Abstract 2568

Poster Board II-545

Reversing the perinatal switch from fetal to adult hemoglobin synthesis has been an attractive therapeutic goal for β-hemoglobinopathies such as sickle cell disease (SCD) and β-thalassemia. Fetal hemoglobin (Hb F) inhibits the polymerization of deoxy Hb S (anti-sickling effect) in SCD and ameliorates the globin chain imbalance by compensating for severely diminished or absent β-globin synthesis in β-thalassemia. Different classes of compounds have been used for this purpose; only hydroxyurea (HU), an S-phase specific chemotherapeutic agent, an inhibitor of ribonucleotide reductase, has been FDA approved for use in adults with SCD and is currently in phase III trials for infants and children. Despite the established efficacy of HU in many patients with SCD, there is a need for alternative Hb F inducing agents and therapies; an estimated 30% of patients do not respond to HU therapy. In addition, some patients are intolerant of HU due to a number of side effects. The development of novel, more effective anti-switching agents is hampered by a lack of a clear and complete understanding of the molecular mechanism(s) underlying the perinatal switch from fetal (γ-globin) to adult (β-globin) synthesis despite three decades of intensive research. Nevertheless, it has been established that epigenetic mechanisms such as histone deacetylation and DNA methylation do play an important role in the silencing of the γ-globin genes during the perinatal period. In vitro studies and early phase clinical trials in a small number of patients have provided the proof-of-principle for the efficacy of a number of histone deacetylase (HDAC) inhibitors and hypomethylating agents (DNA methyl transferase I inhibitors). Butyrate derivatives are an example of HDAC inhibitors whose efficacy in inducing Hb F has been proven in both SCD and β-thalassemia. More recently, other HDAC inhibitors (SAHA, Depsipeptide, Trichostatin A) have been shown to induce Hb F synthesis in erythroid cultures. DNMT-1 inhibitors, 5-Azacytidine and decitabine, have also been used in small clinical trials to enhance Hb F production and ameliorate the course of severe SCD. LBH589 (panobinostat, Novartis Pharma) is a pan-HDAC inhibitor that belongs to the hydroxamic acid class of HDAC inhibitors that is currently being investigated in Phase I/II trials in hematologic malignancies and a number of solid tumors. We monitored the Hb composition of 21 patients with relapsed/refractory hematologic malignancies enrolled into a Phase I/b trial of panobinostat conducted at the MCG Cancer Center. Hb quantification was done by a cation exchange HPLC procedure. Eight patients were on panobinostat for 2 months or longer with a starting dose of 40–60 mg PO administered thrice weekly (MWF). Three patients carried a diagnosis of Primary Myelofibrosis and one each had Chronic Lymphocytic Leukemia, Mantle Cell Lymphoma, Multiple Myeloma, Refractory Non-Hodgkins Lymphoma, and Chronic Myelogenous Leukemia-accelerated phase. Of these, 4 patients displayed an increase in Hb F over baseline values. None of the patients had an inherited hemoglobinopathy (SCD or β-thalassemia). The median Hb F was 0.33% at entry (range: 0–2.3) and increased to 1.1% (range 0–17%) at the end of the study period. The maximal response was seen in a patient with Primary Myelofibrosis whose Hb F increased from a pretreatment value of 0.2% to 17.0% over a period of 16 months. Overall, patients who were on panobinostat for longer periods of time (≥ 2 months) had a more pronounced increase in Hb F. The remaining 13 patients were on study drug for <2 months. In studies of other Hb F inducing agents, optimal response is not generally reached in less than 6 months. The slight but significant increase in Hb F in this small group of patients without an underlying hemoglobinopathy is encouraging and provides the rationale for a trial of panobinostat as an anti-switching agent in clinically significant hemoglobinopathies such as SCD and β-thalassemia. This effect will likely be enhanced in patients with hemoglobinopathies given the erythropoietic stress and the selection of RBCs containing Hb F. Studies in transgenic mouse models of SCD and a phase I study in patients with SCD who have failed or intolerant of HU are underway.


Kutlar:Novartis Pharmaceuticals, Inc.: Research Funding; Celgene Corporation: Research Funding; HemaQuest Pharmaceuticals, Inc.: Research Funding. Meiler:Celgene Corporation: Research Funding; Novartis Pharmaceuticals, Inc.: Research Funding. Bhalla:Novartis: Honoraria, Research Funding; Merck: Honoraria.

Author notes


Asterisk with author names denotes non-ASH members.