Stronger therapy better for AML with normal genetics

New research is helping select which therapies improve the chances of remission in the largest category of people affected by acute myeloid leukemia (AML) – those whose cancer cells have normal-looking chromosomes.

The findings suggest that people receiving more intense therapies are more likely to enter remission and to remain there longer than those receiving lower-dose therapies.

The study was published online Nov. 8 by the Journal of Clinical Oncology.

The Cancer and Leukemia Group B (CALGB) study was initiated by researchers at the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSU CCC-James). It is part of a larger CALGB cytogenetic trial chaired by Clara D. Bloomfield, professor of internal medicine and the William G. Pace III Professor in Cancer Research, OSU Cancer Scholar and senior adviser to the OSU cancer program.

Unexpectedly, the current study also found that patients who had an enlarged spleen at the time of their initial treatment were less likely to enter remission. AML patients are in remission when leukemic cells are not microscopically detectable among their bone-marrow cells.

“These preliminary findings raise the question of whether additional treatment directed specifically to the spleen might improve remission rates,” says first author Sherif S. Farag, assistant professor of internal medicine and a medical oncologist with the OSU CCC-James. “At this point, this is just a hypothesis that needs to be tested, but it may be that the spleen is a sanctuary site for leukemic cells and needs separate treatment.”

A diagnosis of AML routinely includes studying patients’ leukemic cells for chromosome damage, a process known as cytogenetic analysis. The information helps determine the best therapy and a patient’s chance of remission and cure. But 40 percent of AML patients have leukemic cells with normal-looking chromosomes. Without chromosomal abnormalities to guide treatment, several therapies are usually used.

“This study is important because it is the first large study to examine different types of therapy that is restricted to patients with normal chromosomes,” says Krzysztof Mrózek, an internationally recognized cytogeneticist, research scientist in internal medicine and one of the paper’s coauthors. “Yet, they make up the largest single group of people with AML.”

The multi-institutional study analyzed data from 490 patients treated for AML through five clinical trials conducted over nearly 20 years. Only adult patients under 60 years of age were included.

Overall, three quarters of the patients achieved complete remission. The average overall survival for the patients was 1.9 years, with 35 percent of patients still alive and disease-free after five years (these patients were considered cured).

The researchers first compared the outcomes of patients receiving one of two drug regimens given to bring the disease into remission. The study compared 350 patients receiving the drugs cytarabine plus daunorubicin to 140 patients receiving cytarabine plus increasing doses of both daunorubicin and etoposide. They found that both treatments induced remission about equally well. But to their surprise, they also found that patients with a normal spleen were four times more likely to enter remission than patients with an enlarged spleen, regardless of therapy. The researchers then looked at the second phase of treatment, known as intensification therapy, which is intended to keep patients in remission and to enhance the rate of cure.

The study compared four intensification therapies. Of these, the two more-intense therapies each produced longer remission periods and a better chance of cure than did the two less-intense therapies. That is, four cycles of high-dose cytarabine or one cycle of high-dose cytarabine and etoposide followed by stem-cell transplant were more effective than was one cycle of high-dose cytarabine alone. “There are many different approaches to post-remission therapy, and they include using fewer cycles of high-dose cytarabine or reducing the dose of the drug, but our study suggests these treatments are inferior,” Farag says.

At the same time, the study suggested that using very high doses of cytarabine may also be unnecessary. Using an intermediate dose seems equally effective but has fewer side effects, which can include toxicity to the kidneys and brain. “This has been suspected, but it hasn’t been carefully studied,” Farag says. “Again, we need a larger randomized study in the future to verify this, but our data show that we don’t need to push the dose to the maximum to have equal anti-leukemic effect.”

The study also suggested, however, that while two of the four therapies might produce longer remission periods—also known as periods of disease-free survival—no one treatment improved overall survival. The study followed patients for an average 7.4 years. “More research and some different strategies are still needed to give higher cure rates in these AML patients,” Farag says.

Statistician Amy S. Ruppert, research specialist with the OSU Comprehensive Cancer Center and CALGB, also contributed to this study.

Funding from the National Cancer Institute (NCI) supported this study. The CALGB is a multicenter NCI clinical trials group.