A Phase I Study of LBH589, a Novel Histone Deacetylase Inhibitor in Patients with Primary Myelofibrosis (PMF) and Post-Polycythemia/Essential Thrombocythemia Myelofibrosis (Post-PV/ET MF).
Authors: Mascarenhas John , Wang Xiaoli , Rodriguez Amelyn , Xu Mingjiang , Gorman Elaine , Zhang Wenyong , Goldberg Judith D. , Najfeld Vesna , Hoffman Ronald 
Published: October 2019

Abstract
Abstract 308

Background:
Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by progressive constitutional symptoms, cytopenias, splenomegaly and constitutive mobilization of CD34+ cells. The JAK2V617F mutation is present in approximately 50% of MF patients and the mutational burden has been used as a surrogate marker of disease burden and treatment response. LBH589 (Panobinostat), is a novel histone deacetylase inhibitor (HDACi) with potent inhibitory activity against HDAC and HSP90. CXCR4 has previously shown to be down-regulated in PMF CD34+ cells but can be up-regulated by in vitro treatment with sequential chromatin modifying agents (CMA). In addition, the number of JAK2V617F + progenitor cells (PC) can be reduced by treatment of MF CD34+ cells with CMA. (Shi et al, Cancer Research 67: 6417, 2007) Our working hypothesis is that restoration of CXCR4 expression by PMF CD34+ cells would redirect these cells to the bone marrow niche and reduce extramedullary hematopoiesis and promote elimination of MF PC. In order to test this hypothesis, a series of preclinical studies with purified CD34+ cells isolated from peripheral blood of untreated PMF patients were performed. Cells were cultured with SCF, IL-3, FLT3 and TPO ± LBH589 for 2 days and assayed for total number of cells, CD34+ cells, and % CD34+ cells expressing CXCR4. Both total and CD34+ cell numbers were reduced following LBH589 treatment. CXCR4 expression by cultured CD34+ PMF cells was up-regulated in the presence of LBH589. Cells were placed in semi-solid culture and hematopoietic colonies were enumerated, plucked and genotyped for JAK2V617F. CD34+ cells from 2 of 4 PMF patients treated with LBH589 had a decrease in the number of JAK2V617F homozygous colonies. Based on these data, we are presently conducting an ongoing investigator initiated phase I/II study of LBH589 in patients with MF at our institution.

Methods:
Patients with Lille class I/II PMF, post-ET/PV MF, collectively referred to as MF were eligible if they had an ANC >1000 and platelet count > 60,000. The primary endpoint of the study is to assess the safety and tolerability of LBH589. Secondary endpoints include measurement of clinical response as assessed by IWG-MRT criteria and assessment of change in JAK2V617F burden, histone acetylation, peripheral blood CD34+ cell number and cytogenetics. DLT was defined as an AE that occurred in the first 28 days on study and judged unrelated to disease progression, intercurrent illness or concomitant medications. AEs were graded by CTCAEv3.0 criteria. LBH589 was given to patients in the first cohort at an oral dose of 20mg TIW and the second cohort at 30mg TIW for 28 days and were eligible to receive additional cycles if no DLT was seen.

Results:
A total of 12 patients (6 in cohort 1 and 6 in cohort 2) have been enrolled and 8 patients (6 in cohort 1 and 2 in cohort 2) are evaluable to date. Thrombocytopenia is the only DLT observed as of yet and was seen in 2 patients. Grade 3 soft tissue hemorrhage requiring platelet and red blood cell transfusion occurred in a single patient in the first cohort who developed worsening thrombocytopenia from a baseline count of 61,000. In the second cohort at a 30mg TIW dose, Grade 3 thrombocytopenia occurred in 1 patient with a baseline normal platelet count after only 3 doses and resolved within 1 week off the drug. Grade 3 anemia is the only other hematologic AE seen in subsequent cycles in 25% of patients (2/8; a patient in both cohorts). The most common non-hematologic AEs noted were grade 1 nausea, fatigue, diarrhea and musculoskeletal pain. Two patients in cohort 1 have had a greater than 50% reduction in spleen size. One of these patients has also had a significant reduction in RBC transfusion requirements and has complete resolution of splenomegaly at 7 months. By IWG consensus criteria for treatment response, 2 patients (1 JAK2V617F + and 1 -) experienced clinical improvement and 4 patients had stable disease.

Conclusion:
Treatment of MF patients with LBH589 is associated with acceptable hematologic and non-hematologic toxicity and can result in clinical improvement in patients with advanced MF. Based on these observations, LBH589, an oral HDACi, appears to be a promising new agent for the treatment of both JAK2V617F positive and negative MF. Accrual continues in the phase I portion of this study and data on the effects of LBH589 on a variety of biomarkers including JAK2V617F allele burden, will be presented at the meeting.

Disclosures:
Off Label Use: LBH589, panobinostat, is a novel oral histone deacetylase inhibitor that is being investigated in myelofibrosis to reverse the splenomegaly and improve cytopenias as well to modulate the JAK2V617F allele burden and potentially change the natural history of the disease. .