and functional assessment, treatments, disease relapses, and deaths). All of this information was collected by surveys that the patients took when they were diagnosed and then every year after that, along with medical records. The idea was to try to measure changes in the patients' lives that could measure their Quality of Life -- the physical changes to their bodies as a result of the cancer and its treatments, but also the emotional changes that they went through. 

They divided up the patients into three groups, based on how their disease was managed at diagnosis -- Observation (those who watched and waited), Treatment (those who received systemic treatment right away, like chemotherapy or immunotherapy), and Local (those who had radiation right away).

The results were very interesting.

The patients in the Treatment group had the worst measure of Quality of Life at diagnosis. This makes sense -- patients who watched and waited probably had less aggressive disease, and those in the radiation group were likely stage 1 or 2 with fewer symptoms.

But as time went on, the watch and wait and radiation groups had a lower Q of L as time went on, probably because their physical symptoms got worse. Also interesting -- for all three groups, some of the less physical measures got worse over time, including social/family relations and emotional well-being. 

In some ways, all of that makes sense. I know from experience and fro talking to so many of you that watch-and-waiters can feel the emotional burden of their decision over time. We get used to it, but for many of us, knowing that we have cancer but not actively treating can have a real negative effect on us.

So why did Dr. Leonard include both of these studies as his #1? Well, the CLL patients in the other study (remember, it's an indolent lymphoma, and lots of CLL patients watch and wait, too) study had the opposite results -- their Quality of Life improved over time. 

Dr. Leonard has a few things to say about this.

First is that we need to consider the value of early treatment. In other words, doctors often recommend watching and waiting for patients with FLL or CLL or other indolent blood cancer, assuming it's always a good thing. No treatment (and thus none of the physical side effects) is a good thing, right? 

Maybe that's not always the case. Maybe the better approach would be to determine the circumstances for individual patients. Some of us might be better off with treatment right away, even if the disease is stable and their isn't a physical need.

For what it's worth, I've been telling other FL patients this for a long time. If the emotional (not just the physical) symptoms suggest that treatment is better -- because the emotional burden of living with cancer without treating it might be too much -- then treatment should be an option. And for patients who have watched and waited for a few months, who discover that it's just too hard to live with, delayed treatment should be an option, too.

The other big lesson?In Dr. Leonard's wise words:

"But this really highlights the fact that we need to focus in follicular lymphoma and in CLL for watch and wait patients in particular, but in all patients, we need to have better tools to focus on quality of life because frankly for many patients who will not die of these diseases, but with these diseases, targeting quality of life and the choice of to treat or not to treat or what treatment to choose is really a key important factor in making this selection."

And he goes on:

"It strikes me that some patients might benefit from intervention, and we should identify those patients and maybe treat them a little earlier to improve their quality of life or give them some strategies to cope with the disease. And others may benefit from a different approach. Whether it's intervention or observation, trying to figure out who manages better based on the nature or the choice of intervention or just doing an intervention or not is really important and valuable and something that I think we need to focus more and more of our efforts on as we look at patients and think about what is the best way to approach their disease when they have many options."

And that's key. As patients, we do have options. The beginning of our lives as cancer patients is the worst time to make any kind of decisions. Our brains just aren't as rational as wed like them to be. So having a doctor take the time to lay things out for us is vital -- especially if we're in a place where the disease is stable and we don't need to make a decision immediately, as patients with more aggressive cancer have to do.

I do hope that researchers continue to pay attention to Quality of Life issues, both the physical ones and the emotional ones, and as a community, we continue to find ways to make it easier to live with the disease.

In some ways, I with that Dr. Leonard's #1 had been about a breakthrough treatment that would change it all for FL patients. That would always be ideal. But if that can't happen, and our best option to to find ways to live with the disease, then something like this works for me, too.

I'll keep reading and (I hope) finding times to share what I've learned with you. We're already moving toward the post-ASH write-ups of which research presentations generated the most excitement. I'll share those, too, when I see them.

FDA Investigation of CAR-T

Last week, the FDA announced that it was "investigating serious risk of T cell malignancy" in patients who have received CAR-T treatment. 

Obviously, any time the FDA issues a statement like that, it's worth looking into and being concerned about. But it's also worth noting that the statement also says that the benefits of CAR-T outweigh the risks. 

The statement from the FDA points out that they have received reports of CAR-T patients developing T cell cancers. In other words, the T cells that were manipulated as part of the treatment have become cancerous. Some of those patients then had to be hospitalized or died. This is alarming. Any treatment that results in death of the patient is problematic.

I realize that I'm walking a fine line with this post. I want to look at both sides of the issue but not minimize the problems that CAR-T might be creating. I'm also trying to stay positive, keeping in line with what I see the FDA statement as doing. 

The website Fierce Pharma has a good article on the FDA statement, providing a good bit of context. They provide some good numbers about CAR-T. Maybe most relevant is the data related to Kymriah and Yescarta, the two CAR-T treatments that can be used to treat some Follicular Lymphoma patients, and are the most-used CAR-T treatments (there are six in total). 

From those six versions of CAR-T, there have been 12 reported cases of T cell cancers. (I have seen elsewhere that it might be 19 cases). Ten of those 19 came from Kymriah and Yescarta patients. In statements from both of the manufacturers of these CAR-Ts, they pointed out that they are aware of the problem and are monitoring all of their patients (there have been over 27,000 patients who have received either Kymriah or Yescarta).

Again, I want to be clear that I know I am walking a fine line. 10 cases of T cell cancer out of 27,000 isn't many. But it's the entire world to those 10 patients. Even 1 more cancer in the world is 1 too many. And 12 (or 19) is enough to get the FDA concerned that more might be coming.

I've spent a week or so trying to find more context for all of this, and it's hard to find. One really good source, though, is the podcast Tumor Talk from Dr. Wes Wilson, a cancer researcher at the University of Pennsylvania. I'm having a hard time finding a good link to Tumor Talk, but you should be able to google the podcast name and find ways to access it through Twitter/X, which is how I found it.

Dr. Wilson points out that the FDA has not imposed any restrictions on CAR-T (which happens with some FDA warnings). Dr. Wilson also points out that CAR-T patients who received the treatments had already been heavily pre-treated, and so may have had weakened immune systems and been more susceptible to cancer. CAR-T can also suppress cells that fight cancer, making patients more susceptible. All of that said, he also has not heard of any UPenn patients (there have been over 100) who have developed T cell cancers. There are also several ways that T cells are created for CAR-T treatments, and it is possible (but not yet shown) that processes that were developed before FDA approval are the ones that have caused the problems -- that is presumably part of the FDA investigation. Finally, when the treatments were approved, one of the published potential side effects is the development of secondary cancers. That's true of many cancer treatments -- certainly true of traditional chemotherapy. Secondary cancers are common, unfortunately.

The question becomes one of risk tolerance. As Dr. Wilson says, CAR-T is still more beneficial than not receiving treatment. As of now, the data shows that the risk-benefit is "strongly weighted" toward getting the treatment. And it seems that many cancer hospitals are saying the same thing. And so is the FDA.

So what do I think about all of this? 

Who cares? I'm just a patient. The best person to talk to about this is your oncologist. Every cancer treatment has side effects, and thus come with risks. What's important is being aware of the possible treatments, how effective they might be for your situation, and how the potential side effects will affect your life, given your goals (are you looking for a cure? for long-term remission? for the least aggressive treatment that lets you maintain your quality of life?). Only you and your oncologist can answer those questions. 

In the meantime, I will certainly keep looking out for more news about this. (The FDA statement doesn't give a whole lot of detail, unfortunately.) If you are unfortunately in need of treatment soon, talk to your oncologist about all of your options, including CAR-T, and decide what's best for you.