Abstract
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.
Disclosures
No relevant conflicts of interest to declare.
Phase II Study of Bendamustine and Ofatumumab in Elderly Patients with Newly Diagnosed Diffuse Large B‐Cell Lymphoma Who Are Poor Candidates for R‐CHOP Chemotherapy