Physicians Respond to 5-Year Tafasitamab/Lenalidomide Data for R/R DLBCL

Stephen J. Schuster, MD

Director, Lymphoma Program

Director, Lymphoma Translational Research

Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research

Penn Medicine

Philadelphia, PA

DISCUSSION QUESTION

• What is your reaction to the safety data for combination tafasitamab (Monjuvi) plus lenalidomide (Revlimid) for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) from the L-MIND study (NCT02399085)​?

STEPHEN SCHUSTER, MD: What’s your reaction to the data for the combination? What’s the most striking feature about the safety data? How would you want to counsel patients who receive it?

DAYA SHARMA, MD: I would say it is very well tolerated. The data are very good, at least for duration of response.¹ If there are some AEs, would you adjust the lenalidomide dose, but not the tafasitamab dose?

SCHUSTER: Yes [I would adjust the lenalidomide dose], because it’s almost always a hematologic AE. I have not treated 80 patients like on this trial, but I have treated a handful, and I can tell you that it is blood counts in all my patients, nothing other than blood counts and loose stools and it is related to the lenalidomide…. Twenty-five milligrams [of lenalidomide] is hard for these patients. They’re not like patients with multiple myeloma who tolerate 25 mg, and I don’t know why. There’s one important thing I want to counsel you on, if you’re not counseling your patients [on it already], with lenalidomide you have the IMiD [immunomodulatory] thalidomide safety issue, so patients have to say they’re not going to [become pregnant] and they’re going to use barrier contraception. [So they have to] keep this drug out of the reach of children and sexually active people, however, most of my patients…are older and it’s not a big issue for them.

SHARMA: Do you use prophylaxis for deep vein thrombosis?

SCHUSTER: Yes, I do. I use aspirin, and if patients are already on an anticoagulant for cardiac issues or prior blood clots, then I won’t use aspirin.

SHARMA: Can you use CAR [chimeric antigen receptor] T-cell therapy after tafasitamab?

SCHUSTER: Yes, we’ve done it. The concern is that you may lose antigen expression of CD19 and therefore they won’t respond to the [CAR T-cell therapy]. It’s more of a theoretical concern than a real concern. There are a lot of in vitro studies showing that. These bonds are not covalent, so if the CD19 is not internalized or the cell doesn’t die with the tafasitamab on it, a CAR T cell can compete with tafasitamab for that same CD19. But biopsies have been done in patients that show after a few weeks tafasitamab is out of the system and not blocking any of the CD19.

Then there are studies which everybody ignores because they’re published in the supplements. Like in the JULIET trial [NCT02445248], in the supplement, we stained everybody’s biopsy for CD19 and we had the same response rate in patients. This is immunohistochemistry, not flow [cytometry], not very sensitive, but we had the same response rate in patients who stained negative and stained positive to CD19-directed CAR T-cell therapy.² I don’t know how few molecules it actually takes to maintain sensitivity to CAR T cells, but immunohistochemistry is not good at predicting it, so I wouldn’t let this scare you off.

If, for some reason, somebody does great, go with it. There seems to be a plateau for responders on these curves. If it looks like it’s not going to do it, either get an appointment with a CAR T-cell therapy [center] and they can certainly [perform] apheresis while they’re on this therapy. Unlike with the bendamustine-containing regimens, you’re not going to be poisoning T cells. In fact, what lenalidomide does, it actually upregulates NK cells a bit and changes the cytokine milieu, [which] actually activates the T cells a bit. I usually hold the aspirin and lenalidomide for 3 days before apheresis and then collect the T cells and restart them if I’m going to do it. We can generally make good products out of that. These are just things that I can report from my own practice.

ARUN BHANDARI, MD: [I heard that] because of the bone marrow suppression, if patients got leukopenia or neutropenia, you could use G-CSF [granulocyte colony-stimulating factor]. Is that really required though? Already…the regimen is probably close to a monthly cost of $35,000 to $40,000 and then you add G-CSF on top of that.

SCHUSTER: You can use G-CSF with it, meaning G-CSF will work with this much more quickly than it works in patients who have had chemotherapy because the precursor cells are not alkylated or depleted, so it does work. I’ve seen patients that get neutropenic, use a few [doses of] G-CSF, then…recover and not get neutropenic again without changing therapy. I don’t know why that is, somehow or other, the bone marrow gets used to it…so I wouldn’t hesitate to use G-CSF.

If they get neutropenic more than once, and particularly if they’re elderly, I’ll oftentimes reduce the dose of lenalidomide. I’d give them some G-CSF to get them through it and then I’ll reduce the lenalidomide a little bit, but I don’t know of any [patient] for whom I’m going to G-CSF every month. Every now and then with rituximab [Rituxan] you’ll see neutropenia, and if you give some G-CSF, it tends never to come back. Somehow or other, the marrow gets used to it. I don’t know what the physiology is, but you can use it, and again it’s very unlikely you’ll…need to do it chronically. Particularly if you do [tafasitamab/lenalidomide] in the second line and they haven’t had a lot of chemotherapy.

DISCUSSION QUESTIONS

• What do you view as the pros and cons of this regimen?​
• Would you consider CAR T-cell therapy after tafasitamab if there is disease progression? ​

SCHUSTER: I think the biggest con is the fact that they never tested an end point. I suspect that if you have an aggressive lymphoma and you’re on tafasitamab/lenalidomide, you go into complete remission, and you do tafasitamab for another year or 2, and you’re still in a complete remission, those patients are probably going to stay in remission even if you stop. They probably should have [chosen] a time [to stop tafasitamab], or at least looked at what happens to the patients on the L-MIND study who do stop. Because, as we all know, the aggressive lymphomas either remit or they don’t. It’s not like maintenance therapy or ongoing therapy has ever [shown] a big impact in this group of diseases. Would you consider CAR T-cell therapy after? I would, but what about you?

SHARMA: I would use [CAR T-cell therapy]. It all depends upon the data.

SCHUSTER: If you have any doubt, you can biopsy them and you can do flow cytometry or a fine needle aspiration [to look for] CD19. Make sure you’re 3 or 4 weeks after tafasitamab. I think you [can] send them to a center and we can evaluate them at the center. [By] immunohistochemistry, they could be [CD19]-negative and still respond beautifully to CAR T-cell therapy. I would not consider this to be an absolute barrier. I wouldn’t give it right before CAR T-cell therapy, but if you want to have somebody on this and then do apheresis, it’s fine. But, before you actually deliver the CAR T cells, you may want to stop it for 3 or 4 weeks, but you…can continue the lenalidomide but stop the tafasitamab.

_References:

_{1. Duell J, Abrisqueta P, Andre M, et al. Five-year efficacy and safety of tafasitamab in patients with relapsed or refractory DLBCL: Final results from the phase II L-MIND study. Presented at: American Association for Cancer Research Annual Meeting 2023; April 14-19, 2023; Orlando, FL. Accessed June 5, 2023. https://bit.ly/3MmShus}

_{2. Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in Adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56. doi:10.1056/NEJMoa1804980}