Study of AR-67 (DB-67) in Myelodysplastic Syndrome (MDS)

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.