Low-dose cytarabine maintenance therapy vs observation after remission induction in advanced acute myeloid leukemia: an Eastern Cooperative Oncology Group Trial (E5483)

Abstract

The Eastern Cooperative Oncology Group (ECOG) conducted a prospective phase III study in patients with relapsed/refractory acute myeloid leukemia (AML) to evaluate whether administration of repeated courses of low-dose cytarabine (LDAC) maintenance therapy after induction of complete remission in advanced AML would improve disease-free and overall survival. Patients with AML in second/later relapse or refractory disease were first treated with a combination of high-dose cytarabine and amsacrine. Those who achieved complete remission were then randomized to observation or to receive LDAC, 10 mg/m 2 subcutaneously twice a day ؋2 21 days every 2 months until relapse occurred. Of 86 patients eligible for randomization, 41 patients were assigned to receive LDAC and 45 patients to observation. The median disease-free survival was 7.4 months for patients assigned to LDAC compared to 3.3 months for patients receiving no additional therapy, P = 0.084. The median survival from randomization was 10.9 months and 7.0 months for patients receiving LDAC maintenance chemotherapy and observation, respectively (P = 0.615). The data from this study suggest that LDAC maintenance therapy given to patients with advanced AML who achieve complete remission can increase disease-free survival compared to observation, but does not improve overall survival. Nevertheless, because of the ineffectiveness and toxicity of intensive post-remission chemotherapy in this circumstance, LDAC maintenance therapy, a tolerable outpatient regimen, offers the potential for improved quality of life. Leukemia (2000) 14, 1349-1353.

The Combination of Conventional Chemotherapy with New Targeted Therapy in Hematologic Malignancies: The Safety and Efficiency of Low- Dose Cytarabine Supports its Combination with New Therapeutic Agents in Early Clinical Trials

“…The observation that some patients respond to this treatment without developing marrow hypoplasia may support the presence of a clinically relevant differentiation-inducing effect, but could also be explained by a weak and selective cytotoxic effect. However, even low-dose cytarabine is associated with hematological toxicity and treatment-related mortality (Tables 1, 2), observations strongly supporting the view that even low-dose therapy mainly acts through its cytotoxic effect on the leukemia cells [73][74][75][76][77][78][79][80][81][82][83][84][85][86]. However, such observations should be interpreted with great care as both mechanisms may be operative and the relative contribution of differentiation versus cytotoxicity will then be difficult to define for individual patients.…”

“…This treatment can be given alone or in combination with other cytotoxic agents, growth factors or all-trans retinoic acid (ATRA) [2]. The results from studies of low-dose cytarabine therapy in human AML are summarized in Tables 1 and 2 [73][74][75][76][77][78][79][80][81][82][83][84][85][86]. This therapeutic approach can induce complete hematological remissions for a subset of patients, and these responses may last for several months.…”

“…However, it should be emphasized that even this low-dose strategy can induce severe hematological toxicity, and it can be seen from the previous studies that there is a risk of treatment-related mortality especially due to serious infections for elderly patients or patients with complicating disorders (see Table 1). For such patients one should consider individual adjustments by using the lowest single doses investigated in the previous studies (10 mg/m 2 ) [73,76,78] for the shortest time interval examined (not longer than 10 days of treatment) [74].…”

Novel Approaches to the Treatment of Acute Myeloid Leukemia

“…42 Postremission maintenance therapy with low-dose ara-C and long-term, low-dose multi-agent chemotherapy have been shown to improve disease-free survival but not overall survival. 43,44 The anti-CD33 immunotoxin conjugate gemtuzumab ozogamicin was compared with no postremission therapy in older patients and showed no benefit. 45 Finally, allogeneic stem cell transplantation with reducedintensity conditioning is increasingly feasible for patients well into their 70s, and registry data suggest that age is not the major predictor of transplantation outcome in these patients.…”

Gemtuzumab ozogamicin as postremission treatment in AML at 60 years of age or more: results of a multicenter phase 3 study

“…Studies 11,12 performed on the basis of the use of cytarabine according to various doseintensification schedules did not produce therapeutic benefits. Two studies 3,13 have produced an improvement of disease-free survival (DFS) in a comparison between low-dose cytarabine and no maintenance chemotherapy, but overall survival outcome was not different. A comparison between one additional cycle of combination chemotherapy for remission consolidation with 4 additional cycles showed no differences in survival.…”