COLUMBUS, Ohio -- A drug given at levels substantially higher than the standard dose can cure nearly five times as many patients who have a certain type of acute myeloid leukemia (AML), new research shows.
The study revealed that 78 percent of patients with “core binding factor” AML who received the drug cytarabine at high dose were in complete remission five years after treatment (and therefore potentially cured) compared to only 16 percent who received the standard dose.
“It is truly remarkable to achieve a cure rate of over 75 percent in a subgroup of adult leukemia patients; this rate approaches that for some types of childhood leukemia,” said Clara Bloomfield, director of Ohio State University's Comprehensive Cancer Center and William G. Pace III Professor of Cancer Research.
“Because high-dose cytarabine is quite toxic, especially for older people, we want to use it only with those patients who will benefit. These results tell us which patients we can cure, and which ones should receive other therapy.”
The finding is considered particularly strong because the study had followed patients for more than seven years after treatment; most such studies rely on models to project estimates of five-year remission rates.
The study, which was led by Bloomfield, appeared in the September issue of the journal Cancer Research. It involved 285 newly diagnosed AML patients aged 16 and older who were in remission. During the second phase of their treatment, a phase known as “intensification therapy,” the patients were randomly assigned to receive cytarabine at either standard dose (100 milligrams per square meter of body surface), intermediate dose (400 mg/m2), or high-dose (3,000 mg/m2, equivalent to 3 grams of drug/m2).
These groups of patients were then subdivided into three categories according to their cytogenetics; that is, according to the type of chromosome damage present in their malignant cells. Patients showing damage to chromosome 16 or to chromosomes 8 and 21 were assigned to the “core binding factor” (CBF) group; those with no visible chromosome damage were assigned to the “normal” group; and those with other types of chromosome damage were assigned to the “other abnormalities” group.
The outcome of the patients in each chromosome group and at each dose was then examined.
Of the 57 patients in the CBF group, 78 percent of those who received the high drug dose were in complete remission, versus 57 percent receiving the intermediate dose, and 16 percent receiving the standard dose.
Of the 140 patients in the “normal” group, 40 percent of those receiving the high drug dose were in complete remission, compared to 37 percent receiving the intermediate dose, and 20 percent receiving the standard dose.
Last, of the 88 patients in the “other abnormalities” group, 21 percent of those receiving the high drug dose were in complete remission, compared to 13 percent receiving the intermediate dose, and 13 percent receiving the standard dose.
“In the ‘other abnormalities’ group, the dose of cytarabine made no difference,” said Bloomfield. “But in the normal group, using high-dose cytarabine doubled the number of patients cured, and in the CBF group, the high-dose treatment increased the number by nearly five times. Because of these results and this astronomical difference, we now routinely treat CBF patients using high-dose cytarabine.
“The ramifications of these findings are tremendous,” said Bloomfield. “A lot of people are now working to understand why patients with core binding factor leukemias are particularly sensitive to this drug, and that may help us design more rational treatments in general. It’s an excellent example of how clinical findings can spur new laboratory research and perhaps improve cancer treatment in the future.”
The standard treatment for adults with AML occurs in two phases: induction therapy and post-remission therapy. Induction therapy is intended to drive the leukemia into remission (i.e., malignant cells are not visible when a bone marrow sample is examined by microscope).
Post-remission therapy is intended to destroy any remaining leukemic cells; it is essential for long-term remission or cure in AML patients. The most commonly used forms of post-remission therapy are bone marrow transplantation and intensification therapy using high-dose cytarabine.
This study, the first to look at the influence of dose and cytogenetics on cytarabine intensification therapy, was funded by grants from the National Cancer Institute.
Contact: Clara Bloomfield, (614) 293-7518;
bloomfield-1@medctr.osu.edu
Written by Darrell E. Ward, (614) 292-8456; Ward.25@osu.edu
Journal
Cancer Research