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abnormalities in AML are discussed in Chapter 2. Whether functionally relevant to leukemic pathogenesis or not, the presence or absence of cytogenetic abnormalities provides important prognostic information that is relevant to both younger and older adults with AML.42

Three large, multi-institutional efforts have explored the prognostic significance of cytogenetics in detail. As displayed in Table 8.2, there is general agreement as to the prognostic significance of many, but not all, abnormalities.43-45 Some of the discrepancy may lie in the patient population analyzed. For example, the CALGB study included all patients up to age 86 years, while the other two studies limited their analysis to patients less than 56 years of age. The CALGB study also excluded patients with the t(15;17). The MRC study included children. The SWOG/ECOG and MRC studies each analyzed the results of one study, while the CALGB study compiled data from several clinical trials (as shown in Figure 8.1).

Another complicating factor with regard to the prognostic role of cytogenetics is that all three studies analyzed patients treated differently from the patients in other studies. For example, the CALGB has argued that patients with favorable risk cytogenetics should be treated with multiple cycles of high-dose cytara-bine.46 47 However, other studies, such as the one analyzed by the MRC, show similar survival rates without such therapy.44'48

Allogeneic stem cell transplant is often recommended for patients with poor-risk cytogenetics and an available HLA-matched donor. In the SWOG/ECOG study, this approach led to a 5-year overall survival of 44%, compared to 13-15%, in patients treated with chemotherapy alone or autologous stem cell trans-plant.43 In contrast, the MRC study showed no benefit to allogeneic transplant for patients with poor-risk cytogenetics in first CR.49 Nonetheless, the poor results of chemotherapy in all studies, and the relatively better results with allogeneic transplant in most studies, suggest that transplant remains the treatment of choice for patients with poor-risk cytogenetics in first CR.50,51

The study of clonal cytogenetic abnormalities has led to the discovery of abnormal and dysregulated genes that result in specific AML phenotypes. Gene expression profiles by microarray analysis confirm the prognostic relevance of cytogenetic risk groups and suggest that other risk groups may yet be identified.52,53 For example, patients with normal cytogenetics have a

Figure 8.1 Five-year overall survival in AML varies by cytogenetic risk group. SWOG/ ECOG, Southwest Oncology Group/Eastern Cooperative Oncology Group43; MRC, Medical Research Council of Great Britain44; CALGB, Cancer and Leukemia Group B45

poor prognosis when FLT3 mutations are identified.54-59 Conversely, the presence of CCAAT/enhancer binding protein-alpha (CEBP-a) mutations60 and the presence of cytoplasmic nucleophosmin due to translocations involving the NPM gene seem to result in a more favorable prognosis.61 The identification of prognostically relevant molecular pathways should allow for the development of small molecules capable of targeting these pathways and improving survival.

Follow up

Recommendations for follow up of patients diagnosed with AML who undergo remission induction and postremission therapy and who attain a CR are somewhat arbitrary. While they are based on the recommendations of leukemia experts, they are not grounded in any evidence-based literature that the degree and frequency of surveillance translates to earlier detection of recurrent leukemia, or that this would result in improved survival.

The National Comprehensive Cancer Network has published guidelines on surveillance of AML patients who have attained a remission.62 This group recom mends routinely following patients with complete blood cell counts every 2-3 months for the first 2 years following attainment of remission, and then every 4-6 months for 3 more years, for a total of 5 years of follow up. Bone marrow biopsies should be obtained only in the setting of worrisome peripheral blood counts, and not otherwise regularly, unless a patient is enrolled in a clinical trial that calls for this surveillance.

We recommend obtaining a bone marrow biopsy and aspirate at the conclusion of postremission therapy to document a CR. As is shown in Figure 8.2, we then follow patients with complete blood cell counts every month for 1 year after the postremission therapy CR, and then every 2 months for 1 year. For the third year, we follow patients every 3-4 months for 1 year, and then for years 4-5, every 4-6 months for 2 years, for a total of 5 years of follow up. We further recommend obtaining bone marrow biopsies only in the setting of worrisome blood counts, and urge assessment of cytogenetics at those times to document persistent disease on a molecular level or cytogenetic evolution, which could indicate disease progression and/or treatment-related bone marrow disorders. During the

Figure 8.2 Routine follow up of AML patients. CBCD, complete blood cell count with differential follow-up period, patients should also resume contact and routine checkups with their primary care physicians.

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