The management of MDS has been, until recently, based mostly on supportive care. This includes transfusion support, hematopoietic growth factors, and management of complications. With this management, the disease would run its natural course and the patient eventually died either from progression to acute leukemia or from complications associated with MDS itself (e.g., infections, hemorrhage). Recently, hypomethylating agents have offered promise for the management of patients with MDS. Although both agents have shown efficacy in a subset of patients, responses are usually either partial or hematologic improvement only, with CR rates \<10%. In addition, responses have a median duration of less than 12 months. Thus, although both of these agents have improved the outcome of patients with MDS and been approved by the FDA for this purpose, there is clearly need for additional and more effective agents for this disease.

In vitro data suggested that topoisomerase I inhibitors could have activity in MDS, and a prolonged exposure appeared to be particularly effective. Topotecan was the first agent of this class explored for this purpose. A phase I study established the maximum tolerated dose (MTD) at 2 mg/m2/day as a continuous infusion for 5 days. Using this dose, a phase II study in patients with MDS and CMML, a complete remission rate of 31% was achieved. These agents are now considered the most effective available to date in the treatment of MDS and constitute standard therapy. Because of the different times when the studies were conducted and the different eligibility criteria used (e.g., patients with secondary MDS not eligible for decitabine, only patients with high-risk MDS eligible for topotecan), comparisons are somehow limited. However, results with topotecan compare favorably to those obtained with both 5-azacytidine and decitabine. The CR rate is the highest achieved with any of these agents. Response duration is shorter than that reported for AZA, but the remission duration for AZA includes hematologic improvements which constitute most of the responses with AZA. In addition, the AZA study continued therapy until the response was lost, while the topotecan study (as well as the decitabine study) administered by design only 4-6 cycles of therapy. Survival was shorter for patients treated with topotecan, but this is not unexpected considering that this population included 50% of patients with CMML and 32% with secondary MDS, both important adverse prognostic characteristics in MDS. The AZA study had the best survival, but it included 37% patients with RA or RAES and only 20% with intermediate-2 or high IPSS. Because the eligibility included patients with greater than 10% blasts, all MDS patients would have had a score of at least 1.5 and thus be classified in the intermediate-2 risk group.

Based on the favorable activity of topotecan as a single agent, topotecan was also used in combination with cytarabine in high-risk MDS (i.e., RAEB with \>10% blasts or RAEBt). A CR rate of 56% was achieved, with a low rate of induction mortality (7%) in a population with a median age of 68 years. These results were at least equivalent to those achieved with an idarubicin and cytarabine combination both in a retrospective comparison of two different trials, and in a prospective randomized trial.

Overall, these results suggest that additional exploration of topoisomerase I inhibitors in myelodysplastic syndrome is warranted.