Younger Patients

TRM rates are usually less than 10% in patients under the age of 60. Partly as a consequence of lower TRM rates and again in contrast to older patients, younger patients with secondary AML/MDS generally have CR rates of more than 50% (Tables 7.3 and 7.4). As a result, a case could be made for beginning investigational therapy only once CR has occurred. This approach avoids the ethical issue that might arise consequent to giving investigational therapies to patients with such CR rates, which may be worse than SCH. On the other hand, there is evidence that an induction regimen can influence CR duration.47 As a practical issue, patients in CR are often ineligible for trials of new agents; this is unfortunate given the short remissions seen in many such patients. Under these circumstances, it is reasonable to administer investigational regimens to younger patients undergoing remission induction for secondary AML/MDS, provided appropriate statistical designs are used (see next section). In younger patients with secondary AML/MDS and abnormalities of chromosomes 5 and/or 7, new regimens should be used at the time of diagnosis since the CR rate in such patients with SCH is less than 40% (Table 7.3). Because younger patients have relatively low TRM rates, reasons to avoid HIs in these patients are less compelling than in older patients, particularly in combination with LIs such as PKC412 or R115777; indeed, trials combining these and similar agents with HI (such as 3 + 7 or even high-dose ara-C) have been proposed or are in progress. Investigational treatments in younger patients thus include both the agents discussed in the section on older patients and exploration of further dose intensification. As an example of the latter, the Cancer and Leukemia Group B (CALGB) has reported that patients under age 60 tolerate daily daunorubicin doses of 90 mg/m2 in combination with ara-C at 100 mg/m2 given daily for 7 days and etoposide 100 mg/m2 daily.48 Heretofore, daunorubicin doses rarely exceeded 60 mg/m2 daily. The CALGB is now comparing the 90- and 60-mg/m2 doses.

As noted above, patients with a normal karyotype or abnormalities other than -5/-7 can plausibly begin investigational therapy once CR has occurred. While pharmaceutical companies have provided only a limited number of agents intended for use in patients in remission, commercially available agents can be used for investigational purposes in this setting. For example, 5-azacytidine and decitabine have been approved for use in MDS.36 The drugs' effectiveness may reflect their ability to demethylate inappropriately hyperme-thylated genes,36 thus inducing reexpression of these genes, which might include various "tumor suppressors." There are reasons to think that combinations of demethylating agents and HDAC inhibitors might be particularly effective in this regard. Valproic acid, a pediatric anticonvulsant, is an HDAC inhibitor, although a less potent one than SAHA or depsipeptide. Thus, a combination of 5-azacytidine and valproic acid could be investigated, for example, in patients in remission. Analogous trials could be formulated using commercially available drugs or focusing on the inves-tigational approaches to transplantation, which are described at the conclusion of the section on older patients.

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