Yared Considers Referral and Bridging Decisions for Early Relapse in DLBCL

Jean A. Yared, MD

MODERATOR

Associate Professor

Director, Allogeneic Transplantation Clinic

Associate Director, Clinical Research

University of Maryland School of Medicine

Baltimore, MD

EVENT REGION District of Columbia, Maryland, Virginia

PARTICIPANT LIST Nelson G.N. Kalil, MD | Daya Sharma, MD | Huzefa Bahrain, MD | Nataliya Melnyk, MD | Arun Bhandari, MD | Aarthi G. Shenoy, MD

DISCUSSION QUESTIONS

• How do you define primary refractory disease and early relapse?
• What is the prognosis for a patient like this?
• What therapeutic options would you consider for this patient?

YARED: Primary refractory disease is defined by a patient who has either persistent PET activity, a Deauville score of 4 or 5, or clinical evidence of persistent or progressive disease that can be defined either by persistent B symptoms or a new site of disease during or soon after initial systemic therapy for DLBCL. “Soon” means within 3 to 6 months, especially within 3 months; it’s called primary refractory disease. Even if you had some initial interim response but shortly after you finish the treatment, there is evidence of progressive disease, this is primary refractory. Early relapse means this patient has documented a complete metabolic remission at some point during their initial treatment, and the patient has enjoyed a relative period of complete remission but, unfortunately, has evidence of relapsed disease within 12 months of finishing the frontline treatment.

There are several things you need to think of when you are defining the prognosis of a patient like that. Either early relapse or primary refractory disease, we know these patients don’t do well in general. Any patient who has a disease that is primary refractory to your frontline treatment, or any patient who has early relapsed disease…is considered to have a poor prognosis.

KALIL: For high risk in the front line, I tend to offer more often pola-R-CHP [polatuzumab vedotin (Polivy) plus cyclophosphamide, doxorubicin hydrochloride, and prednisone]. Are you seeing that it improves progression-free survival? Are you seeing the same percentage of recurrence with polatuzumab at the University of Maryland?

YARED: I don’t treat a lot of patients in the front line. I get referred a lot after frontline treatment. Many of my early lymphoma colleagues who treat these types of diseases have not adopted much of pola-R-CHP compared with R-CHOP. There are some advantages, although there is no advantage in terms of overall survival, and it has a bit more toxicities and is a little more cumbersome than R-CHOP.

CASE UPDATE

The patient was referred to the nearest transplant and cellular therapy center for evaluation.

DISCUSSION QUESTIONS

• What treatment options would you consider for second-line treatment for this patient?
• What patient factors—disease or lifestyle related—are significant in your decision-making?
• In which instances would you consider continuing to manage the patient vs referring for chimeric antigen receptor (CAR) T-cell therapy in the second line?

YARED: This patient has early relapse, so by definition, they probably will need some advanced treatment. But what are the factors that would push you to think this patient might benefit from going to the University of Maryland or Johns Hopkins Medicine, [whereas for a different] patient, maybe that’s not a good idea?

SHARMA: For a patient who relapses within 12 months, stem cell transplant is not an option; they don’t do well. So, the only preferred treatment will be CAR T-cell therapy. I will refer the patient to a CAR T-cell center for one of the CAR T-cell therapies. I would not even consider bone marrow transplant in this patient because they’re not going to do well.

YARED: Would you refer them regardless of the patient’s age, comorbidities, or social and economic support?

SHARMA: I’m talking about a fit patient, but for somebody who’s a 75-year-old with a lot of comorbidities, I would consider something in my office. I will not send them a patient who has [more comorbidities]. Age is not a big factor, but still, at 85 or 90 years old, I would not do that. For the rest, I will send them. [If they have fewer] comorbidities, a good performance status, good organ function, and are relapsing within 12 months, they are the right candidate for CAR T, not for transplant.

BAHRAIN: If the patient has an adequate performance status and they’re willing to, I would refer them—100%. Sometimes even these older patients who are fit, I don’t think I would exclude them. [The University of Maryland] is local, so access is easy. Everyone who is basically willing or has an adequate performance status would show up on your doorstep.

MELNYK: I agree…anyone who is fit and interested in a CAR T therapy, I will refer to a transplant center, and [they can] decide whether that’s a fit patient for transplant…. I will be referring unless someone is not fit, older, and there are some problems with transportation. But that’s usually not a problem anymore because we have support and can provide transportation and whatever needs to be provided. I don’t think I have any limitation to sending patients for evaluation and treatment.

KALIL: Do you have any age limit? I tend to pay more attention to patients’ performance than age.

YARED: There’s no age limitation…it doesn’t mean that all patients will receive CAR T-cell therapy, and…the toxicities are not trivial. But to answer your question…we initially had an age limit at the University of Maryland and other centers, but right now, most of us are comfortable looking at the patient, their performance status, comorbidities, and their understanding of the process to offer them CAR T-cell therapy. You have to have a strong case not to give CAR T cells rather than [a strong case] to give CAR T cells.

How comfortable are you explaining to the patient about CAR T-cell therapy or autologous stem cell transplantation? Are you comfortable enough? Do you have enough information, or do you just tell them [they will be referred to a tertiary care center]?

BHANDARI: I generally have difficulty explaining these things. I generally say, “I’m going to send you to a CAR T-cell center or stem cell transplant center. They will go over more information with you,” and your team does a great job.

MELNYK: Regarding transplant, I feel comfortable talking about the basics. But for CAR T, I will just give very brief information because I have never had the experience of giving it to anyone. I will give them basic information and possible toxicities because there is some toxicity [that] could be serious. But the rest, I will not [say, so as not] to confuse the patient [before] they [get] more information from a transplant center.

YARED: That sounds good. It’s important to have some familiarity with this treatment to explain in a big outline what CAR T-cell therapy is and why you’re referring them to a CAR T-cell center. Sometimes, it puts patients at ease and prepares them to read about it and have some reflection before they get to see us, and it tells them that this is a promising treatment. [You can tell them there are] more details to come.

BAHRAIN: When the patient is getting prepared for CAR T-cell therapy and they’re having relatively quick progression, what is your favorite bridging regimen?

YARED: This is a very common question that is back and forth between the referring physician and the CAR T-cell center, and different things are different for patients… Right now, there are 2 CD19 CAR T-cell therapy products on the market: axicabtagene ciloleucel [Yescarta] and lisocabtagene maraleucel [Breyanzi]. These are considered category 1 [NCCN recommendations] for patients who have either early relapsed disease or primary refractory disease.¹ The NCCN guidelines list the therapies that are acceptable as bridging therapy.

Bridging therapy is a therapy that is administered between the collection date and the lymphodepleting date, lymphodepleting meaning that before CAR T-cell therapy, all patients will receive lymphodepleting chemotherapy that is mostly cyclophosphamide and fludarabine. You have a manufacturing time from the day you collect [cells] from the patient, which can take anywhere from 2 to 4 weeks, until the date [when the manufacturer] will give me a call and tell me the patient’s product is ready to be shipped to the University of Maryland. This time can sometimes be valuable and critical for a patient who has aggressive disease that is progressing fast, and these are the options that are acceptable for the patient.

To answer your question, the most benign treatment that I ask referring physicians whether they are comfortable doing is R-GemOx [rituximab, gemcitabine, and oxaliplatin] or polatuzumab plus rituximab. These are the things that most oncologists are familiar with giving, and they usually have low toxicity. What you are trying to achieve in the bridging treatment is… to debulk the disease as much as you can without being overly aggressive. The goal is to keep the patient there with acceptable toxicity before they are ready to start their CAR T journey.

What I tell a referring physician is to use whatever you’re familiar with, whatever you think you can administer safely, and what you think that your patient can [tolerate] with it. There are a few things that I [warn] not to use before CAR T therapy, and these are profound lymphodepleting chemotherapies that can cause prolonged myelosuppression and anything that targets CD19, as the commercially available CAR T-cell therapies are CD19 directed. If we target CD19 by loncastuximab tesirine [Zynlonta] or tafasitamab [Monjuvi], we don’t have enough evidence of whether this is detrimental or beneficial, but it makes sense to avoid them if we can.

SHARMA: Do you do bridging therapy before apheresis?

YARED: Good question, Dr Sharma, because right now, as a community of transplanters and cellular therapists, we’re trying to define things. Bridging therapy, by definition, is a treatment that is given between the collection and the lymphodepleting chemotherapy. What you are talking about before the collection is what we call holding or intermediary therapy. This is given while the patient is waiting to get an appointment at the University of Maryland. [When a patient] needs to be treated, this is what we call holding or intermediary treatment. This is a treatment that is given before the collection of the cells. Real bridging therapy, by definition, is after the collection.

SHARMA: So, a patient will end up getting 2 or 3 lines [if] you do lymphodepleting treatment after bridging therapy?

YARED: We consider it a bridging treatment [rather than a line of therapy because], in most of these patients, we just don’t evaluate for the response because, when talking about bridging therapy, we have 3 to 4 weeks. How many cycles are you going to give in 3 to 4 weeks? Most of the time, you’re going to give 1 cycle of R-ICE [rituximab, ifosfamide, carboplatin, and etoposide] or R-GemOx…. We’re not going to reevaluate this patient after 1 or 2 cycles of R-GemOx. The goal here is just to keep the disease at bay and keep the patient around, with our ultimate goal being to get them to CAR T-cell therapy because we know this is where the benefit will be.

SHARMA: But bridging therapy is not always necessary to do that.

YARED: Absolutely. Bridging therapy, in real-world data, is administered in approximately 50% of the patients.2 Many patients don’t need bridging therapy. For a patient who comes in and is not symptomatic and you think the pace of disease is acceptable, many of them don’t require bridging therapy. The real-world data showed that patients who do not require bridging therapy do better than those who receive bridging therapy. [That is] because you are dealing with a more aggressive disease that pushes you to give bridging [therapy], but many of these patients don’t need anything before we get them to the CAR T-cell treatment.

SHENOY: In my experience, they have [a need for treatment], not [for the reasons] you said but [because] by the time you check their insurance, they get in, and they do those initial [evaluations] to make sure that they are a CAR T– eligible patient, there is time that is taken there.

YARED: Exactly. That’s why…early referral is paramount. The earlier you’re going to refer, the earlier they will get a spot through my clinic, and the earlier we can get things started. We all know the hoops between scheduling, getting the patient in, and getting the insurance approval.

Like I said, approximately 50% of the patients required bridging treatment. This bridging treatment, most of the time, is chemotherapy [Figure²]. The other type of bridging treatment includes corticosteroids and radiation treatment. The most common bridging treatments are the ones that we know can be efficient without being extremely toxic. R-GemOx and polatuzumab/ rituximab are my favorite bridging treatments, in addition to radiation therapy and sometimes simply a course of corticosteroids. Just give them 5 days of prednisone [as you would with] R-CHOP, and that keeps things a little bit in check. Or, if you have a mass that is pressing against something or is bothering the patient, we can give them a short course of radiation.

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 3.2024. Accessed December 16, 2024. https://tinyurl.com/yjkcxh5b}

_{2. Cook MR, Shouval R, Perales MA, et al. Real-world evidence in the United States (US) of the impact of bridging therapy prior to axicabtagene ciloleucel (axi-cel) for the treatment of relapsed or refractory large B-cell lymphoma (R/R LBCL). Blood. 2023;142(suppl 1):103. doi:10.1182/blood-2023-175034}