Aml Transplant Prognosis

Although many clinical and pathologic features of AML have prognostic relevance, only a few prognostic factors are universally agreed upon, validated, and impact clinical practice. Nonetheless, newer biologic markers of prognosis are likely to supplant older clinical markers in the near future.

As discussed further, and in greater detail in Chapter 5, age greater than 60 years invokes many adverse features that make separation of age from other poor prognostic markers difficult. Nonetheless, the prognosis gets progressively worse for patients with AML and age greater than 60 years, with each incremental decade of age above 60 years. For patients less than age 60, however, age has proven more difficult to prove as an adverse risk factor, suggesting that biologic features of the leukemia, rather than age alone, are most important in predicting outcome.

In the large trial of cytarabine dose-intensification reported by Mayer et al., the remission rate was 75% in patients of age below 40 years and 68% in those of age 40-60 years, but 4-year disease-free survival was 32 and 29%, respectively.18 Similarly, Zittoun et al. failed to find an adverse impact of increasing age between 10 and 59 years on disease-free survival in a large trial testing the value of stem cell transplant.19 In contrast, both the Medical Research Council (MRC) and the Southwest Oncology Group and Eastern Cooperative Oncology Group (SWOG/ECOG) intergroup trials found worse survival with age increasing from 18 to 55 years.2021 Thus, the impact of age on prognosis in patients less than 60 years of age is uncertain.

APL has an incidence that is similar among all age groups, including the group greater than 60 years of age. There is no evidence that the biology of APL is different in older versus younger patients. Yet, the survival for older patients with APL is significantly worse than it is for younger patients, and it cannot be explained by an inability to tolerate treatment, since remission rates are similar. The experience of APL supports the contention that age is an independent adverse prognostic factor in AML.

Antecedent hematologic disorders

Some hematologic disorders, such as advanced my-elodysplastic syndrome (MDS) and CML, invariably result in transformation to acute leukemia. Others, such as myelofibrosis with myeloid metaplasia, polycythe-mia rubra vera, and aplastic anemia, do not always terminate in acute leukemia. However, all hematologic disorders that do transform to acute leukemia share an equally poor prognosis with available therapies. In fact, many clinical trials of treatment for acute leukemia exclude patients with antecedent hematologic disorders (AHD) for this very reason. The influential Cancer and Leukemia Group B (CALGB) study that found higher doses of cytarabine after remission improve survival compared to lower doses excluded patients with AHD.18 Other studies group patients with AHD with those previously exposed to cytotoxic treatments, such as chemotherapy, making distinctions with regard to one group or another difficult.

However, some studies included patients with AHD and analyzed them separately from those with treatment-related AML. One study retrospectively compared 44 patients with an AHD to 152 patients without such a history. The remission rate was lower in patients with an AHD (41% vs 73%), and was only 23% in AHD patients older than 64 years.22 For patients with AHD who achieved remission, disease-free survival was 17% at 3 years versus 29% (P = 0.02) in patients without AHD. Others have reported similar results, but the confounding variables of age and cytogenetics cloud the potential independent adverse prognostic impact of an AHD.

Some patients with AML present with no history of AHD, but have dysplastic changes in their marrow at diagnosis. These patients also have a worse prognosis compared to patients without such morphologic abnormalities.2324

Although some patients who transform from a myeloproliferative disorder into AML achieve remission with standard induction chemotherapy, the duration of response is brief.25 In a study of 91 cases of myelofibrosis that transformed into AML, 24 patients were treated with standard induction chemotherapy.26 Of these, none achieved a CR. Although 10 patients reverted to chronic phase disease, their median survival was only 6 months. Importantly, the treatment-related mortality rate was 33% and the median survival of patients treated with chemotherapy (3.9 months) was not significantly different than that achieved without intensive chemotherapy (2.1 months).

Prior cytotoxic therapy

Patients treated with cytotoxic chemotherapy or radiotherapy for both malignant and nonmalignant conditions are at risk for subsequent, or secondary, AML. Patients with secondary leukemia have an extremely poor prognosis with standard treatments. Secondary leukemias are frequently characterized by clonal cyto-genetic abnormalities that by themselves connote a worse prognosis (see below). In one series, only 29% of patients with secondary AML or MDS achieved remission with standard induction chemotherapy, and only 13% of patients survived 2 years.27 Other recent series confirm these dismal results.2829

However, some secondary leukemias have a more favorable prognosis and should be recognized. Patients with secondary AML characterized by favorable cyto-genetics, such as t(8;21) and inv(16), have a worse prognosis compared to patients with favorable cytoge-netics and de novo AML, but have a significantly better prognosis than other patients with secondary AML and should be treated with curative intent.3031 Rarely, APL is induced by exposure to chemotherapy.32 When this happens, remission rates and survival are similar to those achieved in the setting of de novo APL.33

Other clinical factors

Some studies suggest that higher white blood cell counts correlate with a worse prognosis,34 but other studies refute this assertion.35 In a large study of over 1000 patients, no clinical factor was found to significantly influence survival when cytogenetics and response to treatment were factored in.21 A recent study suggests that race may be an important, and heretofore unrecognized, prognostic factor. African-American men with AML have a significantly worse remission rate and survival compared to other patients with AML, including African-American women.36

We have reviewed our own experience in older patients with AML treated with a uniform induction chemotherapy regimen.37 Patients who present with a high lactate dehydrogenase level or significant anemia have a survival of less than 5 months.38 Consistent with reports from larger trials, we found that a delay from diagnosis to the institution of therapy adversely impacts survival.39 40 In aggregate, these observations suggest that those patients may be identified at diagnosis who will not benefit from standard induction chemotherapy. Furthermore, a leukocyte nadir count of less than 0.04/^L correlates with a poorer prognosis.41

Biologic factors

Evidence is quickly accumulating that biologic factors intrinsic to the leukemic clone have as much, if not more, prognostic significance as do more traditional clinical factors. Cytogenetic analysis has become critical to the management of AML. Further details as to the molecular aberrations induced by cytogenetic

Table 8.2

Pretreatment cytogenetic risk groups for overall survival in AML

SWOG/ECOG43

MRC44

CALGB45

Number of patients Favorable risk

Intermediate risk

Poor risk

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