A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ⩽30% blasts

Abstract

Treatment with azacitidine (AZA), a demethylating agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is <2 years, novel agents are needed to improve outcomes. This phase 1b/2b trial (n=113) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of panobinostat (PAN)+AZA (phase 1b) and evaluate the early efficacy and safety of PAN+AZA vs AZA monotherapy (phase 2b) in patients with higher-risk MDS, chronic myelomonocytic leukemia or oligoblastic acute myeloid leukemia with <30% blasts. The MTD was not reached; the RP2D was PAN 30 mg plus AZA 75 mg/m2. More patients receiving PAN+AZA achieved a composite complete response ([CR)+morphologic CR with incomplete blood count+bone marrow CR (27.5% (95% CI, 14.6–43.9%)) vs AZA (14.3% (5.4–28.5%)). However, no significant difference was observed in the 1-year OS rate (PAN+AZA, 60% (50–80%); AZA, 70% (50–80%)) or time to progression (PAN+AZA, 70% (40–90%); AZA, 70% (40–80%)). More grade 3/4 adverse events (97.4 vs 81.0%) and on-treatment deaths (13.2 vs 4.8%) occurred with PAN+AZA. Further dose or schedule optimization may improve the risk/benefit profile of this regimen.

Clinical developments in epigenetic-directed therapies in acute myeloid leukemia

“…62 However, a phase 2b trial randomizing 82 patients with MDS, CML, or AML to panobinostat and azacitidine or azacitidine alone found that patients derived no benefit from the addition of panobinostat. 63 No differences were observed in response rates or OS; in fact, patients receiving the combination experienced more grade $3 AEs (97.4% vs 81%) and on-treatment deaths (13.2% vs 4.8%) than did those receiving azacitidine alone.…”

Histone deacetylase 6 in cancer

“…However, the non-selectivity of the HDAC inhibitors leads to obvious toxicity and side effects and limits the clinical application [92, 93]. …”

The genetic and molecular pathogenesis of myelodysplastic syndromes

“…16 19,20 Despite sound rationale for the combining standard of care hypomethylating agents with histone deacetylase inhibitors such as vorinostat, entinostat, or panobinostat to enhance gene silencing, no added benefit has been detected to date. [21][22][23][24][25][26] First associated with myeloid neoplasms in 2009 by Delhommeau et al and since noted to have incidence of about 22% in MDS (and up to 60% in CMML), the most prevalent recurring mutations with regards to DNA methylation in MDS are that of TET2, which catalyzes the CpG demethylation of methylcytosine to 5-hydroxymeth ylcytosine. 5,13,18,27,28 One study noted that 26% of cases of TET2mutated MDS possess a second TET2 mutation which supports the notion that biallelic functional TET2 loss likely contributes to MDS pathogenesis.…”