Safety and Clinical Activity of Combined Romidepsin and Azacitidine Therapy in High Risk Acute Myeloid Leukemia: Preliminary Results of the Romaza Trial

Introduction: Azacitidine (AZA) represents an important advance in the management of patients with acute myeloid leukemia (AML) in whom intensive chemotherapy (IC) is contra-indicated. However complete response (CR) rates are low and disease progression is inevitable. Romidepsin (ROM) is a potent Class I histone deacetylase inhibitors (HDACi) which demonstrates synergistic anti-leukemic activity with AZA in vitro and represents a plausible strategy by which its clinical activity can be increased. Despite this, the clinical impact of co-administration of ROM to AZA has not been evaluated in myeloid disorders. We therefore wished to both establish the maximum tolerated dose (MTD) of combined AZA/ROM therapy and determine the clinical activity of this novel combination in high risk AML.

Patients and Methods: 46 patients with AML deemed ineligible for IC were studied. 16 patients had relapsed after previous IC, 15 after a previous allogeneic stem cell transplantation, 11 patients had de novo AML and 4 primary refractory AML. The median age of the treatment population was 68 years (range: 19-84). Patients were assessed for response, using modified Cheson criteria, after 3 and 6 cycles of therapy. The MTD of ROM/AZA combination therapy was estimated by using an escalating, de-escalating 3+3 cohort design in 13 patients and the clinical activity studied in an additional expansion cohort of 33 patients.

Results: The MTD of combination ROM/AZA therapy was established as ROM 12 mg/m² on days 8 and 15, in combination with AZA 75 mg/m² administered for 7 days in a 28 day cycle. The most common grade 3-4 non-haematological serious adverse events experienced in patients treated at the MTD were: pulmonary infection (8%), vomiting (6%) and syncope (6%). 9 of 18 evaluable patients who had received at least three cycles of ROM/AZA combination therapy in whom an informative bone marrow was available achieved a major clinical response (CR/CRi n= 7, PR n=2). Survival was increased in patients achieving a major clinical response.

Discussion: Combined ROM/AZA therapy is well tolerated and clinically active in patients with AML ineligible for intensive therapy. The observed response rates in this very high-risk patient population support further prospective evaluation of the role of ROM as a novel agent with the potential to increase clinical response rates to AZA monotherapy.