Activity of Oral Panobinostat (LBH589) in Patients with Myelofibrosis.
Authors: DeAngelo Daniel J. , Spencer Andrew , Fischer Thomas , Kindler Thomas , Ottmann Oliver G. , Prince Miles , Giles Frank J. , Cortes Jorge , Liu Angela , Parker Kathryn , Yan Ying , Scott Jeffrey W. , Bhalla Kapil N. 
Published: October 2019

Abstract
Abstract 2898
Poster Board II-874

Introduction:
Panobinostat (LBH589) is a potent pan-deacetylase inhibitor (DACi) targeting epigenetic and non-epigenetic oncogenic pathways. Panobinostat is currently under clinical investigation in a variety of solid tumors and hematologic malignancies. A Phase IA/II trial evaluating oral panobinostat in patients (pts) with advanced hematologic malignancies is currently ongoing, and encouraging clinical activity has been reported previously in pts with lymphoma, myeloma, or leukemia. Here, preliminary activity of oral panobinostat in pts with myelofibrosis (MF) is described.

Patients and methods:
Pts with advanced hematologic malignancies were treated in cycles of 28 days with two schedules of oral administration: Monday/Wednesday/Friday (MWF) every week or MWF every other week. Each schedule is being assessed in two pt groups that differ by disease and the definition of hematologic dose-limiting toxicity (DLT): Group X includes pts with MF, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL), chronic myelomonocytic leukemia (CMML), chronic myeloid leukemia (CML), or chronic lymphocytic leukemia (CLL); and Group Y includes pts with Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), or multiple myeloma (MM). For MF patients, response was assessed according to the 2006 International Working Group (IWG) consensus response categories. Presence of an activating mutation (JAK2V617F) of the Janus kinase 2 (JAK2) tyrosine kinase was assessed.

Results:
To date, a total of 176 pts have been treated at 20–80 mg/dose MWF every week, or 30–80 mg/dose MWF every other week. The adverse event (AE) profile has been similar between the two schedules. In Group X (n=119), the most common drug-related Grade 3/4 AEs (≥10%) have been thrombocytopenia (28%), fatigue (22%), neutropenia (18%), and anemia (10%). The maximum tolerated dose (MTD) for Group X, in which cytopenia(s) in the presence of persistent disease is not considered dose limiting, was 60 mg/dose MWF every week, and the principal DLT was fatigue. MTD was not determined for the every other week schedule. In Group Y (n=57), the most common drug-related Grade 3/4 AEs (≥10%) have been thrombocytopenia (72%), neutropenia (26%), and fatigue (16%). The MTDs for Group Y, in which cytopenias are considered dose limiting, were 40 mg/dose MWF every week or 60 mg/dose MWF every other week, and the principal DLT was thrombocytopenia. Thirteen patients (10 male) with MF have been treated, including 10 pts with idiopathic MF and 3 pts with post-polycythemic disease. Eight patients were transfusion dependent at study entry and two pts had no prior therapy for MF. Median age is 59 years (range 31–86). Among previously treated pts (11 pts), the median number of prior therapeutic regimens was 3 (range 1–6); prior therapies included chemotherapy, which may have included hydroxyurea (11 pts), radiotherapy (1 pt), splenectomy (1 pt), and stem cell transplantation (2 pts, both with prior chemotherapy). JAK2 status has been identified as wild-type for 1 pt and mutant (JAK2V617F) for 9 pts (unknown for 3 pts). Pts received panobinostat at 30 (n=1) or 60 mg/dose (n=11) MWF every week, or 80 mg/dose (n=1) MWF every other week. A preliminary assessment of efficacy has been performed by the investigators. Among 12 pts evaluable for response, one previously untreated pt (JAK2V617F) has demonstrated a partial response, including an 85% reduction in spleen size; treatment is ongoing in Cycle 9. Three pts demonstrated clinical improvement lasting ≥8 weeks: 1 pt, ongoing in Cycle 39, has demonstrated an 86% reduction in spleen size and transfusion independence for >1 year; another pt, ongoing in Cycle 19, has demonstrated an 83% reduction in spleen size; the third pt demonstrated a 57% reduction in spleen size and improvement in other disease-related symptoms. An additional 4 pts had stable disease, ranging from 4 to 8 cycles, with 1 pt ongoing in Cycle 8.

Conclusions:
Panobinostat shows promising clinical activity, with disease control for up to 39 cycles, in patients with MF. These encouraging preliminary data support the investigation of panobinostat activity in patients with MF in subsequent studies. Updated safety and efficacy data will be presented.

Disclosures:
DeAngelo: Bristol-Meyers Squibb: Consultancy, Research Funding; Celgene: Speakers Bureau; Enzon Pharmaceuticals: Speakers Bureau; Novartis: Speakers Bureau. Ottmann:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Prince:Novartis: Consultancy, Honoraria, Research Funding. Giles:Novartis: Research Funding; Merck: Research Funding; BMS: Research Funding; Vion: Research Funding. Cortes:Nerviano: Research Funding. Liu:Novartis: Employment. Parker:Novartis: Employment. Yan:Novartis: Employment. Scott:Novartis: Employment. Bhalla:Novartis: Honoraria, Research Funding; Merck: Honoraria.