Outpatient Azacitidine for Selected AML Patients

Abstract & Commentary

By William B. Ershler, MD, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.

Synopsis: A review of twenty AML patients who were treated with azacitidine demonstrated a response rate of 60% and for those that responded, a median survival of 15+ months. Patients included were those who were initially considered to have myelodysplastic syndrome (refractory anemia with excess blasts) or acute leukemia but unsuitable for more intensive chemotherapy. Azacitidine was administered by daily subcutaneous injection (out patient) for seven days, repeated monthly. Although generally well tolerated, four patients required hospitalization during the first cycle and infection occurred on 8 occasions. Single-agent, outpatient azacitidine may prove to be a useful treatment choice for selected patients with AML.

Source: Sudan N, et al. Treatment of acute myelogenous leukemia with outpatient azacitidine. Cancer. 2006;107:1839-1843.

Azacitidine has been used clinically to treat both myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). When used to treat MDS, the dose and schedule is different, typically with lower doses administered subcutaneously for seven days, repeated monthly. For AML, azacitidine is usually given in larger doses, intravenously. Although clearly active, its use has been limited by toxicity. Investigators at the Western Pennsylvania Cancer Institute have reviewed their experience with azacitidine given to 20 patients who were either treated for MDS, but under current classification schemes would be considered to have AML (n = 12) or to patients with AML but for whom standard intensive chemotherapy was considered too risky (n = 8).

The overall response rate was 60%; complete responses occurred in 4 (20%), partial response in 5 (25%) and hematologic improvement in 3 (15%). The median survival of responders was 15+ months compared with 2.5 months in nonresponders. During therapy, responders had an ECOG performance status of 0 to 1. The most common toxic event was infection (n = 8) but four patients (20%) required hospitalization during the first cycle of treatment.

Commentary

Less-than-intense therapy for AML has usually proven to be of little benefit in terms of remission induction, survival or quality of life. Low-dose cytosine arabinoside, for example, was commonly used for AML in high-risk patients, such as the elderly, but studies revealed little added benefit and definite toxicity.1,2 Azacitidine, a derivative of the nucleoside cytosine, is a cell cycle specific agent which, when incorporated into DNA produces a marked decrease in activity of DNA methyltransferase.3 In vitro exposure of leukemia cells resulted in differentiation, presumably due to the hypomethylation of DNA.4 When administered in high doses, it has demonstrable activity in patients with AML with an overall response rate of 27% and remission duration of just over 100 days.5 When given subcutaneously at lower doses, the drug has proven effective in MDS, with response rates approximating 60%.

Elderly patients with AML are a challenge.6 For those with excellent performance status, standard intensive chemotherapy and even allogeneic transplant have been effectively used. However, the majority of elderly patients, particularly those older than 70, have existing comorbidities and/or functional impairments that preclude the safe use of such an intensive approach. Because the median age for AML is older than 60 years, it is an imperative that more effective and less toxic treatments be developed.

Azacitidine may well be a cornerstone of future treatment strategies for elderly AML patients. The current report suggests that when administered on a typical MDS-like schedule, it is relatively safe and somewhat effective. The fact that the majority responded and maintained an ECOG performance status of 0 to 1 is notable. However, complete remissions were few, survival for non responders was dismal (2.5 months) and the analysis was of insufficient duration to be confident about overall response duration. Certainly, we have a way to go in providing effective management for AML in the elderly. Also of consideration is the population studied. The majority of patients had a smoldering picture with the average time interval between diagnosis and chemotherapy of 11 months (range, 1 to 48 months). Thus, although in using the current WHO classification scheme, these patients had AML, at least some had a smoldering picture not entirely typical for AML. Nonetheless, azacitidine administered subcutaneously was shown to have activity in these patients and the relatively low toxicity profile and subcutaneous route of administration make it an appealing choice for some patients with this disease. Hopefully, additional agents will be developed that will enhance treatment success in this setting.

References

1. Cheson BD, et al. A critical appraisal of low-dose cytosine arabinoside in patients with acute non-lymphocytic leukemia and myelodysplastic syndromes. J Clin Oncol. 1986;4:1857-1864.

2. Bolwell BJ, et al. Low dose cytosine arabinoside in myelodysplasia and acute myelogenous leukemia: a review. Leukemia. 1987;1:575-579.

3. Creusot F, et al. Inhibition of DNA methyltransferase and induction of Friend erythroleukemia cell differentiation by 5-azacytidine and 5-aza-2'-deoxycytidine. J Biol Chem. 1982;257:2041-2048.

4. Christman J, et al. Correlation between hypomethylation of DNA and expression of globin genes in Friend erythroleukemia cells. Eur J Biochem. 1977;81:53-61.

5. Saiki JH, et al. 5-azacytidine in acute leukemia. Cancer. 1978;42:2111-2114.

6. Buchner T, et al. Treatment of older patients with AML. Crit Rev Oncol Hematol. 2005;56:247-259.