A Pilot Study of Epigenetic-Differentiation Therapy with Decitabine to Treat β-Thalassemia Intermedia
Authors: Olivieri Nancy F , Saunthararajah Yogenthiran , Thayalasuthan Vivekanandan , Kwiatkowski Janet , Ware Russell E. , Kuypers Franz , Kim Hae-Young , Vichinsky Elliott P 
Published: October 2019

Abstract
Abstract 2078
Ineffective erythropoiesis, the hallmark of ß-thalassemia, is a result of the myriad deleterious effects of globin chain imbalance. A major translational research goal in thalassemia is to restore α/non-α globin chain balance by inducing expression of γ-globin synthesis from the intact γ-globin gene (HBG). Repression of HBG in adult erythroid cells involves DNA methylation and other epigenetic changes; one possibly useful strategy to re-induce HBG expression is to deplete DNA methyl-transferase 1 (DNMT1) in hematopoietic cells using the cytosine analogue decitabine. A dose and schedule of decitabine intended to deplete DNMT1 without causing significant cytotoxicity was examined in a pilot safety study in ß-thalassemia intermedia, a condition which, despite a lack of requirement for monthly transfusions, is often associated with significant long-term clinical complications. Six patients (≥18 years of age) with ß-thalassemia intermedia were enrolled on study to receive decitabine 0.2 mg/kg subcutaneous 2x/week on consecutive days each week for 12 weeks followed by 12 weeks of follow-up. One patient withdrew from study because of fatigue requiring transfusion after week 2. Of the five evaluable patients, two patients received 24 of the 24 planned doses of drug, one patient received 21 of 24 planned doses, and two patients received 16 of 24 planned doses. Doses were missed because of treatment-associated increases in platelet count to >1000 × 109/L which according to protocol, required interruption of therapy. The primary outcome, an increase in total hemoglobin (Hb) of ≥1.5 g/dL above that determined at baseline, was achieved in two of five evaluable patients. In the group overall, Hb increased from a baseline of (mean ± SEM) 7.88 ± 0.88 g/dL to a peak of 9.04 ± 0.77 g/dL (P = 0.004); peak values in Hb were observed from the 6th to 12th week of treatment. Absolute fetal Hb increased from a baseline of (mean ± SEM) 3.34 ± 0.97 g/dL to a peak of 4.39 ± 1.15 g/dL (P = 0.021); peak values in fetal Hb were observed in the 4th to 12th week of treatment. Reflecting decreased hemolysis and more effective erythropoiesis, indirect bilirubin declined from (mean ± SEM) 3.2 ± 1.0 mg/dL to a nadir of 2.2± 0.8 mg/dL, while reduction in serum LDH from (mean ± SEM) 479.4 ± 125.8 U/L to 362.8 ± 100.4 U/L was not significant (P =0.083). Platelet counts increased from a baseline of (mean ± SEM) 585.2 ± 90.6 (x109/L) to a peak of 940.2 ± 184.3 (x109/L) (P = 0.007); peak platelet values were observed between the 6th to 12th weeks of treatment. These increases triggered interruption of therapy in three of the five evaluable patients. In the only patient not previously splenectomized, minimal change in platelet count was observed (baseline, 233 ×109/L; peak, 296 ×109/L). No clinical events were associated with the increased platelet counts. Changes in neutrophil count, from (mean ± SEM) 6.51 ± 1.20 (x109/L) to 3.36 ± 0.63 (x109/L) were not significant (P = 0.069). The lowest neutrophil counts were observed between the 4th and 10th week of treatment. Two quantitative in vitro assays for mutagenicity, specifically enumeration of illegitimate VDJ recombination events and micronuclei within early reticulocytes, were performed at baseline, midpoint, and study exit. No significant changes were identified between baseline and 24-week values from either laboratory assay. In this first clinical study of decitabine in patients with β-thalassemia, drug dose was aimed at induction of DNMT1 depletion; the frequent but intermittent schedule of administration was intended to modify differentiation without causing prolonged cytostasis resulting in cytopenia. Consistent with a non-cytotoxic/cytostatic, differentiation-altering mechanism of action, the dose-limiting toxicity observed was not thrombocytopenia or neutropenia, but asymptomatic increases in platelet count. In conclusion, decitabine therapy was well-tolerated in thalassemia intermedia. Significant mean and individual increases in total and fetal hemoglobin concentrations observed in this study may direct the selection of patients in extended trials, to explore the potential of chromatin-relaxing therapy for β-thalassemia.

Disclosures:
Off Label Use: FDA approved decitabine for use in MDS, therefore, its use in thalassemia is off-label. Furthermore, the dose, schedule and route of administration used is also not on the label. Decitabine was used in a study to augment production of fetal hemoglobin in an NIH sponsored trial.