A Bayesian Phase II Randomized Trial of Azacitidine Versus Azacitidine + Vorinostat in Patients with Newly Diagnosed AML or High-Risk MDS with Poor Performance Status, Organ Dysfunction, or Other Comorbidities
Authors: Garcia-Manero Guillermo , Huang Xuelin , Cabrero Monica , DiNardo Courtney D. , Pemmaraju Naveen , Daver Naval G. , Borthakur Gautam , Wierda William G , Kadia Tapan , Alvarado Yesid , Cortes Jorge E. , Jain Nitin , Ravandi Farhad , Jabbour Elias , Brandt Mark , Sneed Troy , Sukholutsky Victoria , Pierce Sherry , Bohannan Zachary , Kantarjian Hagop M. 
Published: October 2019

Abstract
The prognosis of patients with untreated MDS or AML with poor performance, organ dysfunction, or other comorbidities is very poor. Most patients do not receive therapy, and a large majority of them are excluded from investigational clinical trials. We hypothesized that this group of patients would significantly benefit from participation in clinical trials.
To test this concept, we performed an initial proof-of-principle study of 30 patients with these characteristics using a combination of azacitidine and vorinostat, a histone deacetylase inhibitor, with the stopping rules being survival at 60 days, a response rate (30%), and toxicity. This study indicated that treatment was associated with longer-than-expected survival and response rate and acceptable toxicity as well as demonstrating that this group of patients can be safely and efficiently enrolled in clinical trials (Garcia-Manero ASH 2010 abstract #604).
To further verify these results, we subsequently expanded this trial as a randomized study comparing azacitidine versus azacitidine + vorinostat, the results of which are shown here. This study would allow further experience in the development of clinical trials for this at-risk population as well as explore the role of vorinostat in combination with azacitidine. The primary objective was survival at 60 days.
The study was independently monitored by the Dept of Biostatistics at our institution. Patients were randomized using an adaptive procedure. The first 40 patients were randomized in a 1:1 ratio, and after that will be unbalanced in favor of the superior arm as efficacy (survival at 60 days) data accrue. Inclusion criteria included patients with newly diagnosed AML or higher-risk MDS who were not eligible for high-dose chemotherapy or clinical trials due to comorbidities, organ dysfunction, or poor performance status. Treatment consisted of azacitidine 75 mg/m2 IV daily x 5 (A arm) or azacitidine at the same dose schedule with vorinostat at 200 mg 3 times a day on days 1 to 5 (A+V arm).
From September 2011 to March 2014, 79 patients were enrolled: 27 (34%) in the A arm and 52 (66%) in the A+V arm. Median age was 70 (30-90); median bone marrow blasts were 8% (1-89), median WBC 2.8 (0.2-102.0), median peripheral blasts 0% (0-78), poor cytogenetic risk in 41 (52%), diploidy in 20 (25%), and intermediate risk in 18 (22%). Reasons for inclusion were concurrence or previous history of other malignancies (36; 46%); ≥2 ECOG performance status (9; 11%); comorbidities including lung fibrosis, renal or liver dysfunction, or HIV positive status (17; 21.5%); or non-eligibility for others trials due to higher priority (17; 21.5%).
The number of median cycles was 1 (1-12) for the A arm and 3 (1-12) for A+V arm. Study drugs were tolerated with no drug-related early stoppage (8 week mortality). Incidence of any grade 3-4 toxicity was less than 9%. Sixty-day survival was seen in 18 patients (67%) for the A arm and 44 patients (85%) for the A+V. The A+V arm was associated with a better outcome (OR 0.311, 95% CI [0.101-0.962]; p=0.043). The ORR (CR+CRp) was 12 (44%) for the A arm and 18 (35%) for the A+V arm (p=0.395). The median number of cycles for response was 1 in the A arm and 1.5 in the A+V arm.
Survival was confounded by death unrelated to leukemia. The median overall (OS) and relapse-free survival (RFS) for the whole group were 7.1 months (5.5-8.7) and 5.9 months (3.1-8.7), respectively. Median OS for the A and A+V arms was 6.1 and 5.9 months, respectively (p=0.9), and median RFS for the A and A+V arms was 5.9 and 8.7 months (p=0.5), respectively. Patients who achieved CR/CRp had better OS: median 12 vs 6 months (HR: 0.41, [0.22-0.78] p=0.007). After a median follow-up of 9.5 months, 23 patients (29%) are alive at last follow-up.
In conclusion, azacitidine+vorinostat was associated with a better 60-day survival than single-agent azacitidine in a patient population that is generally excluded from clinical trials. This study confirms the possibility of treating patients that are generally not considered eligible for clinical trials.

Disclosures
No relevant conflicts of interest to declare.