Abstract
Background: Diffuse Large B cell Lymphoma (DLBCL) is the most common type of non-Hodgkin Lymphoma (NHL), with R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) serving as the established first-line treatment regimen. Despite a 5-year survival rate approaching 70%, a significant portion of patients, approximately one third, fails to achieve a satisfactory response, leading to dismal prognosis (Coiffier and Sarkozy 2016). Previous studies indicated that for those with specific gene mutations, R-CHOP demonstrated limited efficacy. However, promising response rates with BTKi suggests the potential for combined therapeutic regimens within this patient cohort (Wilson, Young et al. 2015).
Aims: This single-center, single-arm phase II clinical trial aims to assess the efficacy and safety of ZR-CHOP regimen in treatment-naïve DLBCL patients with activation of the BCR signaling pathway, and who harbor mutations in any of the following genes: MYD88, CD79B, NOTCH1, TP53, or c-Myc gene translocation which may cause a worse outcome.
Methods: DLBCL patients aged 18-75 years with activation of the BCR signaling pathway, and who harbor mutations in any of the following genes: MYD88, CD79B, NOTCH1, TP53, or c-Myc gene translocation will be enrolled. They will undergo 1 cycle of R-CHOP and 5 cycles combined treatment with zanubrutinib and R-CHOP (ZR-CHOP). The primary endpoint will be the 3-year progression free survival (PFS). Secondary endpoints will encompass objective response rate (ORR), 3-year event free survival (EFS), overall survival (OS), and safety parameters. The Lugano (2014) criteria will be employed for assessing treatment outcomes.
Results: From February 2022 to April, a total of 62 subjects were recruited and treated according to the protocol. 59 completed treatment and had a tumour assessment. Among these, 25 patients were MCD, 3 patients were N1, 16 were A53, 10 were others by LymphGen algorithm, and 4 patients had Myc translocation. Out of the 58 subjects, 53 exhibited a response to the combined therapy, resulting in an ORR of 91.4% (53/58). The complete response rate (CR) is 79.3% (46/58). Notably, 21 (84%) subjects with MCD achieved complete metabolic response (CMR). After a medium follow up of 27 months, The estimate 3-year PFS rate was 82.2% (refer to Figure 1), with a subgroup analysis suggesting a 3-year PFS rate of 96.2% in MCD subtype. The overall 3-year OS rate was 89.1%, with a 3-year OS rate of 100% observed in MCD subtype and in subjects with MYC translocation only, also a 2-year OS rate of 33.3% observed in N1 subtype.
Out of 62 enrolled subjects, 55.9% (33/59) experienced AE, with 6 subjects dying from disease progression. Remarkably, there have been no cardiovascular adverse events reported, and the incidence of atrial fibrillation is 0. In addition, 18.6% (11/59) of the subjects reported grade 3 or higher treatment-related AEs, including neutropenia (n=5), myelosuppression (n=4), leukopenia (n=2) and thrombocytopenia (n=1).
Summary/ conclusion: The preliminary results of this phase II clinical trial have shown encouraging antitumor activity of R-CHOP combined with zanubrutinib in DLBCL patients who harbouring MCD subtype. In addition, our findings also suggest an acceptable safety profile for the combined regimens.
