Low-Grade Lymphomas: Dr. Joshua Brody on Treatments, Strategies, and Innovations

Chandler Park: Welcome back. We’re here on the OncoDaily show here. And we’re very happy to have an international leader in lymphoma and immunotherapy studies.

We’re going to be talking about bispecific T cell engagers. And, you know, we got Dr. Joshua Brody. He’s the director of the Lymphoma Immunotherapy Program at the Tisch Cancer Institute at Mount Sinai.

Since he joined Mount Sinai, he’s developed this robust cancer immunotherapy lab. He’s done a lot of cool things and we’re very happy to have him today. Dr. Brody, can you tell us a little about yourself?

Dr. Park, thank you.

Joshua Brody: It’s an honor to be here. I appreciate it. Thank you for the introduction.

Yeah, I take care of patients here at Mount Sinai in New York, patients with lymphoma and CLL. And I also run a lab where we try to develop novel immune therapies for all of our patients. And we’ve been very, very lucky to bring some of the most promising things from the lab into early phase clinical trials.

And extremely fortunate to get to publish some of the early results from some of those trials in high-impact journals. So we’ve been very fortunate so far. And some of our patients have been as well.

Chandler Park: Yeah, I think it’s great. Just following some of your work and some of the stuff that you’ve done. And the different publications and presentations.

But you know, I know one thing about all of us is we all have a story. And I just found your story very interesting. Where you were like a teenager and you were following your dad to the lab.

And you kind of started looking at things under the microscope. Can you kind of tell us about that story? I think it’s very fascinating.

Joshua Brody: Well, speaking of lucky. Yeah, this is a very lucky thing. Because I came from a lucky place in that I had a lot of good role models and inspirations.

My dad, Neil Brody, MD, PhD, is just that. He’s an MD, PhD. So he’s been a physician scientist for many, many decades.

And you know, I was lucky to have him as an inspiration. But also, I’m kind of lucky to be doing what he was trying to do in the more modern era. Because the tools and techniques and everything we have.

You know, it’s stuff that he only dreamed about. So I think he is a little jealous and he lives vicariously through some of the work that we do here. But he is an MD and a PhD.

And his goal and his dream for many years was to try to cure cancer. And he focused on melanoma. So a little different than what we study here.

But similar ideas. And he was trying to use the immune system to cure cancer. And that’s, as you can hear, not that different from what we’re trying to do.

Even though the approaches are a little bit different. So yeah, he was the vice chairman of dermatology over at SUNY Brooklyn, SUNY Downstate. And when we couldn’t – I wasn’t even a teenager.

Before a teenager, when I was a little kid, we couldn’t find the babysitter. And there was no school that day. Yeah, and he just picked me up by the scruff of my neck, threw me in the car.

And I go to the lab with him. And I would be looking under the microscope at the cancer cells that him and the folks in his lab were trying to eliminate using the immune system. And I thought it was pretty cool.

And even more so, I guess I had some knowledge even from family and friends about cancer being a terrible disease. So it just seemed like a very worthwhile thing to try to just get rid of it. I was mostly just a comic book kid.

And justice is all I would be reading about all day between this superhero and that superhero. So I thought, okay, this would be a justice thing that we could do in the real world. Try to get rid of cancer.

And my dad’s approach of using the immune system, which a few people were doing back in the day, but it was nothing like today, where cancer immunotherapy is an oblived and accepted thing. Back in that day, it was kind of ridiculed. If it’s not chemotherapy, if it’s not radiation or surgery, then it’s not real.

So my dad was really swimming upstream for those many years he was working on it, as a lot of other physician scientists were. So maybe that was all inspirational to me, I think.

Chandler Park: I think it’s phenomenal. And a couple of things that you kind of mentioned. One, just kind of growing up and seeing your dad as kind of like a role model.

And things that we don’t even think about when we’re younger, that kind of has an impact on us. And it’s like a family day at work. And all of a sudden, that spark of following your dad and looking in the microscope.

And this is very interesting. And it just kind of started the whole process, you know?

Joshua Brody: Yeah, all these ideas we have came from somewhere. We don’t always know where they came from. But this one feels to me like you couldn’t ignore it.

It would be too big of a coincidence for me to say, yeah, I use the immune system to cure cancer. What did your dad do? Well, the exact same thing.

Seems like a pretty big coincidence otherwise. So yeah, it must have been the inspiration. And I mean, that’s just extremely lucky, because I was just lucky to have that type of inspiration.

Actually, my mom and dad met in med school in this combined undergraduate medical school six-year program they had then. So I was just lucky to be inspired by parents that were trying to do helpful things for the world.

Chandler Park: Wow. Great minds. And just listening to you, just the profound impact your parents had on you, you know, I think is wonderful.

So you went off to college and then medical school. And then you went into He-Mong Fellowship. And, you know, He-Mong Fellowship, there’s so many pathways that you can go.

And so what kind of drove you into, you know, the hematological malignancies, any role models, any clinical research that kind of lit your path down this road?

Joshua Brody: Yeah, that’s a good question. You know, as you can hear, this is where I finally start to diverge from that path that maybe I was just trying to steal from my father, because he was focused on melanoma. And I was just interested in any cancers that I thought the immune system had a good precedent of being able to defeat.

And, you know, many years later now, it seems like lymphoma was kind of either the precedent or the lucky choice, because lymphoma has a greater precedent of immune, you know, susceptibility than almost any other cancer. And we have got Hodgkin’s lymphoma, where anti-PD-1 is the most effective thing. And there’s no cancer, even though anti-PD-1 is the Nobel Prize winner and great for melanoma, lung cancer, bladder cancer.

None of those other cancers are nearly as susceptible as Hodgkin’s lymphoma. I mean, so that lymphoma, you know, uniquely susceptible to PD-1 blockade. And then on the other side, we have all these B-cell lymphomas, which are very susceptible to, you say, passive immunotherapy, targeted immunotherapy, CAR-T cells, bispecific antibodies.

And so it’s just a great precedent. And I think, really, when I was picking a clinical focus on lymphoma, also, as you say, the clinical aspects did drive me, because I wanted to be able to work with kind of all kinds of people, men and women, old people, young people, people with a terrible prognosis, as we have some of in lymphoma, and people with a good prognosis. I don’t get too discouraged every single day.

And lymphoma is just a great, you know, cancer to be able to study, because some people, you can cure them and give them, you know, 80 years of additional life of high quality. And then other people, there’s still a huge unmet need. So science and translational science are, you know, sorely needed to try to improve some of the bad outcomes we have with certain lymphoma subtypes.

So it was a little bit about the clinical situation and a little bit about the scientific opportunities, someplace where the immune cells could have a good precedent for killing the cancer cells.

Chandler Park: I think it’s very well put. I mean, you think about, like, lymphoma and just the diversity. I mean, you have something, like, that might be a follicular lymphoma with, like, a low GELF score, all the way to Burkitt’s lymphoma.

I mean, it runs the spectrum. I mean, you got diffuse large B cell in there, mantle cells, like a tweener. I mean, you’re right.

I mean, there’s so many different lymphomas. T-cell lymphomas, we didn’t even get to the T-cells. So it’s so heterogeneous.

And all of them have different treatments. I mean, it’s so intellectually stimulating. What are your thoughts?

Joshua Brody: Yeah, I mean, that, I think, was a big part of it for me clinically, that it was, as you say, extremely diverse. I mean, as we become more expert in pancreas cancer, breast cancer, we realize, of course, there’s not one breast cancer. You know, at first glance, there’s three.

But as you’ll think more, there’s really many subtypes. But even out of the gate, lymphoma, I mean, it’s 80 or more subtypes. So, you know, it’s not just academic or different subtypes.

It’s, like you say, a different medicine for every person. Whereas, you know, back in the old days, when I was looking at some of these other tumor types, it was just carbotaxel, carbotaxel, carbotaxel. Which, okay, you know, we’re helping some of those people.

But it was a little bit more interesting for me to think about 80 diseases with probably, you know, 81 different, you know, best optimal therapies. So, yeah, I found that a little bit intellectually intriguing and stimulating. And I still think today we are even finding more subtypes.

Every few years when the WHO meets, the World Health Organization, turns out, no, there’s 82 types. There’s 83 types. And sometimes those different types, it’s not just academic mumbo-jumbo.

It makes a difference if you are hairy cell leukemia typical or hairy cell leukemia variant because we treat them differently. So, yeah, it’s a pretty intellectually stimulating group of cancers, I think.

Chandler Park: Yeah, yeah. Absolutely. Like even follicular lymphoma.

You have follicular 3A and 3B and there’s a treatment difference right there. You know, one you probably treat like a diffuse large B cell lymphoma and 3A is lumped in with 1 and 2.

Joshua Brody: Exactly that. And also, Chandler, I’m going to guess when you and I were both kids, they just called it 3. They didn’t call it 3A or 3B.

So, not only is it a lot, but you’ve got to stay tuned in every year for the advances. And it’s not like a little nothing academic thing. I have follicular lymphoma 3A patients who we give active surveillance, watchful waiting to, and they’re doing great for years.

Whereas a 3B is absolutely a different disease. It’s like DLPCM, like you say. So, these little things that we didn’t even appreciate 15 years ago, even 10 years ago, are hugely different.

So, yeah. You’ve got to stay with your ear to the ground, nose to the grindstone. You’ve got to keep something connected to the world so that you can hear about these advances for sure.

Yeah, yeah.

Chandler Park: And you know, one of the advances you kind of highlighted, it was a Hodgkin’s lymphoma. I mean, you think about back in the day, overtreatment, right? I mean, ABVD, radiation in the whole mantle field.

And now we went ABVD to, you know, Brintuximab, Vedodin, and then VD. And then now you’ve got with Nivolumab. And so, it is so much better for our patients in terms of less radiation exposure and less toxicity, less neuropathy.

What are your thoughts about that improvement in terms of the Nivolumab being in the first-line setting?

Joshua Brody: As you say, we are still taking care of these patients that got old-fashioned therapy and some of it very aggressive therapy. And, you know, they’ve got all kinds of problems from 20 and 30 and 40 years ago. I mean, so, you know, we should acknowledge the limitations of it.

Nonetheless, we’re still lucky to have, even though they were toxic, still good therapies. When my grandpa, my dad’s dad’s sister had Hodgkin’s in 1947, it was 100% lethal disease or almost 100, and she died of it. He had three sisters.

Two of them weren’t that nice, and one of them was super nice. And the nice one died of oncology. The nice one died.

And so, Hodgkin’s went from, you know, just those few decades from universally lethal, just about, to, you know, nowadays, like you say, 85% cure rates. Even with advanced stage disease, 80% cure rates almost. So, it’s a huge amount of progress.

And then now the progress has been even a little less about getting higher cure rates and more about making safe, highly curative therapies. So, a big advance, big randomized phase three trial a few years ago, Echelon 1, showing the addition of brentuximab-vidotin to frontline therapy, increased overall survival, gold standard of an accomplishment for a randomized trial, frontline therapy for advanced stage. And now we have this SWOG S1826 randomized trial.

I honestly, I was surprised because, you know, brentuximab-vidotin AVD is so good. I really thought it would be hard for nivolumab AVD to beat it. And yet, even one and two years into the follow-up, nivolumab plus AVD seems to be both better and maybe even safer in some ways.

So, you know, even when you think you’ve maxed out a certain disease’s, you know, opportunity for great efficacy, there’s still a little bit room for improvement. Maybe we feel a little guilty because we have other cancers where the progress has not been nearly that good. We have great progress and then great progress on top of that.

So still, these are young kids, most of them, 20-year-old, 30-year-old kids. We call 30-year-olds a kid. And so, yeah, we care about all of our patients equally.

But, you know, curing a young kid and giving them 80 years of high-quality life afterwards somehow does even come, we take it home with us even a bit more. It’s extremely gratifying. So, yep, nivo AVD, awesomely effective, pretty well-tolerated frontline therapy and becoming a standard of care.

It’s not an absolute, you know, Brintoximab, Vidodin, AVD still may have a space in certainly different patients, sometimes different therapies. But, yeah, awesome results for nivolumab AVD frontline therapy, bringing immune therapy right into the frontline for these patients, yeah.

Chandler Park: Absolutely. And like you mentioned, like other cancers, we might need more progress. Like a good example is like diffuse large B-cell lymphoma.

I mean we have six cycles of RCHOP. Some tried, what, eight cycles, four cycles. And now we had this antibody drug conjugate, right?

Joshua Brody: Antibody drug conjugate.

Chandler Park: Yeah. And then the question is, is there a specific with the activated B-cell that might benefit? Because it didn’t really look like there was any difference in PFS and OS it seemed.

What are your thoughts about that for first-line diffuse large B-cell lymphoma and the advances that we need there?

Joshua Brody: Right. So since DLBCL is the highest incident lymphoma, it’s the thing we see every single day, and, you know, it’s a common disease. I mean, first of all, people don’t fully appreciate lymphoma is a common disease.

People sometimes think of it as rare. Lymphoma is the fifth most common cancer in America. It doesn’t quite always get the recognition because we don’t have as famous of a ribbon as some other cancers.

But it’s a common disease. And DLBCL, the most common amongst lymphoma subtypes. So we see it every day.

We are wonderfully able to cure the majority of patients. But, you know, that means 55, 60 percent, not 90 percent. So a lot of room for improvement.

And we’ve been trying years and years to, you know, beat RCHOP, to improve upon RCHOP. And a lot of failures, you know, left in the wake of those attempts, which I won’t get into all the failures. So now Pola, Polatuzumab, PolaRCHIP.

So Polatuzumab, this antibody drug conjugate targeting CD79. PolaRCHIP, getting rid of the O and making it much harder to pronounce. PolaRCHIP versus RCHOP, this Polarix trial.

It’s kind of the first success after years of failures of trying to beat RCHOP. But as you’re hinting, the success was moderate. You know, overall, there’s this 6 percent PFS delta.

So it’s real, but it’s not huge. And there’s still, it’s a little bit more toxic. Because if you just pick one side effect, like febrile neutropenia, it’s about 6 percent more in the PolaRCHIP group.

So you kind of get what you pay for. You pay a little extra toxicity and you get a bit of benefit. But as you said, there was this interesting post hoc analysis.

It was a planned analysis, but still post hoc, where the activated B cell, we call non-GC subset of DLBCL. It’s about half of the patients or so, did seem to get almost all of the benefits. So we’re always a little shy to kind of consider these subset analyses in our decision making.

But it’s also hard to ignore it. So honestly, I’ll just give you my personal approach. And I think it’s common for a lot of the lymphoma docs around here.

Yeah, non-GC DLBCL, we’re much more enthusiastic to give them PolaRCHIP. And then the GC DLBCL, a little less enthusiastic. So that’s not a simple one size fits all answer.

And we have this discussion with the patients because if there’s no OS benefit yet, like you say, you can’t say it’s the right answer for everyone. That’s not fair to say. But yeah, we are giving PolaRCHIP more so for the younger, healthier, maybe higher risk non-GC patients.

And maybe RCHOP still for the other patients. But to be fair, I think in a few years, we are going to be beating RCHOP with some of the new medicines that you and I are going to talk about. So I think we’re going to finally have that real success that we’ve been looking for for decades now.

Chandler Park: I hope so. I know some of the medications are so elegant and it just makes sense. If you think about at the basic science level, you think about BTKs, brutant tyrosine kinase, lymphomas, BCL2 inhibitors.

And yet when that transitions to the clinical, it hasn’t really translated. I mean, what are your thoughts about at the basic science level, BTKs, BCL2 inhibitors, but yet it hasn’t panned out in diffuse large B-cell lymphoma?

Joshua Brody: Absolutely. So you’re saying like these things maybe sometimes should work and then when they don’t, you’re all surprised. It doesn’t make sense at the cellular level in terms of the mechanism of action.

I couldn’t agree with you more. So BCL2, I mean, it stands for B-cell lymphoma 2. And we used to always call it the sort of pathognomonic translocation or mutational event of follicular lymphoma.

So we used to say, I mean, because 1418 translocation makes BCL2 be super high in follicular lymphoma. Therefore, at first glance, you’d say, oh, so a BCL2 inhibitor should be great. Or similarly for DLBCL, especially if it came from follicular lymphoma.

Like a transform or something.

Chandler Park: Yeah, like a CD10 positive or something.

Joshua Brody: You’d still think BCL2 might be critical there. The truth is, okay, first we saw the clinical attempts and some of those were failures. BCL2 inhibitor, really just a failure in follicular lymphoma.

At the same time, an incredible home run superstar in CLL, where it induces these amazingly deep remissions, molecular, you know, MRD negative disease in CLL. So it’s a great medicine and also good for mantle cell, good for a few others as well. A couple of others, also a role in myeloma, which is beyond my expertise.

So the medicine itself is great. Venetic lax BCL2 inhibitor and some others that are coming down the pipe. But for follicular, we thought it would be good.

Yeah, an absolute loser. And I mean, the first answer of that is, number one, we model things in the lab of how they should go. But the models are all limited, you know.

So their models are just, maybe this should be great in the clinic. You know, we shouldn’t oversell the models that we develop in the lab, number one. And number two, sometimes a simple story is not the whole story.

BCL2 translocation is the first event in follicular lymphoma. But then there’s many events afterwards. KMT2D mutations, we more recently found out is an important one in follicular lymphoma.

So the BCL2 is kind of just getting it started. And then a little bit, you know, mutationally, the tumor cells are out of the gate. So going back and inhibiting BCL2, you’re fighting yesterday’s problem.

But BCL2 just got it started. This is kind of the way I explain it to myself and some of my patients. And so maybe not surprising after the fact that BCL2 inhibitor, not great for DLBCL, not great for follicular lymphoma, but still great for some other lymphoid malignancies.

Chandler Park: I think in a way, when the IRIS study came out with the imatinib, I think in a way it kind of spoiled us. Because we’re like, okay, we got this elegant inhibitor TKI, and then we kind of used it for other malignancies. It hasn’t really panned out.

What are your thoughts from the IRIS study to now? I mean, that was like the beginning, but yet we’re still finding that these cancers are very complicated, you know?

Joshua Brody: They are. And like you say about imatinib, I mean, people remember where they were when JFK was shot, when 9-11 happened. People remember where they were standing exactly, in what building, in what room.

And I remember, probably you might remember as well, I remember where I was standing when I heard about imatinib and the first results. I was standing in the Yale New Haven VA, in the Veterans Affairs Hospital, where I was working that day. And I remember when I was sitting there and I heard, I said, oh my God, this is awesome.

This is going to be for all cancers, kinase inhibitor for every cancer, and we’re done. Because for CML, imatinib is, yeah, I mean, transformative, revolutionary, and like the perfect medicine. And right, the next 20 kinase inhibitors after that are not amazing as imatinib.

Many of them helpful. A lot of them great. And let me say, you know, luckily in lymphoma and lymphoma malignancies now, BTK inhibitors have not quite been imatinib, but they have been absolutely revolutionary, but mostly for CLL, and then also for mantle cell and a few others as well.

So right, after that imatinib story, our expectations got a little too high. It’s kind of like, you know, when you feel like the science fiction guys promise jetpacks and moving sidewalks, and then the future doesn’t have them, say, oh, where’s that jetpacks? Where is the imatinib for every single cancer?

All right, we don’t have imatinib for every cancer. But at least in lymphoma malignancies, BTK inhibitors, great, amazing, and a few lymphoma malignancies. And then you’re asking about DLBCL specifically.

So let me say, we had this big trial, frontline, R-CHOP plus or minus ibrutinib, we call it the Phoenix trial. And it was overall a fail, and people remember it as a fail. But actually, there was a little bit nuance there, because in the young patients, it was actually not a fail.

It was a great benefit. But when you averaged out the young patients and everybody, it washed out to be a fail, mostly because there was a bit of toxicity in the older patients. It’s a pretty safe medicine, but giving it together with chemo, it got a little bit toxic, and the patient didn’t get all of the chemo that they probably needed or should have gotten.

So now that trial is being redone, not with ibrutinib, but with acalabrutinib, a little bit safer, and only focusing on younger patients. So that’s called the Escalade trial. And the Escalade trial is finished with accrual, probably will read out in the next year or so.

And actually, I’m pretty optimistic for that one. So, you know, that’s a great overall lesson, which is sometimes a fail is not just a fail. It’s a fail plus a lesson learned.

And if you can, you know, exploit that lesson, you know, you can have success for the next go-around.

Chandler Park: And I think that could happen here. That’s why we need great minds like yourself, to constantly look over the landscape. I mean, if you think about it, like the model T of BTK is ibrutinib.

Then you’ve got the acalabrutinib. Now you’ve got the xanabrutinib. And now what is it, the Bruin study?

And you’ve got this non-covalent BTKs. And so it’s like now we’re at the, I guess, what do we call it? You know, like the Porsche.

From the model T to Porsche with less afib. What are your thoughts about that?

Joshua Brody: Well, it’s true. But, I mean, really, if you think about model T to Porsche, what was the huge revolution? It was the model T.

Model T. The Porsche is just tweaking the model T. Same idea.

Same, you know, same carburetor, same combustion until we get to Tesla or whatever. But, you know, the revolution is the model T. And ibrutinib was the revolution and was absolutely, I mean, come on.

In terms of transformation, how we take care of patients, CLL. I don’t think there’s any other cancer other than maybe imatinib and CML. We went from 100% chemo to basically 0% chemo.

Front line, second line, and even third line. We don’t even talk about chemo for the first three lines of therapy because we have BTK, the old-fashioned, but there’s still, you know, the current cutting edge. Covalent BTK, non-covalent BTK, like pert-ibrutinib, the Bruin study that you’re mentioning, and also BCL-2 inhibitors.

So, you know, chemo isn’t anywhere on the list, whereas 10 years ago, chemo was what you got. So, I mean, that is awesomely revolutionary, and the model T is what got us most of the way there. But, yeah, if you beat the model T by just a couple miles per hour, yeah, then model T’s got very little place.

But you have to still give credit to the model T because it was the one that made, you know, really made the advance, and then we’ve really improved on that great advance by, you know, by a bit now. So we’re looking for that.

Chandler Park: Absolutely. Now, on a similar note, you know, because you think about COL, it’s very similar in terms of follicular lymphoma. You know, COL, sometimes we do observation.

Follicular lymphoma, sometimes we do observation. And, you know, just kind of a highlight, and let me know if there’s anything new, but, like, if we have stage 1 or stage 2 contiguous follicular lymphoma, no symptoms, maybe image, sight, radiation therapy, is that something that’s still standard of care, maybe? No systemic treatment?

Joshua Brody:  Yeah. As you’re saying, we’re lucky to have these low-grade indolent diseases, a few of them, follicular, SLL, CLL, even the others, marginal zone, even Waldenstrom’s and LPL, lymphoplasmicytic lymphomas. We’re lucky to have these low-grade lymphomas that can be sometimes pretty easy to manage.

I feel like I’m putting a lot of family stories in here, but I got permission from my grandma. My grandma died at the age of 101 a couple of years ago. She was a very nice grandma, and she had CLL, SLL for 37 years.

We never treated her at all. It wasn’t because we didn’t love her. She was a good grandma, a very good grandma.

But she didn’t need it. I mean, in active surveillance, watchful waiting, you know, still, no treatment is the best treatment if you can use it. So that is still our favorite.

And now, like you say, for an early-stage follicular lymphoma, you know, can we give no systemic therapy? Well, certainly we can give watchful waiting. But specifically with a stage 1, yeah, radiotherapy is still super reasonable.

And then the old standard there was standard dose radiation, which is still a standard. But sometimes we have these low-grade stage 1s in places where the radiation could be a little tough, you know, nasopharynx, anywhere over here that’s very radiosensitive. So even for some patients that may not tolerate the standard dose radiation, we have what we call baby dose radiation.

Instead of 36 gray or something around there, just 4 gray, 2 gray times 2. We sometimes call it boom, boom, 2 days, and you’re done, super low dose, super gentle. And we don’t have a precedent of it being long-term curative like 36 gray.

But, yeah, it can put people into long remissions. And if you’re 80 and we gave you a 10-year remission, you’re doing pretty well still with almost no therapy. So, yeah, we have these early stage 1s, which can still avoid systemic therapy completely and sometimes for many years.

Chandler Park: And then when you start going to stage 3, stage 4s, you do the Ann Arbor criteria, above and below the diaphragm, you start thinking symptoms. Then you start thinking like Delft criteria. You start thinking about should we treat, should we watch.

Any advice for people in the audience in terms of, you know, stage 4, follicular lymphoma, maybe 3A, 1 or 2, you know, should we pull the trigger there? Are we looking very close with the Delft criteria? What are your thoughts there?

Joshua Brody:  I will say that, you know, I feel like we’re lucky in lymphoma that I never wanted to have to memorize all the TNM staging for lung cancer, breast cancer. It just seems too hard and complicated for me. I have to go to Google every single time and look at the table.

So I feel like we’re lucky in lymphoma that actually all that stuff, this staging and the prognostication is in many ways a little bit simpler. So your question is when do you pull the trigger? When do you go from active surveillance to active therapy?

And the answer is there’s a quick catchphrase that we use. You don’t have to memorize everything, Delft criteria, this stage, this grade. Here’s a simple catchphrase.

If the cancer is either hurting you or about to hurt you, then we treat. And I will say this is actually maybe one of the bigger differences between my community oncology buddies and the academic guys that I work with. I mean, I have a lot of, most of my buddies are in community oncology, and they don’t want to have to memorize every little thing.

The more common difference in low grade lymphoma when the patient goes to the academic is we’re more likely to say, no, you don’t need therapy, because we’re, I guess, just maybe more comfortable because we’re seeing this disease all day long. So the simple, simple rule is if it’s hurting you or about to hurt you, you need to treat. Hurting you can be simple.

It can be symptoms like you say. It can be cytopenias. It can be anything that’s hurting you with an organ or symptomatically.

About to hurt you is a little trickier because what do you got to do? Take the last two or three PET scans or CAT scans or whatever you have and try to make a trend to say, oh, yeah, if I keep getting another scan in four months, now that ureter is going to be impinged upon. So that’s going to be hurting you.

It’s not hurting you today, but I think when I look at these pictures, it’s going to be hurting you in two months from now. So now we’ve got to start. So we don’t have to memorize GALF criteria.

I mean, they’re always there.

Chandler Park:  They’re always Googleable. No more flipping. The only thing you’ve got to memorize is G-O-G-G-L-E.

Joshua Brody: Memorize how to find the answer, right? But the simple concept is not complicated. It’s not TNM, memorize stuff.

If it’s just hurting you or about to hurt you, then we’ve got to treat. Yeah, I mean, without that, we can keep watching patients for a long time. I think that’s wonderful.

Chandler Park: Easy to understand. Is it going to hurt you or is it going about to hurt you? Like just a simple think about, you know.

So now we talk about first-line follicular lymphoma. We decided that the patients in front of us need treatment, okay? And then we’re thinking BR, you know, because I guess because of toxicity profile kind of beat RCHOP here.

But then there’s some data for, you know, R-squared, rituximab with Revlimid. So what are your thoughts about like first-line treatment there for the community oncologist?

Joshua Brody: Yeah, this one, you know, in some places in cancer and oncology, we have wrong and right answers, black and white. Luckily, as I think people know, in follicular lymphoma, there’s a little less black and white. So we know some things are probably wrong.

Quite honestly, for most patients, RCHOP is wrong because we have these couple of randomized trials of R-BENDA versus RCHOP. And the BENDA seemed both a bit more effective and in most ways better tolerated. So, you know, when a lot of folks, you know, in the audience were young, RCHOP was just what everybody got.

Now we’d like to avoid RCHOP for most follicular lymph patients. There’s a couple of patients where you can’t say for sure if it maybe is transforming, but the needle didn’t quite catch it on the biopsy. So there’s still a few patients that get RCHOP, but for most of them, not RCHOP.

And like you say, we have a few options. We have R-BENDA. We have R-squared.

Rituximab, Revlimid, R-squared, we say it to be cutesy. And actually, we haven’t gotten rid of even old-fashioned, just RCVP. I actually gave RCVP to a couple of patients with follicular lymphoma in the last couple of months because there’s a right patient for it.

You know, maybe they’re a little older, a little higher risk for infections. Nowadays, we are all a little bit more tuned in for every infection that all of our patients are getting. They’re still wearing masks.

They’re still afraid to go on planes. So RCVP, gentle, you know, maybe probably not as effective as R-BENDA, but gentler than R-BENDA. So I give RCVP to a lot of patients.

I don’t give RCHOP, but I give RCVP to the right patient. And as you say, then we have this randomized trial of Rituximab, Revlimid versus kind of dealer’s choice. It could be chemoimmunotherapy of your choosing, and they were really just overall very similar.

The problem is that the trial was intended or powered for superiority, and R-squared was not superior. And it wasn’t powered for non-inferiority, so a bunch of statistical nuance there that we’re not technically supposed to say that R-squared is equivalent to chemoimmunotherapy. But in practice, I think people are pretty accepting that R-squared is a reasonable frontline option.

It’s definitely an FDA-approved second-line option, so we’re already very comfortable with it. And to be fair, I don’t think there is a right or wrong answer between R-squared or R-chemo. They’re both reasonable.

We discuss them with patients and give them some choice. R-chemo is done a little sooner. You know, the R-squared is 12 months, and the R-chemo is shorter than that.

R-BENDA is six months. RCVP is four and a half months. Patients just don’t like the word chemo, so if they feel strongly, you know, R-squared is good.

If they want to be done in four and a half months, six months, we have options for that. And to be fair, honestly, again, I think some of these new, awesomely effective immunotherapies that are now getting approved for third-line NFL will, in the near future, become part of frontline therapy, I think.