Mitoxantrone hydrochloride liposome-based CMOP±R regimen achieves superior response in treatment-Naïve non-Hodgkin lymphoma: A phase III clinical trial with matching-adjusted indirect comparison

Abstract

Abstract Background: Non-Hodgkin lymphoma (NHL) represents a heterogeneous group of malignancies originating from lymph nodes and lymphoid tissues. Despite advancements in first-line treatment strategies for NHL, significant unmet clinical needs persist. The CMOP regimen, comprising cyclophosphamide, mitoxantrone hydrochloride liposome (Lipo-MIT), vincristine, and prednisone, has demonstrated efficacy in treating newly diagnosed peripheral T-cell lymphoma (PTCL) (Huang et al., ASH 2022, Abstract #1632). However, its efficacy in other NHL subtypes remains unclear. This study aimed to evaluate the efficacy and safety of the Lipo-MIT-based CMOP regimen with or without rituximab (CMOP±R) as first-line therapy for treatment-naïve NHL. Methods: This prospective, single-arm, open-label, multicenter phase 3 study enrolled adult patients with newly diagnosed NHL. Patients received CMOP±R every four weeks for up to six cycles (with an option for two additional cycles of rituximab monotherapy in CD20-positive patients), or until disease progression or unacceptable toxicity. The primary endpoint was the complete response rate (CRR). Secondary endpoints included objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Unanchored matching-adjusted indirect comparison (MAIC) was conducted using historical references from the POLARIX and Ro-CHOP study. Treatment-related adverse events (TRAEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. The study is registered with ClinicalTrials.gov (NCT06486337). Results: As of August 2, 2025, twenty-seven patients were included in the analysis. The median age was 56 years (range: 33–71 years). Four patients (14.8%) had stage III disease and 9 patients (33.3%) had stage IV disease, and 33.3% had an International Prognostic Index (IPI) score ≥3. Sixteen patients (59.3%) were diffuse large B-cell lymphoma (DLBCL), and 8 patients (29.6%) were PTCL. Nine patients (33.3%) presented with B symptoms at diagnosis. At the time of data analysis, the median number of treatment cycles administered was 6 (range: 2–6), and the median administered dose of Lipo-MIT was 16.1 mg/m². The CRR was 70.4% (19/27) and the ORR was 100% (27/27). Twenty-one patients completed the planned treatment. Among these, those who achieved the full 6 treatment cycles (n=17) demonstrated a CRR of 76.5% (13/17). With a median follow-up of 5.3 months, only two disease progression events were observed among the twenty-seven subjects, and no deaths occurred. Consequently, neither median PFS nor median OS was reached. MAIC demonstrated that CMOP±R achieved superior responses over conventional regimens in DLBCL (weighted ORR: CMOP+R 100% vs. RCHOP 83.8% or Pola-R-CHP 85.5%, P<0.05; weighted CR rate: CMOP+R 56.3% vs. RCHOP 74.0% or Pola-R-CHP 78.0%, P>0.05), or in PTCL patients (weighted ORR: CMOP 100% vs. CHOP 60.5%, P<0.05; weighted CR rate: CMOP 75.9% vs. CHOP 37.1%, P<0.05). The most common grade 3–4 treatment-related adverse events (TRAEs) were neutropenia (33.3%), leukopenia (25.9%), anemia (11.1%), and thrombocytopenia (11.1%). No cases of atrial fibrillation or clinically significant arrhythmias were observed. Conclusion: The CMOP±R regimen demonstrated promising efficacy as a first-line treatment for NHL, while maintaining a manageable safety profile. Updated data incorporating additional patients will be reported subsequently.