Phillips Discusses Treatment Options for Early-Relapsed DLBCL

Tycel J. Phillips, MD (MODERATOR)

Associate Professor, Division of Lymphoma

Department of Hematology & Hematopoietic Cell Transplantation

City of Hope

Duarte, CA

EVENT REGION Maryland; Virginia; Washington, DC

PARTICIPANT LIST Xinting Fu, MD | Andrew Pham, MD | David Shin, MD | Sharon Yee, MD | Albert Dekker, MD | Neeraj Agnihotri, MD | Arati Chand, MD | Melody Benjamin, MD | Preeti Chaudhary, MD | Sassan Farjami, MD | Swarna Chanduri, MD | Merin M. Stephen, MD

CASE SUMMARY:

A 67-year-old man presented with fatigue, back pain, and lymphadenopathy. He had prior hypertension, which was well controlled with medication. Physical examination showed a left posterior cervical lymph node of 1.5 cm, a right anterior cervical lymph node of 2.5 cm, and a left supraclavicular lymph node of 2.0 cm. His PET/CT scan showed multiple enlarged mesenteric and retroperitoneal lymph nodes, with the largest measuring at 5.3 × 3.1 cm. His bone marrow biopsy is negative. The biopsy confirmed diffuse large B-cell lymphoma (DLBCL), non–germinal center B-cell, double-expressor lymphoma.

Immunohistochemistry is positive for CD20, BCL6, BCL2 (50% of cells), MYC (> 30% of cells), Ki-67 (85% of cells), and MUM1 but is negative for CD10. His complete blood count is normal and lactate dehydrogenase [level] is elevated. His has stage III disease, with International Prognostic Index high-intermediate risk, and an ECOG performance status of 1. Fluorescence in situ hybridization is negative for translocations involving MYC, BCL2, and BCL6.

R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone; 6 cycles) was initiated and his back pain resolved. Posttreatment PET demonstrated a complete response with a Deauville score of 2; patient was observed. Eight months after completion of therapy, he complained of fever, night sweats, and back pain. A palpable lymph node in the left groin was discovered on physical examination. PET/CT scan shows new left inguinal lymph node, increase in size of residual node, as well as multiple metabolically active lesions in lymph nodes of the retroperitoneum, abdomen, and pelvis. Biopsy confirmed DLBCL, and next-generation sequencing was not performed.

The patient was referred to the nearest transplant and cellular therapy center for evaluation, but he ultimately opted not to pursue chimeric antigen receptor (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 QUESTION

• What second-line regimens are preferred by the National Comprehensive Cancer Network for the treatment of transplant-ineligible DLBCL (diffuse large B-cell lymphoma), and how do their supportive data compare?

PHILLIPS: For second-line therapy for transplant-ineligible DLBCL, we are looking at a comparison of patients enrolled and treated with various options: 196 patients treated with Gem-Ox/R-GemOx [gemcitabine plus oxaliplatin with or without rituximab (Rituxan)]; 40 treated with the combination of polatuzumab vedotin [Polivy], bendamustine [Treanda], and rituximab [pola-BR]; and 81 treated with lenalidomide [Revlimid] plus tafasitamab [Monjuvi].^1-4 The median ages in the respective studies were 72, 67, and 72 years. The median number of prior lines of therapy was 1 with R-GemOx and 2 with [both] pola-BR and lenalidomide/ tafasitamab. We see 57% of the patients continued to be refractory with R-GemOx, 75% with pola-BR, and 44% with lenalidomide/tafasitamab. The overall response rates [ORRs] were 38%, 45%, and 57.5%, respectively. The CR [complete response] rates were 33% with R-GemOx and 40% with [both] pola-BR and lenalidomide/tafasitamab. The median progression-free survival [PFS] was 5 months, 9.5 months, and 11.6 months, respectively. The median overall survival [OS] was 10 months, 12.4 months, and 33.5 months, respectively, with a median follow-up of 22 months with R-GemOx, 27 months with pola-BR, and 42.7 months with lenalidomide/tafasitamab.

DISCUSSION QUESTIONS

• What are your clinical goals for this patient?
• How do you discuss the options during shared decision-making with your patients?
• What are key factors that influence your therapeutic recommendations for a patient with primary refractory DLBCL?

FU: At this point, the 2 primary goals would be to prolong patient survival and preserve the patient’s quality of life. The patient declined CAR T-cell therapy, so the treatment would be palliative.

PHAM: I would agree. If he’s not a transplant [candidate] or going to CAR T-cell therapy, then you’re not likely to cure him, so choosing the regimen that would prolong survival and improve [or maintain] his quality of life would be important. Both [pola-BR and lenalidomide/tafasitamab] have a good chance to do that. The nice thing with pola-BR is its defined treatment duration, so if he wants to stay more active and doesn’t want to be tied to the infusion center, that’s something you’d talk to the patient about. Lenalidomide/tafasitamab is also a good option. I’ve heard good results with that. It may be more cumbersome to start with getting lenalidomide, and the infusion schedule is probably more frequent, but either option would probably meet those goals for the patient.

PHILLIPS: Dr Shin, how do you discuss the options during a shared discussion with this type of patient?

SHIN: I don’t think the sequencing matters that much. Hopefully, patients will be able to benefit from both regimens one after the other. I just tend to recommend one and then the other one next.

PHILLIPS: Dr Yee, what are the factors that influence your therapeutic recommendations for a patient with primary refractory disease? Is there anything that stands out that you focus more on, or do you take a more global approach and incorporate everything you see?

YEE: I take a global approach. I look at their overall quality of life, overall performance status, and how they tolerated the prior therapy. If they’re markedly debilitated after 2 lines of therapy, they’re not going to want to do more therapy.

DEKKER: [This patient] refused CAR T-cell therapy because he does not have a support system, so any further treatment will have to be tailored around him to enable him to sustain himself without any support system, because he will not be able to receive any treatment at all [otherwise]. If you give him something, it may be a better treatment, but if there is nobody to take him to the emergency department in the middle of the night, it’s all a moot point.

PHILLIPS: That is important. The patient’s preference was outpatient therapy due to lack of support, so that’s an important thing to consider.

AGNIHOTRI: I agree. The quality of life probably takes precedence, especially if the treatment is looking more palliative at this point. I also agree that most of my patients who have good performance status will see all the therapies— whatever they can tolerate and whatever the insurance authorizes. I’d probably go with lenalidomide/tafasitamab first, then pola-BR.

CASE UPDATE

After discussing the treatment options, tafasitamab plus lenalidomide is initiated.

DISCUSSION QUESTION

• Please describe your experience with tafasitamab plus lenalidomide.

CHAND: I have used lenalidomide/tafasitamab for one of my older patients with primary refractory disease. He had a mixed response, where some of the sites of disease responded, and then there was progression in other sites of the disease. It’s a well-tolerated regimen, provided you use a lower dose of lenalidomide in older patients because the adverse events [AEs], most of the time, are from the lenalidomide rather than from the tafasitamab. In my experience, it didn’t debulk the disease as I would have expected with pola-BR, which I have also used in the past. The other thing about the lenalidomide/ tafasitamab regimen is that [the tafasitamab component] is an indefinite treatment until progression, so you have to talk to patients about that as well.

PHILLIPS: Was your patient relapsed or refractory?

CHAND: She relapsed early, in less than 12 months. But she’s 89 years [old], so she’s not a CAR T-cell therapy candidate. She has an ECOG performance status of 1, if I’m generous. She’s very independent in her daily activities, is able to come to the clinic, never misses an appointment, does not have too many comorbidities, and has normal kidney and liver function. Everything else is good. I had to eventually stop treatment and switch to loncastuximab tesirine-lpyl [Zynlonta]. I am still waiting to see what kind of response she has, [as] I just started the treatment.

DISCUSSION QUESTIONS

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

PHILLIPS: Dr Chand, [because] I know you’ve used lenalidomide/tafasitamab, what is your impression of the results?^5-8

CHAND: The data are impressive, but the real-world and clinical trials are too different. The ORR [in the clinical trial]⁶ is higher than what we see [in the real world]. I don’t know about other physicians’ experiences, but the little bit of experience I had was very different from the data. The data are impressive, and I think it’s a well-tolerated regimen. If you find the right patient, I think it’s definitely something to consider.

DEKKER: Yes, I would agree. In my experience, the regimen was very well tolerated with only mild fatigue. One of the patients who I had was also rather elderly, in their late 80s, and managed to stay on the treatment, so it’s clearly very tolerable. I’ve not had CRs; I’ve had partial responses, and 1 patient has been on treatment [ for approximately] 6 months now.

BENJAMIN: I haven’t used this, but I think the data are impressive because these are previously heavily treated patients. There seem to be very few AEs, certainly with the monotherapy. It seemed that maybe diarrhea was one of the more common AEs on the monotherapy, and even the combination isn’t that bad. We’re used to the lenalidomide AEs, and we could probably manage these patients well. But I think the ORR is impressive in these patients.⁶

CHAUDHARY: I don’t have any personal experience with the regimen, but I think the ORR is impressive.⁶ I know that may not mean much. I’m not sure how to interpret the real-world data.⁷

FARJAMI: I am very surprised by the real-world data.⁷ [Those data] suggest to me that the study population was probably a pretty selected group of patients [From the Data^5,7]. Otherwise, I cannot explain this much difference.

CHANDURI: These are all infusions, and the patients have to come to the clinic 3 or 4 times a month. In the real world, did that make a difference [with respect to] access to the clinic or how much the patients can come for these treatments? I think for the 2 years they are responding, they’re running their life between clinic and home.

PHILLIPS: Yes, it’s hard to know for sure the difference between what we see in the real-world setting [and in the clinical trial]. We all know that patients who can enroll in clinical trials are probably healthier than most of the patients we see in the “real world,” because they can go through screening processes in the time it takes to enroll them in a clinical trial.

[However], one of the major criticisms of the L-MIND trial [NCT02399085] is the exclusion of primary refractory patients, [because] relapsed patients typically probably have a different biology to their disease than those who are refractory to initial chemotherapy.

We probably will never know the major difference between the real-world vs the clinical trial. The clinical trial did not have CAR T-cell therapy failures, [but these] were [included] in the real-world setting, which we know is a very hard-to-treat patient population, [which] will impact the PFS. [However], if you look in the clinical trial, those who did not get lenalidomide/tafasitamab after their first line of therapy and got it as second line or later did have worse outcomes.⁶

I think it does suggest that the more pretreated the patient is, the worse they’re going to do with lenalidomide/ tafasitamab, which is why, if physicians are going to use this treatment, it is typically reserved for the second-line setting [in most situations]. [And] physicians do select their patients a bit in the real-world setting to those who are relapsed or older—but not necessarily fitter—who can tolerate more intensive therapy. Because, again, most of the patients we see probably would not necessarily fit what was treated on a clinical trial, and it’s hard to extrapolate how they will respond, given that we typically have more refractory patients than late relapses [as] were enrolled on the study.

STEPHEN: Just for clarification, is lenalidomide/tafasitamab approved in the primary refractory setting or is it not?

PHILLIPS: The label itself is fairly broad. It is approved for those who are relapsed or refractory and not considered eligible for an autologous stem cell transplant, so the label itself did not specify relapsed or refractory. It just has a second-line indication, so any patient [whose] frontline therapy [fails can] get lenalidomide/tafasitamab if they show up in your office.⁹

FARJAMI: Dr Phillips, what was the OS for lenalidomide/ tafasitamab in the clinical trial?

PHILLIPS: It was approximately 33 months for all patients and [57.6 months] for those [who] had 1 prior line of therapy.⁶

FARJAMI: That is strikingly different from other agents, right?

PHILLIPS: Correct; that is quite a bit more than what we see with pola-BR,³ R-GemOx,¹ and some of the other [regimens].

FARJAMI: Does that suggest that was a very selectively biased group of patients? It’s just very different from other second-line therapies. I’m wondering [whether] using CD19-targeted therapy has anything to do with the improvement of the OS that makes us believe we have to incorporate that in our sequence of the treatments we are selecting.

PHILLIPS: I don’t necessarily know [whether] it’s the CD19 part that anybody is holding onto, but I will say the regimen in the right patient is quite effective, and you can get some durable responses. There are plateaus on the curve, especially for those who had 1 prior line of therapy.^3,6,8 For the right patient, lenalidomide/tafasitamab is a very good option and can give you some durable remissions, and these patients can stay in remission for quite a bit of time. It’s just [a matter of ] picking the right patient for lenalidomide/tafasitamab and [considering] what [population] was enrolled in the clinical trial vs [who] you are going to see in your office.

FARJAMI: Does it have any impact on your future decisions to move on to CAR T-cell therapy?

PHILLIPS: That is a very good question that nobody has an answer to. There are no data.

DEKKER: But this is [targeting] CD19, so theoretically, it’s difficult to use CAR T-cell therapy after a patient has tafasitamab.

PHILLIPS: Because of the lack of data, most physicians are not recommending or using lenalidomide/tafasitamab prior to taking a patient to CAR T-cell therapy, because we don’t know what it would do to the CD19 receptor. Alternatively, there are data showing that loncastuximab does not seem to impact CAR T-cell therapy outcomes with a CD19 antibody-drug conjugate.¹⁰ But an antibody-drug conjugate and a naked antibody have 2 different mechanisms of action, and we don’t necessarily know that we can extrapolate one to the other. To speak from personal experience, we have not recommended or used lenalidomide/tafasitamab in a patient whom we’re trying to take to CAR T-cell therapy, and I don’t know many transplant centers or CAR T-cell centers that would recommend lenalidomide/tafasitamab in a patient they plan to take to CAR T-cell therapy.

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