ASH 2023: Novel treatment options for patients with high-burden newly diagnosed FL

The current standard of care for patients with newly diagnosed high-burden follicular lymphoma (FL) is chemotherapy plus anti-CD20 antibodies. Although this regimen has proven to be effective, it is associated with substantial toxicities and some patients experience early relapse; therefore, there is a need for novel therapies to improve outcomes and safety in this high-risk population.^1–3

In this article, we summarize three key presentations on the treatment of newly diagnosed high-burden FL, presented during the 65th American Society of Hematology (ASH) Annual Meeting and Exposition.

Ysebaert presented outcomes of tazemetostat plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) from the Epi-RCHOP study,¹ Falchi presented results of subcutaneous mosunetuzumab from a phase II study,² and Morschhauser presented safety and efficacy outcomes of mosunetuzumab plus lenalidomide from a phase 1b/II trial.³

Epi-RCHOP: Tazemetostat plus rituximab¹

Epi-RCHOP (NCT02889523) is a phase II study investigating tazemetostat plus R-CHOP and rituximab maintenance in patients aged 18–80 years with newly diagnosed FL Grade 1–3A, and a Follicular Lymphoma International Prognostic Index score of 3–5. Treatment consisted of induction with six cycles of R-CHOP, two cycles of rituximab alone plus 800 mg of tazemetostat twice daily from Day 2, Cycle 1 followed by maintenance 1 (one to three cycles of tazemetostat + rituximab) and maintenance 2 (4–12 cycles of rituximab alone). The primary endpoint was complete metabolic response (CMR) at the end of induction assessed by investigators.

Results

Of the 74 patients who were enrolled between April 2020 and August 2022 across 23 Lysa sites in France and Belgium, 62 patients were included in the full analysis set.

• The CMR rate was 53.2%, with a higher CMR rate observed amongst patients with mutated EZH2 vs wild-type (73.3% vs 46.8%, respectively)

• Among patients in partial metabolic response, the CMR (assessed by bone marrow involvement by central positron emission tomography review) increased to 74.2%
• Among patients assessed by positron emission tomography considering only lymphoid and organ responses, the CMR increased to 79%

• At median follow-up of 19 months, the 18-month progression-free survival (PFS) was 89.3%

• There was no impact of EZH2 status on PFS

• Overall, seven patients experienced disease progression, five of whom received a new line of therapy
• There were a total of two deaths in the study due to lymphoma (n = 1) and COVID-19 (n = 1)

The rate of hematologic toxicities was consistent with that of R-CHOP regimens, these did not significantly change with the addition of tazemetostat. The most common non-hematological toxicities were peripheral neuropathy (35%) and gastrointestinal hypomobility (40%); the rate of these events decreased once the vincristine dose was capped at 1 mg.

Presenter’s conclusion

In this first trial of tazemetostat plus R-CHOP for patients with newly diagnosed high-risk FL, the primary endpoint of 80% was not met but encouraging efficacy was reported for patients harboring the EZH2 mutation. This combination had an acceptable safety profile and the overall tolerability improved after the vincristine dose was reduced.

Subcutaneous mosunetuzumab²

This is a multicenter phase II study (NCT05389293) evaluating single agent, fixed duration subcutaneous (SC) mosunetuzumab as first-line therapy in patients aged ≥18 years with CD20⁺ FL Grade 1−3A, and an Eastern Cooperative Oncology Group Performance Status of 0−2. Treatment consisted of a step-up dosing regimen with SC mosunetuzumab administered at a dose of 5 mg on Day 1 and then 45 mg on Day 8 and Day 15 of Cycle 1 followed by 45 mg on Day 1 of each subsequent 21-day cycle.

The primary endpoint was complete remission (CR) per Lugano criteria. Secondary endpoints included overall response rate (ORR), treatment-emergent adverse events (TEAE), PFS, duration of response, time to next treatment, and overall survival.

Results

Of the 56 patients enrolled, 45 were included in the efficacy analysis. At a median follow-up of 5.8 months, four patients discontinued therapy due to disease progression (n = 1) and AE (n = 3). The ORR was 96%, with a CR rate of 76%, most of which were achieved early; these responses were consistent across different risk groups.

No new safety signals were observed with a consistent TEAE profile to that seen within the relapsed/refractory setting. The most common TEAEs were injection-site reaction, cytokine release syndrome (CRS), skin rash, fatigue, and liver enzyme elevation. The incidences of CRS were mostly Grade 1, all were resolved with a median time to resolution of 22 hours, only two patients required treatment with corticosteroids and tocilizumab, and most were in C1D1. There were no cases of immune-effector cell-associated neurotoxicity syndrome or tumor lysis syndrome reported.

Presenter’s conclusion

Subcutaneous mosunetuzumab yielded high and deep responses in patients with newly diagnosed high-burden FL. It also demonstrated a manageable safety profile with low-grade CRS and no neurotoxicities reported, thus supporting further exploration of this treatment as a first-line therapy in this high-risk population. Longer follow-up is needed to confirm the durability and safety.

Subcutaneous mosunetuzumab plus lenalidomide³

This is an ongoing phase Ib/II trial (NCT04246086) of SC mosunetuzumab plus lenalidomide in patients in patients aged ≥18 years with previously untreated CD20⁺ FL Grade 1−3A, and an Eastern Cooperative Oncology Group Performance Status of 0−2. Mosunetuzumab was administered in up to 12 cycles in a similar step-up dosing described above alongside 11 cycles of lenalidomide at 20 mg on Days 1–21 of Cycles 2−12. The primary endpoints were safety and tolerability, and the secondary endpoint was efficacy.

Results

At a median follow-up of 5.2 months, the best ORR was 91.9% and the CR rate was 89.2% amongst efficacy evaluable patients (n = 37). All patients who responded were still in ongoing response at the data cut-off. Early and sustained CD8⁺ T-cell activation was observed with this combination.

Treatment-related serious AEs were seen in 32.5% of patients and Grade 3 and 4 AEs were reported in 55% of patients, most of which were related to neutropenia. The most common AE were injection-site reaction, rash, CRS, and neutropenias.

The CRS incidences occurred in 50% of the patients and were mostly Grade 1, occurred in Cycle 1, all were resolved, and none required vasopressors, supplemental oxygen, or ICU admission. Similarly, injection-site reactions were mostly Grade 1 (40%) and Grade 2 (22.5%) and most occurred between Cycle 1 and Cycle 2 and did not lead to treatment discontinuation.

Presenter’s conclusion

This ongoing study demonstrated a promising efficacy and manageable safety profile of SC mosunetuzumab plus lenalidomide in patients with frontline FL; these data support the further exploration of this combination regimen in this patient population. A phase III study investigating this combination vs standard of care is currently being planned.