Chidamide Plus R-CHOP21 in Elderly Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma: Results of a Phase II Study

Background: Diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin's lymphoma and is heterogeneous in clinical, immunophenotypic and genetic features. More than 50% of patients with DLBCL are older than 60 years at diagnosis. Among them, up to 40% of patients relapse or develop refractory disease upon R-CHOP treatment. Dose-dense R-CHOP14 failed to show superior efficacy or survival compared with standard R-CHOP21 in elderly patients and intensive chemotherapy followed by autologous stem cell transplantation was difficult due to toxicity. Therefore, development of new first-line therapy remains great interests to improve disease outcome in elderly patients with DLBCL.

Perturbation of the epigenome plays a crucial role in lymphoma progression. Several histone deacetylase inhibitors (HDACIs) have been investigated in relapsed or refractory DLBCL as mono- or combination treatment, showing promising activities to suppress lymphoma growth and overcome resistance to immune-chemotherapies. This prospective phase II study was to evaluate the efficacy and safety of chidamide in combination with R-CHOP21 in elderly patients with newly diagnosed DLBCL (NCT02753647).

Methods: Patients with newly diagnosed DLBCL, aged 61 to 75 years, Eastern Cooperative Oncology Group performance status of 0 to 2, IPI>1 were enrolled. The dose and administration schedule were as follows: rituximab 375 mg/m² on day 0, cyclophosphamide 750mg/m² on day 1, doxorubicin 50mg/m² on day 1, vincristine 1.4 mg/m² on day 1, prednisone 60 mg/m² from day 1 to day 5, chidamide 20mg/d on days 1, 4, 8 and 11, every 21 days for 6 cycles. The primary endpoint was complete response (CR) rate assessed by PET-CT, and secondary endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and main adverse events (AEs).

Results: From March 2016 to April 2018, 49 patients were enrolled; 41 patients completed all treatment and 8 patients were still in the treatment cycles. Median age was 67 years (range, 61-75) and 28 patients (57.1%) were male. Thirty-eight patients (77.6%) presented advanced Ann Arbor stage, and 41 patients (83.7%) showed elevated serum LDH level. Thirty-one patients (63.3%) had multiple extra-nodal sites, mainly involving bone, gastrointestinal, liver, and bone marrow. Forty-one patients (83.7%) had IPI scores ≥3 at diagnosis. By immunohistochemistry, 12 (24.5%) patients were categorized as germinal center B-cell (GCB) subtype based on Hans algorithm, and 12 (25.5%) patients were defined as BCL-2 and MYC double expression. Among 41 patients available for evaluation, the CR rate was 85.4% (35/41), and the ORR was 90.3% (37/41). After a median follow-up of 18 months (range, 3-30), the 1-year PFS was 92.1% and 1-year OS was 94.7%. There were 2 deaths due to disease progression, of which 1 had triple-hit lymphoma. Regarding toxicity, grade 3-4 neutropenia was observed in 167 cycles (60.5%), grade 3-4 thrombocytopenia in 27 cycles (9.8%), and grade 3 anemia in 11 cycles (4.0%). However, febrile neutropenia was reported in significantly fewer cycles (6.1%) and was a maximum of grade 3. Grade 3 liver dysfunction was observed in 7 cycles (2.5%). No grade 4 non-hematological events were reported. Of note, 2 patients positive for EBER-ISH at diagnosis remained in EBV-DNA negative during treatment and follow-up.

Conclusion: Chidamide with R-CHOP21 is effective and safe in elderly patients with newly diagnosed DLBCL.