10Hypomethylating agents and chemotherapy in MDS
Introduction
Although numerous prognostic factors have been proposed over the past 20 years in MDS, the most widely used prognostic system for therapeutic purposes remains the International Prognostic Scoring System (IPSS), based on the percentage of bone marrow blasts, bone marrow cytogenetics and number of cytopenias [1]. This system is able to stratify patients into four distinct groups, with different outcome in term of survival and risk of AML evolution. For clinical purpose, this prognostic scoring system is usually simplified to discriminate only two risk groups, defining Lower and higher risk MDS. This latter group is characterized by a median overall survival of less than 12 months and by a high risk of AML evolution [1]. For these reasons, in higher risk MDS patients, the main goal of therapy is to alter the natural history of the disease. The current options having demonstrated such an impact in higher risk MDS are allogeneic stem cell transplantation [2], remaining the only potentially curative treatment in MDS, hypomethylating agents [3], [4], [5] and -to a much lesser extent intensive chemotherapy [6]. In this paper, we will review the role of chemotherapy and hypomethylating agents in the management of high risk MDS patients.
Very recently, a modification of IPSS scoring system has been proposed (IPSS-R) and already validated in several MDS patient cohorts [7], [8], [9]. Its novelty resides in the different and greater weight given to the cytogenetics. It is anyhow still to evaluate its strength and importance in therapeutic decision making.
Section snippets
Intensive chemotherapy
Intensive chemotherapy in higher risk MDS have schemes and drug associations largely similar to those proposed in AML patients, based on anthracycline–AraC combinations [6], [10], [11], [12], [13]. However, when applied to MDS (or AML post MDS), these chemotherapy regimens are associated with a lower complete remission (CR) rates (40–60%) and a shorter CR duration (median duration of less than 12 months) compared with de novo AML [6], [10], [11], [12], [13]. With long term follow-up, the
Other chemotherapeutic agents
Different schedules of the so-called low dose Ara-C have been employed: Ara-C 20 mg/m2/day, 14–21 days every month are the most widely used for many years in higher risk MDS, and yielded CR and PR rates of 15–20% and 15–20%, respectively, although with relevant myelosuppressive effects [22], [23]. As for intensive chemotherapy, response were mainly restricted to patients with normal karyotype and myelosuppression remained a major issue with up to 10% toxic deaths [20]. Of note, once again in
Azacitidine
Azacitidine was first tested at high doses in the 80's, as a cytotoxic chemotherapy in acute leukemia [42], (but also in solid tumors) where its results were considered equivalent to those achieved with conventional dose and later at lower doses, for its hypomethylating activity, in the treatment of MDS [3], [4], [43].
In a first randomized phase III study conducted by the CALGB (CALGB-9221 trial) evaluating azacitidine versus best supportive care (BSC) in MDS patients, the overall response rate
Conclusions
Azacitidine is the first drug to significantly improve survival in higher risk MDS, although it is not curative. This survival improvement generally does not result from achievement of CR (with possible “eradication” of the malignant clone), but rather from disease stabilization or even return of the disease to an earlier phase of MDS, with less cytopenias and delayed progression to AML (both probably accounting for the survival advantage). A survival advantage with azacitidine is seen in all
Conflict of interest statement
None.
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