A Phase II Study of Chidamide Plus R-CHOP in Elderly Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma: An Interim Analysis

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, accounting for 30%-40% of all cases. Although rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) significantly improves the outcome of the patients, approximately 50% of the elderly patients eventually experience disease progression or relapse, particularly in the intermediate and high risk group (International prognostic index (IPI)>1). Therefore, novel agents along with R-CHOP have been applied to increase treatment efficacy and long-term outcome in this subset of DLBCL patients.

Perturbation of the epigenome plays a crucial role in lymphoma progression. Mutations in histone modifier enzymes are frequently observed in DLBCL patients. Through targeting epigenetic lesions, HDAC inhibitors (HDACIs) are emerging as feasible therapeutic approaches to suppress lymphoma growth and to overcome resistance to immuno-chemotherapy. Chidamide, an orally active and subtype-selective HDACI, was developed in China. However, its anti-tumor activity has not yet been assessed in DLBCL. This prospective phase II study is to evaluate the efficacy and safety of chidamide in combination with R-CHOP (CR-CHOP) in elderly 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 are enrolled. The doses and administration schedule are as follows: rituximab 375 mg/m² on day 0, cyclophosphamide 750 mg/m² on day 1, doxorubicin 50 mg/m² on day 1, vincristine 1.4 mg/m² on day 1, prednisone 60 mg/m² from day 1 to day 5, chidamide 20 mg/d on days 1, 4, 8 and 11, every 21 days for 6 cycles. The primary endpoint is complete response (CR) rate assessed by PET-CT, and secondary endpoints include progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and main adverse events (AEs).

Results: To date, thirty-two patients have been enrolled, with median age of 67 years (range, 61-75). At diagnosis, twenty-two patients (68.8%) presented advanced Ann Arbor stage and 26 cases (81.3%) showed elevated serum LDH level. Twenty-one patients (65.6%) had multiple extra-nodal sites mainly involving bone, gastrointestinal, liver, and bone marrow, and 26 patients (81.2%) had IPI scores ≥ 3. By immunohistochemistry, eight (25.0%) patients were categorized as germinal center B-cell (GCB) subtype based on Hans algorithm, and 8 (25.0%) patients were defined as BCL-2 and MYC double expression (DE).

For 16 patients available for response evaluation, the CR rate was 87.5% (14/16), and the ORR was 93.8% (15/16). No difference of the CR rate was observed between GCB and non-GCB subtype (75% and 90%, P=0.555), or DE and non-DE subtype (100% and 87.5%, P=1.0). Grade 3-4 neutropenia was found in 27 cases (84.4%), grade 3-4 thrombocytopenia in 11 cases (34.4%), and grade 3-4 anemia in 6 cases (18.8%). For non-hematological AEs, grade 3 liver dysfunction and prolonged QTc interval were observed in 3 cases (9.4%) and in 1 case (3.1%) respectively, while no grade 4 non-hematological AEs were observed.

Conclusion: CR-CHOP as first-line therapy for elderly intermediate and high risk (IPI>1) patients with DLBCL showed encouraging response and good tolerability.