Orelabrutinib Plus R-CHOP Regimen in Treatment-Naïve Patients with TP53-Mutated Diffuse Large B-Cell Lymphoma (DLBCL)

Background: TP53-mutated DLBCL may be refractory to rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). The A53 subtype was reported to be sensitive to Bruton's tyrosine kinase inhibitors (BTKi). Orelabrutinib (O), a novel BTKi with high selectivity for B-cell lymphomas, combined with R could produce higher anti-tumor effects. O plus R-CHOP-like regimens have shown an encouraging efficacy and acceptable safety in the first-line therapy of DLBCL. Methods: This study retrospectively collected data on the efficacy and safety of patients (pts) with TP53-mutated DLBCL who received OR-CHOP-based regimens as the first-line therapy between Mar 2021 and Mar 2023. The primary endpoint was complete response (CR) rate at the end of treatment (EOT). Results: Seven pts (4 males; median age, 56.0 years) were included. Key baseline characteristics included 71.4% IPI score 2-5, 57.1% Ann Arbor stage III-IV, 57.1% non-GCB, 28.6% ECOG PS 2-3, 42.9% MYD88&CD79B co-mutations, 57.1% extranodal lesions, 14.3% HBV and 0% EBV. Two pts had transformed DLBCL from follicular lymphoma. Of 7 pts, 5 pts received OR-CHOP, 2 OR-CHOP plus lenalidomide. With a median follow-up of 9.1 months (range, 3.5-11.8 months), 4 pts completed first-line therapy and 1 died due to progressive disease after 2.5-month discontinuation of medication for economic reasons. Of these 5 pts, 4 (80.0%) achieved a CR at the EOT. During the whole therapy, 4 of 7 (57.1%) pts had a CR as best response; 2 (28.6%) pts with a PR remained on treatment (Table 1 and Figure 1). As cut-off date (March 26, 2023), median progression-free survival and overall survival were not reached, with 12-month PFS rate of 80.0% and 12-month OS rate of 75.0%. Most common adverse events (AEs) of any grade were erythropenia (6 [85.7%]), infection (5 [71.4%]), fever (4 [57.1%]), and anemia (4 [57.1%]), with 71.4% grades 3-4. AEs associated with BTKi off-target activities such as atrial fibrillation, hypertension, and hemorrhage were not reported. Conclusions: These data supported that OR-CHOP-based regimens had favorable anti-tumor activity and manageable safety profile in pts with TP53-mutated DLBCL. BTKi related off-target AEs were rarely observed. More prospective studies are warranted to validate our findings.