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

Abstract

BACKGROUND More 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. METHODS Patients 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/m2 daily (dose levels 1–3), followed by oral vorinostat (1000 mg once daily on days −11 through −3), gemcitabine (2775 mg/m2 over 4.5 × 2), busulfan (at an area under the receiver operating characteristic curve of 4000 daily × 4), and melphalan (60 mg/m2 × 2). Patients who had tumors that were positive for CD20 (cluster of differentiation 20; B-lymphocyte antigen) received rituximab on day −9. RESULTS In 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/m2 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. CONCLUSIONS Double 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.

Combination of a hypomethylating agent and inhibitors of PARP and HDAC traps PARP1 and DNMT1 to chromatin, acetylates DNA repair proteins, down-regulates NuRD and induces apoptosis in human leukemia and lymphoma cells

“…DNA alkylators are common components of pre-transplant conditioning regimens for leukemia and lymphoma patients [ 22 ]. Epigenetic modifiers are known to improve their efficacy [ 22 – 25 ]. We therefore sought to determine if addition of a DNA alkylating agent to [Npb+DAC+Rom/Pano] would further improve its anti-proliferative/cytotoxic activity.…”

Synergistic combination of flavopiridol and carfilzomib targets commonly dysregulated pathways in adrenocortical carcinoma and has biomarkers of response

“…To overcome the prohibitive cost and time needed for developing a new therapy for rare cancerssuch as ACC, we previously demonstrated that drug repurposing using quantitative high-throughput screening (qHTS) of a clinically approved drug library is an effective and efficient way to identify active drugs in rare cancers [ 7 – 9 ]. The combination of active drugs that results in a synergistic effect can further enhance anti-cancer treatment efficacy, and this approach has been used in several hematologic and solid cancers [ 10 , 11 ]. Because the pharmacokinetic, pharmacodynamic, and toxicity profiles of the drugs are well known, an immediate translation into clinical trials can be performed.…”

Evaluation of the bioequivalence and food effect on the bioavailability of CC-486 (oral azacitidine) tablets in adult patients with cancer

“…Injectable azacitidine 75 mg/m 2 /day, administered intravenously (IV) or subcutaneously (SC) for 7 days per 28-day treatment cycle, is approved in several countries for treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) [1,2]. Azacitidine has also been investigated in a variety of other hematologic malignancies and solid tumors [3][4][5][6]. In addition to direct cytotoxicity of proliferating malignant cells, azacitidine is incorporated into both RNA and DNA (in human AML KG1a cells, the RNA:DNA incorporation ratio was 65:35 [7]) and reduces hypermethylation in promoter regions of DNA, leading to re-expression of tumor suppressor genes and promoting differentiation of hematopoietic progenitor cells [7][8][9].…”