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Topotecan Plus Cytarabine Promising in MDS

Topotecan Plus Cytarabine Promising in MDS

ASH—Topotecan (Hycamtin) given in combination with cytarabine (ara-C) produced a complete response rate of 63% in 35 patients with previously untreated, poor-prognosis myelodys-plastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML), Miloslav Beran, MD, PhD, said at the American Society of Hematology annual meeting in San Diego.

Myelodysplastic syndrome is a preleukemic disorder characterized by an abnormal maturation of bone marrow cells, while CMML is a slowly progressive form of leukemia. Both are most common in persons over the age of 60. These blood disorders are among the few malignant diseases in the United States with 100% mortality that lack a standard of care, said Dr. Beran, professor of medicine, M.D. Anderson Cancer Center.

Generally, these diseases progress slowly, but high-risk patients (for example, those with an increased number of immature cells in the bone marrow or a low platelet count) will likely die from their disease within 1 to 2 years.

“In those patients who have a higher risk of dying because of failing bone marrow or transformation into active leukemia, we are justified in trying new regimens,” Dr. Beran said in an interview with Oncology News International.

The topotecan/cytarabine combination, he said, “seems to be the least toxic of the combination chemotherapy regimens being studied in this disease, and is very active in high-risk patients.”

More important, he continued, in the subcategories of patients who have abnormal cytogenetics (most often, involvement of chromosomes 5 and 7), “we see a very good complete response rate of 80%, compared with 20% to 30% with other regimens. That is the major impact of this new regimen.”

In this phase II trial, patients with either MDS (21 patients) or CMML (14 patients) received topotecan (1.25 mg/m2 by continuous infusion over 24 hours daily for 5 days) plus high-dose cytarabine (1 g/m2 given over 2 hours daily for 5 days). Of the 22 patients who achieved a complete response, 80% did so after only one course of therapy with this regimen.

Lower Response With FAI-G ATRA

By comparison, in a study performed simultaneously at M.D. Anderson, in which 55 similar-risk patients received an investigational regimen known as FAI-G ATRA—fludarabine, high-dose ara-C, idarubicin with or without G-CSF, and ATRA (all-trans-retinoic acid)—the complete response rate was 40%, with higher toxicity.

The median duration of remission in the topotecan/cytarabine study is approximately 9 months, and median survival has not been reached, Dr. Beran said, stressing that the results from this small study are very preliminary.

The investigators are also comparing the topotecan/cytarabine results achieved at M.D. Anderson with the same regimen being used through the center’s Community Oncology Program. “This study will continue for another half year or so, with accrual of about 120 patients,” he said.

In addition, Dr. Beran said, the M.D. Anderson group has begun a randomized study comparing topotecan plus cytarabine with the FAI-G ATRA regimen, with results expected in about a year.

New treatments for MDS and CMML are especially important, Dr. Beran said, because the incidence of these diseases is increasing as the population ages. Also, he pointed out, MDS is a disease that may develop after treatment of other malignancies with mutagenic chemotherapy, which more and more patients are receiving.

“You may cure the patient’s breast cancer, or ovarian cancer, or lymphoma, and then 4 or 5 years later, they develop myelodysplastic syndrome,” he said. “Importantly, this category of patients also responds very well to the topotecan plus cytarabine regimen.”

Exposure to toxic environmental agents, such as pesticides, may also lead to an increased frequency of the disease, he added.

Finally, the actual number of newly diagnosed cases of MDS may be twice the 15,000 reported annually, Dr. Beran said. This is because, with no treatment available until now, physicians and their elderly patients often may decide against pursuing the diagnosis with the bone marrow tests required to confirm the presence of the disease.

 
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