Alencar Discusses Treatment Choices After Early Relapse of DLBCL

Alvaro Jose Alencar, MD (MODERATOR)

Associate Professor of Clinical Medicine

Chief Medical Officer

University of Miami

Sylvester Comprehensive Cancer Center

Miami, FL

EVENT REGION North Carolina and South Carolina

PARTICIPANT LIST Anusha Madadi, MD | Niyati Nathwani, MD | Alexandra Stefanovic, MD | Louay Hanna, MD | Gary Thomas, MD | Matthew McKinney, MD | Maurizio Bendandi, MD | Charles Kuzma, MD | Xuezhong Yang, MD

MADADI: If they relapse in less than 12 months or have primary refractory disease, they are considered high-risk patients with poor prognosis. If the patient is eligible for CAR [chimeric antigen receptor] T-cell therapy, this would be the ideal setting for CAR T-cell therapy demonstrating better overall response rate and PFS [progression-free survival] compared with stem cell transplant.

NATHWANI: I would say less than 12 months definitely would be early relapse and they do worse, and now that CAR T-cell therapy is [available] for the second line, at least for us in a small community practice, we end up referring these patients to the closest CAR T-cell therapy center for second line.

STEFANOVIC: Sometimes the [progression] of the disease is so fast that we have to bridge them before we can get them to CAR T-cell therapy, and some patients do not survive until they can get CAR T-cell therapy, particularly if they don’t respond to the bridge.

ALENCAR: Initially, primary refractory disease was defined as 12 months from the initial diagnosis, and that’s probably the more accurate way. But to make it easier for eligibility…the studies defined the eligibility based on the end of the therapy, so [primary refractory would be] 12 months from the end of induction. Those patients are hard to treat. If you remember the SCHOLAR data with patients with refractory disease, these patients have an extremely poor survival and it’s generally less than 6 months, extremely refractory to cytotoxic therapy.¹

One thing that is very important is that you not only have primary refractory but those who progress on first-line anthracycline-based therapy. Those patients tend to do even worse. Today we know that cellular therapy is the best intervention that we have for these patients. But to Dr Stefanovic’s point, the issue is that a lot of times these patients are either progressing too fast or…sometimes you don’t have a CAR T-cell program close to you, so patients cannot get CAR T-cell therapy early enough. A lot of times you will be using bridging therapies or alternative approaches. In this setting… what do you usually prefer to use as a bridging option or [to] try to control the disease?

HANNA: Especially when patients relapse within a year, I look at those as chemotherapy refractory. We have to get them on something more targeted or a different mechanism of action other than chemotherapy. We have quite a few options; you can make a case that you can use pola-BR [polatuzumab vedotin (Polivy), bendamustine, rituximab]. That’s one option. The other option is anti-CD19 plus lenalidomide [Revlimid].

ALENCAR: [Not only] are they chemotherapy refractory, but chemotherapy will also start impacting your marrow function and start [causing] complications with cytopenias after CAR T-cell therapy. Not only [is there] the issue with the myelosuppression but also the lymphopenia and the lymphotoxicity from some chemotherapy agents, such as bendamustine. I agree that in this setting, chemotherapy is not the best option, and we will end up using alternative options, as you mentioned, polatuzumab-based therapy or tafasitamab [Monjuvi]–based therapies.

THOMAS: I usually check with the [cellular therapy physician] to whom I’m referring and get their advice on which regimen they would recommend in a situation like this. We’ve used tafasitamab/lenalidomide more than any other.

ALENCAR: Have you had any concerns with the targeting of CD19 prior to CAR T-cell therapy?

THOMAS: I don’t have enough experience with it. I [must] rely on the physician to whom we’re referring [the patient]. I would worry about it, but I don’t know enough, as a general oncologist, whether that’s important or not.

ALENCAR: There were recent data that were published in Blood, and it seems that tafasitamab prior to CAR T-cell therapy may populate the CD19 receptors that are not from the lymphoma and improve the efficacy of CAR T-cell therapy, which was completely opposite to what we initially believed: that by targeting CD19, you might decrease the efficacy of the targeting with CAR T-cell therapy.² We tried to put together data from patients treated with anti-CD19 agents prior to CAR T-cell therapy, and it was just a small number of patients, but it seems that it’s acceptable and does not seem to impact the efficacy of CAR T-cell therapy.³ Obviously, patients who require bridging are more complicated. Those are the ones whose disease is progressing, and CAR T-cell therapy tends to have a harder time having good efficacy in actively growing tumors. But tafasitamab/lenalidomide tends to be a very reasonable option. Is anyone concerned with polatuzumab as bridging, [especially] now that we’re using more polatuzumab in first-line therapy?

MCKINNEY: Having done a lot of CAR T-cell therapy, the key is to line patients up for cell collection as soon as possible, and then you have different options for bridging them. I am gun-shy about using bendamustine immediately after cell collection; then you run into issues with not being able to manufacture cells. Axicabtagene ciloleucel [Yescarta] is…reliable, but I backed off after a couple of bad experiences doing that and then tried to use some milder bridging schemes.

My issue with doing tafasitamab/lenalidomide is it takes… 2 or 3 weeks just to get that approved through insurance and set it up. As a bridging regimen, it’s a lot of work to get a patient to cell collection and then to do that. By the time they get loaded with tafasitamab, you’re doing CAR T-cell therapy anyway. [I use] a variety of different bridging regimens, and maybe radiation. Your goal is just to temporize disease, so even R-ICE [rituximab, ifosfamide, carboplatin, etoposide phosphate] or some sort of platinum-based regimen [could be used].

These patients who have this primary refractory disease to R-CHOP or pola-R-CHP [polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin hydrochloride, prednisone], if they’re rapidly progressing, are also patients you’re not going to get to CAR T-cell therapy and they’re probably going to pass away.

CASE UPDATE

The patient was referred to the nearest transplant and cellular therapy center for evaluation but opted not to pursue CAR T-cell therapy. The patient prefers to stay with his current care team but is still seeking further treatment. He wants to receive outpatient treatment due to lack of a support system.

DISCUSSION QUESTIONS

• What are your clinical goals for this patient?
• How do you discuss the options during shared decision-making with your patients?

ALENCAR: This patient is not going to receive CAR T-cell therapy. What is the goal when you’re treating like this? The patient [whose disease is] primary refractory is expected to have a difficult-to-control disease and will likely die from his disease. How do you use these factors to define the therapy?

BENDANDI: I would choose pola-BR precisely because collection is a moot point, and this is the last shot at a bit of chemotherapy. Bendamustine is not a miracle drug but is not terrible either in terms of the results. Polatuzumab was not added in the first line, so in the second line it’s appropriate. We don’t have any evidence that tafasitamab/ lenalidomide would be better or worse. The populations of patients [in the trials] resemble each other, but they’re not comparable.

KUZMA: I would choose tafasitamab. I thought the data [show it is] less toxic with better chance of durable responses with a different novel mechanism of action than the chemotherapy that the patient already failed. The likelihood of this patient having a long-term response is greater with a tafasitamab regimen than with pola-BR, with that choice becoming more solidified with polatuzumab moving up to the frontline setting.

YANG: I think I’m still undecided at this point. My guess is for a patient like that, we’ll probably circle through each line until they [receive] CAR T-cell therapy or bispecific. Otherwise, it’s a matter of order.

MCKINNEY: I don’t see any reason not to do tafasitamab/lenalidomide. My experience with pola-BR is it’s hard to do more than 3 or 4 cycles in these patients, whereas tafasitamab/lenalidomide in the second line, if they’re willing to come in for all the infusions for tafasitamab… that’s a nice way to go. I have a ton of patients who are more than a year out for tafasitamab coming back, and it’s a discussion about when we are going to stop doing this. The FDA label says you continue every 2 weeks. I don’t have anyone who did 4 to 6 cycles of pola-BR and…they’re coming back in remission doing fine.

ALENCAR: Do they stop because of progression, or do they stop because of toxicity?

MCKINNEY: I would say both.

ALENCAR: Do you take into consideration the schedule with the loading of the tafasitamab in the beginning? Does the fact that one is an infusion every 3 weeks and one has this weekly infusion [plus] a pill every day matter?

MCKINNEY: It’s a discussion in the third line with loncastuximab tesirine [Zynlonta] vs tafasitamab. In older patients who don’t want to come to the clinic very much, that’s the downside. It’s just a lot of infusions trying to keep patients on tafasitamab. That is less of a difference in the discussion for the schedule for pola-BR vs tafasitamab/ lenalidomide because if you describe [to patients that] you’re going to get chemotherapy, you have to deal with those adverse events, and you may be back and you may be getting growth factor; [the schedule of tafasitamab] is less important for that distinction. But vs loncastuximab or bispecifics, that’s where it comes up.

ALENCAR: Does the cell of origin make a difference? This patient had a non-GCB cell of origin.

STEFANOVIC: It does make a difference, and I think for non-GCB, lenalidomide is a great drug, either by itself or in combination with tafasitamab. Patients who live far away might not find it easy to come every week for the tafasitamab. But also lenalidomide lends itself to easy dose adjustments if needed for cytopenias. One can go down on the dose easily, and one can keep patients on both treatments. We don’t have the same cumulative toxicities that we would see with polatuzumab or with bendamustine. For a patient who responds to a combination, it is a good option, and…it can keep the door open for the other third-line treatments that have great promise.

ALENCAR: Do you have any concern with the co-payments for the oral agent?

STEFANOVIC: With the lenalidomide, it’s a question of delays with the patient going through the authorization and co-pay assistance. It can be up to 2 weeks, and tafasitamab by itself isn’t that great. One needs the lenalidomide onboard to get a response there. That is a moment of anxiety where we sometimes wish we could get the treatment faster.

ALENCAR: If you get the tafasitamab approved but are still waiting on the lenalidomide, do you just get the tafasitamab started and you pick up with the lenalidomide whenever you can or do you wait until you have both in hand before you start?

STEFANOVIC: Ideally, one should have both. I have gone with tafasitamab and then started the lenalidomide after 2 weeks or so, but it is ideal to have both at the same time. I don’t think the tafasitamab has great efficacy on its own.

CASE UPDATE

This patient is started on tafasitamab plus lenalidomide.

DISCUSSION QUESTION

• What is your experience with tafasitamab plus lenalidomide?

THOMAS: I used it on one patient and the patient stayed in control of the disease for about probably a year, and they tolerated it very well.

ALENCAR: Were there any issues with toxicity, or tolerability, or problems that you have noticed in these patients? We discussed the schedule with the frequent infusions, the cytopenias, and kidney dysfunction.

KUZMA: I have run into some problems with myelosuppression that have led to lenalidomide dose modification.

ALENCAR: Did you drop the dose, or did you try to use some growth factors before that?

KUZMA: I dropped the dose.

ALENCAR: Did you start with 25 mg, or did you start already with a lower dose?

KUZMA: I’ve only used it a total of 3 times. Two times, I started with 25 mg. One time, due to frailties and comorbidities, I did start at 20 mg. But 2 of the 3 patients ended up at 15 mg.

ALENCAR: For those patients who had long-term disease control and you reach that point when, according to the study, you drop the lenalidomide and keep the tafasitamab, are you happy to drop the lenalidomide and keep the tafasitamab? Do you think you still need to keep the tafasitamab at that same frequency or do you get creative and start spreading it out?

MCKINNEY: I drop the lenalidomide. A year is enough. That seems [clearer] to me. I haven’t thought about prolonging it. These patients will go another 6 to 12 months with tafasitamab, and I’ve had some discussions where we spread it out every 3 weeks. I have no real data to support that. I know there are different preparations of tafasitamab out there in trials investigating that. I just have a discussion with the patient.

ALENCAR: Do they get tired of coming in every 2 weeks?

MCKINNEY: It’s a long time for every-2-week infusions to go beyond 2 years.

ALENCAR: The company is looking into alternative schedules and trying to work with patients because it’s very tough after a year to come every 2 weeks to get infusions. But you have those patients who have excellent responses and it’s very hard to just abandon a drug that seems to be working [in] these patients with tough-to-treat [disease] and a finite number of options.

REFERENCES:

1. Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800-1808. doi:10.1182/blood-2017-03-769620

2. Sakemura RL, Manriquez Roman C, Horvei P, et al. CD19 occupancy with tafasitamab increases therapeutic index of CART19 cell therapy and diminishes severity of CRS. Blood. 2024;143(3):258-271. doi:10.1182/blood.2022018905

3. Veeraputhiran M, Mehta A, Alencar AJ, Modi D, Voorhees TJ, Narkhede M. Tafasitamab (TAFA) plus lenalidomide (LEN) prior to chimeric antigen receptor T-cell (CAR-T) therapy in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): case series of 8 patients. Blood. 2022;140(suppl 1):12089-12091. doi:10.1182/blood-2022-158595