Topotecan/High-Dose Cytarabine Shows Promise in MDS/CMML

HOUSTON—Treatment with topotecan (Hycamtin) and high-dose cytarabine can produce high complete remission rates in patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML), even in patients with poor-prognosis cytogenetic features and secondary MDS, Miloslav Beran, MD, PhD, DVM, of M. D. Anderson Cancer Center, said at ASH.

In previous studies, the researchers had observed a 34% complete remission rate with topotecan monotherapy in 32 previously untreated patients with MDS/CMML, Dr. Beran said. Median duration of complete remissions was 7.5 months, and median survival was 10.5 months.

Fifty-nine patients with MDS (38 patients) or CMML (21 patients) were enrolled in the current phase II study. Sixteen (28%) had secondary MDS. These were patients who were previously untreated (66%), had received only biologic agents (12%), or had received chemotherapy with or without biologic agents (22%).

Most patients were International Prognostic Scoring System (IPSS) group 2. The IPSS incorporates variables unique to an individual patient such as bone marrow blast percentage, karyotype, and the number and severity of peripheral cytopenias.

Treatment consisted of topotecan, 1.25 mg/m² by continuous intravenous infusion daily for 5 days, and cytarabine, 1 g/m² infused over 2 hours daily for 5 days. Patients received 3 to 6 courses of treatment, 4 to 6 weeks apart.

Prophylaxis included antibac-terial, antifungal, and antiviral agents; 66% of patients were treated in laminar-air-flow rooms. Growth factors were used as the attending physician thought necessary, but Dr. Beran pointed out that this is “not a tremendously myelosuppressive regimen, considering the patient population.”

Response Rates

At a median follow-up of 7 months, all 59 patients were evaluable for response and toxicity. Complete response, defined as decrease of marrow blasts below 5% and increase of blood neutrophils over 1,500/mm³ and platelets over 100,000/mm³, occurred in 35 patients (59%), most after the first course of treatment.

A significantly higher proportion of patients with MDS than with CMML experienced CR (66% vs 47%, P = .04). Complete response rates were similar for MDS patients with good-risk and poor-risk prognostic factors (79% and 58%, respectively).

Topotecan/high-dose cytarabine was able to induce complete remission in patients with poor-prognosis karyotype involving chromosomes 5 and 7 (63%) and secondary MDS (69%).

“Karyotype did not seem to matter very much,” Dr, Beran said. “Most patients with transformed disease converted from abnormal to normal karyotypes when in remission.”

In response to a question, Dr. Beran said that the remission rate in bad karyotype disease was significantly higher with topotecan/cytarabine than had been observed with cytarabine alone.

Median duration of response for the entire group was 32 weeks: 41 weeks for MDS and 33 weeks for CMML. Median survival was 42 weeks for patients with MDS and 35 weeks for patients with CMML. Eighteen of the 59 patients (31%) had resistant disease.

In response to a question, Dr. Beran said that patients who relapsed typically relapsed as MDS, seldom as CMML. After relapse, patients who had received two or fewer courses of treatment were sometimes treated with topotecan/cytarabine again, but most went on to salvage regimens. “Once they relapse, the chance of reinduction is poor,” he said.

Relatively Mild Toxicity

He reported that toxicity was relatively mild. Mucositis and/or diarrhea were observed in 4% of patients, mostly during the second week of treatment and mostly self-limited. Skin rashes were observed in 15 patients (28%) but were severe in only two. Fever of undetermined origin was seen in 72% of patients, and infection was documented in 59%. Six patients (10%) died during induction, five of infection and one of bleeding.

“This is an active induction regimen with low mortality—the lowest of all regimens tested in our institution,” he said, “but in the future we must focus on post-remission management.”