R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy in newly diagnosed diffuse large B-cell lymphoma (DLBCL) leads to 40 to 90 percent long-term remission rates, depending on the international prognostic index (IPI) risk score.1 When patients relapse after R-CHOP, outcomes are typically poor. Second-line combination chemotherapy regimens that include a platinum agent have response rates of approximately 50 to 60 percent.2 Patients with chemosensitive disease and without significant comorbidities are then consolidated with high-dose chemotherapy and an autologous hematopoietic stem cell transplant (SCT).3 However, in patients who do not respond to second-line therapy or those who relapse after autologous SCT, only approximately 25 percent of transplant-eligible patients attain a durable remission. For the remaining patients, the CD19 chimeric antigen receptor T-cell (CAR-T) therapies axicabtagene ciloleucel (axi-cel) and tisagenlecleucel are now considered standard of care. However, 60 percent or more patients will not obtain durable responses after CAR-T therapy.4,5 New therapies are clearly needed.
L-MIND is an international multicenter phase II clinical trial that combines an investigational Fc-enhanced humanized anti-CD19 antibody, tafasitamab (MOR208), with the oral immunomodulatory agent lenalidomide for adult patients with relapsed DLBCL. Patients with disease relapse following one to three lines of systemic therapy were eligible. Double-hit patients were excluded, as were primary refractory patients relapsing within three months of frontline therapy (later amended to 6 months). All patients had previously received R-CHOP as one of their prior lines. On trial, patients received up to one year of both tafasitamab (12 mg/kg every 2 weeks) and lenalidomide (25 mg daily, 21/28 days) followed by tafasitamab monotherapy until progression. A total of 156 patients were screened, with 80 patients going on to receive both tafasitamab and lenalidomide.
The combination regimen was tolerable, with the most common treatment-emergent adverse events (AEs) of grade 3 or worse including neutropenia (48%), thrombocytopenia (17%), and febrile neutropenia (12%). These AEs were managed by lenalidomide dose reduction. Serious AEs occurred in 51 percent of enrolled patients, with pneumonia (6%) and febrile neutropenia (6%) being the most common. Other AEs were less severe, though diarrhea (33%) and rash (36%) were common. With a median follow-up of 13.2 months, the objective response rate was 60 percent (48/80 patients; 95% CI, 48-71), and the complete response rate was 43 percent (34/80 patients; 95% CI, 32-54). Median progression-free survival (PFS) was 12.1 months, and patients continued to respond to tafasitamab monotherapy after lenalidomide completion. Longer follow-up is required, but relapses seemed uncommon in patients observed beyond one year.
L-MIND patients were enriched for those ineligible for standard therapy with autologous SCT (with age 70 years or older as one criterion for transplant ineligibility) and those with lower lymphoma risk at relapse. For example, the highest-risk patients at relapse include those with primary refractory disease (especially those who do not respond to R-CHOP or who relapse within 3 months) or double-hit genetics (translocations of Myc and BCL2 and/or BCL6).6 The L-MIND study excluded patients with these high-risk characteristics. Furthermore, half the patients on trial had a low IPI score of 0-2, which is a good risk feature. Most clinical trials for relapsed DLBCL do not specifically exclude high-risk patients.
It is difficult to generalize the results of this trial to the broad relapsed/refractory DLBCL patient population because of the enrichment for patients with a lower risk of relapse. However, considering this caveat, we can contrast to patient populations treated with alternative approved treatments. First, with the CAR-T therapy axi-cel, PFS and durable remission rates are higher for patients who do not have primary refractory disease, and outcomes are not worse in older patients.7,8 Similarly, patients treated with polatuzumab vedotin, bendamustine, and rituximab do well across lower-risk patient subgroups.9 Therefore, while it is impressive that the combination of tafasitamab and lenalidomide leads to some durable responses, it is not clear that it is the best option even for the narrowly defined group of patients treated on L-MIND who were low-risk and transplant ineligible. Furthermore, a year of lenalidomide followed by indefinite tafasitamab maintenance might impact patient quality of life for a longer period than other approved therapies. However, as a nonchemotherapy option that is likely straightforward to use in the community setting, tafasitamab and lenalidomide could benefit some patients with low-risk DLBCL relapses. A final consideration is that both tafasitamab and approved CAR-Ts target CD19. It is unknown whether tafasitamab use after one or more lines of therapy would limit future CD19 CAR-T options owing to shared resistance mechanisms. Overall, the treatment options for relapsed/refractory DLBCL continue to expand. Appropriate selection of therapy based on risk factors, and the sequencing or combination of these therapies, will require further exploration.
Dr. Jain and Dr. Locke indicated no relevant conflicts of interest.