Background: NLPHL often affects young patients, who have an excellent prognosis irrespective of therapy and are frequently overtreated with cytotoxic therapies. 77% of causes of death of NLPHL patients treated in the trials HD7-HD15 with cytotoxic therapies and radiotherapy used for classical Hodgkin lymphoma (cHL) were non-NLPHL related. NLPHL expresses CD20 and is usually characterized by an indolent behavior, similar to B-cell indolent non-Hodgkin lymphomas. Mosunetuzumab is an anti-CD20/CD3 T-cell-dependent bispecific antibody with a complete response rate of 60% in relapsed/refractory follicular lymphoma. The discovery of novel efficacious targeted therapies for NLPHL is essential to avoid overtreatment, decrease toxicities, and improve patient quality of life.
Objectives: This study aims to compare the progression-free survival (PFS), safety and antitumor activity of mosunetuzumab versus rituximab in NLPHL patients.
Methods: We are conducting a phase II, randomized multicenter trial with either rituximab or mosunetuzumab of patients 18 years or older with previously untreated NLPHL stage IB to IV and previously treated NLPHL of any stage, requiring systemic therapy. Patients with transformed NLPHL and patients previously treated with rituximab will be ineligible. Patients will receive either rituximab (375 mg/m2 IV on Cycle 1 Day 1, followed by rituximab 1400 mg/hyaluronidase 23,400 units SC on C1D8-C2D22, 2 cycles of weekly rituximab 4x, 8 weeks apart) or mosunetuzumab (SC with step-up dosing Cycle 1 Day 1, 8, and 15 and Day 1 of subsequent cycles (5/45/45 mg), up to 8 cycles). Consolidative XRT for patients with stages I and II is optional, to be declared prior to randomization. The primary endpoint is the 2-year PFS for both arms. The secondary endpoints will include the response rate at the interim and EOT, landmark survival outcomes and safety. Exploratory analyses include assessing molecular response by sequencing cell-free DNA, RNAsequencing and whole exome sequencing. We base our sample size justification on a log rank test comparing PFS between the two treatment groups with assumed 2-year PFS rates of 50% (rituximab) versus 75% (mosunetuzunab) with a one-sided type I error rate of 10% and 85% power, accrual period of 3 years and the maximum trial duration of 5 years. The expected sample size is 56 under the null hypothesis and 62 under the alternative hypothesis. The study is open for accrual in the US and Canada since January 2024.
Raphael E. Steiner, Hun Ju Lee, Michael Green, Ruitao Lin, Chelsea Pinnix, Alison Moskowitz, Joachim Yahalom, Dai Chihara