Bridging Options for CAR T-Cell Therapy in R/R DLBCL

Christopher R. Flowers, MD, MS

Chair and Professor

Department of Lymphoma – Myeloma

Division of Cancer Medicine

The University of Texas MD Anderson Cancer Center

Houston, TX

DISCUSSION QUESTIONS

• What therapies would you consider for a patient like this? ​
• Who is involved in the decision making?​

CHRISTOPHER R. FLOWERS, MD, MS: More than half of you would think about tafasitamab [Monjuvi] plus lenalidomide [Revlimid] and then a little bit more than a third would consider the polatuzumab [Polivy] combination [with bendamustine and rituximab (Rituxan)], and some would consider a gemcitabine-based regimen.

It sounds like nearly all of you would treat this patient within the context of your practice …while waiting for cell therapy as opposed to referring for a clinical trial or [stem cell] transplant. I’d love to hear from somebody who chose the polatuzumab option. It gives you a lot of plus/minuses there. Would you add rituximab or bendamustine to this [regimen], and how would you use that combination?

QUILLAN HUANG, MD: I voted for that. What I’ve seen our transplanters prefer is to do polatuzumab/rituximab without the bendamustine pending collection.

FLOWERS: So you base that on your prior experience with the CAR T-cell therapy group that you work with and that being their preference. What’s your experience with using that? How comfortable are you with it? How well does it work to control disease?

HUANG: It’s reasonably tolerated. It’s not clear that the bendamustine adds much besides toxicity. In my limited experience, it’s helped people and it’s gotten people to CAR T-cell therapy. It’s been OK.

FLOWERS: It does what you’re expecting it to do.

HUANG: Right.

FLOWERS: Let’s go on to someone who uses a tafasitamab/lenalidomide regimen; does anyone want to comment on your experience with that?

ANANTH ARJUNAN, MD: I’ve used tafasitamab/lenalidomide in this setting. The main reason is because I find it easy to manage in terms of adverse events. It mostly seems to be driven by the lenalidomide which we can easily dose modify, and we’re used to doing that with not just lymphoma but myeloma, etc.

FLOWERS: What dose of lenalidomide do you find you end up giving most of those patients?

ARJUNAN: I feel like my patients don’t tolerate the lenalidomide as well as what I see typically in the trials. I’m often going down to 10 mg for a lot of my patients…that’s what I’ve been seeing.

FLOWERS: There is nothing [unusual] about your practice. Patients don’t tolerate lenalidomide at the starting dose [of 25 mg] that they’re using in most of the trials.

ASHWANI AGARWAL, MD: I agree with Dr Arjunan. Lenalidomide is the 1 I always adjust. I’m using [closer to] 15 mg lenalidomide. Ten milligrams is even better [tolerated] but I push 15 mg.

INNA SHMERLIN, MD: I agree with my colleagues. I like the idea that you can give tafasitamab for a limited period of time and then continue on lenalidomide. There’s a lot of familiarity with lenalidomide from other malignancies, and we know how to dose adjust and what to monitor for.

FLOWERS: Does anybody worry about giving a CD19-directed therapy with tafasitamab before giving a CD19-directed CAR T-cell therapy?

SHMERLIN: I’ve talked to my transplant specialists and CAR T cell specialists about it…and they seem comfortable. I don’t know why, but they feel very comfortable with tafasitamab/lenalidomide prior to CAR T-cell therapy as a bridging therapy.

AGARWAL: That’s true. There was some concern about the CD19, but I don’t think they’re worried about it.

FLOWERS: There has been a continual concern about giving CD19-directed therapy before another CD19-directed therapy in either direction, giving CAR T-cell therapy before tafasitamab/lenalidomide or giving tafasitamab/lenalidomide or loncastuximab tesirine [Zylonta] before giving CAR T-cell therapy.

There have been retrospective observational studies presented at national meetings that show it can be done successfully, and that you can still get good responses from the second CD19 therapy in both directions.^1,2

DILIP SOLANKI, MD: In those patients who relapse on the lenalidomide/tafasitamab combination, have they looked at what their CD19 status is?

FLOWERS: The studies that I’ve mentioned are all small studies and in relatively few patients that have gone on to subsequent therapy. CD19 as an antigen is tricky to look at, too, because there are multiple ways that you can have CD19 loss in terms of the ways it affects its expression. We know about CAR T-cell therapy and CAR T-cell failure and that CD19-low is one of the pathways for CAR T-cell failure in about 25% to 30% of patients.³ And there’s a concern that if you give a CD19 therapy before another CD19 therapy that you might have CD19 loss as a mechanism, but that pathway has not been studied.

SOLANKI: In the trial, bridging chemotherapy was forbidden. So I don’t know how one would apply those data if you’re going to use some chemotherapy, which sometimes we end up having to do if steroids don’t seem to be enough. But those are usually patients who have a very aggressive disease with high lactate dehydrogenase and so on. So what is your assessment of that, what we do in the community as opposed to what was done in the trial?

FLOWERS: You are correct, there are some challenges there. One is the practicality of getting a patient to CAR T-cell therapy; getting all the insurance approvals can be challenging and making sure that those are in place, so the patients can go on to therapy. There oftentimes is a need for therapy to get a patient to the CAR T cells. There are patients who can get the CAR T cells more quickly or can have just simple steroids as a therapy.

I think 1 of the things that we did have concerns about early on is that if you gave steroids, that they would inhibit the ability of CAR T cells to work. We now know that’s not true and that bridging with steroids was a reasonable and effective approach in the axicabtagene ciloleucel [Yescarta] randomized trials, the ZUMA-7 trial [NCT03391466], and in other studies.⁴

We’ve also found from our University of Texas MD Anderson Cancer Center group led by Chelsea C. Pinnix, MD, PhD, that bridging radiation can be quite an effective therapy, particularly when the disease is in a relatively limited area.⁵

Those are the kinds of approaches that we think about when you want to limit what’s given for bridging therapy. But, oftentimes, you do need to pursue another regimen. What I typically recommend is the use of polatuzumab without bendamustine as an off-label approach for being able to treat patients and to get them to CAR T-cell therapy [without] giving a CD19-directed therapy. But we have also seen that people get regimens like tafasitamab/lenalidomide as a bridging therapy or get a chemoimmunotherapy regimen as a bridging therapy. I think all of those are potential approaches in real life that can get people to CAR T-cell therapy.

_References:

_{1. Thapa B, Caimi PF, Ardeshna KM, et al. CD19 antibody-drug conjugate therapy in DLBCL does not preclude subsequent responses to CD19-directed CAR T-cell therapy. Blood Adv. 2020;4(16):3850-3852. doi:10.1182/bloodadvances.2020002587}

_{2. Caimi PF, Ardeshna KM, Reid E, et al. The antiCD19 antibody drug immunoconjugate loncastuximab achieves responses in DLBCL relapsing after antiCD19 CAR-T cell therapy. Clin Lymphoma Myeloma Leuk. 2022;22(5):e335-e339. doi:10.1016/j.clml.2021.11.005}

_{3. Jacobson CA, Hunter BD, Redd R, et al. Axicabtagene Ciloleucel in the Non-Trial Setting: Outcomes and Correlates of Response, Resistance, and Toxicity. J Clin Oncol. 2020;38(27):3095-3106. doi:10.1200/JCO.19.02103}

_{4. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133}

_{5.Pinnix CC, Gunther JR, Dabaja BS, et al. Bridging therapy prior to axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma. Blood Adv. 2020;4(13):2871-2883. doi:10.1182/bloodadvances.2020001837}