Anti-PD-1 Antibody (Tislelizumab) Combined with R-CHOP for the Treatment of Previously Untreated Primary Mediastinal B-Cell Lymphoma: A Prospective Phase II Study

Background: Primary mediastinal B-cell lymphoma (PMBCL) is a rare aggressive B-cell lymphoma of thymic origin. Due to the low incidence rate of PMBCL, there is currently no internationally accepted standard first-line treatment regimen. Dose-adjusted (DA) EPOCH-R which is the more commonly used first-line therapy plan is not so effective because patients usually cannot tolerate it. The R-CHOP regimen is comparable to the R-DA-EPOCH for the first-line treatment of PMBCL in terms of survival and has a better safety profile (Bhatt, V.R. et al, Cancer Treat Rev 2015; Iwanicka el al., Curr Hematol Malig Rep 2014). Meanwhile, patients with PMBCL usually have alterations of 9p24.1, leading to overexpression of PDL-1/2. Previous studies have found that PD-1 monoclonal antibody shows good efficacy in recurrent and refractory PMBCL (Steidl et al., Blood 2011; Zinzani et al., Blood 2017). Tislelizumab, a humanized IgG4 antibody that binds PD-1 with high affinity, minimizes binding to Fcγ receptor 1 (FcγRI) on macrophages by the genetic engineering of Fc segment, abrogating antibody-dependent phagocytosis (ADCP)-induced T-cell clearance. The efficacy and safety of its combination with R-CHOP in previously untreated PMBCL is not yet clear. We speculate that the combination of both may be a new option for the first-line therapy for PMBCL patients with good efficacy and low toxicity.

Methods: This is a single-arm, multi-center, phase II clinical study (ChiCTR2100044313). Patients aged 18 years or older with a diagnosis of PMBCL and previously untreated were eligible. Eligible patients received 6 cycles of Tislelizumab (200 mg D1), Rituximab (375 mg/m ² D1), Cyclophosphamide (750 mg/m ² D2), Pirarubicin (50 mg/m ² D2), Vincristine (1.4 mg/m ², maximum dose 2 mg, D2), Prednisone (100 mg/d D2-6), every 21 days for 1 cycle. Disease response assessments were performed by positron emission tomography and computed tomography (PET-CT) or enhanced CT every two cycles, meanwhile peripheral blood ctDNA was monitored, and treatment-related adverse effects were assessed and recorded. The primary endpoint was objective remission rate (ORR). The secondary endpoints included treatment safety, progression-free survival (PFS) and overall survival (OS), and the exploratory analyses of the correlation between PD-L1 expression in tumor tissues, tumor-associated macrophages (TAM) phenotype in tumor microenvironment and efficacy.

Results: From June 2020 to June 2023, 12 patients were enrolled and 9 patients had evaluable efficacy with the median age of 34 years, 3 males and 6 females, all patients had large mediastinal mass at initial diagnosis. 7 patients had PD-L1 expression (VENTANA SP263) above 80% and 2 cases could not be further tested due to insufficient tissue specimens. The ORR was 100%, and the CR rate was 77.8% (7/9) after 6 cycles of treatment. The 5 ^th and 9 ^th patient reached PR after 6 cycles of treatment due to irregular hospitalization. And CR was achieved after 2 cycles of regular treatment for the 5 ^th patient. NGS from formalin-fixed paraffin-embedded (FFPE) and circulating tumor DNA (ctDNA) evaluation from blood were performed across all patients before treatment. 5 patients underwent end of treatment-ctDNA test. Median follow-up 15m (6.8m-26.3m), the third patient was lost to follow-up at 9m. The other patients who achieved CR are still at complete remission. Moreover, we found SOCS1, TNFAIP3 are the most frequently mutated genes in biopsies of PMBCL and only the 5th patient had RHOA mutation which is highly related to PMBCL. The PET-CT and ctDNA assessments were negative in three patients at the end of 6 cycles with 60% concordance, and the 5 ^th and 9 ^th patient achieved PR on PET-CT, but the ctDNA assessments were negative. The most common adverse events (AEs) were gastrointestinal reactions, 2 patients experienced grade IV myelosuppression and 1 patient had grade I hyperthyroidism. No treatment-related deaths occurred.

Conclusion: Tislelizumab combined with R-CHOP for the treatment of previously untreated PMBCL had good efficacy and sustained response with low toxicity. Longer follow-up is required to access the survival benefit of this regimen.

Figure 1: Disease Remission in the Included Patients