Double epigenetic modulation of high-dose chemotherapy with azacitidine and vorinostat for patients with refractory or poor-risk relapsed lymphoma

BACKGROUNDMore active high-dose chemotherapy (HDC) regimens are needed for refractory lymphomas. The authors previously combined infusional gemcitabine with busulfan and melphalan (Gem/Bu/Mel) pursuing DNA damage repair inhibition. Subsequently, they combined Gem/Bu/Mel with vorinostat, which facilitates chemotherapy access to DNA. The resulting regimen was safe and synergistic. However, vorinostat induced DNA methyltransferase up-regulation, which could be preclinically abrogated by azacitidine, increasing tumor-cell kill. Those observations led to a clinical combination of azacitidine with vorinostat/Gem/Bu/Mel. METHODSPatients ages 12 to 65 years with refractory or poor-risk relapsed lymphomas were eligible. They received intravenous azacitidine on days -11 through -3 at doses from 15 to 35 mg/m(2) daily (dose levels 1-3), followed by oral vorinostat (1000 mg once daily on days -11 through -3), gemcitabine (2775 mg/m(2) over 4.5 x 2), busulfan (at an area under the receiver operating characteristic curve of 4000 daily x 4), and melphalan (60 mg/m(2) x 2). Patients who had tumors that were positive for CD20 (cluster of differentiation 20; B-lymphocyte antigen) received rituximab on day -9. RESULTSIn total, 60 patients were enrolled, including 26 with diffuse large B-cell lymphoma (DLBCL) (10 double hit/double expressors), 21 with Hodgkin lymphoma, 8 with T-cell lymphoma, and 5 with other B-cell lymphomas. The median patient age was 41 years (range, 16-65 years), patients had received a median of 3 prior lines of chemotherapy (range, 2-7 lines of chemotherapy); and 32% of tumors were positive on positron emission tomography studies at the time of HDC. Two patients died from treatment complications (respiratory syncytial virus pneumonia and sepsis, respectively). The maximum tolerated dose of azacitidine was encountered at dose level 1 (15 mg/m(2) daily). The toxicity profile (mainly mucositis and dermatitis) was manageable and was identical to that of vorinostat/Gem/Bu/Mel. Neutrophils and platelets engrafted promptly. At a median follow-up of 15 months (range, 8-27 months), the event-free and overall survival rates were 65% and 77%, respectively, among patients with DLBCL; 76% and 95%, respectively, among patients with Hodgkin lymphoma; and 88% for both among patients with T-cell lymphoma. CONCLUSIONSDouble epigenetic modulation of Gem/Bu/Mel with azacitidine/vorinostat is feasible and highly active in patients with refractory/poor-risk relapsed lymphomas, warranting further evaluation. Cancer 2016. (c) 2016 American Cancer Society. Cancer 2016;122:2680-2688. (c) 2016 American Cancer Society. With the objective of developing more active high-dose chemotherapy for patients with refractory or high-risk relapsed lymphomas, infusional gemcitabine/busulfan/melphalan is combined with vorinostat and azacitidine (which enhanced antitumor activity in preclinical work). This clinical trial demonstrates that double epigenetic modulation of high-dose chemotherapy is safe and highly active in patients with refractory lymphomas.