Prolonged Maintenance Therapy Improves AML Outcome More Than Intensive Consolidation

ORLANDO—Prolonged maintenance treatment improves long-term outcome in acute myeloid leukemia (AML) more than intensive consolidation, even in those patients with poor prognosis, according to a study reported by Thomas Buchner, MD, professor of internal medicine, hematology and oncology at the University of Muenster in Germany (ASCO abstract 1046).

"Maintenance produced significant benefit in relapse-free survival and higher cure rate than seen with first-line therapy alone," he said. The benefits of prolonged maintenance in the poor prognostic subgroup are considered especially encouraging, because this subgroup represents more than half of the patients.

Although recent studies have enhanced understanding of prognostic factors and subgroups in AML, data concerning specific effects of particular treatments in each subgroup are still lacking. Because 18% of all patients in the first Acute Myeloid Leukemia Cooperative Group (AMLCG) study in 1981 were still alive and in remission after 10 years, investigators began to consider the role of prolonged maintenance.

Groups Well-Balanced

In this large randomized trial, 837 patients received treatment with either TAD (thioguanine/cytarabine [Ara-C]/daunorubicin)-HAM (high-dose Ara-C/mitoxantrone [Novantrone] induction, TAD consolidation, and S-HAM (sequential HAM) second consolidation, or with TAD-HAM-TAD and monthly reduced TAD maintenance for 3 years.

Average age was 55 years; age range was 16 to 82 years; and 36% of patients were age 60 or older. In the maintenance and S-HAM arms, groups were well balanced for age, LDH, cytogenetic groups, and day 16 blasts. In addition, members of the two groups had nearly identical response to induction, with complete remission in 69% and 70%, respectively.

In the maintenance arm, median relapse-free survival (RFS) was 19 months and 5-year survival was 31%. In the S-HAM arm, RFS was 12 months and 5-year survival was 24% (P = .014). "This difference is not an effect of an inadequate intensity of the S-HAM regimen, as the S-HAM regimen was highly myelotoxic, causing 6 weeks of severe neutropenia and thrombocytopenia," Dr. Buchner said.

Prognostic Subgroups

Based on previous studies involving multiple regression analysis (Blood 98 Suppl 1:1932, 2001), patients with poor prognosis had at least one of the following: age 60 or older, unfavorable karyotype, LDH greater than 700U, or blasts on day 16 greater than 40%. Patients with good prognosis had none of these features.

In the poor prognostic subgroup, relapse-free survival was 12 months and 24% in the maintenance arm vs 10 months and 12% in the S-HAM arm (P = .011). Survival of responders was 22 months and 24% in the maintenance arm, compared with 19 months and 20% in the S-HAM arm (P = .097).

In the subgroup with good prognosis, relapse-free survival was 27 months and 32% for the maintenance arm, vs 38 months and 48% for S-HAM. Survival was 49 months and 45% for maintenance and 51% for S-HAM, but these differences did not reach statistical significance.

"Relapse-free survival was better in the maintenance arm," Dr. Buchner said. "If we divide patients into a poor risk and good risk group, we still see a significant effect of maintenance on survival for high risk patients as well as in younger patients." Over 3 years of maintenance treatment, tolerance was acceptable in the poor prognostic subgroup, and a study in 110 patients showed improved quality-of-life scores during induction and consolidation which held up during maintenance.

Even though the European Organization for Research and Treatment of Cancer (EORTC) showed that allogeneic bone marrow transplant might benefit poor-prognosis patients, Dr. Buchner recommends prolonged maintenance as primary therapy in these patients. "There is an impression of increased relapses in the maintenance arm which may not be definite, so longer follow-up is required to answer this question," he cautions.

‘A Good Idea’

In a subsequent discussion, Clara D. Bloomfield, MD, director of the Ohio State University Comprehensive Cancer Center, in Columbus, offered her perspective on maintenance therapy. She reviewed the definition of maintenance as therapy given after achievement of complete remission, usually of lesser intensity than of induction therapy, and duration usually at least 1 year. It typically consists of chemotherapy, but immune modulation and other biological therapies are increasingly being considered.

Based on the results of two recent large randomized trials, she believes that all should agree on the benefit of 1 to 2 year maintenance with all-trans-retinoic acid in acute promyelocytic leukemia (APL).

Compared with other studies, Dr. Bloomfield noted that Dr. Buchner’s study differs in the time of randomization, the patient mix, and clinical characteristics of the patient populations. The outcome for the S-HAM arm appeared low, based on age, compared to that in other studies, but prospective data other than in Dr. Buchner’s trial are limited.

"Others said maintenance wasn’t a good idea, but Dr. Buchner stuck with it and took us to the next level," Dr. Bloomfield said.

Dr. Bloomfield recommends additional research on novel maintenance therapies and on quality of life, cost and effectiveness of salvage therapy, especially in favorable risk groups whether defined by clinical or molecular parameters.