Considering Alternatives to CAR T-Cell Therapy for Primary Refractory DLBCL

Jakub Svoboda, MD (Moderator)

Associate Professor of Medicine

Hospital of the University of Pennyslvania

Philadelphia, PA

CASE SUMMARY

A 68-year-old man presented with fatigue, back pain, and lymphadenopathy​, and had a prior medical history of medically controlled hypertension. A ​physical exam showed a 1.5-cm left posterior cervical node, a 2.5-cm right anterior cervical node, and a 2.0-cm left supraclavicular node. PET-CT scans showed multiple enlarged mesenteric and retroperitoneal nodes, the largest measuring 5.3 x 3.1 cm​. A biopsy confirmed diffuse large B-cell lymphoma (DLBCL), non-germinal center (non-GC). Immunohistochemistry was positive for CD20, BCL-6, BCL-2 (50% of cells), MYC (greater than 90% of cells), Ki67 85%, MUM1, but was negative for CD10​. Fluorescence in situ hybridization was negative for translocations involving MYC, BCL2, BCL6​.

Laboratory results showed normal complete blood count, elevated lactate hydrogenase. He received a diagnosis of stage III DLBCL with IPI high-intermediate risk and ECOG performance score of 1. R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, prednisone) was initiated for 6 cycles and back pain was resolved​. Post-treatment PET demonstrated a complete response with Deauville score of 2, and the patient was observed​.

Eight months after completion of therapy, he complained of fever, night sweats, and back pain. A palpable lymph node in left groin was discovered on physical examination​.

PET and CT scans showed a new left inguinal lymph node, an increase in size of a residual node, as well as multiple metabolically active lesions in lymph nodes of the retroperitoneum, abdomen, and pelvis​. DLBCL was confirmed by biopsy.

The patient was referred to nearest transplant and cellular therapy center for evaluation, but ultimately opted not to pursue CAR (chimeric antigen receptor) T-cell therapy​.

DISCUSSION QUESTION

• What factors influence your choice of treatment for this patient?
• What are your goals for treatment?

JAKUB SVOBODA, MD: For patients who you feel would not go through transplant and wouldn’t go through CAR T-cell therapy, the options are GemOx [gemcitabine/oxaliplatin], polatuzumab vedotin [Polivy] with or without bendamustine and rituximab, tafasitamab [Monjuvi] plus lenalidomide [Revlimid], or probably some other [options]. What would you do in this setting?

ARUN BHANDARI, MD: Is polatuzumab approved as second line? Or first line?

SVOBODA: Not really [either]. It’s part of the NCCN guidelines—you can usually get polatuzumab in second line.¹ But when you look at the label, it would say 2 or more regimens prior.²

None of you would use GemOx. GemOx was often used as a treatment for the unfit, older patients who didn’t go for transplant. But, I agree, I haven’t used it in a long time.

This patient is 68 years old, has hypertension, and relapsed after 8 months. Now what do you discuss with that type of patient; what is the clinical goal? How do you discuss the options?

BHANDARI: My goal would be to guess the longest response with a novel agent, such as tafasitamab plus lenalidomide. You can give treatment to disease progression with tafasitamab plus lenalidomide. My goal is to get the maximum response and duration of response.

SVOBODA: I think that that’s a valid point. When I see patients referred to us in our tertiary center, they trust you in the community when they ask “What are my shots? What should I go for?” These discussions are important for them, and your view on this is very important. So which are the factors that influence your recommendations for a patient with a kind of lymphoma that would relapse within 12 months?

HARISH MADALA, MD: I work in a rural part of Virginia, and this sounds like a very common issue I deal with. Patients don’t want to travel for CAR T-cell therapy or stem cell transplant. We do have an older population, so patient preference or goals would be a very important factor for me, especially in choosing the regimen of tafasitamab plus lenalidomide versus polatuzumab. I would take the number of times they have to come to the cancer center for infusion, especially in this day and age with COVID-19, into consideration. None of my patients are older, but once healthy 70-year-olds start treatment, their age really shows. With their multiple comorbidities, I try to pick the lesser toxic regimen, but with longer response.

SVOBODA: I keep thinking about what I can do to keep the disease under control without necessarily damaging the stem cells, or affecting the immune system as much. So, for that, I think using something that is like a novel agent, since patients may need other drugs in the future. The subtype of the DLBCL, GC versus non-GC, can really be important in the selection.

CASE UPDATE

After discussing the treatment options, tafasitamab plus lenalidomide was initiated​.

SVOBODA: This regimen has been around for only a short time, and, this is a bit of a unique patient. Anybody willing to share their experience with the regimen?

ANUSHA MADADI, MD: It seems to be better tolerated, similar to rituximab. I admit that I have used it in malignant pancytopenia to watch for some mild reactions in each, but otherwise, pretty well tolerated.

MATT MCKINNEY, MD: I agree. [I have seen patients who were] progressing through CAR T-cell therapy, or [autologous stem cell] transplant, or allogeneic [stem cell] transplant go on tafasitamab plus lenalidomide and come in with disease shrinking or no disease. So it is definitely effective.

SVOBODA: My experience is similar to what you both mentioned. I think tafasitamab is like rituximab, but it just attacks different antigen on the B cells. So, you know, it is very similar to if many of you have had experience with R2[rituximab plus lenalidomide], and so this is very similar in terms of that. When you look at the L-MIND study, [it is given on] days 1 and 4, but the first week of tafasitamab, I usually skip day 4 and just do weekly tafasitamab for the first 3 months, and then switch to every other, as per the label.³

DISCUSSION QUESTIONS

• What is your reaction to the efficacy data for combination tafasitamab plus lenalidomide? ​
• What data are most striking to you? ​

DAYA SHARMA, MD: The duration of response [DOR] is very impressive, much better than the CAR T-cell therapy, if I have to put those data side-by-side. It is very well tolerated, and there are many complete responses, so I think these are the very impressive end points. Although it is a phase 2 trial, it is still very impressive.

SVOBODA: It is a little bit difficult to compare it with CAR T-cell therapy because they didn’t have all of the patients [such as] the primary refractory patients. I agree, it surprised me that they were able to generate such long term DOR. Any other feelings about these data sets from the L-MIND study [NCT02399085]?

BHANDARI: The data seems quite impressive. How long can they be given lenalidomide?

SVOBODA: For 1 year.

BHANDARI: And tafasitamab for 1 year, or longer?

SVOBODA: Then [after 1 year] tafasitamab is continued as a maintenance. We’ve seen that prior in literature where in mantle cell lymphoma, they use rituximab maintenance until progression. And so they’ve designed this study the same way, that they used the tafasitamab maintenance until progression. I am not sure how much the tafasitamab maintenance plays a role, but if you want to follow the data, you will follow that. In some of our patients we didn’t continue for the whole duration until progression. They opted to hold it after some time because they were in remission.

BHANDARI: The reason I asked is because I wanted to see which was more cost effective: CAR T-cell therapy, or this regimen.

SVOBODA: It’s a good question, and the CAR T cell price tag is huge. Again, I am sure any of these treatments will be very expensive. That is a great question for health care economist, but I can’t answer that well.

CHARLES KUZMA, MD: Can you comment on the lenalidomide dose? In my limited experience, I find that the 25 mg dose quite myelosuppressive.

SVOBODA: You’re right. The majority of the patients were at 20 mg or higher. But, surprisingly, they were able to do 20 mg. I agree with you. When I use R2, hematological toxicities were the issue there. Grade 3 to 4 adverse events were definitely seen in those patients: neutropenia, anemia, thrombocytopenia, as expected, and I feel that is very comparable to the R2 data, just from the lenalidomide itself.⁴ I don’t really feel that the tafasitamab contributes to the cytopenias, personally. They did have a 10% rate of febrile neutropenia. There was 1 patient with grade 4 agranulocytosis.

KUZMA: How important do you feel that maintaining dose intensity with the lenalidomide is in this regimen?

SVOBODA: I don’t think it’s as important, to be honest. We did some very early studies with lenalidomide/rituximab at least 10 years ago, and we used 10 mg daily without 3 weeks on and 1 week off, and patients did very well. I feel that with these immunomodulatory agents, and other agents, the dose is not as critical as conventional chemotherapy.

_REFERENCES:

_{1. NCCN. Clinical practice guidelines in Oncology. B-cell lymphomas, version 4.2022. Accessed June 17, 2022. https://bit.ly/3xylMAF}

_{2. Polivy. Prescribing information. Genentech, Inc; 2019. Accessed June 17, 2022. https://bit.ly/39wfGsy}

_{3. Monjuvi. Prescribing information. Morphosys US Inc; 2020. Accessed June 17, 2022. https://bit.ly/3A1wumn}

_{4. Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4}