Sequential high-dose ara-C and asparaginase versus high-dose ara-C alone in the treatment of patients with relapsed and refractory acute leukemias.

In consideration of the full spectrum of hematologic and nonhematologic toxicity juxtaposed to the response rates (Tables 2-5), it appears that for relapsed patients with AML, six to eight consecutive doses of HDara-C or four doses started on days 1 and 8 have the optimal therapeutic index. These regimens are associated with a 25% CR rate and have comparable tolerable and reversible toxicity spectra. An increase in the total number of doses to 12 does not appear to increase the remission frequency in relapsed patients but does decidedly increase the spectrum, frequency, and severity of toxic manifestations. Studies of important pharmacologic determinants such as membrane transport and cellular accumulation of ara-CTP suggest that a lower unit dose may be just as effective, an approach that could potentially lower the frequency and severity of toxicity. However, these concepts must be tested in suitably designed clinical trials. In contrast to the response rate noted in patients with relapsed AML, patients with refractory AML have a substantially lower CR rate (approximately 10%) when treated with HDara-C alone. These lower CR rates are comparable to those reported for other recently introduced new drugs such as m-AMSA and mitoxantrone. In this setting of primary refractory leukemia, multi-institutional and cooperative group trials of HD-ara-C----ASNase show a consistently higher response rate in the range of 30% to 50%. Why ASNase should especially contribute to this particular group is unknown at present. Studies show that the gene for asparagine synthetase is repressed in AML cells. It is speculated that in the initial leukemia cell population (as encountered in refractory AML), the gene for asparagine synthetase is repressed and hence, the leukemia is sensitive to ASNase. In contrast, in the relapsed patient with recurrent leukemia, the gene for asparagine synthetase may be derepressed and the leukemia would be ASNase-insensitive. The therapeutic index of HDara-C----ASNase is schedule dependent. In leukemic mice, pretreatment or concurrent administration of ASNase and HDara-C leads to antagonism of both the therapeutic and toxic effects of HDara-C. These effects are consistent with similar effects of other protein synthesis inhibitors on ara-C toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)