A Phase II Study of Azacitidine (Vidaza™) for Patients with Myelofibrosis (MF).
Authors: Quintas-Cardama Alfonso , Kantarjian Hagop , Garcia-Manero Guillermo , Thomas Deborah , Kornblau STeven , Estey Elihu , Nemri Marilyn , Cortes Jorge , Giles Francis , Verstovsek Srdan 
Published: October 2019

Abstract
Aberrant DNA methylation of promoter-associated CpG islands is a mechanism of epigenetic silencing frequently encountered in human neoplasia. Hypermethylation of several genes such as p15INK4B, p16INK4A, progesterone receptor, and the retinoic acid receptor β have been detected in patients (pts) with advanced-stage MF. Azacitidine (Vidaza™) is a hypomethylating agent that induces reactivation of methylated genes and has been approved for the treatment of pts with myelodysplastic syndromes. The objective of this phase II trial was to study the efficacy of azacitidine in pts with relapsed or refractory MF (primary, or secondary to essential thrombocythemia or polycythemia vera) or newly-diagnosed with a Lille risk score 1 or 2 (risk factor are white blood cell [WBC] count >30x109/L or <4x109/L, and hemoglobin [Hb] <10 g/dL). Azacitidine was given at 75 mg/m_ daily (dose level [DL] 0) for 7 days every 4 weeks for 6 cycles but this could be reduced to 50 (DL -1), 25 (DL -2), or 12.5 (DL -3) or increased to 100 (DL +1) mg/m_ according to toxicity or lack of response, respectively. Thirty-four pts have been treated, median age 66 years (range 39–82), time from MF diagnosis to azacitidine therapy 21 months (range 1–361), median Hb 10.3 g/dL (range 8.2–14.3), WBC 10.7x109/L (range 1.7–57.7), and platelets 205x109/L (range 11–1216). Pts had received a median of 1 prior therapy (range 0–6), including hydroxyurea (HU; n=16), anagrelide (AG; n=8), lenalidomide (n=6), thalidomide (n=6), etanercept (n=2), and pegylated interferon (n=2). Six pts had not received any prior therapy. The JAK2 V617F mutation was detected in 19 (70%) of 27 tested pts and 12 of 34 (35%) had abnormal cytogenetics. A total of 142 cycles have been administered. All 34 patients are evaluable for response and toxicity. Responses have been observed in 10 (29%) pts so far, including complete response (CR) in 1 (normal blood counts and <5% bone marrow blasts; off HU, AG, growth factors, and no transfusions), partial response (PR) in 7 (defined as at least 2 of the following: Hb increase by ≥2 g/dL, 50% increase in platelets, decrease of bone marrow blasts or organomegaly by ≥50%, normalization of WBC count without blasts, or reduction in bone marrow fibrosis), and hematologic improvement (HI) in 2 (defined as at least 2 of the following: decrease by ≥25% of pretreatment leukocytosis, splenomegaly, or marrow blasts, or increase of Hb by ≥1g/dl or platelets by ≥25%). The median time to best response was 7.5 weeks (range, 3 to 26). Fifteen (44%) pts discontinued azacitidine due to: lack of response in 7, transformation to acute myeloid leukemia in 2, death (unrelated to azacitidine therapy) in 1, pt’s decision in 1, grade 3–4 toxicity in 2, and other medical reasons in 2. Azacitidine has been generally well tolerated; 10 pts (29%) had grade 3 or 4 toxicity; neutropenia was the only grade 4 toxicity (in 4 pts). Eleven pts (32%) have required dose reduction to DL -1, of which 3 reduced to DL -2, and 9 pts (26%) escalated the dose to DL +1. In summary, azacitidine is well tolerated and has activity in a subset of pts with MF, with current overall response rate of 29%. Updated clinical results will be presented.