Azacitidine with or without Entinostat for the treatment of therapy-related myeloid neoplasm: further results of the E1905 North American Leukemia Intergroup study

Among the new entities of the 2008 World Health Organization (WHO) classification (Vardiman et al, 2009), one subtype was not defined either by pathological or cytogenetic/molecular features but by its causality: therapy-related myeloid neoplasms (tMN), which are defined as myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) arising after exposure to chemotherapy or radiation therapy. As cancer care has improved, more patients are exposed to the risk of developing tMN. Depending on the causal agents, tMN displays recurrent genetic lesions, such as translocations (implicating KMT2A [MLL], RUNX1, CBFB, or RARA) or multiple aberrations including chromosome 5 or 7 deletions within complex karyotypes (Rowley & Olney, 2002; Stone, 2009; Dohner et al, 2010). The prognosis of tMN treated with conventional therapy is usually considered to be poor and is strongly influenced by cytogenetics and performance status, potentially impaired by prior cancer and treatments. In this context, the use of alternative treatments is warranted and azacitidine (AZA) may represent a suitable option. Azacitidine is the standard of care of treatment for high-risk MDS (Silverman et al, 2006; Fenaux et al, 2009) and is also effective in AML (Fenaux et al, 2010). Several studies have shown that AZA could be safe and effective in patients with poor general condition performance status and/or comorbidities (Garcia-Manero et al, 2014) and may be associated with significant response rate in patients with high risk cytogenetics. Three retrospective studies (Fianchi et al, 2012; Bally et al, 2013; Duong et al, 2013) suggested significant activity of AZA in patients with tMN with ORR ranging from 39% to 43% and median overall survival from 10 to 14 months. However, no prospective data have been presented so far. More importantly, AZA results still need to be improved. Histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) combine synergistically in their interactive epigenetic effects when appropriately sequenced (Cameron et al, 1999; Gore, 2006). The orally bioavailable benzamide HDACi entinostat inhibits the Class I HDAC enzymes and had shown activity in a monotherapy phase I trial (Gojo et al, 2007). In a previous phase I pilot study (J0443 study, ClinicalTrials.gov Identifier NCT00101179), we found that the combination of AZA and entinostat was effective and tolerable for patients with MDS and AML. This trial, built on a 10 d schedule of AZA that had been developed to optimize DNA methylation through prolonged administration of lower daily dose AZA, was designed to cause less cell cycle inhibition (Fandy et al, 2009). The recommended phase II schedule was AZA 50 mg/m2/d s.c. for 10 d (500 mg/m2/cycle) and entinostat 4 mg/m2/d orally on day 3 and day 10 of AZA each 28 d. The Eastern Cooperative Oncology Group (ECOG) and North American Leukemia Intergroup subsequently conducted a randomized Phase II trial, E1905 (ClinicalTrials.gov Identifier NCT00313586), aiming to improve the response rate of AZA through administration of the 10 d schedule with or without addition of entinostat. Results for de novo MDS and AML with myelodysplasia-related changes (MRC) have already been published (Prebet et al, 2014). A dedicated tMN cohort was accrued following an amendment of the original protocol. Results for this specific cohort are described in the present report.