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Hypomethylating agents and chemotherapy in MDS

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Until recently, the treatment of higher risk myelodysplastic syndrome was based on [1] Intensive chemotherapy using anthracycline–AraC combinations, leading to a lower complete remission rates and a shorter CR duration compared with de novo AML [2], low dose chemotherapy with limited CR rate mainly restricted to patients with normal karyotype. Azacitidine was the first drug to significantly improve survival in higher risk MDS, although it is not curative. Thus, the survival improvement obtained with azacitidine must be the starting point for combination studies, and for utilization of this drug in other situations (before allo SCT, or after chemotherapy or allo SCT as maintenance treatment).

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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