Dosing and Management: Optimal Use of Tafasitamab/Lenalidomide for Relapsed DLBCL

Bruce D. Cheson, MD (Moderator)

Hematologist/Oncologist

The Center for Cancer and Blood Disorders

Bethesda, MD

CASE SUMMARY

A 68-year-old man presented with fatigue, back pain, and lymphadenopathy. He had a prior 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. A PET-CT scan showed multiple enlarged mesenteric and retroperitoneal nodes, the largest measuring 5.3 × 3.1 cm. A biopsy confirmed diffuse large B-cell lymphoma (DLBCL), nongerminal center. Immunohistochemistry was positive for CD20, BCL6, BCL2 (50% of cells), MYC (> 30% of cells), Ki67 85%, and MUM1; negative for CD10. Fluorescence in situ hybridization was negative for translocations involving MYC, BCL2, and BCL6.

Laboratory results showed a normal complete blood count but elevated lactate hydrogenase levels. He received a diagnosis of stage III DLBCL with International Prognostic Index high-intermediate risk. His ECOG performance status was 1. He received 6 cycles of R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, prednisone), and his back pain resolved. At the end of treatment, a PET scan showed a complete response (CR) with Deauville score of 2.

Eight months later, he presented with 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, and multiple metabolically active lesions in lymph nodes of the retroperitoneum, abdomen, and pelvis. A biopsy showed relapse of DLBCL.

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

CHESON: Have you used tafasitamab plus lenalidomide?

STEFANOVIC: Yes, I have.

CHESON: What is your experience with it?

STEFANOVIC: It hasn’t worked, but I have used lenalidomide by itself and it has worked. It is not possible for me to tell if that was just coincidence or if lenalidomide is the more active component here. But I use lenalidomide as a bridge to CAR T-cell treatment.

CHESON: That’s an interesting observation. They did a propensity analysis of the L-MIND [NCT02399085] regimen [tafasitamab plus lenalidomide] vs lenalidomide alone [the RE-MIND study; NCT04150328]. RE-MIND had a higher complete overall response rate [ORR], progression-free survival, and overall survival.¹ So some of this may be patient selection or bad luck.

ARCE-LARA: I haven’t used it. But if a patient has severe neutropenia, which medicine are you going to cut on dose?

CHESON: Lenalidomide. There was an interesting analysis where they showed the various toxicities during the first 12 months of tafasitamab plus lenalidomide. And then they showed the toxicities after you drop the lenalidomide and the patient is just on tafasitamab maintenance, and pretty much everything went away [Figures 1 and 2²]. Most of the toxicities in the combination are lenalidomide related. They start with a pretty hefty dose of lenalidomide, 25 mg. But 80% of patients are still able to stay on at least 20 mg of the drug [Table³]. It is not surprising [that] patients get some neutropenia because of the lenalidomide.

ARCE-LARA: I had a similar experience. I had to drop the lenalidomide after the second cycle, and the patient didn’t want to dose reduce [though he had] adverse events [AEs] and cytopenias. But for the rest of the treatment he did well. The progression was rapid; he progressed within 4 to 5 months, but [there were] significant cytopenias at the beginning.

MCKINNEY: We have active therapy at Duke [Cancer Center in Durham, North Carolina]. I’ve had a pretty good experience [with] responses I don’t think you’d see with…any other lenalidomide combination you can think of, so I think it is very active. I’ve had some second-line older patients for whom we weren’t going to do aggressive therapy [who received tafasitamab plus lenalidomide]. I’ve had dramatic long-term responses, [as were] described.

CHESON: The L-MIND study, which got this regimen approved, was a phase 2, single-arm, open label, multicenter study in patients who had 1 to 3 prior regimens and were considered not eligible for stem cell transplant. Primary refractory patients were supposed to be excluded, but [some who relapsed between 3 and 6 months] weren’t excluded [prior to a protocol amendment].³

The tafasitamab and lenalidomide were given according to this schedule: [12 mg/kg] tafasitamab on days 1, 8, 15, and 22 for cycles 1 to 3, except for cycle 1 where it was also given on day 4. From cycle 4 to 12 and thereafter it was given twice monthly, [which was] great during the COVID-19 [pandemic]. Lenalidomide’s dose [was] 25 mg/kg daily on days 1 to 21 [each cycle for 12 cycles].

BHIMANI: If [a patient was] not able to tolerate the [reduced] dose of 20 mg lenalidomide, was there any further decrease?

CHESON: Yes, you can go down to 15 mg. There were patients [who] did have durable responses.³ I’m not sure I would go below 15 mg. If I had to go below that, I’m pretty much just giving the antibody, and so I’d switch to something else.

ARCE-LARA: If the patient is very symptomatic or becoming very symptomatic, eg, pleural effusions, etc, and you want a faster response, is that going to change your recommendation for second-line therapy?

CHESON: Yes. This is designed for relapsed patients. If you have someone who’s [progressing] quickly, I would consider something else first and save this for another relapse.

CHESON: [In the L-MIND trial], neutropenia was seen in approximately 45% of patients, grade 4 in approximately 20%.³ But as far as the other hematologic toxicities, you don’t see much grade 4. They also saw 12% grade 3 thrombocytopenia. In terms of [nonhematologic] toxicities, there were very few grade 4, a few grade 3, and those were mostly due to the lenalidomide. Serious AEs occurred in about half the patients, [but] serious treatment-related AEs occurred in less than 20% [of patients]. The therapy was discontinued because of an adverse event in only 12%. Treatment-emergent AEs occurred in 13% of patients; most were infectious.

KAHN: From a personal experience, my patient didn’t have any of the adverse events that were described [but] they didn’t respond very well.

CHESON: You raise an important issue: If you use it once and have a bad experience, you are not going to use it again. Now that [we have discussed] the efficacy and safety data, perhaps you will try it again in [a patient] who is appropriate for it, and then see how you like it.

LITAM: I agree that in patients who are very symptomatic, it is probably not a good regimen because the patient needs to be treated right away or needs to have the symptoms under control. But for somebody who is relapsed and probably can wait for a month or 2 for response, then it will be a good regimen.

CHESON: [In the RE-MIND study], they took patients from the L-MIND study and did a match comparison of approximately 9 covariates, and they showed that the ORR for tafasitamab plus lenalidomide was 67%, lenalidomide alone was 34%, and everything else was better.¹ The CR rate was 40% vs 13%. So in this analysis, tafasitamab plus lenalidomide appears to be significantly better than lenalidomide alone. In the original exploration of tafasitamab, the ORR was 26% as a single antibody.⁴

BHIMANI: I don’t see any barrier, per se.

CHESON: Let me suggest [that use of] lenalidomide [can be] a barrier.

BHIMANI: Yes, lenalidomide is a challenging drug. That is why I asked about [using] 15 mg. Since it is a 21-day cycle, were there any [data] on the growth factors used to keep the patients on the regimen?

CHESON: There were [36 of 81 patients (44%)] who had growth factor support.³

BHIMANI: Short of that or getting tafasitamab approved in the second line, I don’t see any other barrier. The data seem very impressive. Concerning the phase 2, single-arm, clinical trial data response rate of 57% [in L-MIND] vs 67% [in RE-MIND], I have been finding this in other trials where real-world data are coming out. Which one should we rely on more? Because sometimes I am seeing the real-world data are disproportionally very impressive, but I don’t know how the data are captured or who is collecting these data. I don’t know which [are more] reliable.

CHESON: They [currently] are doing the realMIND study [NCT04981795] where they are capturing [data from] hundreds of patients; it’s a [prospective observational study]. Patients [who are initiating] any treatment in second and [or third] lines are participating in this study. They are capturing the data and trying to see if [these treatments] still look better than loncastuximab [Zynlonta], gemcitabine/oxaliplatin, or whatever else patients are getting. Hopefully we will see these data soon.

Which would I rely on more? I’d have to think about that, since the phase 2 L-MIND study had 81 patients. This is likely to be hundreds of patients. Will that be more reliable? Hopefully it will be consistent with this study. I’d have to see what the data look like and [who the participants are].

Clinical trial data are different from real-world data. The patients [must] have [better performance status], and real-world [patients] are whoever walks in your door. I think [real-world data] are more applicable to your practice. [But] under the best of circumstances this is what you can get, and so you can use that perspective to use it as you will.

Is there anybody who would [avoid] using CAR T-cell therapy after tafasitamab/lenalidomide?

MCKINNEY: I don’t think we know enough….I’d avoid CD19 if I’m definitely going to do CAR T-cell therapy. I am not that worried about it.

[Another] barrier is patients who do not have an oral prescription benefit. There may be out-of-pocket costs or financial toxicity. And then [what about] about the schedule of indefinite therapy every 2 weeks [beyond] the first year? [My patients] have enough success to have discussions about discontinuing tafasitamab at some point.

CHESON: Yes, lenalidomide can be expensive. As far as [giving tafasitamab] every other week [indefinitely], I find my patients fall into 2 obvious groups. One says, “I’m tired of this,” and the other says, “I’m in remission. Let’s keep doing it.” It is a personal decision to work out with your patients. There are some patients who have come off for toxicity and remained in remission. As far as retreatment, [I have] an anecdote of a patient who stopped, got retreated after they progressed, then went into remission again, but [an] anecdote is not data; it is a personal decision.

_REFERENCES

_{1. Zinzani PL, Rodgers T, Marino D, et al. RE-MIND: comparing tafasitamab + lenalidomide (L-MIND) with a real-world lenalidomide monotherapy cohort in relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res. 2021;27(22):6124-6134. doi:10.1158/1078-0432.CCR-21-1471}

_{2. Salles G, Duell J, González Barca E, et al. Primary analysis results of the single-arm phase II study of MOR208 plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (L-MIND). Hematol Oncol. 2019;37(S2):173-174. doi:10.1002/hon.130_2629}

_{3. 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}

_{4. Jurczak W, Zinzani PL, Gaidano G, et al. Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma. Ann Oncol. 2018;29(5):1266-1272. doi:10.1093/annonc/ mdy056}