Phase I Study of Panobinostat Plus Decitabine In Elderly Patients with Advanced MDS or AML.

Panobinostat (LBH589) is pan-deacetylase inhibitor of both histones and nonhistone proteins such as HSP90 and HIF-α which are implicated in leukemogenesis. Panibinostat has demonstrated activity in a broad range of hematologic malignancies including AML with in vitro studies demonstrating synergistic mechanism of action with a number of agents including DNA hypomethylating agents.

We conducted a phase I study of panobinostat plus decitabine in elderly patients with advanced MDS/AML. Patients age ≥ 60 years with advanced MDS (IPSS ≥ 1.5) or AML who had not been previously treated with a hypomethylating agent were eligible for the study. Decitabine 20mg/m²/d IV on days 1–5 was administered with panobinostat po 3x/wk on nonconsecutive days of a 28 day cycle for up to 12 cycles. panobinostat started at 10 mg/d and was escalated to a maximum of 40 mg/day in 5 cohorts using a 3+3 design. The 40 mg dose group was the highest allowed in the study based on anticipated cytopenias from both drugs in an elderly population.

Twenty-eight patients (21 AML/7 MDS) with a median age of 71 years (range 60–86), median WBC 12.7 (range 0.9–73.5) were treated in the Phase I study. Twelve of these patients had previously been treated with regimens that included 7+3 or high dose cytarabine (6 pts, 21%) or high dose lenalidomide (6 pts, 21%). The dose of panobinostat was escalated to a maximum of 40 mg 3x/wk. Of the first 27 evaluable patients there were 7/27 (22%) complete responses with 4 of 8 patients in the 30 mg/day cohort achieving a CR (1 CR, 3 CRi). Of the patients with a CRi, two had baseline cytogenetic abnormalities and both experienced disappearance of the abnormality at the time of response. These patients had persistent thrombocytopenia which may be a consequence of treatment rather than the presence of residual leukemia. Side effects included a dose-limiting asthenia (1 pt /each) which occurred in both the 30 mg and 40 mg/day cohorts. Disease progression was the most common reason for discontinuation of study treatment occurring in 8 pts (four of which occurred in the first cycle of therapy). These early cases of disease progression may suggest that “low-dose” therapies in patients should be avoided in patients with hyperproliferative disease. We conclude that the combination of panobinostat plus decitabine can be safely administered to patients with AML/MDS. The response rate observed at higher doses (’ 30 mg/d) is encouraging and warrants further investigation. Based on this phase I data which demonstrates encouraging evidence of clinical activity for the combination, a phase II cohort using a dose of panobinostat 40 mg po 3x/wk is currently being enrolled.

Uy:Novartis: Research Funding. Off Label Use: Panobinostat for MDS/AML. Abboud:Novartis: Honoraria. Vij:Novartis: Honoraria; Eisai: Speakers Bureau. Westervelt:Novartis: Speakers Bureau.