Lower Cytarabine Doses Effective and Less Toxic in AML Patients

Roxanne Nelson

March 16, 2011

March 16, 2011 — High doses of cytarabine are more effective than conventional doses in inducing relapse-free survival in patients with acute myeloid leukemia (AML). Now, data suggest that an intermediate dose might be just as effective as a high dose, but with less toxicity.

At a median follow-up of 5 years, the authors observed no significant differences between the group receiving intermediate doses and the group receiving high doses of cytarabine. The rates of complete remission were 80% and 82%, respectively; the probability of relapse/event-free survival at 5 years was 34% and 35%; and overall survival was 40% and 42%.

However, treatment with high doses of cytarabine resulted in a greater incidence of grade 3 and 4 toxic events.

The study appears in the March 17 issue of the New England Journal of Medicine.

A New Standard of Care?

"We assume that the current study settles a new standard of care," said lead author Bob Löwenberg, MD, PhD, professor of hematology at Erasmus University Medical Center, Rotterdam, the Netherlands. "Doctors will deviate from the use of the high-dose cytarabine schedules that have been used for more than 15 years in the treatment of acute myeloid leukemia."

"The intermediate dose of cytarabine produces equivalent results as regards antileukemic efficacy — response rates, relapse probabilities, and survival," he told Medscape Medical News. It "will most probably become standard of care because it allows for a treatment with lower costs."

Cytarabine has been a "cornerstone" drug in the treatment of AML for more than 30 years, and studies have shown that high doses (2000 to 3000 mg/m2 of body-surface area) result in improved rates of relapse-free survival, compared with the conventional dose of 100 to 400 mg/m2, note the authors.

No Differences Seen

Dr. Löwenberg and colleagues note that intermediate-dose levels of cytarabine have not been thoroughly evaluated. High doses of cytarabine are currently used for induction and consolidation therapy, but have not been compared with intermediate-dose cytarabine.

The authors compared 2 induction regimens in newly diagnosed AML patients, aged 18 to 60 years, who were randomized to either intermediate- or high-dose therapy. The intermediate-dose group (n = 431) received cytarabine 200 mg/m2 given by continuous intravenous infusion for 24 hours during cycle 1 of induction therapy and 1000 mg/m2 by infusion for 3 hours twice daily during cycle 2 of induction therapy. The high-dose group (n = 429) received a dose-escalated regimen of 1000 mg/m2 cytarabine every 12 hours in cycle 1 and 2000 mg/m2 twice daily in cycle 2.

Patients who achieved a complete response (n = 694) received a third cycle of consolidation chemotherapy or underwent autologous or allogeneic stem cell transplantation.

In the intermediate-dose group, 170 patients relapsed and 260 died (31 in their first complete remission). In the high-dose group, 157 patients relapsed and 251 died (46 in their first complete remission).

At 5 years, there were no significant differences between the 2 groups in terms of event-free or overall survival. The authors note that the cumulative 5-year probabilities for the competing risks for failure after complete remission were similar in the 2 groups (39% vs 37% for relapse, and 7% vs 11% for death during first complete remission).

Prognostic Factors

The strongest prognostic factors were cytogenetic features, they note. Patients with a monosomal karyotype, for example, had a low complete remission rate (52%) and very poor rates of event-free survival (5%) and overall survival (7%).

Conversely, patients with adverse cytogenetic abnormalities but without a monosomal karyotype achieved a higher complete remission rate (77%); event-free survival was 21% and overall survival was 31%. In addition, those with intermediate-risk AML had a higher complete remission rate (85%), and 5-year event-free and overall survival rates of 39% and 44%, respectively.

Favorable results were also observed in patients with abnormalities of the core-binding factor, with a complete remission rate of 91%, and 5-year event-free and overall survival rates of 52% and 65%, respectively.

"AML is not a homogeneous disease, with some patients presenting with more favorable and others with more aggressive forms of acute myeloid leukemia," Dr. Löwenberg explained. "This distinction is made according cytogenetics established at diagnosis."

"The second conclusion from this study is that the equivalence of antileukemic benefit of the intermediate-dose levels of cytarabine holds up for any of the widely accepted prognostic forms of AML," he added.

More Toxicity

There was more toxicity in patients who received the high-dose regimen. The incidence of grade 3 to 4 adverse effects after cycle 1 was greater in the high-dose group than in the intermediate-dose group (61% vs 51%; P = .005).

In particular, skin reactions and gastrointestinal and ocular toxic effects were noted after cycles 1 and 2 in the high-dose group.

There were no significant differences between the 2 groups in 30-day mortality (10% for both), but during the first 3 months, the death rate was significantly higher in the high-dose group than in the intermediate-dose group (72 vs 52; hazard ratio, 1.41; P = .057).

The time to neutrophil or platelet recovery was similar between the 2 groups after cycle 1, but was delayed in the high-dose group after cycle 2. Patients in the high-dose group also spent more nights in the hospital after cycle 2 and received significantly more platelet transfusions after both cycles.

"High-dose cytarabine results in excessive toxic effects without therapeutic benefit," the authors write, noting that they "did not see a therapeutic benefit of cytarabine escalation above 1000 mg/m2 in any particular subgroup of patients with AML."

Dr. Löwenberg reports consulting for Millennium Advisory Board and having related patents pending. Coauthors Gert J. Ossenkoppele, MD, from VU Medical Center, Amsterdam, the Netherlands, and Pieter Sonneveld, MD, from Erasmus University Medical Center, report relationships with several pharmaceutical companies, as noted in the paper.

N Engl J Med. 2011;364:1027-1036.

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