Treating Primary Refractory DLBCL


Ian W. Flinn, MD, PhD: Unfortunately, not all patients are candidates for CAR [chimeric antigen receptor] T-cell therapy. Maybe this is because of comorbidities, maybe it is because of access issues. Amit, can you walk us through some of the considerations that go into selecting a therapy for a patient who’s not a candidate for CAR T-cell therapy?

Amitkumar Mehta, MD: As I mentioned, identifying the patient for any therapy is important, including CAR T. If we decide that the patient is not eligible for CAR T treatment, and if they have failed 1 or 2 lines of therapy, we luckily have many therapies approved. Of course, we are to be in alignment with the label so that we can get the insurance approval.

As we discussed, BR [bendamustine, rituximab]–polatuzumab is an option, tafasitamab-lenalidomide is an option, and selinexor is an option. Tafasitamab-lenalidomide is approved in the second-line setting. Those patients are not eligible for transplant or aggressive therapy. Tafasitamab-lenalidomide is a good combination. As I mentioned, the management of lenalidomide and dose of lenalidomide is critical in that setting. I’ve used also polatuzumab with Rituxan alone, rather than adding bendamustine. But if you are planning for CAR T down the line and have a collection plan, I would not use a bendamustine-based therapy. If the patient is not eligible, that’s a great regimen to use. I’ve seen great responses with BR [bendamustine, rituximab]–polatuzumab.

We touched on selinexor a little. Managing the toxicity profile of selinexor is key. As I mentioned, I used the drug in a patient with CNS [central nervous system] involvement and had successful outcomes. That could be a niche in that area.

With all these agents, we have to be very careful with their adverse effects, especially bendamustine. As we all know, these patients may have received a couple of lines of therapy before. Bendamustine has been very lymphotoxic. Maybe the patient is at high risk of infections, especially in the COVID-19 [coronavirus disease 2019] era. We were talking about CAR T and long-term adverse effects of CAR T—hypogammaglobulinemia and high risk of infections. That’s something that we should be mindful of when managing these patients.

Ian W. Flinn, MD, PhD: John, 1 thing we didn’t hear Amit talk about was the time from last therapy. For instance, the patient who is primary refractory. Does that weigh in on your decisions as to which therapy you might use for a patient? For instance, another chemotherapy vs an immunotherapy? What would sway your vote on what to give a patient in the primary-refractory setting? 

John M. Burke, MD: We all know those patients have the worst outcomes in this disease. Historically, I have used standard-of-care chemotherapy—second-line salvage therapy with ICE [ifosfamide, carboplatin, etoposide] or DHAP [dexamethasone, cytarabine, cisplatin] or something—and I try to get them lined up for autotransplant. Should they be receiving a targeted agent like tafasitamab-lenalidomide instead? That’s a really good question. I don’t know. I don’t have data to answer that question. It certainly seems that it would be a reasonable thing to try. 

That said, if you have a patient lined up for an autotransplant, we really don’t have super data about tafasitamab-lenalidomide in that patient population. I would probably do what I’ve been doing, knowing that the outcomes are suboptimal. Those are the patients I would line up for CAR T-cell therapy sooner rather than later.

Ian W. Flinn, MD, PhD: Loretta, let’s get your thoughts on this. For the people who have been referred to you and are primary refractory and not going to make it to CAR T-cell therapy, what would you use as treatment? Are you going back to cytotoxic chemotherapy?

Loretta J. Nastoupil, MD: Traditionally, that’s what I’ve done. I’m holding out optimism that the randomized studies are going to be positive and that I’ll have CAR T in the second-line setting. But what will still happen is I’ll probably cool them off with a platinum-based approach while they’re undergoing manufacturing. I don’t know that my practice is going to change dramatically just yet. I have used tafasitamab-lenalidomide in that setting with the idea that if I switch the mechanism of action, particularly in patients who are over 70 years of age, I may be able to change them from this poor trajectory. 

I have limited experience, and I want Kami’s input. They excluded a lot of these patients from that study. I’ve not had good success in taking a patient who is rapidly progressing off CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] and salvaging them with tafasitamab-lenalidomide, but that is a potential option and is something I intend to explore further. We need good therapies in that space, and it’s traditionally been an area that drug companies have not gone after. I’m glad that studies like L-MIND and the randomized phase 3 studies are opening up that second-line space. I still think that’s an area where we don’t have a great strategy, particularly for chemotherapy-refractory patients in the frontline setting.

Kami J. Maddocks, MD: Though the primary-refractory patients were excluded from L-MIND, there were a handful of patients who were treated on the study before the inclusion changed. When you look at the data, there were better overall responses in the nonrefractory or nonprimary-refractory patients, but duration of response wasn’t great. This has been approved only since July, but I have been using the treatment in this exact situation, and I use it if they don’t respond to R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone].

I’ve had a few patients who have done really well. The biggest thing is getting lenalidomide approved. Once you get it approved, there’s almost always a co-pay that nobody can afford, and you still have to get assistance. The biggest thing is trying to turn that around fast enough that I can start them on treatment. When I have been able to do that, I’ve actually had reasonably good luck. I have done a short course of treatment in some patients to get them there if I’m close but not quite there, and occasionally I have had to use a cycle of chemotherapy. 

Transcript Edited for Clarity

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