Azacitidine plus vorinostat does not improve the response or survival of AML patients – RAvVA study

Co-administration of azacitidine (AZA) with vorinostat (VOR), a Histone Deacetylase (HDAC) inhibitor, does not improve the outcomes of patients with Acute Myeloid Leukemia (AML) or high-risk Myelodysplastic Syndrome (MDS) according to results from the UK Trials Acceleration Programme RAvVA randomized phase II study (NCT01617226), published in Clinical Cancer Research by Charles Craddock, Queen Elizabeth Hospital, Birmingham, co-chair of our European Steering Committee, and colleagues.

In this study, Craddock et al. aimed to compare AZA monotherapy with AZA plus VOR combination therapy on the outcomes of AML and high-risk MDS patients. Additionally, the impact of AZA based therapy on Leukemic Stem Cell (LSC) frequencies have not been elucidated yet. Hence, the study also aimed to assess the impact of AZA based therapy on the LSC numbers as well as identify molecular predictors of patient outcomes.

In total, 259 patients with AML (n = 217 [newly diagnosed (n = 111), relapsed/refractory (n = 106)]) and MDS (n = 42) were randomized to receive either AZA monotherapy (n = 129) or AZA/VOR (n = 130). Next Generation Sequencing (NGS) and immunophenotypic quantification were used to identify genes and LSCs in patient samples.

The key results of the study were:

• Overall Response Rate (ORR) in patients treated with AZA and AZA/VOR; 41% vs 42%, Odds Ratio (OR) = 1.05, P = 0.84
• Median Overall Survival (OS) in patients treated with AZA and AZA/VOR; 9.6 vs 11.0 months, HR = 1.15, P = 0.32
• Reduced OS was significantly associated with mutations in CDKN2A (a cell cycle checkpoint activator [P < 0.001]), IDH1 (P = 0.001), and TP53 (P < 0.001)
• Lymphoid-Primed Multi-Potential Progenitor (LMPP)-like LSC (a measure for residual disease in AML patients in CR) population was greatly expanded in patients (42/45) at diagnosis
• In responding patients (n = 22), there was a significant reduction in LMPP frequencies but it was not eradicated

In an interview with the AGP, Prof. Charles Craddock commented on the findings of this study. The addition of VOR to AZA resulted in “no increase in response rate or survival in either de novo or relapsed disease” when compared to AZA monotherapy, which he said was “disappointing”. Furthermore, “molecular predictors of response and survival” were identified, most “importantly CDKN2A”, and “mutations in this gene were associated with poor response and survival”. The authors noted that the “correlation between heterozygous loss of function CDKN2A mutations and decreased OS implicates induction of cell cycle arrest as a mechanism by which AZA exerts its clinical activity”.

Additionally, evaluation of the LSC population showed that, even in patients in CR, the LSC population was not eradicated with AZA therapy. Prof. Charles Craddock further added that the RAvVA study identified a “molecular footprint that predicts response and also identifies a potential mechanism of action of AZA” and suggested that new combination partners for AZA are required for therapy in AML patients.

Abstract

Purpose: Azacitidine (AZA) is a novel therapeutic option in older patients with acute myeloid leukemia (AML) but its rational utilization is compromised by the fact that neither the determinants of clinical response nor its mechanism of action are defined. Co-administration of histone deacetylase inhibitors, such as vorinostat (VOR), is reported to improve the clinical activity of AZA but this has not been prospectively studied in AML. Experimental Design: We compared outcomes in 259 adults with AML (n=217) and MDS (n=42) randomized to receive either AZA monotherapy (75 mg/m2 × seven days every 28 days) or AZA combined with VOR 300 mg bd on days 3-9 po. Next generation sequencing was performed in 250 patients on 41 genes commonly mutated in AML. Serial immunophenotyping of progenitor cells was performed in 47 patients. Results: Co-administration of VOR did not increase the overall response rate (P=0.84) or overall survival (OS) (P=0.32). Specifically, no benefit was identified in either de novo or relapsed AML. Mutations in the genes CDKN2A (P=0.0001), IDH1 (P=0.004) and TP53 (P=0.003) was associated with reduced OS. Lymphoid multi-potential progenitor populations were greatly expanded at diagnosis and although reduced in size in responding patients remained detectable throughout treatment. Conclusion: This study demonstrates no benefit of concurrent administration of VOR with AZA but identifies a mutational signature predictive of outcome after AZA based therapy. The correlation between heterozygous loss of function CDKN2A mutations and decreased OS implicates induction of cell cycle arrest as a mechanism by which AZA exerts its clinical activity.