HOUSTONTreatment 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.
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 mortalitythe
lowest of all regimens tested in our institution, he said,
but in the future we must focus on post-remission management.