Response-Driven Dose-Intensified Immunochemotherapy ± Autologous Stem Cell Transplantation in Previously Untreated Patients with High-Risk Aggressive B-Cell Lymphoma: Results of the DLCL002 Phase 2 Trial

Background: Aggressive B-cell lymphoma is a highly heterogeneous group of tumors, with a cure rate of less than 50% in high-risk patients undergoing treatment with the R-CHOP regimen. Multiple studies have indicated promising efficacy for dose-enhanced immunochemotherapy in high-risk patients. Few studies on aggressive B-cell lymphoma have prospectively explored treatment strategy modifications guided by interim positron emission tomography (PET) responses. To address this gap, we conducted a prospective, multicenter, single-arm, phase 2 trial to evaluate the efficacy and safety of response-driven dose-intensified immunochemotherapy with or without autologous stem cell transplantation (ASCT) in young previously untreated patients with high-risk aggressive B-cell lymphoma. Methods: Eligible patients for the DLCL002 protocol were previously untreated individuals aged 18 to 65 years, diagnosed with high-risk aggressive B-cell lymphoma, as defined by an International Prognostic Index (IPI) score of 3 to 5 or an age-adjusted IPI (aaIPI) score of 2 to 3, double protein expression lymphoma (immunohistochemistry MYC≥40% and BCL2≥50%) with Ann Arbor stage of III-IV or aaIPI 2-3 or IPI 3-5, or CD5 positivity. Additionally, patients with high-grade B-cell lymphomas (HGBCL) characterized by MYC and BCL2 and/or BCL6 rearrangements, as well as those with HGBCL not otherwise specified (NOS) or transformed lymphoma, were included. Patients received 4 cycles of R-DA-EDOCH chemotherapy (Rituximab, Etoposide, Vincristine, Doxorubicin, Dexamethasone, Cyclophosphamide). Efficacy was evaluated using PET-CT imaging following the completion of these four cycles. Those who achieved a partial response (PR), as indicated by a Deauville score of 4-5, subsequently received two cycles of R(X)-DHAP salvage chemotherapy. At the discretion of the treating clinician, patients could undergo ASCT. The primary endpoint of the study was the 2-year progression-free survival (PFS) rate. Results: Between January 2019 and August 2023, a total of 107 patients were enrolled, with a median age of 54 years. Of these, 100 patients (93.5%) presented with Ann Arbor stage III-IV disease, and 89 patients (83.2%) had an IPI score of 3-5 or an aaIPI score of 2-3. A total of 104 patients (97.2%) received between 4 and 8 cycles of induction therapy. At the time of the interim evaluation, 106 patients were assessable for efficacy. The complete response (CR) rate and overall response rate (ORR) were 79.2% (95% confidence interval [CI]: 70.6, 85.9) and 94.3% (95% CI: 88.2, 97.4), respectively. Eight patients who achieved a PR subsequently adjusted their treatment regimen to R(X)-DHAP. Following this adjustment, the CR rate and ORR were 83.0% (95% CI: 74.8, 89.0) and 88.7% (95% CI: 81.3, 93.4), respectively. Subsequently, 45 patients (42%) underwent ASCT after immunochemotherapy. At the end of treatment, the ORR remained at 88.7%, while the CR rate increased to 87.7% (95% CI: 80.2, 92.7). At the data cut-off date of April 1, 2024, the median follow-up was 32.9 months (range: 5-64 months), and the median PFS and overall survival (OS) were not reached. The 2-year PFS and OS rates were 78.2% (95% CI: 70.2, 86.2) and 86.7% (95% CI: 80.0, 93.4), respectively. The predominant adverse events (AEs) associated with the treatment were hematologic toxicities. Grade 3/4 AEs observed in ≥10% of patients included neutropenia, anemia, thrombocytopenia, and pulmonary infection. Conclusions: Response-driven, dose-enhanced immunochemotherapy, with or without ASCT, demonstrated promising long-term outcomes and was well tolerated in young, previously untreated patients with high-risk aggressive B-cell lymphoma. This therapeutic strategy warrants further clinical investigation.