SUMMARY: It is estimated that in the US approximately 13,000 people are diagnosed with MyeloDysplastic Syndromes (MDS) each year. The prevalence has been estimated to be from 60,000 to 170,000 in the US. MyeloDysplastic Syndromes are a heterogenous group of stem cell disorders characterized by marrow failure resulting in cytopenias, mainly symptomatic anemia, with associated cytogenetic abnormalities, and abnormal cellular maturation with morphologic changes in clonal cells. Majority of the individuals diagnosed with MDS are 65 years or older and die as a result of infection and/or bleeding, consequent to bone marrow failure. About a third of patients with MDS develop Acute Myeloid Leukemia (AML).
The International Prognostic Scoring System (IPSS) for MDS has 4 risk groups based on Total Risk Score (Low, Intermediate-1, Intermediate-2 and High). The three prognostic factors scored to predict the course of the patient’s disease include, percentage of blast cells in the bone marrow, type of chromosomal changes in the marrow cells and number of cytopenias (anemia, neutropenia or thrombocytopenia). Patients with low-risk MDS have an indolent disease course with a median survival of about 6 years with no therapeutic intervention. Patients with intermediate and higher-risk disease however have a shorter median survival even with treatment, with approximately a third of the patients progressing to AML within 3 years.
Patients with Low-risk MDS often present with symptomatic anemia and these patients are in chronic need for RBC transfusions. These patients are treated with Erythropoiesis Stimulating Agents (ESAs) as first line therapy. ESAs such as Darbepoetin alfa and Epoetin alfa are re-engineered and recombinant DNA technology products of Erythropoietin (EPO), and they stimulate erythropoiesis by binding and activating the EPO receptor. However, transfusion-dependent patients with serum EPO levels above 200U per liter are less likely to respond to ESAs. A majority of patients with higher-risk MDS are treated with hypomethylating agents such as VIDAZA® (Azacitidine) and DACOGEN® (Decitabine) and these agents can favorably modify the natural history of the disease, and have been shown to improve survival. However, the role of the hypomethylating agents in lower-risk MDS has not been established.
To better understand the role of hypomethylating agents in adult patients with previously untreated MDS, with low or Intermediate-1 risk MDS or Chronic MyeloMonocytic Leukemia (CMML), the researchers conducted a long-term analysis, of a previously reported randomized Phase II study of low dose Decitabine versus low dose Azacitidine, in lower-risk MDS and MDS/myeloproliferative neoplasms (Jabbour E, et al. Blood. 2017;130:1514-1522). The aim of this study was to better understand the impact of attenuated hypomethylating agents dosing, in patients with lower-risk MDS.
A total of 113 patients (N=113) were randomly assigned with a Bayesian response-adaptive design to receive either Decitabine 20 mg/m2 IV daily (N=73) or Azacitidine 75 mg/m2 IV daily (N=40) on days 1-3 of every 28-day cycle, between November 2012 and February 2016. Responding patients were allowed to continue therapy indefinitely. Bone marrow aspiration and/or biopsy were performed at the end of course 2 and every 3 months during the first year, and then every 3 to 6 months thereafter. Patients who had received other prior treatments for MDS, including growth factors, were eligible. Hydroxyurea treatment was permitted to control leukocytosis before study therapy. The authors in their previous publication reported that at a median follow up of 20 months, hypomethylating agents induced high response rates in patients with lower-risk MDS. The researchers in this extension analysis of lower-risk MDS patients, evaluated the Duration of Response, Event-Free Survival (EFS), and Overall Survival (OS), with a median follow-up of 68 months. The median number of treatment cycles was 15.
The Overall Response Rate was 67% in the Decitabine group and 48% in the Azacitidine group (P=0.042). Of the 59 patients who were transfusion dependent, 32% became transfusion independent (Decitabine 41% and Azacitidine 15%; P=0.039). The median duration of transfusion independency was 22 months. Among those patients who were transfusion independent at baseline, 9% became transfusion dependent after therapy. With a median follow-up of 68 months, the median overall Event-Free Survival was 17 months and median Overall Survival was 33 months. No early deaths were observed.
The authors concluded that low dose hypomethylating agents can induce durable response of transfusion independency in patients with lower-risk MDS, and response to hypomethylating agents can be associated with favorable clinical outcomes in this patient group.
Low-Dose Decitabine versus Low-Dose Azacitidine in Lower-Risk MDS. Sasaki K, Jabbour E, Montalban-Bravo G, et al. DOI:https://doi.org/10.1056/EVIDoa2200034
