Treatment of Acute Myelogenous Leukemia

There are three broad treatment options for patients with acute myelogenous leukemia (AML): palliative care only, standard approaches involving chemotherapy with or without hematopoietic stem cell transplantation, and investigational approaches studied in the context of a formal clinical trial, also involving chemotherapy and transplantation. Given the natural history of the illness (as established by Freireich et al in the 1950s and 1960s),[1] it would be difficult to recommend a purely palliative strategy except perhaps in the elderly and/or infirm, as discussed below.

The choice between standard and experimental therapy largely depends on the prognosis following use of the former, and disease prognosis is so variable that it suggests AML is, in fact, several different diseases. This article considers the various prognostic subsets and therapies for AML.

Standard Therapy for AML

In the United States today, most AML patients receive standard therapy under the care of their private physician as described in this article. The two phases of standard treatment of AML are induction of a complete remission (CR) and postremission therapy. Terms such as consolidation, maintenance, or intensification often are used in connection with postremission therapy. Consolidation refers to treatment that is only slightly less intense than induction therapy, maintenance therapy is relatively less intense than consolidation, and intensification therapy rivals or surpasses induction in dose intensity.

The goal of therapy is achievement of a CR (< 5% blasts in the marrow, a neutrophil count exceeding 1,000-1,500/µL, and a platelet count greater than 100,000/µL)[2]; such a remission generally has been assumed necessary, although not adequate, for prolonged survival. The differences in survival rates between patients who achieve complete remissions and those who do not have been shown to be almost entirely dependent upon the time they spend in CR. This observation suggests that the achievement of CR per se, rather than a difference in inherent prognosis between responders and nonresponders, is paramount.[1]

The disease recurs in the majority of patients who achieve CRs, making it likely that not all of these remissions are a result of the same degree of antileukemic activity. A future clinical challenge will be to distinguish between significant and cosmetic CR, since the latter predicts especially high relapse rates unless therapy is changed. Such distinctions eventually will be made by using polymerase chain reaction (PCR) technology to detect persistent evidence of a presenting cytogenetic abnormality,[3-5] immunophenotyping to identify persistent aberrant patterns of cell surface antigens,[6] or simple clinical observation based on data suggesting that the longer the time required to achieve CR, the shorter the subsequent CR.[7,8]

At any rate, once 2 years have elapsed from the onset of CR, the risk of relapse declines precipitously, with this risk continuing to decrease thereafter. Once 3 years have elapsed from the CR date, the likelihood of relapse becomes < 10%, and it is reasonable to consider patients potentially cured at that time.[9]

Induction Therapy

Standard induction therapy generally consists of a combination of an anthracycline and cytarabine(Drug information on cytarabine) (ara-C), with the anthracycline often administered for 3 days and ara-C for 7 days ("3 + 7" regimens). Numerous randomized studies have compared the efficacy of the anthracyclines daunorubicin(Drug information on daunorubicin) (Cerubidine), mitoxantrone(Drug information on mitoxantrone) (Novantrone), and idarubicin(Drug information on idarubicin) (Idamycin) when all are given with 7 days of ara-C.[10-12] In general, most studies, including a large meta-analysis,[13] found idarubicin to be superior, although differences are less apparent in older patients.

Several comments about standard anthracycline regimens should be considered:

• Results may vary if different doses (eg, 60 mg/m², rather than 45 or 50 mg/m², of daunorubicin daily) of the several anthracyclines are used.
• Survival gains among the various anthracyclines are relatively modest (ie, median survivals generally differ by only several months).
• Results from the same treatment regimen (eg, daunorubicin plus ara-C) in several trials at times exceed the differences among other regimens in the same trial.

These observations make it difficult to attach great significance to the choice of anthracycline regimens for untreated AML.

Randomized trials have found essentially the same results regardless of the dose of ara-C (100 or 200 mg/m² daily by continuous infusion for 7 days)[14] or the addition of either thioguanine[15] or etoposide(Drug information on etoposide)[16] to the 3 + 7 regimen (with the latter finding obtained in the largest related trial conducted to date).

Postremission Therapy

Once patients achieve CR, they typically receive several cycles of consolidation or maintenance therapy employing the initial drugs; treatment is then stopped and the patient observed. Current data indicate that some postremission therapy is beneficial, but how much therapy remains unclear, since durations of therapy are 2 years vs 3 months and 16 vs 7 months in supporting studies.[17,18]

Again, several comments may be in order. First, benefits generally relate to disease-free survival rather than to overall survival, and have not been universally noted.[19,20] Second, the reasons for these discrepancies are unclear, but they might reflect the myelosuppression produced by the maintenance, the intensity of the therapy given prior to maintenance, or, given the variability of AML, the particular mix of patients treated. In any event, we will assume that prolonging maintenance with these agents for more than 6 months has relatively little effect on survival, while recognizing that the issue has not been, and is unlikely to be, unequivocally resolved because of other pressing questions.

Other standard approaches to postremission therapy are allogeneic or autologous hematopoietic stem cell transplantations, using cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar) plus total-body irradiation or busulfan(Drug information on busulfan) (Myleran)/cyclophosphamide and high-dose ara-C.

Results

On average, standard therapy produces median survival durations of 6 to 12 months and CR rates of approximately 60% to 65%; the median duration of remission is approximately 1 year, with 15% to 20% of the patients potentially cured. However, these results are inherently misleading, because only a minority of patients can be considered to conform to an average. For most patients, outcome is either better or worse than this average, depending on a well-defined set of prognostic factors.