Pomalidomide, Rituximab, Orelabrutinib, and Minichop-like (PRO-miniCHOP) in Elderly Patients with Newly Diagnosed Diffuse Large-B Cell Lymphoma: Updated Results from a Phase II Study
Authors: Ping Nana , Qu Changju , He Jiajie , Liu Hailing , Zou Rui , Zhu Qian , Zhang Xiao , Wu Depei , Jin Zhengming 
Published: December 2024

Introduction: Elderly patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL) frequently face challenges related to comorbidities and poor tolerance to standard-dose chemotherapy, necessitating dose reductions that can negatively impact prognosis (Di M, et al. Oncologist, 2021). Consequently, there is a pressing demand for novel therapeutic approaches that offer improved efficacy and reduced toxicity. The Smart Start study illustrated that the utilization of rituximab (R), lenalidomide, and ibrutinib as induction therapy yielded a notably high overall response rate (ORR) among pts with newly diagnosed DLBCL (Westin J, et al. J Clin Oncol, 2023). Additionally, Orelabrutinib (O), a newly developed covalent Bruton's tyrosine kinase inhibitor known for its high target selectivity, has been shown to maintain the NK-cell-mediated antibody-dependent cellular cytotoxicity induced by R, thereby augmenting the antitumor efficacy of the R-based regimen (Yu H, et al. Mol Ther-Oncolytics, 2021). Here, a prospective study was conducted to investigate the efficacy and safety of pomalidomide (P; a third-generation immunomodulatory drug), R, O, and a miniCHOP regimen in elderly pts with newly diagnosed DLBCL.

Methods: Pts aged ≥70 years with newly diagnosed DLBCLwere enrolled in an open-label, single-arm, phase II study (NCT05809180). All eligible pts received one 21-day cycle of induction therapy with PRO (P, 4 mg, d1-7; R, 375 mg/m2, d1; O, 150 mg, QD). Subsequently, pts who achieved at least mini response (miniR, a reduction in tumor lesions by 25%-50%) were administered additional 6 cycles of PRO-miniCHOP regimen (PRO with a reduced-dose CHOP regimen [cyclophosphamide, 400 mg/m2, d2; doxorubicin/liposomal doxorubicin, 25 mg/m2/15 mg/m2, d2; vindesine, 2 mg, d2; and dexamethasone, 7.5 mg/m2, d2-6]). Following the completion of 6 cycles of the PRO-miniCHOP regimen, subsequent treatment decisions were made based on the tumor response. This included cessation of treatment for CR, initiation of 2 years of pomalidomide maintenance therapy for partial remission (PR), and removal from the study for stable disease or disease progression. The primary endpoints of the study were ORR and complete response rate (CRR) after 6 cycles of the PRO-miniCHOP regimen. Secondary endpoints included ORR and CRR at the conclusion of the induction therapy, as well as 2-year progression-free survival (PFS), 2-year overall survival (OS), and assessment of safety.

Results: By the cut off date (June 26, 2024), a total of 23 pts were enrolled in this study. Two pts chose to withdraw voluntarily prior to the administration of the drug, leaving data from the remaining 21 pts available for analysis. The median age of the participants was 74.0 years (72.0-79.0 years). Baseline characteristics of the pts included 85.7% with an International Prognostic Index score of 2-5, 52.4% with extranodal involvement, 38.9% with MYC/BCL-2 double expression lymphoma, and 38% with non-germinal center B-cell-like subtype. Following one cycle of induction therapy with PRO, 90.5% (19/21) of participants achieved at least a miniR, including 4 CR, 12 PR, and 3 miniR. Eighteen pts successfully completed ≥3 cycles of the PRO-miniCHOP regimen, resulting in a CR rate of 66.7% and a PR rate of 33.3%, yielding an ORR of 100%. Of the sixteen pts who completed the full six-cycle therapy, 93.75% achieved a CR, while one patient experienced progressive disease. After a median follow-up period of 12.2 months, the median PFS and OS have not yet been reached. The 12-month PFS and OS rates were 93.3% and 100%, respectively. Nine pts underwent efficacy evaluation during follow-up, all of whom sustained CR. Twenty (95.2%) pts reported any-grade adverse events (AEs), with 18 pts (85.7%) experiencing ≥3 grade AEs. The most common AEs (any grade, ≥3 grade) were thrombocytopenia (71.4%, 23.8%), anemia (71.4%, 14.3%) and neutropenia (66.7%, 61.9%). There were no AE-related drug discontinuations, regimen changes, or treatment-associated deaths.

Conclusions: The PRO induction therapy demonstrated favorable response rates in elderly pts. Those who responded to the induction therapy may experience a synergistic antitumor effect and achieve a high CRR with subsequent PRO-miniCHOP therapy and during follow-up assessments. While AEs were prevalent, the majority were controllable and did not hinder the continuation or efficacy of treatment.