Novel ADC Therapies for Relapsed/Refractory Large B-Cell Lymphoma: Translating the Latest Advances Into Community Oncology Practice

First, we thought we would start out with just a little bit of background on diffuse large B-cell lymphoma.

[00:11:13]

Epidemiology of DLBCL: Age, Presentation, and Survival Rates

And this, of course, is the most common lymphoma that we see. The median age in the U.S. is about 66 and it is about half localized and half advanced disease, perhaps 55% more advanced. B-symptoms, about 30% and elevated LDH in over half. Extranodal, about 40%. And you can see their percentages for bone marrow involvement and CNS involvement is in the 2-4% range.

And you can see the age distribution there. The five-year survival rate with our current therapy is actually not too bad, 64.7%.

[00:11:54]

Cell of Origin in DLBCL NOS

And as you know, we now know much more about the biology of diffuse large B-cell lymphoma and use this in some of our therapies, such as two major molecular subtypes, the activated B-cell subtype of B-cell receptor-driven and germinal center B-cell type. You can see that the outcomes with respect to prognosis are a bit different, with the GCB subtype having a bit better prognosis three-year progression-free survival of 77% versus ABC type with close to 60%.

We are understanding more and more of these subtypes and trying to target them with our current therapies.

[00:12:32]

Early Relapse Associates With Poor Survival in DLBCL

Early relapse, unfortunately, as we know for most diseases, has a poor survival. And I think that the colors are reversed here, but the patients who have primary refractory disease do very poorly with really any of our treatments, unfortunately, and the cure rate is probably less than 20%.

[00:12:55]

High-Dose Chemotherapy + ASCT in Relapsed NHL

In the pre-rituximab era, certainly transplantation, autologous transplant was what we use for many years before having a lot of the therapies we do now. Prior to rituximab, the patients then could be salvaged much more frequently than our current availability for those patients.

[00:13:16]

CD19-Targeted CAR T-Cell Therapy Has Dichotomized the Management of R/R DLBCL

This is the current schema with respect to dichotomizing the management for relapsed/refractory diffuse large B-cell. When they relapse with respect to, is it greater than or less than one year, the majority of patients do relapse less than one year, unfortunately, and I am looking at if they are CAR T-cell eligible, that may be the preferred way to go. If they are not, there are a number of different options that are listed there that we will talk about some of those today.

So the projected cure rate for those patients of all patients is probably about 20%. If patients relapse greater than one year, it may be less than that. They may be eligible for transplant and then go on to CAR T if they do relapse after that time.

[00:14:04]

CD19-Targeted CAR T-Cell Products in DLBCL

As we all know, the CD19 CAR T-cell products have now been around for a while, and we have some good experience with them. These are the three that are currently FDA-approved and available: axicabtagene ciloleucel, tisagenlecleucel or tisa-cel, and lisocabtagene maraleucel. And they are currently all available for commercial products.

[00:14:28]

ZUMA-7: EFS and ORR Benefit With Second-line Axi-cel vs SoC in Primary Refractory or Early Relapsed B-Cell Lymphomas

ZUMA-7 did demonstrate the improvement in event-free and overall survival with respect to second-line treatment for axi-cel versus standard-of-care, which was salvage therapy plus transplant. And you can see there that the improvement in event-free survival was statistically significant and highly statistically significant.

The different patient populations in axicabtagene ciloleucel versus standard-of-care noted there, but really the benefit was in all of those different patient populations.

[n00:15:02]

TRANSFORM: EFS and ORR Benefit With Second-line Liso-cel vs SoC in Primary Refractory or Early Relapsed B-Cell Lymphomas

TRANSFORM was the study where lisocabtagene maraleucel was compared to standard autologous transplant for second-line. And you can see very similar outcomes there and also benefit in most of the different patient populations in similar proportions.

[00:15:21]

TRANSFORM: Safety Results

Safety is always a concern in any of our CAR T-cell products. And certainly we are learning more and more as we use these agents in these patient populations. Most of the complications as far as toxicities are low-grade, grade 1 and 2 for cytokine-release syndrome, fever, low blood pressure, and eye cancer neurologic toxicity. However, there are a small number of patients who unfortunately have high-grade 4 or 5 complications of a low percentage, but it does happen. And so, these patients still need to be treated in centers that know how to take care of these complications.

Management is more clear now with respect to looking at tocilizumab, corticosteroids or both, and anakinra or other agents for the high-grade ICANS. So we have learned a lot in the use of these agents over the last few years.

[00:16:14]

ZUMA-7: Safety Summary

In a similar way, safety for the ZUMA-7 study showed the same sorts of toxicities, perhaps a little bit higher on the grade 3 or above toxicities for some of these, but still again, very well managed for the majority of patients.

[00:16:32]

When to Use CAR T-Cell Therapy in the Second-line Setting

So when to use CAR T-cell in second-line therapy? This would be for fit patients who are otherwise ineligible for autologous transplant and primary refractory disease or those that have relapsed less than 12 months after the first-line or in third-line therapy.

Choice of the product really depends a lot of times on the apheresis slot. And when we first started using these, we had difficulty getting slots. It is a little bit easier now. So you may be able to use the product of your choice a little bit more easily with respect to getting an apheresis slot.

Median follow-up for the different studies is noted there. And the liso-cel studies do have a little bit less median follow-up, but many treating physicians feel that there is somewhat equivalency between the different products. Tisa-cel is not available for those in second-line therapy currently.

[00:17:30]

Unmet Needs in R/R DLBCL: Patient Relapse After SoC, Chemotherapy, and CAR T-cell Therapy

There is unfortunately still an unmet need for these patients who either do not respond to a standard therapy and CAR T-cell therapy or relapse after that. And unfortunately, there are still some primary refractory patients to all of those or relapse after all of those different types of treatments.

So we still need lots of new options for those patients. We are going to talk about some of those options today and also hopefully talk about some of the ways to combine these agents together.

[00:18:00]

Overall Survival for CD19 CAR T-Cell in R/R 3L+ LBCL

So the overall survival for a CAR T-cell, you can see here for third-line from the original studies, the ZUMA-1, TRANSCEND and JULIET studies, are very similar with respect to about 40% of patients with long-term disease-free survival are doing well with no relapse.

So now I am going to turn this over to Dr. Kahl, who is going to talk about ADCs and identifying some patients who may benefit from these novel therapies. Thanks, Brad.

[00:18:31]

Understanding ADCs and Identifying Patients Who May Benefit From These Novel Treatments

Dr. Brad Kahl (Washington University in St. Louis): Okay, thank you, Julie.

[00:18:34]

Structural Characteristics of ADCs

I am sure most people are familiar with the structure of ADCs, but just to review, there is a monoclonal antibody, which targets the cytotoxic payload to the target cell. And so the monoclonal antibody needs a target antigen to bind to. The antibody is tagged with a cytotoxic payload, and those are connected by a stable linker that hopefully releases the payload only once inside the cell. So after binding, the cell is internalized, it undergoes lysosomal degradation with release of the cytotoxic payload, and hopefully, death of the malignant cell.

[00:19:21]

Available ADCs and Their Payloads in R/R DLBCL

And these are the ADCs that are available right now for relapsed/refractory diffused large B-cell lymphoma.

We have brentuximab vedotin which targets CD30 and uses an MMAE payload. We have loncastuximab tesirine which targets CD19 and uses a pyrrolobenzodiazepine payload. And we have polatuzumab vedotin which targets CD79B, and also similar to brentuximab vedotin, uses an MMAE payload.

[00:19:56]

Polatuzumab Vedotin: Mechanism of Action

So let us just review the data for polatuzumab vedotin quickly. Mechanism of action we already discussed, and just remember that if the payload is an MMAE cytotoxic agent, then it causes cell death by microtubule disruption, and so whenever you are disrupting microtubules as your mechanism of cell killing, peripheral neuropathy becomes really the main toxicity one has to be cognizant of.

Polatuzumab vedotin is approved for use in the first-line in combination with rituximab, cyclophosphamide, doxorubicin and prednisone or the R-CHP regimen, and we will go through that data. And this is for patients who have an IPI score of 2 or higher. And polatuzumab vedotin is also approved for combination with bendamustine and rituximab in patients with relapsed diffuse large B-cell lymphoma whose disease has recurred after two or more prior lines of therapy.

[00:21:06]

Polatuzumab Vedotin + BR vs BR in R/R DLBCL: Efficacy Summary

This is the data that got polatuzumab its approval in combination with BR. This was a randomized Phase II study, just 40 patients in each arm, where Pola-BR was compared to BR alone. These are relapsed large cell lymphoma patients who have had at least two prior lines of therapy.

And what you can see in the table is the probability of complete response was much higher with Pola-BR, 42% compared to 17% with BR. And if you look at the Kaplan-Meier curve, you see a fairly significant improvement in the progression-free survival compared to BR alone. And there was a small but statistically significant improvement in overall survival, which led to the approval.

So this regimen could be considered in patients who are not candidates for stem cell transplant or CAR T-cell therapy. It could be considered post-transplant or CAR T failure. And a portion of the regimen is sometimes used as bridging to CAR T-cell therapy.

A lot of investigators will use Pola plus rituximab as the bridging to get to CAR T. It is important to delete the bendamustine because bendamustine is quite hard on T-cell numbers, and you do not want to do that to a patient's T-cells prior to apheresis for T-cell collection.

And then, as we discussed earlier, peripheral neuropathy is one of the major toxicities to be aware of when using an MMA-containing agent. And the risk was 31% to any grade in this trial, 2% grade 3 or higher.

[00:22:59]

POLARIX: Polatuzumab + R-CHP vs R-CHOP in Previously Untreated DLBCL

And then the POLARIX trial is the trial that led to the approval of polatuzumab in combination in the frontline setting. So this was a big global randomized Phase III trial now published with longer-term follow-up. It took patients with previously untreated diffuse RGB cell lymphoma. They had to have an IPI score of 2-5. And they were randomized to standard R-CHOP chemotherapy or the regimen of R-CHP-Pola where vincristine is subtracted and polatuzumab vedotin is substituted in. Patients would receive six cycles of the combination and then two cycles of single-agent rituximab which constituted cycle seven and eight.

The primary input in this trial was progression-free survival.

[00:23:44]

POLARIX: PFF and OS Update, and Response Summary

And you can see on the Kaplan-Meier curve on the left that there was a small but statistically significant improvement in progression-free survival for the Pola-R-CHP regimen. At four and five years, it is about a 7% absolute difference in progression-free survival. There is no difference in overall survival, but the toxicity profiles between the two regimens were very similar. And so, I think most people came away thinking that this is a positive trial because you are curing more patients in the frontline with this Pola R-CHP regimen, which then means fewer patients will need second-line therapy with stem cell transplant or CAR T-cell therapy.

[00:24:30]

Loncastuximab Tesirine: Mechanism of Action

Moving on to loncastuximab tesirine. This is an antibody-drug conjugate that targets CD19 and uses this pyrrolobenzodiazepine dimer, which causes DNA cross-links, and that is how the drug works as a cytotoxic agent.

[00:24:50]

LOTIS-2: Loncastuximab Tesirine (Anti-CD19 ADC) in R/R Aggressive DLBCL

And its approval was based on this LOTIS-2 study. This was a single-arm study that enrolled 145 patients. These are patients with relapsed large cell lymphoma, had to have failed two or more prior lines of therapy. And the dosing is a little unusual in the sense that patients receive a loading dose for the first two cycles. It is 150 ug/kg. The treatment is given in three-week cycles, and then after cycles one and two, the dose is cut in half to 75 ug/kg. And then the cycles are continued at three-week intervals until progression or unacceptable toxicity.

I think most people who have used this drug realize that after multiple cycles, there tends to start to be cumulative toxicities. And so, I do not think most people are going to receive this drug beyond four, six, maybe eight cycles at the most, and then you will just need to stop it for toxicity or intolerance or some reason that the patient will make you aware of.

[00:25:57]

LOTIS-2: Patient Characteristics and Efficacy/Safety Summary

So the primary input in this study was on the overall response rate. The overall response rate ended up being 48%, so right around 50%, with half of those being complete responses. And the median progression-free survival for the whole population is only about five months, but if your patient is in that lucky group who gets a complete remission, then the responses can have pretty good durability.

Major toxicities from loncastuximab include some neutropenia, some thrombocytopenia. There can be some liver toxicity. You have to follow the GGT levels. There can be third spacing of fluid, so you have to monitor that carefully in your patients on it. There is a photosensitivity, so you have to counsel your patients on sun exposure.

[00:26:52]

Brentuximab Vedotin: Mechanism of Action

And then shifting gears now to brentuximab vedotin. Folks are probably used to this drug as an option for Hodgkin lymphoma and T-cell lymphoma because brentuximab vedotin targets CD30, which is usually strongly expressed in Hodgkin's disease and reasonably expressed in many T‑cell lymphomas. What was less well appreciated is that some diffuse large B-cell lymphoma have some level of CD30 expression, and so the idea was born to test this drug for relapsed/refractory diffuse large B-cell lymphoma. And like polatuzumab vedotin, it works by disrupting the microtubules.

[00:27:36]

ECHELON-3 Study of Brentuximab Vedotin Plus Lenalidomide and Rituximab (R 2) vs R2 Plus Placebo

So this is the so-called ECHELON-3 study. It was a randomized clinical trial of brentuximab vedotin plus the R² regimen, lenalidomide rituximab, versus R² regimen plus a placebo. And this was conducted in patients with relapsed/refractory diffuse large B-cell lymphoma who had failed at least two prior lines of systemic therapy. And interestingly, there was no requirement for CD30 expression to be eligible for this trial, and patients were stratified as to their CD30 expression as either less than 1% or greater than 1% for the analysis.

The primary endpoint is overall survival.

[00:28:22]

ECHELON-3: OS and PFS in ITT Population

And what you can see here, I will start on the right, you see the progression-free survival, and the BV R² regimen did perform better than placebo. R², medium progression-free survival of 4.2 months versus 2.6 months, which seems modest, but it did actually translate into an overall survival benefit, which you see in the Kaplan-Meier curve on the left. And that is what has led to its FDA approval.

[00:28:52]

ECHELON-3: Safety Summary

Toxicities, I think, as one might expect, there is always a degree of cytopenias with lenalidomide-containing regimens, and that is exacerbated a bit by the addition of brentuximab vedotin. There is a little more neutropenia and thrombocytopenia, a little more diarrhea. And then there is more, as expected, more peripheral neuropathy with BV R² compared to R² alone.

[00:29:26]

FDA-Approved Indications for ADCs

So then, again, just to review the FDA indications for these ADCs, brentuximab vedotin is approved for use in relapsed diffuse large B-cell lymphoma after failure of two or more systemic lines of therapy. And establishing CD30-positivity is not a requirement in the package insert.

Loncastuximab is FDA-approved for adults with relapsed diffuse large B-cell lymphoma after two prior lines of systemic therapy. The approval includes patients who have disease that is transformed from an underlying low-grade lymphoma.

And then polatuzumab vedotin has more approvals. It is approved in frontline in combination with the R-CHP regimen if the patients have an IPI score of 2 or higher. And it is approved in combination with bendamustine and rituximab for patients who have failed two or more prior lines of therapy.

[00:30:30]

Role of Biomarker Testing for ADCs in R/R DLBCL

So you might wonder, do I need to then test for the target antigens? And as we mentioned, you do not have to do it for brentuximab vedotin, although many expert opinions suggest that you do test, and I do not know, intuition leads you to think you would be more confident in using this drug if you had some CD30-positivity in the tumor cells. I know I, personally, would like to see that.

CD19 expression is not strictly required before giving loncastuximab tesirine. If your patient has never had prior CD19-directed therapy, you are probably safe to assume that they have CD19 expression, but if your patient has relapsed after a CD19-directed CAR or some other CD19-directed therapy, it is probably wise to test because patients can lose CD19 expression.

And then testing for CD79B is not an absolute requirement. It is fine to do so, but most patients with B-cell malignancies will have CD79B expression.

[00:31:52]

Brentuximab Vedotin: Dosing and Administration

Okay, so how does the dosing and administration work? So BV, it is an IV infusion over 30 minutes given every three weeks. You need to use caution if there is hepatic impairment or renal impairment, and you may need to consult with your pharmacist for dose modifications if you have those comorbidities. And I would be careful to ask your patient about baseline peripheral neuropathy.

[00:32:26]

Loncastuximab Tesirine: Dosing and Administration

Loncastuximab, IV infusion over 30 minutes every three weeks. Remember the dose. It is a higher dose for the first two cycles; lower dose in subsequent cycles. I would monitor blood counts and liver function tests. I would counsel your patient to avoid sun exposure, and I would monitor them for edema and third spacing of fluids.

[00:32:56]

Polatuzumab Vedotin: Dosing and Administration

And then polatuzumab, very similar to brentuximab vedotin, monitor for peripheral neuropathy. But again, it is an infusion given every three weeks. The infusions start out at 90-minute infusions and then can be decreased to 30-minute infusions if well tolerated.

[00:33:20]

Summary Safety Profile of FDA-Approved ADCs

So I think I covered these mostly. These are the main toxicities to monitor for.

Peripheral neuropathy for brentuximab vedotin and polatuzumab vedotin. And then you do need to monitor for cytopenias.

For Lonca, thrombocytopenia, GGT increase, neutropenia. And again, really be careful about sun exposure and really be careful about the edema and third spacing of fluids. The edema and third spacing can be hard to manage. It does not respond terribly well to loop diuretics. Spironolactone has been shown to work better. And it is recommended that you premedicate patients with dexamethasone to try to reduce the risk of the capillary leak that patients can get. And I can tell you from experience, if your patient does start to get the third spacing, probably your best move is to just stop treatment because it can be quite relentless and last for weeks or even months once it starts.

[00:34:27]

Mitigation and Management of Key AEs: Brentuximab Vedotin

I think these are very busy slides that just go through all the AE management that I have already discussed. And some of these AEs are much less common than others. And I think I have hit the high points on the AEs for brentuximab vedotin.

[00:34:47]

Mitigation and Management of Key AEs: Loncastuximab Tesirine

For Lonca –

[00:34:50]

Mitigation and Management of Key AEs: Polatuzumab Vedotin

– and for Pola.

And I seem to be losing my ability to talk. So with that, I am going to turn it back to Julie.

Dr. Vose: Yes, you talk so much you lost your voice. Hey, good discussion.

[00:35:08]

Bispecific Antibodies

I am going to talk a little bit about bispecifics. So that would be the other category of treatment that a lot of times these patients who have failed their prior therapy need to go on to either potentially before or after CAR T or some of the other treatments we just talked about.

[00:35:26]

CD20/CD3 Bispecific Antibodies in B-Cell Lymphomas

So this is a really interesting and exciting class of new agents that we have available for our patients. Although we do need to be very careful about having the infrastructure available to treat these patients. So I am going to go over the currently available data and some of the infrastructure needs. Currently there is the humanized mouse IgG1-based monoclonal bispecific antibodies CD20, CD3.

You can see mosunetuzumab, which is given intravenously, although there is a subcutaneous formulation that is currently also being investigated. And it is currently approved for patients that have relapsed/refractory follicular lymphoma, the second-line or more, but it is currently being studied in other types of lymphomas as well.

Epcoritamab, which is also a CD20, CD3 bispecific that has a slightly different formulation mixed single match point mutation. This is given subcutaneously, so this is a little bit different. And this is approved for third-line relapsed/refractory follicular as well as second-line or above diffuse large B-cell lymphoma. And then there are different combination regimens also approved more recently.

Glofitamab is given intravenously, and it is approved for third-line relapsed/refractory diffuse large B-cell or transformed. And it has a little bit different configuration in that it has a 2:1 ratio, and also we give a dose of obinutuzumab prior to giving this glofitamab IV to try to decrease some of the toxicity. So that is just a little, each one is just a little bit different.

And then odronextamab is also given IV. This is currently not FDA-approved in the U.S., although it is available in Europe and has slightly different configuration, as you can see there. And it is currently under review again for relapsed/refractory follicular and diffuse large B-cell.

[00:37:30]

Glofitamab: Dosing and Administration

So first, to talk about glofitamab dosing and administration. It is given intravenously every 21 days. As I mentioned previously, we give a dose of obinutuzumab before the first dose of glofitamab, and that is to try to reduce the risk of toxicity by decreasing the tumor burden. Obinutuzumab in itself, of course, also sometimes has infusion reactions. So you have to be careful about that.

Hospitalization is typically recommended for 24 hours after the first step-up dose to try to mitigate the CRS. And you can see the infusion duration there. Premedications that are warranted: usually IV dexamethasone, IV diphenhydramine, oral acetaminophen or other potential agents to try to decrease the infusion reaction. Typically, if the patients are going to get a severe reaction, it is at the first full dose, but they can have it before that as well. So patients do need to be monitored carefully for toxicities, and after 24 hours, if they do not have any of those toxicities, can be discharged.

[00:38:41]

Epcoritamab Dosing and Administration

Epcoritamab dosing, again, this is subcutaneous, and this is just a little bit different. We again have step-up dosing. The step-up dosing for follicular patients, it has an extra dose in there than compared to diffuse large B-cell patients. So the first full dose, which is dose three for diffuse large B-cell, patients are recommended to be admitted for that.

Premedications are as noted, again, with steroids, diphenhydramine, acetaminophen, dexamethasone in pretty high doses. And if the patients are going to have that, it is typically on the first full dose, but sometimes patients can have the step-up dosing and not have that toxicity.

[00:39:28]

Deciding Between Available ADCs, Bispecific Antibodies, and CAR T-Cells for R/R DLBCL

So how do we decide between these available opportunities for ADCs, bispecifics or CAR T‑cells?

And thankfully we have lots of different options for our patients nowadays. So that is a good problem to have. How do we compare these?

Certainly, some are more available than others. The bispecifics are more an off-the-shelf option. They do not have to be manufactured, whereas the CAR T-cells have to have the adequate, have to have insurance approval, have to have adequate cell collection, manufacturing time, etc.

So typically, there is at least a month to six weeks delay in that time period. So bridging therapy is typically necessary, whereas insurance approval for the bispecifics usually would be in a more timely fashion. Although sometimes that is a bit delayed as well.

Safety profiles: lower toxicity, possibly a little bit safer with the ADCs and bispecific versus bispecifics, including patients who are not good candidates for CAR T-cell. So certainly, patients need to have certain criteria to be CAR T-cell candidates. So it is not every patient that is eligible for that.

And mostly, there are shortened hospitalization times for the bispecifics, certainly compared to CAR T-cells. Although some patients can have the toxicity, as we noted.

There are different targets for these two. So that means that patients that previously had CAR T-cell does not preclude a specific bispecific antibody and vice versa. So that is a good thing. And that is also the potential for possible sequential therapy as well, which is currently being done in some clinical trials.

So what are the advantages of ADCs and bispecifics over chemotherapy? We can see that in the clinical trials that have been presented there is some improved efficacy, potential for better safety and possibly improved quality of life, depending on the toxicities. So I think we need to take into consideration each individual patient population. What other health issues do they have? What are the support mechanisms? Are they close to centers where CAR T-cells can be done and/or bispecifics? Because you need to have an infrastructure in place, certainly to administer any of these products. It is very important to take that into consideration for each individual patient.

[00:41:53]

Evolving Treatment Algorithm in DLBCL: Sequence Approved ADCs With Other Available Therapies for DLBCL

Our paradigm is really changing as time goes on, as we have these new therapies that come in and certainly sequencing, because in the lifespan of any one patient with diffuse large B-cell, you may need all of these different types of treatments.

So you need to choose wisely with respect to which treatment you are going to use when. Is the patient a younger or healthier patient where you want to perhaps consider the CAR T-cell and refer them to a center that does CAR T-cells? Are they autologous stem cell transplant candidates? Fewer and fewer patients are autologous stem cell transplant candidates, and more and more are CAR T-cell candidates for these other agents, as we discussed. And I definitely want to look at the individual patient, their characteristics of their lymphoma, what their support infrastructure is, what their other health issues are and make a very personalized, independent decision for each patient.

[00:42:54]

Ongoing Healthcare Professionals Challenges Regarding Novel ADC Therapies

So definitely, ongoing health professionals have challenges regarding these novel therapies, and hopefully some programs such as this, trying to give you education, are helpful, not only to the physicians, but also the team, and making sure that the right infrastructure is in place to take care of any side effects or toxicities related to these agents, as they are definitely different than our standard chemotherapy or immunotherapy we used in the past.

You need to have good guidelines and SOPs available for managing toxicities. A lot of these, other than the CAR T-cell, are outpatient and need to have the proper infrastructure there, infrastructure for staffing and their roles, and making sure this is all written out in SOPs and potential for a handoff back to community oncologists after some of these therapies and making sure the right information is handed back to the care team when the patients go back from the academic to the community setting.

Certainly, financial concerns for the facility and for the patient and family and caregiver is important. And we need to make sure that we take that into consideration. There are a lot of important things that need to be looked into for insurance approval for any of these, but we also need to make sure that we look into some of the infrastructure and supportive care for patients and families outside of the insurance. For example, they might need to be able to have local housing available for patients, such as things through Hope Lodge or other things that are available locally, is really important for patients and for families for a lot of these different types of treatments that might not be available to them really at their center close to home.

[00:44:52]

Pearls for the Multidisciplinary Team

Pearls for the multidisciplinary team:

• Older patients are probably less likely to tolerate high doses of steroids, unfortunately, although that can certainly be true of younger patients as well.
• Very close monitoring for infusion reactions is important with all of these treatments. And we need to make sure we can have close observation, 24/7 care, management for infections, infectious disease available, peripheral neuropathy, as you learned, was a toxicity for several of these agents. So, knowing how to manage that when necessary.
• Education of patients or when to report to the emergency department. Do they have the card that is given to them for the CAR T-cell patients and telling them exactly where to go and what to look for? Do they have appropriate support as far as a thermometer, possibly management of taking their blood pressure, those sorts of things, and know exactly who to call when the emergency comes in.
• Preparing patients, but also caregivers, for these common toxicities. Photosensitivity reactions, cutaneous reactions are rare, but that can be a concern. And lots of different specifics for these different types of agents. So you need to look at what the patient's other health issues are, what are the toxicities of the specific agents, especially for combining them together, and be able to make sure that there is infrastructure available to help support all of these possible toxicities.

[00:46:40]

Posttest 1

So, now we are going to go through the posttest and then answer any potential questions. So again, this is the same question as before. Which of the following would be an optimal option for a patient with relapsed/refractory diffuse large B-cell, CD20-positive, CD19-positive, CD30-negative? Please go ahead and answer.

1. Assess for any presence of neuropathy from the previous chemotherapy;
2. Consider bispecific antibody glofitamab;
3. Consider brentuximab vedotin; or
4. Assess patient for a possibility for hematopoietic transplantation eligibility.

Please go ahead and vote.

[00:47:40]

Okay. So you can see there that the answers are kind of all across the board. And I would say there is probably not necessarily one right answer, but probably, in this particular patient, I would consider looking at bispecific antibody.

Probably less likely to worsen the neuropathy. I agree with that. The patient is CD20-positive, so that is an important aspect. And they had previously received lots of chemotherapy. So probably chemotherapy is not necessarily the best option. The patient is CD30-negative, so probably is not a very good candidate for brentuximab vedotin. And the prior history of neuropathy, also from the previous therapy, is kind of guiding us in different options too.

Brad, do you want to comment on this as well?

Dr. Kahl: Yes, I was thinking I would be most likely to choose a bispecific for a patient like this. You know, I think if you look at the efficacy data for glofitamab and epcoritamab, it does look like those two drugs are a bit more active than the currently available ADCs. So I generally save ADCs for later lines of therapy.

Dr. Vose: Yes, I would agree with that. But of course, each individual patient really needs to be looked at with respect to what the opportunities are, what their other health issues are, and all the things that we talked about.

Dr. Kahl: Yes, I can think of a few scenarios where, you know, maybe I had a patient referred in to me who is multiple prior lines. And, you know, the day I meet the patient, their disease is out of control, and they are in pain, and we need something to work like tonight. And I remember thinking, okay, I would love to give you, you know, Glofit or something, but I have to go through this ramp-up, and we need an immediate response.

And so, I think I ended up picking lonca-te for that patient, because you can give it that day, the infusion is done in 30 minutes, they are getting a full dose. If it is going to benefit them, the benefit starts pretty much immediately. And the patient lived a long ways away, and they only have to come back once every three weeks for treatment. So it just ended up being a nice choice for that individual.

Dr. Vose: Yes, and I think that is an important aspect, that you need to look at that individual patient in front of you to see what the best option is for that situation, that patient, their disease, but also their situation. And a lot of us who live in the Midwest, patients travel long distances. So it is a really important aspect.

[00:50:40]

Posttest 2

Posttest two. Which of the following highlights the correct use of brentuximab vedotin plus lenalidomide and brentuximab in patients with relapsed/refractory diffuse large B-cell lymphoma?

1. Patients who received one prior therapy;
2. After at least two prior systemic therapies;
3. Newly diagnosed and ineligible for stem cell transplant or CAR T;
4. A second-line after chemotherapy and CAR T-cell or HSC-eligible; and
5. A second-line CAR T-cell ineligible and CD30-positive greater than 10%.

Please go ahead and vote.

[00:51:44]

Okay, so here again, the answers were a little bit all over the board, but the higher percentage, 39%, voted for B, after at least two prior systemic lines of therapy. And Brad, you went over that data. Do you want to recap that a little bit?

Dr. Kahl: Right, so brentuximab vedotin plus lenalidomide-rituximab is approved for use in relapsed/refractory diffuse large B-cell lymphoma in patients who have failed at least two prior systemic therapies and are considered not appropriate candidates for stem cell transplantation or CAR T-cell therapy. And that was based on the data from the ECHELON-3 trial, where the three-drug combination was better than R² for both progression-free survival and overall survival.

And interestingly, and it is still not totally clear why this is true, but in the trial, a CD30 expression was not mandated. And when they look at the data from the trial, patients who have less than 1% CD30 expression were just as likely to respond and benefit as patients with more than 1% CD30 expression. Why the drug would be useful when you cannot detect CD30 is not totally clear. Maybe there is CD30 present at such a low level that we are just not picking it up with immunohistochemistry, but a lot of lymphoma thought leaders do like to see some CD30-positivity before they recommend this particular combination.

And I can tell our audience from studies in T-cell lymphoma, the T-cell lymphomas that respond best to brentuximab vedotin have higher CD30 expression, like the anaplastic large cell lymphomas. So me personally, if I was to use this BV R² regimen, I, personally, would want to see some CD30-positivity by immunohistochemistry. I do not know how you feel about that, Julie.

Dr. Vose: Yes, I agree. I mean, I look for any, so 1% is fine, but I am a little hesitant about giving it when there is no CD30 expression. Like you said, there is some data that it works, but there are so many other options that maybe we try some other things first, I guess.

Dr. Kahl: Right.

Q&A

Dr. Vose: Let us see. So we got a few other questions here. Is there someone who experienced any ICANS or CRS from bispecific antibodies? So what is your experience with that, Brad?

Dr. Kahl: Yes, I have seen a fair bit of CRS with bispecifics. Usually, it is pretty easily managed. It is not like the CRS you get with CAR T-cell therapy. Usually, we do not need to go to tocilizumab. Usually, you can just tamp it down with dexamethasone. And so, I found the CRS to be pretty manageable with glofitamab and epcoritamab.

And ICANS is pretty rare. I have seen it with bispecific antibodies. But it is pretty uncommon, and it is usually mild. And I would say there is no reason to fear giving a bispecific monoclonal antibody, or there is no reason to avoid it due to fear over ICANS or CRS, because I feel like those things are generally mild, generally manageable. What do you think about that, Julie?

Dr. Vose: Yes, I agree. I guess the patients that have that more so would be patients with bulky disease, higher-risk patients. I think you do have to have the proper infrastructure available though for those patients because if you use bispecifics and something happens and you do not have the infrastructure, I think that is going to be the worst scenario. So the minute you try it without having that, then something bad is going to happen.

Dr. Kahl: You do need to have access to tocilizumab in case the steroids do not cover them.

Dr. Vose: Yes. And that is not necessarily available in all settings, especially in rural settings. So I think that it is important to give education to the patients and families and everyone involved to know what needs to be done if that happens.

Dr. Kahl: And I imagine you have done this scenario. I certainly have done it a few times where I have had a community physician who did not really have those resources that you mentioned, but we talked about a patient over the phone, and we agreed that a bispecific was the right thing to do, and they would send them to me, and I would get the patient through the ramp-up and make sure we are done with CRS risk and ICANS risk, and then if the patient desired, we could hand the patient back to the community physician to finish out the therapy.

Dr. Vose: Yes, and that is what we do as well. So we typically would maybe do cycle one where the risk is there, if any, and then after that they can safely usually get it in the community. But each setting is different, and each patient's different, so you need to make sure to look into that.

Dr. Kahl: And with the bispecifics, I talked about this a fair bit.

With BV and Pola, to me, it is neuropathy, neuropathy, neuropathy. I mean, that needs to be on the top of your radar screen. The other toxicities, the myelosuppression, we are all totally used to dealing with that. But the patient needs to be asked about neuropathy every time before you dose, and they may need dose reductions if the neuropathy is getting to be problematic.

And then with the Lonca, I think you really have to monitor for the third spacing. And I am acutely aware of the photosensitivity because I had a scenario where I had a very nice elderly gentleman from a skilled nursing facility, and we started him on Lonca for his relapsed disease, and he had been brought to the clinic by his son, who would take him back to the skilled nursing facility, and I warned him and the son about sun exposure, but then it was not communicated to the skilled nursing facility. So my fault, really. And then the skilled nursing facility, thinking they were doing the patient a big favor, would take him outside and let him sit in the sun all day long after we gave him Lonca and he came back in with just a horrible photosensitivity rash and really miserable. And so, you just need to be aware of that toxicity, and if you avoid sun exposure, then it is no problem.

Dr. Vose: Yes, yes, I agree. And every agent is different, so you need to make sure you know what you are looking for.