Lenalidomide combined with tafasitamab in relapsed/refractory diffuse large B-cell lymphoma

Despite the approval of chimeric antigen receptor (CAR) T-cell therapies for patients with  relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who fail two or more treatments, and of polatuzumab vedotin in combination with bendamustine and rituximab, there are still multiple toxicity and manufacturing limitations associated with these regimens. Therefore, there is a great need for new treatment options, especially for patients who are ineligible for autologous hematopoietic stem cell transplantation (auto-HSCT) due to age or comorbidities.¹

In a study published in The Lancet Oncology, ¹ our Lymphoma Hub Chair, Gilles Salles, and colleagues investigated whether lenalidomide could be used synergistically with tafasitamab, an Fc-enhanced, humanized, anti-CD19 monoclonal antibody, to treat patients with R/R DLBCL. We hereby provide a summary of the efficacy and safety of this combined treatment as examined in the phase II L-MIND study (NCT02399085).

Methods

This study was a multicenter, prospective, open-label, single-arm phase II study that included patients from 35 hospitals in ten countries. Patients were eligible if they were ≥ 18 years old and had histologically confirmed DLBCL. Other inclusion criteria were defined as follows:

• R/R disease that occurred after 1−3 systemic regimens, one of which being anti-CD20
• Not candidates for high-dose chemotherapy
• Ineligible for auto-HSCT
• Eastern Cooperative Oncology Group (ECOG) performance status 0−2

Relapsed disease was defined according to the 2007 International Working Group criteria²

Key exclusion criteria included:

• Histological diagnosis of any other type of lymphoma
• Double- or triple-hit DLBCL
• Previous treatment with anti-CD19 therapy or immunomodulatory drugs, such as lenalidomide or thalidomide
• Primary refractory DLBCL with no progression during or within 6 months of frontline therapy
• Central nervous system lymphoma

Patients were treated with a combination of intravenous tafasitamab (12 mg/kg) and oral lenalidomide (25 mg/day), for ≤ 12 cycles (28 days/cycle). For the first three cycles, tafasitamab was administered weekly with an additional loading dose in the first cycle. After this, tafasitamab was given every 2 weeks. If specific protocol-defined toxicities occurred, a dose reduction of 5 mg/day of lenalidomide was performed once per cycle, while tafasitamab was interrupted. Patients with stable disease or better were then then treated with tafasitamab alone until disease progression.

The primary endpoint of this study was the proportion of patients achieving a complete response (CR) or partial response (PR). Disease control (CR + PR + stable disease), duration of response, time from first dosing to initiation of next therapy, progression free survival (PFS), and overall survival (OS) were examined as secondary endpoints.

Key findings

Of the 156 patients initially screened, only 81 were included in the study; the majority of exclusions were due to not meeting laboratory criteria, absence of relapsed or measurable disease, or medical history reasons, such as double-hit lymphoma. Patients were predominantly white (89%) and elderly, with a median age of 72 years. The key baseline characteristics are shown in Table 1.

Table 1. Baseline patient characteristics¹

There were discrepancies between immunohistochemistry and gene expression profiling with regard to the proportions of molecular DLBCL types; these can be partly explained by the fact that there was insufficient tumor tissue to perform the latter in 60% of cases (Table 1).

The response rates for patients treated with the tafasitamab and lenalidomide combination are shown in Table 2. In brief, out of the 80 patients who received the combination therapy, 60% achieved either a CR or PR (95% CI, 48−71). CR was achieved in 43% of patients (95% CI, 32−54).

Table 2. Response to treatment¹

The median follow-up was 13.2 months (interquartile range [IQR], 7.3−20.4), with the minimum follow-up length being only 0.5 months. A total of 37% of patients completed the full 12 cycles of tafasitamab and lenalidomide, and at data cut off, 35% were still receiving tafasitamab monotherapy. Treatment discontinuation occurred in 50 patients; 45 discontinued the combination therapy during Cycles 1−12 (there were 32 disease progression discontinuations, 8 adverse events, 2 deaths, 2 withdrawals, and 1 other), four patients stopped lenalidomide in the same period, and one stopped tafasitamab due to adverse events.

Secondary endpoints

Disease control (CR + PR + stable disease) was reached in 74% of patients (95% CI, 63−83), and the median time to initial response was 2.0 months (IQR, 1.9−3.1).

The median exposure to lenalidomide–tafasitamab combination therapy was 9.3 months (IQR, 0.2−32.1), while the median duration of exposure to combination therapy or lenalidomide was 6.2 months (IQR, 2.1−10.9). The median exposure to tafasitamab monotherapy was 4.1 months (IQR, 0.4−12.6).

Of the 48 patients (60%) who achieved CR or PR, the median duration of response was 21.7 months (95% CI, 21.7−not reached). For those achieving CR (n = 34), the median duration was not reached and 93% had a response lasting 18 months (95% CI, 75−98).

In terms of PFS events, 49% experienced disease progression or death. Median PFS was 12.1 months (95% CI, 5.7−not reached) after a median follow-up of 17.3 months. Following lenalidomide discontinuation, median PFS reached 12.7 months (95% CI, 2.3−not reached).

At a median follow-up of 19.6 months (IQR, 15.3−21.9), median OS was not reached (95% CI, 18.3−not reached), and 64% of patients remained alive at 18 months.

Adverse events

No new safety signals were identified for the drug combination or for either single agent compared with their known safety profiles. All 81 patients experienced treatment-emergent adverse events (TEAEs), with neutropenia being the most common (49%, all grades, Table 3). Neutropenia was also the most common Grade 4 TEAE experienced. The next most frequent Grade 3 or higher TEAEs were thrombocytopenia, febrile neutropenia, leukopenia, anemia, and pneumonia. Over half of patients experienced severe adverse events (51%), mostly frequently pneumonia (6%), febrile neutropenia (6%), pulmonary embolism (4%), bronchitis (2%), atrial fibrillation (2%), and congestive heart failure (2%).

Table 3. Key treatment-associated adverse events¹

Serious adverse events with special interest occurred in 9% of patients and included three tumor flare events, one Grade 2 basal cell carcinoma, and three Grade 3 allergic dermatitis events. During the study treatment period, 10% of patients died with a further 27% dying post-treatment. Of these 30 deaths, 77% were associated with disease progression. Fatal adverse events occurred in 13% of patients with none of them being considered as treatment related.

Conclusion

In this population of patients with R/R DLBCL who are ineligible for auto-HSCT, the combination of tafasitamab and lenalidomide led to an overall response rate of 60%, with 43% of patients achieving a CR. Generally, the treatment was well tolerated and provides further options for patients with R/R disease. Other options for this group of transplant-ineligible elderly patients include CD19 CAR T-cell therapy, but this is associated with high cost, significant toxicity, and specialized centers for treatment delivery. Therefore, this novel combination is a promising addition to the therapeutic options for patients with R/R DLBCL who are elderly and transplant ineligible.