Temozolomide Plus Cisplatin Promising in Relapsed/Refractory Leukemia

Last Updated: 2009-06-23 19:30:26 -0400 (Reuters Health)

NEW YORK (Reuters Health) - In a study of heavily pretreated patients with relapsed and refractory acute leukemia, the combination of temozolomide and cisplatin showed significant antileukemic activity and was well tolerated, according to a report posted online May 22 in the Journal of Hematology and Oncology.

Resistance to temozolomide is associated with activity of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), Dr. Karen Seiter of New York Medical College, Valhalla, New York, and colleagues note in their report.

"Laboratory studies have shown that only 25% of leukemia cells demonstrate low levels of MGMT. Therefore, strategies to deplete MGMT in these cells could potentially render them more sensitive to temozolomide," the study team notes. "One such strategy is to combine temozolomide with other agents that deplete MGMT, such as cisplatin."

Based on the favorable toxicity profile of temozolomide and the in vitro sensitivity of leukemia cell lines to the drug, Dr. Seiter"s team conducted a phase I study of temozolomide plus cisplatin in 20 patients with relapsed and refractory acute leukemia.

Fifteen patients had acute myelogenous leukemia (AML), three had acute lymphoblastic leukemia (ALL), and two patients had biphenotypic leukemia. The participants" median number of prior intensive chemotherapy regimens was three (range, 1 to 5).

According to the investigators, treatment was well tolerated up to the maximal doses of temozolomide (200 mg/m²/d for 7 days) and cisplatin (100 mg/m² on day 1), and there were no real dose-limiting toxicities.

In addition, temozolomide plus cisplatin showed "significant antileukemic activity," especially at the highest dose level. Of the eight patients treated at this level, one had complete remission. This patient had de novo AML with normal cytogenetics.

Two other patients treated at the highest dose level saw dramatic reductions in bone marrow blasts (pretreatment 69% and 87% blasts, to post-treatment 3% and 5% blasts, respectively). These patients, however, did not meet criteria for complete remission due to a lack of peripheral count recovery, the investigators note.

The low complete remission rate seen in their study is not unexpected, they point out, noting that this patient population is "notoriously difficult to treat."

Dr. Seiter and colleagues suggest that further studies measuring MGMT could determine which patients might benefit from the combination of temozolomide and cisplatin.

Source:

J Hematol Oncol 2009.


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