25 Years of Rituxan

One of the ways I find out about what's happening in the world of Follicular Lymphoma is by Google Alert. I ask Google to let me know any time it finds something new on the web that mentions FL. So pretty much every day I get an email with some links. They can be anything from an article in a medical journal to a video on a web page for oncologists to a story in a local newspaper about a fundraiser for someone who was recently diagnosed. It gives me a pretty good sense of what's going on with FL.

So I was very intrigued by a notice I got a few days ago about an article in the Journal of Clinical Oncology called "Rituximab Chimeric Anti-CD20 Monoclonal Antibody Therapy for Relapsed Indolent Lymphoma: Half of Patients Respond to a Four-Dose Treatment Program." 

I was also kind of thrown off. I hadn't heard about any real new research in the use of Rituxan (its generic name is rituximab, and it's known in some parts of the world as Mabthera). I think it was the word "chimeric" that really caught my eye. "Chimieric" is the "C" in "CAR-T," so I thought maybe there was some new CAR-T -like version of Rituxan in clinical trials (but, again, I hadn't heard anything about it, and I usually would have). 

I did a little more digging, and it turns out that the article isn't new at all. In fact, it was published 25 years ago, and it's part of the JOC's "Flashback" series, where they republish important articles from the past and then include a commentary about it.

The commentary comes from Dr. Jonathan Friedburg, the editor-in-chief of the journal. His commentary is called "Flashback Foreword: Chimeric Anti-CD20 Monoclonal Antibody Therapy," and it makes clear just how important Rituxan has been to those of us with Lymphoma. 

So, just to be clear here -- This article is the first report from a clinical trial for Rituxan, from 25 years ago. The results were good, though not eye-popping by today's standards. There were 161 patients with several indolent lymphomas in the trial, and 48% had a response. The median duration was just under 12 months. Most side effects happened after the first or second of four infusions, with fever and chills being most common. [That was me -- allergic reaction with chills during the first infusion.] Only 12% had a severe side effect.

But that 48% response, as the article says, was comparable to single-agent chemotherapy at the time. 

It was the beginning of a very important period in Lymphoma research. As Dr. Friedburg's commentary points out, one of the important outcomes of the study was to show that Rituxan was especially effective on Follicular Lymphoma. The study looks at "indolent lymphomas," as the title says. FL is one of several slow-growing lymphomas that were often studied together in clinical trials (and still are). This study showed that the response rate for FL was 60%, while patients with another slow-grower (SLL) had a 13% response rate. This led future research to focus on FL in particular.

It was later on, when Rituxan was added to chemotherapy, that its importance really became clear. Rituxan just made other treatments better. Both single-agent chemo and Rituxan had response rates of just under 50%. But R-CHOP, combining Rituxan with several chemo agents, had a response of almost 90%. Pretty amazing. It's safe to say that Rituxan is at least partly responsible for the median Overall Survival of FL patients jumping from 8-10 years in the 1990s to 18-20 years today.

What amazes me most about Rituxan (and this is confirmed in Dr. Friedburg's commentary) is that researchers still don't exactly how and why it works. They have some very good guesses, but they don't really know for sure. You can watch this video if you want to see how Rituxan operates. Very cool.

As you know if you've been reading for a while, I am a big fan of Rituxan. I had single-agent Rituxan almost 13 years ago, and it has done its job for me all of that time. In years past, when I wrote about Rituxan in this blog, I'd call it "my best friend Rituxan." It's been very good to me, and to a lot of other patients with Follicular Lymphoma.

So there's your history lesson for the day. If you're looking for an excuse to have a drink, pour one and make a toast to Rituxan. My best friend definitely deserves it.

ASH: The Leonard List

Happy New Year!

I'm ready to take on another year of reading, thinking, and writing about cancer, after a few days rest. My wife and I just celebrated our 30th wedding anniversary, and we spent a few days at Rehoboth Beach in Delaware with some family. We have some very nice memories of times we have spent in that area, and we had beautiful mild weather that let us enjoy some walks along the beach.

I want to wrap up my look at the ASH conference with this year's Leonard List. This is a list of ASH presentations put out by Dr. John Leonard, a blood cancer specialist at Weill Cornell Medicine in New York. Every year, just before the ASH conference, he gives a "Top 10" list of the sessions he finds most interesting. They're not all about Follicular Lymphoma, but some are broad enough that they affect many blood cancer patients, including those of us with FL. (There was a lot of talk about Diffuse Large B Cell Lymphoma this year, and that's reflected in Leonard's list.) I'll have a just a few comments on some of the items on his list.

You can find Dr. Leonard's full list here, as a podcast. You can listen to him discuss his list, or read (or translate) a transcript.

#7B. A few times on the list, Dr. Leonard had two discussed two related presentation sat the same time. That's true for item #7, which looked at two presentations on racial disparities. #7B was abstract 2902: "Current Status of Racial and Ethnic Disparities for Follicular Lymphoma: A Surveillance, Epidemiology, and End Results (SEER) Database Analysis with Emphasis on Hispanics." This research looked at the SEER database, with information on almost 60,000 FL patients, and found that Hispanic FL patients were different from the average in the database -- they were diagnosed at a younger age, and were had a better survival probability at 2, 5, and 10 years, and better Overall Survival. Why is that the case? The data does not show why. The researchers seem to suspect there is some ind of biological difference that has yet to be discovered. I'm not sure what it might be, but I do find it fascinating that it might exist. Part of me wants to believe that we are all the same as human beings, but another part known that when we get down to the very smallest parts of us, there are probably some differences.

#5 on the Leonard List is another that is broken up into two parts.

#5A looks at abstract 798: Incidence of Second Primary Malignancies in Lymphoma Survivors: A Prospective Cohort Study in the Modern Treatment Era. I've written about this topic a few times recently -- the idea that as lymphoma patients, our immune systems, and the treatments we might receive, can make us more vulnerable to getting a second type of cancer, in addition to our lymphoma. Like earlier research, this one shows that Lymphoma patients are more likely to get another cancer (often another blood cancer or a skin cancer), and we need to be careful to get additional screenings, especially for skin cancer. A second blood cancer like leukemia would probably be found while we pay attention to our FL, but we need to stay aware of lots of other types.

#5B on the list is related, in that it looks at issues of survivorship -- what happens after treatment is finished. This one looks at abstract 448: "Reproduktiv Patterns Among Non-Hodgkin Lymphoma Survivors By Subtype in Sweden, Denmark and Norway." To summarize, patients with indolent lymphomas like FL had an easier time having children after diagnosis than patients with more aggressive Lymphomas. This could be because many FL patients have less aggressive treatment, or even watch and wait. This personally was not an issue for me, since my wife and I were finished having kids by the time I was diagnosed, and I'm guessing that's true for many FL patients, who are often diagnosed after age 60. But I know of plenty of people who were diagnosed earlier, and who had still hoped to have children. I like to think that oncologists are aware of this issue and make it a regular part of their discussions at diagnosis. There are certainly ways to help cancer patients who may hope to have children after treatment. 

Finally, Dr. Leonard offers five bonus abstracts after his top 10. (It's a good sign that his top 10 actually includes about 20 presentations -- there's lots to be excited about.)

One of the bonus abstracts is number 2907: "Administration of Obinutuzumab, and Not Rituximab, during Induction and Maintenance for Follicular Lymphoma Increases the Likelihood of Developing Delayed Neutropenia." As a reminder, Obinutuzumab is a monoclonal antibody, similar to Rituxan, thought to be an improvement on it. While it has some advantages over Rituxan, it also has some disadvantages, and this research points to another of them. Looking back at patient records, research found that 23% of patients who received Obinutuzumab with Bendamustine had delayed Neutropenia, which is a lowered level of a type of white blood cell that fights infections. While it is usually considered benign, a significant number of patients in this study were hospitalized because of it. This isn't necessarily a sign that Obinutuzumab shouldn't be give to patients, but Dr. Leonard thinks it should probably be a reason for some discussion about options when it's time for treatment.

So that's Leonard's List for ASH 2022. I like it because it covers so many aspects of being a Lymphoma patient -- not just looking at research on new treatments, but also at issues like survivorship, and thinking about how to make current treatments more effective. Our experience is so much more than just "the latest thing" (though I know I tend to focus on that myself).

And that's our lesson as we move into 2023 -- being sure we focus on our whole selves. Not just the physical, but also the emotional, spiritual, and any other aspects of our selves that allow us to live as full a life as we can.

I'll do my best to keep up the conversation.

Have a happy, healthy new year. Thanks for reading.

 

Follicular Lymphoma Approvals and Trials at ASH

Hello all. 

This is probably my last post for 2022, so I was looking for something appropriately "end of the year"-themed. I couldn't find anything like that, and I don't have time to come up with my own Top 10 list, so I'll offer two things that I think kind of sum up The Year in Follicular Lymphoma.

The first is a quick screenshot from the FDA list of approvals in oncology for the year. There were two FDA approvals in 2022 for Follicular Lymphoma: 

In case that's hard to read, the approvals were for 1) Tisagenlecleucel (also known as Kymriah), a CAR-T treatment approved for patients with Relapsed/Refractory FL who have already had at least two treatments, and 2) Mosunetuzumab (also known as Lunsumio), a bispecific that is also approved for patients with Relapsed/Refractory FL who have already had at least two treatments.

That seems appropriate -- two approvals, one for CAR-T and the other for a bispecific. Those seem to be the two treatment categories that have created the most excitement among Lymphoma experts over the last year. They are both very effective and fairly safe, and move us even further away from traditional chemotherapy (though chemo still has a place for many FL patients, and will for a while). 

So that's a good way to end the year -- looking back at the success that researchers have had in changing the way patients are (and will be) treated.

The second things I want to share is one more look back at ASH. This one is from the website Cancer Therapy Advisor, called "ASH 2022: Trials Show Promising Results in Follicular Lymphoma." It highlights four clinical trials that had results presented at ASH this month. 

Interestingly, the first two trials that I already wrote about: one that showed that Rituxan by itself or with maintenance can give some FL patients a long time until next treatment, and one on the bispecific Odronextamab, which had excellent effectiveness, but raised some questions about safety.

The third one highlighted in the article looks at trial results for Tisagenlecleucel (also known as Kymriah), the CAR-T treatment approved earlier this year. This ASH presentation gave some updated results. The original trial report showed that the overall response rate (ORR) was 86%, and the complete response (CR) rate was 69%. The follow-up showed that it remained effective over a longer-term, with Progression-Free Survival at 67% and Overall Survival at 95% at 12 months, and the PFS rate of 57%, and the OS rate was 88%, after 24 months. 

Interestingly, the article includes an interview with an oncologist who says that we likely won't see CAR-T used in a community setting for 10 more years. In other words, patients will have to go to a hospital for CAR-T treatment, rather than going to an oncologist's office, the way some patients can for chemo, or Rituxan, or even bispecifics. There are still just to many risks involved with things like Cytokine Release Syndrome to administer CAR-T outside of a hospital, where such problems can be handled quickly. 

The fourth presentation is for a "triplet" -- a combination of three treatments. Combinations often have good effectiveness (since they usually come at the cancer in three different ways), but often have safety issues (since the side effects from three treatments can pile up and be three times as bad).

This triplet involves Polatuzumab, Obinutuzumab, and Lenalidomide. Obinutuzumab is a momoclonal antibody, used as an alternatuve to Rtuxan. Lenalidomide is also known as Revlimid, and is part of the R-Squared combination. 

Polatuzumab is less commonly used in Follicular Lymphoma. It's classified as an antibody-drug conjugate. It's like Rituxan, in that it attaches to a protein on the surface of a B cell. But it also has a bit of chemotherapy attached to it as well, so it can deliver the chemo directly to the cancer cell (like the way Zevalin delivers radiation, or a bispecific delivers a T cell). 

This triplet is effective and durable. The PFS rate was 83.3% at 12 months, 67.4% at 24 months, 64.6% at 36 months, and 53.4% at 48 months. The median Overall Survival was not reached. Safety is a concern (as it often is with triple combinations). 86% of patients had a grade 3 or higher Adverse Event (a serious side effect), with 3 fatalities. Most patients (77%) had a side effect serous enough to lead to stop treatment temporarily, and 34% had one that led to stopping permanently.

The researchers seem to think that this combination would do well in a larger study, with one commentator suggesting it could be directly compared to R-Squared in a randomized trial.

So there we are, at the end of 2022: lots of promise from some new treatments, lots of refinements to the treatments we already have, and lots of possibilities for the future.

Progress seems slow sometimes, but I continue to think that we're in a good place as FL patients, especially compared to where we were just a few years ago.

My plan for 2023 is to continue to do what I've been doing, keeping up with news in the world of Lymphoma and sharing what I learned. My 15th diagnosiversary is coming up just a few weeks. I'll have some things to say on that day.

I hope everyone has a happy and healthy end to 2022, and a good start to 2023.   

FDA Approves Mosunetuzumab for R/R FL

Yesterday, the FDA approved the bispecific treatment Mosunetuzumab for patients with Relapsed/Refractory Follicular Lymphoma who have had at least 2 prior treatments. The treatment will go by the name Lunsumio (but I'll probably keep calling it Mosunetuzumab anyway).

The approval is based on results from a phase 2 clinical trial, so a phase 3 trial will be necessary to confirm that it works on a larger group of patients. But it will be available in a few weeks while that trial is being run.

It's a big deal. It's the first bispecific approved for FL in the United States (the European Commission approved it using pretty much the same data, back in June). As you know if you've been reading the blog, lymphoma experts have been very excited about bispecifics for a few years. Once data from trials started becoming available, it was pretty clear that bispecifics could be a game-changer -- a non-chemotherapy treatment option that uses the immune system to kill cancer cells. I've been very interested in it for a few years, since I asked my oncologist which treatments he would consider if/when I needed treatment again, and he mentioned this trial.

As a reminder, a bispecific works by targeting two proteins, one on a cancer cell, and the other on a T cell, an immune cell. Mosunetuzumab targets CD20 on the B lymphocyte that turns cancerous in patients with FL (it's the same protein that Rituxan targets), and then targets CD3 on the T cells. It brings them together so the T cell can take out the cancer cell. 

It's very effective. The phase 2 trial that led to FDA (and EC) approval showed an 80% Overall Response Rate, including 60% of patients getting a Complete Response. It was also pretty durable, with the time that the treatment lasted being a median of 22.8 months. The most common side effects were Cytokine Release Syndrome (39% of patients), and fatigue, rash, pyrexia and headache (all more that 20% of patients).

Bispecifics are often talked about at the same time as CAR-T (see my last post, for example). They do have some things in common, including that they work by have T cells go after the cancer cells. They're also different in many ways, including cost (because CAR-T needs to be made specifically for each patient, it can be more expensive). A conversation with your oncologist will help sort out which would be most appropriate. 

As I said above, the approval is for FL patients who have had two or more treatments already, so newly diagnosed patients wouldn't be eligible, and neither would I (not having had a second treatment). But it will benefit a whole lot of FL patients out there.

And of course, it's important to remember that this is a provisional approval, and if the results of the next trial show that, for example, there are some dangerous long-term side effects, then approval would be withdrawn. (It happens, unfortunately.)

But for now, there's lots to be excited about.

More ASH commentary soon.

Stay well.

ASH Review: Blood Cancer Progress

There's still a little more to be said about this year's ASH conference, and I will share that soon. 

One of the great things for me about the things that are published after a conference like this is seeing the excitement in experts' writing or hearing it n their voices, as they talk about what they have just seen at the conference. I want to share one of those commentaries. It's by Dr. Vincent Rajmukar, a blood cancer specialist at the Mayo Clinic in Minnesota (you can read his profile here -- he's clearly someone who knows what's happening in the blood cancer world).

 Right after the conference, Dr. Rajmukar wrote a Twitter thread about why he was excited about the progress being made in blood cancer research. There were a whole lot of things that excited him.

You can read the thread here. You don't need to have a Twitter account to read it -- it got collected on a different website so it could be easily read. It's just a series of short statements, but together, they really do present a whole bunch or reasons to be excited about where we are, and where we're going, in blood cancer research.

It's pretty short and easy to read, but I'll sum it up for you here anyway:

• Immunotherapy is changing everything. Our ability to understand how genes and proteins influence the immune system and its relationship to cancer has completely revolutionized the way researchers approach cancer.
• CAR-T and Bispecifics are the most exciting types of blood cancer treatments happening right now, and they are just beginning. They're already good, and improvements are on the way. They are a direct result of our understanding of genes and proteins and the immune system.
• (When I say "we" and "our," I'm obviously not including myself as part of the research team doing all this. I mean it the same way as someone from Argentina saying "WE won the World Cup!" I let others do the work and then share in the excitement.)
• That understanding of genes and proteins is also creating even more targets for future treatments. (Remember, CAR-T and Bispecifics are general categories, not specific treatments. Future researchers may find different ways to target genes and proteins in ways that improve CAR-T and Bispecifics.)
• That knowledge also allows us to find very small bits of cancer that don't show up on scans -- Minimal Residual Disease -- that could let us find recurring cancer early, making it more treatable.
• mRNA technology, the same approach that created some of the Covid-19 vaccines, is being used as possible cancer treatments as well. We'll be hearing more about that in the near future.
• Technology has allowed researchers to collaborate in ways that weren't possible just a few years ago. Teams from around the world can share data and speak to one another much more easily now.
• Patients can use technology to communicate with doctors much more easily, too. A Zoom meeting can connect a patient with a cancer expert thousands of miles away. We aren't necessarily limited to the doctors that live near us.
• I'll let Dr. Rajmukar's words stand for themselves here: " I am also totally impressed by the talent of the next generation of investigators. These are some brilliant people who are driven to find ways of improving outcomes in cancer."
• Still lots of challenges --  fancy new treatments come with high prices, some of them are/will be complex to administer (like CAR-T), lots of  new treatments means lots of clinical trials, which will require willing participants and high costs, etc. 
• But even with those challenges, there is so much to be hopeful about.
  

I was very happy to have seen that thread on Twitter. There really is so, so much to be hopeful about. And hearing and seeing it directly from a leading lymphoma expert makes it even nicer. 

More ASH information to come soon.

ASH Review: Odronextamab (Bispecific)

 First of all, a couple of photos from the ASH conference (I wasn't there, but there are a whole lot of photos from the conference on Twitter):

 

The first photo is a group of oncologist/hematologists (I blocked out their faces). The second one are the ASH mascots: a white blood cell, a drop of blood, and (I think) a macrophage, another type of immune cell. The blood mascot made an appearance last year, I think, but the other two are new. I'm glad everyone had a good time (that's what conferences are for, in addition to learning about new research). But if I was a platelet, I'd be pretty unhappy that I was left out.

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One the bad things about not being able to go to a conference like ASH in person is that I miss out on things like photo ops and mascots. But ASH happens at the worst time of year for me for my job, and they don't offer discounted registration for independent patient advocates anyway. 

But the other bad thing is that I only get to read the abstracts -- the summaries of the presentations that I always link to. Those presentations are usually presented as posters (with a little more detail than the abstract) or oral presentations (with a lot more detail, plus questions from the audience). For the presentations that seem to make the most impact, there will at least be some discussion on Twitter, or maybe a press release from the researchers, and some discussion online immediately afterwards. 

Today is the last day of ASH, so I'm starting to see some of those press releases and online discussions. And it's clear that bispecifics are the big news for Follicular Lymphoma this year. People seem very pleased with the updated results for Mosunetuzumab, as I discussed in my last post.

But more controversial are the results for Odronextamab, a different bispecific (I gave this a very brief mention in my last post, because the results seemed good, but not overly exciting to me, based on just the abstract.

However, there are two stories being told about Odronextamab today, after the ASH presentation last night. One is very positive, and the other is a lot more cautious. 

The official story from the company that makes Odronextamab is the very positive one, as their press release makes clear. And the results do show some very good effectiveness. Odronextamab is a CD20 x CD3 bispecific -- it attached to the CD20 protein on a lymphoma cell, and then to the CD3 protein on a T cell, an immune cell that can kill the cancer cell. The results from the phase 2 clinical trial show that it had an 82% Overall Response Rate for patients with Relapsed or Refractory Follicular Lymphoma, with a 75% Complete Response Rate. Those are excellent numbers for a phase 2 trial. The company says they are the highest response rates ever for R/R FL patients, and that the trial has set a "new benchmark." And the response was durable, with the Complete Response lasting a median of 20.5 months.

But then there's the other story, which focuses on safety. As several commenters have pointed out, there are some very serious side effects with this trial. In fact, Odronextamab was put on clinical hold two years ago because of serious side effects.

One of the big side effects was Cytokine Release Syndrome (CRS), which seems common in bispecifics, and definitely in CAR-T. And there were others --- all 131 FL patients had side effects, with 118 of them related to the treatment. There were 81 serious events. There were also 17 deaths recorded during the study, with 6 of them related to the treatment (the others were for things like Covid), with causes such as pneumonia, a brain infection and a fungal infection. Another 15 patients had to leave the trial because of problems like CRS, tremor, epilepsy, high liver enzyme s, etc. The company points out that it did take steps during the trial to cut down on some of these side effects like CRS.

 

The company that makes Odronextamab is planning a phase 3 trial immediately, but is also going to apply to the FDA for accelerated approval. It has already been given Orphan Drug Designation was for FL by the European Medicines Agency (which means it will get some special help during the approval process). It will be very interesting to see what regulators have to say about the side effects. As one lymphoma expert pointed out on Twitter, Mosunetuzumab doesn't seem to have these same safety issues, despite using a similar mechanism.

So far, this has been the most-talked-about presentation from ASH this year. It officially ends today, so there will probably be more experts weighing in the days and weeks to come.

I think the big lesson here is a reminder that, for now, cancer treatments are always about the balance between effectiveness and safety. Treatments that are very good at killing cancer cells are also more likely to cause problems. It's pretty hard to avoid. Maybe someone will figure out how to do that in the future, but for now, it's about recognizing them early and managing them well. 

I'll continue to look out for expert commentary from ASH, and share what I find out. 

In the meantime, may your days be filled with large, cuddly pathogen-killing immune cells like the ones in the pictures.

ASH Preview: Bispecifics for Follicular Lymphoma

More on what's happening at ASH this weekend. 

William asked in a comment what I found interesting with bispecifics. There's actually a lot of bispecifics research being presented, some on new treatments, some on treatments that have been in trials for a while. But it's safe to say that bispecifics and CAR-T are still the treatments that get lymphoma experts the most excited these days.

As a quick reminder: bispecifics act sort of like monoclonal antibodies, in that they find a protein on a cancer cell (like CD20) and attach to it. But unlike a monoclonal antibody, they have two sides (that's the "bi" in the name), and the other side attaches to a protein on a T cell (an immune cell), allowing the T cell to eliminate it.  Very effective, and pretty safe.

Right now, there are not any bispecifics approved for use with Follicular Lymphoma in the U.S. The closest we have is Mosunetuzumab, which is currently under review by the FDA, though it has been approved by the EU. The FDA set a target date of December 29 for a decision, so we may hear something soon.

In the meantime, there are a few interesting presentations on Mosunetuzumab at ASH. For example, "610 Mosunetuzumab Monotherapy Demonstrates Durable Efficacy with a Manageable Safety Profile in Patients with Relapsed/Refractory Follicular Lymphoma Who Received ≥2 Prior Therapies: Updated Results from a Pivotal Phase II Study." The phase II clinical trial results are what the FDA will base its decision on, so this update is important. And the results are very good -- the Overall Response Rate was 77.8%, and Complete Response was 60%. And 79.5% of those with a CR remained in remission for 24 months. This treatment was given to patients with 2 or more previous treatments. When the researchers compared the results to the patients' previous treatments (chemo, PI3K inhibitors, CAR-T, or R-squared), the bispecific treatment had a better response rate, Progression-Free Survival, and time to next treatment. And in this update, there were no new major safety issues. It's easy to see why people are excited about it.

There will also be a description of a trial using Mosunetuzumab and Lenalidomide (no results yet). And in another presentation, a subcutaneous version of Mosunetuzumab is shown to be effective and safe. (Subcutaneous means it can be given under the skin, as a "shot," rather than as an IV.)

There are other bispecifics for FL that are getting attention at ASH. 

Plamotamab, for example, showed good effectiveness and safety in a phase 1 trial.

Epcoritamab is being tested on R/R Follicular Lymphoma in a phase II trial. (This is a subcutaneous bispecific.) It is also being tested in combination with R-squared.

Odronextamab is another bispecific with high response rates for FL in a phase II trial.

So, to sum things up, there might not be anything that is really game-changing about bispecifics at ASH this year. But instead of one big impressive presentation, there are a whole lot of very good presentations about bispecifics that show that it is a treatment that will probably be with us for a very long time. That's certainly the story that many are telling -- the future of FL will revolve around CAR-T and bispecifics, and since bispecifics are probably going to be less expensive, and thus maybe more popular.

Of course, we still don't have an approved bispecific in the U.S., and no real long-term data for effectiveness and safety. I'm kind of seeing shadows of PI3K inhibitors -- lots of excitement, priority review and approval, and lots of variations. And we know how that worked out. 

But I'm more optimistic about bispecifics. As a reminder, I'm no expert -- I'm not a medical doctor or  a cancer researcher. But it seems like 25 years of monoclonal antibody research might matter, since bispecifics work by a similar mechanism.

Lots to be hopeful about.

More ASH previews soon.