Older Patients

Detailed studies of the effect of age on outcome in AML suggest that, all else being equal, each additional year increases the risk of death by approximately the same amount.25 Older patients with AML/MDS are commonly defined as those of age 60 years and above. Given that CR rates in older patients with secondary AML/MDS following SCH are less than 50% (Table 7.4), investigational approaches should be employed at diagnosis. There are three general types of investiga-tional therapies that might be offered to these patients: high-intensity (HI) regimens, low-intensity regimens (LI), and nonablative allogeneic transplant. HI regimens [e.g., clofarabine plus ara-C2627 or tria-pene plus ara-C] are those that produce not only several weeks of severe myelosuppression, but also cause damage to organs, such as the gut or lung. This damage contributes to the 20-30% rate of TRM characteristic of previous HI. This rate, as well as advances in molecular biology, have sparked interest in the development of LI. Examples are the farnesyl transferase inhibitor R1157772829; the FLT3 inhibitors PKC412 and CEP70 13031; other tyrosine kinase inhibitors such as PTK787 and SU541632'33; histone deacetylase (HDAC) inhibitors such as SAHA; and hypomethylating agents such as decitabine34 35 and 5-azacytidine.36

Single-agent studies in high-risk MDS/AML suggest that, in addition to being more "rational" than chemotherapy (CT), LI may have beneficial effects.28-36 First, they appear to produce less TRM and morbidity than CT. Second, they can produce so-called minor responses (MRs). An example is of "marrow CR" in which, although blood counts remain low, blasts are reduced to "normal" levels in the marrow (<5%) and blood. However, these studies also suggest that CR rates may be considerably lower with HI than with LI, with CR defined as a marrow CR plus "normal" blood counts.28-36 Thus, most likely, LIs will need to be combined either with each other or with HIs. However, if LI is to be combined with HI in older patients, the HI should presumably be of a type not associated with high rates of TRM. Such combinations, e.g., of LI with low-dose ara-C, can thus be operationally considered "LI" despite the use of chemotherapy. The observations of low CR rates have also prompted an

Figure 7.3 Survival probabilities in patients with a normal karyotype according to de novo versus secondary distinction
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