Final Report of a Phase II Study of 5-Azacitidine and Vorinostat in Patients (pts) with Newly Diagnosed Myelodysplastic Syndrome (MDS) or Acute Myelogenous Leukemia (AML) Not Eligible for Clinical Trials Because Poor Performance and Presence of Other Comorbidities
Authors: Garcia-Manero Guillermo , Estey Elihu H , Jabbour Elias , Borthakur Gautam , Kadia Tapan , Naqvi Kiran , Levine Ross L , Estrov Zeev , Quintas-Cardama Alfonso , Konopleva Marina , Faderl Stefan , Tanaka Maria , Yang Hui , Ravandi Farhad , Wierda William G. , Cortes Jorge E. , Boone Patricia Ann , Kantarjian Hagop M. 
Published: October 2019

Abstract
Abstract 608
Common eligibility criteria for most clinical trials in MDS and AML include acceptable performance status, renal and hepatic functions and lack of other comorbidities including other concomitant malignancies or HIV infection. Median survival without therapy at MD Anderson in this group of pts is less than 60 days. To study the impact of therapy in patients not eligible for clinical trials, we conducted a phase II of the combination of 5-azacitidine and the histone deacetylase inhibitor vorinostat. The combination of these two agents is known to be safe and to have significant activity in MDS and AML. An interim report of this study was presented at ASH 2010. Here, we report the final data on the study. Eligible pts included those with previously untreated MDS (INT-1 or above) or AML and any of these: creatinine or bilirubin greater than 2 mg/dL, ECOG performance status (PS) more than 2 or not eligible for any other protocol. Pts with HIV disease or concomitant malignancies were also eligible. Pts with CBF abnormalities were excluded. Therapy was 5-azacitidine 75 mg/m2 IV daily × 5 every 3 to 6 weeks and vorinostat 200 mg orally three times a day on days 1 to 5 with 5-azacitidine. The clinical trial was designed to stop if expectations for survival at 60 days and/or achievement of complete remission (CR) rates were not achieved based on priors derived from historical experience at MD Anderson. The study was to stop if the # pts alive at > 60 days was < 0/3, 2/6, 3/9, 5/12, 6/15, 8/18, 10/21,11/24, or 13/27 evaluable or if the number of pts with no CR was > 6/6, 11/12, 16/18,21/24, 26/30. A maximum of 30 pts could be treated if none of the stopping rules was met. Operating characteristics targeted a 20% improvement in response and survival. As pharmacodynamic endpoints, global and gene specific hypomethylation, induction of histone acetylation, TET2 mutations and miRNA 29b levels were evaluated. The study has been completed. In total 30 patients were treated. The characteristics are as follows: median age 74 years (range 44–83), median WBC 3 K/uL (range 0.6–112), median % bone marrow blasts 10% (range 1–78), complex cytogenetics in 16 pts (53%), Flt-3 or Ras mutated 4 (13%), median creatinine 0.9 mg/dL (range 0.3–2.4), median bilirubin 0.7 mg/dL (range 0.3–4.1). Using WHO criteria, 16 pts (53%) had MDS, 2 CMML and the rest AML. Eligibility criteria included: presence of another malignancy 16 pts (53%) and others including: liver cirrhosis, liver failure, cardiac dysfunction, severe COPD and poor PS (ECOG 4). Treatment was well tolerated with only 1 pt (3%) developing severe (nausea, vomiting) non-heme related toxicity. Only 1 (5%) pt died during induction therapy. The first pt was enrolled on 9/09 and the last 12/10. The median number of cycles administered was 3.5+ (1 to 11+). All 30 patients were evaluable for survival and 24 (80%) survived longer than 60 days (median survival 7 months: range 1 to 16). Therapy was active: 8 patients achieved a complete remission and 1 had a complete marrow response for an overall response rate of 9 (30%). Of the 16 non-responding patients, 8 had stable disease for more than 8 weeks. At the present time 9 of the 30 patients are alive. All deaths were related to primary disease progression (other than leukemia). We calculated comorbidity score using the ACE-27 scale: 3 patients had 0 points, 7 1 point, and 20 2–4 points. No association between response and survival was documented with ACE-27. TET2 mutation and miRNA29 levels were analyzed at baseline. Of the 17 pts analyzed, 5 harbored a TET2 mutation but only 1 had achieved response. Baseline miRNA29b levels were not different in responders versus non responders. Global and gene specific hypomethylation was observed with therapy. In summary, the study did not meet the stopping rules for survival and response. No significant toxicity was documented. The combination of 5-azacitidine and vorinostat is safe and active in this poor prognosis population resulting in levels of activity and safety similar to those observed in populations eligible for clinical trials. These results support treatment of these pt population and question current eligibility for phase I/II trials.

Disclosures:
No relevant conflicts of interest to declare.