A 77-Year-Old Woman with DLBCL - Episode 6

Implications for Treating R/R DLBCL With the L-MIND Regimen

September 25, 2020
John M. Burke, MD

John M. Burke, MD: L-MIND is a study that led to the FDA approval of the combination of tafasitamab plus lenalidomide. What is tafasitamab? Tafasitamab is a humanized anti-CD19 monoclonal antibody. It has what’s called an engineered Fc portion of the antibody. There are 2 amino acid substitutions in the Fc portion that increase the binding affinity of that Fc portion to the Fc gamma receptors on effector cells like NK [natural killer] cells and macrophages. Tafasitamab leads to NK cell-mediated, antibody-dependent cellular cytotoxicity, or ADCC. It also leads to macrophage-mediated antibody-dependent cellular phagocytosis, or ADCP, and it can cause direct cell death of lymphoma cells.

Why combine tafasitamab with lenalidomide? As single agents, tafasitamab and lenalidomide don’t have great responses. There are responses, but the thought was they could provide better responses. Lenalidomide stimulates proliferation and activation of those NK cells that could mediate that ADCC. We know that in vitro, the combination of lenalidomide plus tafasitamab successfully increased NK cell-mediated ADCC compared with tafasitamab alone. That was the rationale to combine these 2 drugs, and that’s what led to the design of the L-MIND trial.

L-MIND was a phase 2 trial. Eligible patients had relapsed/refractory diffuse large B-cell lymphoma [DLBCL] and had been treated with 1 to 3 prior regimens. Patients with primary refractory DLBCL were excluded. Eighty-one patients were enrolled on the trial. All patients received the combination of tafasitamab plus lenalidomide. Tafasitamab is given intravenously on a weekly schedule for the first 3 months and then every other week thereafter. The dosing of lenalidomide was 25 mg by mouth daily on days 1 through 21 of a 28-day cycle. The combination was continued for a year, after which tafasitamab was continued alone. So, lenalidomide was stopped at 1 year.

The primary end point of the study was overall response rate. The patients enrolled had a median age of 72 years. They had a median number of prior therapies of 2, and almost half of the patients had received only 1 prior therapy. They weren’t the most heavily pretreated population. Forty-four percent of such patients were refractory to their previous therapy, and 11% of patients had received a prior autologous stem cell transplant.

The efficacy results were reported at a median of 27 months; this was the latest report as of EHA [the European Hematology Association annual meeting]. The overall response rate was 59%, the complete response rate was 41%, the median duration of response was 35 months, the median progression-free survival was 16 months, and the median overall survival was almost 3 years—32 months. Certainly, these are pretty good results for a relapsed/refractory lymphoma population.

In regard to toxicities, the most common hematologic toxicity was neutropenia. They saw grade 3 or 4 neutropenia in 48% of patients, febrile neutropenia in 12% of patients, and grade 3/4 thrombocytopenia occurred in about 17% of patients. Nonhematologic toxicities seen included rash, diarrhea, and fatigue. Serious adverse events occurred in 18% of patients. Infusion reactions were not common. They were reported in only 6% of tafasitamab-treated patients, so probably fewer infusion reactions with tafasitamab than things we’re used to, like rituximab.

Lenalidomide dose intensity was maintained fairly well. Seventy-eight percent of patients were able to stay on at least 20 mg per day, or higher. Dose reductions were required in 43% of patients.

Based on these results and also on the results of a retrospective comparison with lenalidomide alone called Re-MIND, the FDA saw fit to approve the combination of tafasitamab plus lenalidomide very recently.

The primary and secondary end point outcomes are fascinating. We saw an overall response rate of about 60%, and a complete response rate of about 40%. In the CAR [chimeric antigen receptor] T-cell results, we see complete remission rates of 50% to 70%. These results are fairly impressive for a salvage chemotherapy-type treatment. This isn’t conventional chemotherapy. I think people are pretty impressed by the data here. That said, it’s risky to compare across trials. You shouldn’t be doing it, because there are different patient populations in some of these different relapsed lymphoma trials. It’s possible that the drugs are just darn effective. They clearly are, but as I mentioned before, it wasn’t the most heavily pretreated population—with a median of 2 prior therapies but 49% of patients having received only 1 prior therapy. Again, there are other trials out there that have more heavily pretreated patients.

The other factor here is that they excluded primary refractory disease, which we know has a less favorable outcome and less chemotherapy sensitivity compared with patients who relapse a year later, like the patient in our case. While they excluded primary refractory disease, about 18% of the patients on the trial did have primary refractory disease that had relapsed between 3 and 6 months. But again, that factor might have impacted the response rates that we’re seeing. But, clearly it’s still an effective treatment that’s nice to have available for patients.

In terms of the toxicities, there’s a comparison between the toxicities that occurred on the combination part of therapy and the toxicities that occurred on the tafasitamab-alone arm after 1 year of therapy. You can see that the toxicities go down significantly for the patients who are on tafasitamab alone. A lot of the toxicities from this combination are coming from the lenalidomide. We think most of the neutropenia, certainly the rash, some of the diarrhea, may be coming from the lenalidomide. For doctors who are accustomed to treating patients with lenalidomide, as most of us are, we’re pretty good at it and we feel that lenalidomide has manageable toxicities. This is a relatively well-tolerated regimen that any oncologist should be comfortable giving once you get the hang of it.

Transcript edited for clarity.


Case: A 77-Year-Old Woman With DLBCL

Initial Presentation

  • A 77-year-old woman presented with loss of appetite, fatigue and shortness of breath
  • PMH: post-menopausal; DM, medically controlled
  • PE: palpable inguinal lymphadenopathy; splenomegaly
  • ECOG PS 1

Clinical Work-up

  • Labs: Hb 9.8 g/dL; all others WNL
  • FEV1 45 %
  • Hepatitis B, C and HIV negative
  • Core needle biopsy of the inguinal node: CD20-positive diffuse large B-cell lymphoma, non-GCB subtype. FISH panel: t(14;18) with a BCL2 rearrangement; no MYC or BCL6 rearrangement
  • Imaging:
    • Whole body PET/CT scan showed FDG avidity the inguinal lymph node region, largest node 3.3 cm; splenomegaly; and a small suspicious lung lesion
  • Bone marrow biopsy: involvement with DLBCL
  • Conclusion: stage IV DLBCL, non-GCB subtype
  • IPI score high-risk; CNS relapse score intermediate risk

Treatment

  • Treated with R-CHOP for 6 cycles
  • End-of-treatment PET/CT demonstrates a Deauville 2 complete remission
  • 1 year later while in surveillance she presents with new cervical, axillary, mediastinal, and abdominal lymphadenopathy
  • Core needle biopsy of an axillary node confirms a relapse of DLBCL, non-GCB subtype
  • Based on her age of 78 years and performance status, you consider her to be transplant-ineligible
  • You elect to initiate tafasitamab + lenalidomide