Dose-Adjusted EPOCH Regimen as First-Line Treatment for Non-Hodgkin's Lymphoma with Hemophagocytic Lymphohistiocytosis: A Single-Arm, Open-Label, Phase 2 Trial

Background: The treatment of malignancy-associated HLH especially NHL-associated HLH has not been prospectively studied. The objective of this study was to evaluate the efficacy, safety and feasibility of DA-EPOCH±R regimen which contains etopooside, cyclophosphamide, doxorubicin, vincristine, prednisone with or without rituximab as a first-line treatment for NHL with HLH. Methods: In this prospective, single-arm, multicenter phase II clinical trial, we enrolled patients with previously untreated, histologically confirmed NHL aged 17-80 years and diagnosed as HLH according to HLH 2004 standard. A total of 6 cycles were planned if the patient achieved at least partial remission after the interim assessment. The cycle was repeated every 3 weeks. The primary endpoint was the overall response rate (ORR). Also, after achieving more than partial response (PR) after six cycles of DA-EPOCH±R regimen, autologous stem cell transplantation (ASCT) for B-NHL or allogeneic stem cell transplantation (allo-SCT) for T/NK-NHL was followed as consolidation therapies. This study was registered with Clinical Trials.gov, number NCT01818908. Findings: Fifty-nine patients were enrolled and evaluated in the study. Twenty-six patients (44.1%) were B-NHL with HLH and the other 33 patients (55.9%) were T/NK-NHL with HLH. The median cycle was six (range 1-6) for all B-NHL patients and three (range 1-6) for T/NK-NHL patients. The ORR at the end of the treatment was 80.7% for B-NHL with HLH while only 12.1% was for T/NK-NHL with HLH. With a median follow-up of 54 months (30-72 months) for B-NHL with HLH, 5-year progression-free survival (PFS) was 56.7 ± 9.9% and 5-year overall survival (OS) was 73.1 ± 8.7%. For the T/NK-NHL with HLH, 3-month PFS and OS rate was 30.3 ± 8.0% and 51.5 ± 8.7%. For the 21 B-NHL patients who achieved more than PR, 12 patients (57.1%) received ASCT as the consolidation therapy. B-NHL patients who received ASCT have significantly superior PFS (P<0.001) and OS (P=0.033) than patients who did not. Grade 3/4 neutropenia toxicities occurred on 43% of all cycles. Grade 3/4 thrombocytopenia occurred on 14% of all cycles. Interpretations: DA-EPOCH-R regimen as front-line treatment followed by ASCT as consolidation treatment demonstrates a highly effective and safe strategy for B-NHL patients with HLH while DA-EPOCH cannot improve outcomes for T/NK-NHL patients with HLH. Funding: National Natural Science Foundation of China Declaration of Interest: We declare no potential conflicts of Interest. Ethical Approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.