Topotecan/Ara-C Promising, Not Standard in MDS

FORT LAUDERDALE, Fla--The combination of topotecan (Hycamtin) and cytarabine (ara-C) has shown promising results in patients with myelodys-plastic syndrome (MDS), especially those with abnormalities of chromosomes 5 and/or 7 (-5/-7), but the findings for the combination are too preliminary to be included as standard of care in the NCCN’s practice guidelines for MDS.

The National Comprehensive Cancer Network (NCCN), a coalition of 16 leading US cancer centers, presented the new MDS guidelines at its third annual meeting, and Elihu Estey, MD, discussed the topotecan findings.

Dr. Estey and his colleagues at M.D. Anderson, where he is professor of medicine, are currently investigating the combination of cyclophosphamide, cytarabine, topotecan, and all-trans-retinoic acid (ATRA) in MDS patients. "This is the direction we need to follow, to build on the topotecan/cytarabine regimen," he said.

In an M.D. Anderson trial led by Miloslav Beran, MD, PhD, topotecan/cytarabine produced a complete response rate of 74% in 35 previously untreated MDS patients (RAEB or RAEB-t patients plus five patients later found to have AML rather than MDS).

This compared favorably with a 64% complete response rate in a separate trial of 151 AML patients (excluding APL patients) who received high-dose cytarabine alone in the mid-1980s.

Subset With -5/-7 Abnormality

This slightly higher rate was achieved despite the fact that the topotecan group was older (median age, 63 years vs 49 for the cytarabine alone group), was more likely to have abnormal blood counts (54% vs 31%), and had worse karyotypes (34% normal vs 40% normal).

Even more impressive, in a small subset of patients with -5/-7 cytogenetic abnormalities, the topotecan combination produced an 80% complete response rate vs 26% for cytarabine alone. "To me, 80% is an astoundingly high figure," Dr. Estey said, "so perhaps the real benefit of topotecan/cytarabine is in patients with these poor prognostic cytogenetics."

While calling topotecan "a very interesting drug" in MDS, Dr. Estey said it would "be a mistake for topotecan/cytarabine to become the standard treatment for patients with untreated MDS."

The problem is, he said, that median survival in the 35 patients who received the combination was not very good--36 to 50 weeks. "Of the 35 patients, 15 are dead," he said, "and the average follow-up of the patients who remain alive is only 6 months."

Thus, further improvements are needed, for example, with the addition of ATRA, cyclophosphamide, or fludarabine to topotecan, and Dr. Estey echoed the MDS guidelines panel’s recommendation that this should be done in the context of clinical trials.

As an aside, Dr. Estey called into question the usual method by which agents are brought into frontline treatment, that is, by first showing effects as salvage therapy in relapsed or refractory patients. He pointed out that topotecan combinations have not proved effective in relapsed or refractory AML, "and yet they appear very promising in people with newly diagnosed AML with -5/-7 abnormalities."