The efficacy of Obinutuzumab , zanubrutinib combined with pomalidomide and Venetoclax for the treatment of high-risk mutated Mantle Cell Lymphoma (MCL): A prospective, open-label, single-arm study

Abstract High-risk MCL lacks effective treatment options and has a poor prognosis, posing challenges in management. The guidelines recommend clinical trials as the first choice, the combination regimens of multiple targeted agents have become a common clinical option, yet no standardized regimen has been established. We investigated the application of Obinutuzumab, Zanubrutinib combined with Pomalidomide and Venetoclax for the treatment of high-risk MCL to provide a new treatment evidence for clinical practice. This was a prospective, single-center, clinical study. All patients receive Obinutuzumab (1000 mg d1), Zanubrutinib (160mg bid) combined with Pomalidomide (4mg, d1-14) and Venetoclax (200mg, d1-14) for 6 cycles, every 28 days as a cycle. If the treatment is effective, patients receive Obinutuzumab (1000 mg d1, every 3 months/time) combined with Zanubrutinib (160mg bid) for 2 years and Pomalidomide (4mg, d1-14) and Venetoclax (200mg,d1-14 ) for 1 year as maintenance therapy. The primary endpoint was overall response assessed by Lugano criteria. Minimal residual disease was assessed by NGS in blood. The study enrolled 15 high-risk patients with previously untreated MCL (12 patients) or relapsed/refractory MCL (3 patients), who harbored at least one of the following risk factors: blastoid variant, TP53 mutation, or TP53 deletion. Patients were 44 to 78 years with a male-to-female ratio of 4:1. 80% patients were high-risk/high-intermediate risk prognostic score of MIPI-c. 73.3% of patients were blastoid variant and 66.7% had a higher ki67≥50%. 66.7% had TP53 aberration and 53.3% had TP53 aberration combined with high-risk within gene mutations. The complete response rate at 6 course was 86.7% and the overall response rate was 100%. 12 patients underwent MRD testing after 6 cycles of treatment, and MRD negative was confirmed in 100% of the patients by NGS. The most common grade 3-4 adverse events were neutropenia (in 9 [60.0%] of 15 patients), thrombocytopenia(in 3 [20.0%] of 15 patients), infections (in 2 [13.3%] patients). Conclusions Our results provide preliminary evidence that the quadruple-drug combination of Obinutuzumab, Zanubrutinib combined with Pomalidomide and Venetoclax is an active regimen in high-risk MCL, and should be evaluated in a prospective randomised controlled trial.