Evolving Treatment Options for Older Patients with AML

About 13,300 new cases of acute myeloid leukemia (AML) are diagnosed yearly, and nearly 9,000 deaths occur in the United States. It is a rapidly progressive disease that results in the accumulation of immature, functionless cells in the marrow and blood, leaving the body unable to fight infections or produce enough normal red blood cells, white blood cells, and platelets. The disease primarily affects people age 60 and older and is the second most common form of leukemia in adults.

Almost two-thirds of AML patients over age 65 do not receive treatment for the disease because standard therapy can be risky. The traditional, harsh chemotherapy approach is difficult for anybody, but particularly so for older patients who don’t tolerate the “thunderbolt” of intensive chemotherapy well. Many patients are judged not to be candidates for any treatment at all because they likely would not survive the traditional, harsh chemotherapy approach. Furthermore, the AML seen in elderly patients is also more likely to have evolved from a prior hematologic disorder, and the leukemic blasts are more likely to have poor-risk structural and numeric cytogenetic abnormalities and expression of multidrug resistance protein (MRP1). These blast features have been associated with greater resistance to therapy, which makes the response rate lower, the risk of relapse higher, and the cure rates lower. On average, such patients survive only 1.7 months after diagnosis.

The development of a less toxic therapy has enabled such patients who would have never received treatment for their disease to actually benefit from prolonged remissions with improved quality and length of life, without paying the price exacted by intensive therapy regimens.

Researchers at Washington University School of Medicine in St. Louis and collaborating institutions found that decitabine might benefit older AML patients by reactivating genes that cancer cells turn off. It works by reducing the amount of DNA that is marked with a chemical tag called a methyl group. Scientists think that the excess methylation found in cancer cells inactivates genes that normally suppress tumor development.

The study published in the Journal of Clinical Oncology by Cashen et al was conducted at three sites: Washington University School of Medicine; the University of California, Los Angeles; and the City of Hope National Medical Center in Duarte, California. The researchers tested decitabine in 55 AML patients with an average age of 74 years. All patients received the same decitabine dose for five consecutive days every 4 weeks until their disease stopped responding to the drug and began progressing or until an adverse event occurred to prevent further participation. By comparison to standard chemotherapy and stem cell transplantation, the treatment was considered a low-intensity treatment and was more tolerable for elderly patients, especially those with accompanying medical problems. In 24% of the study participants, blood counts and bone marrow returned to normal, which is considered a complete response. It took 4.5 cycles of decitabine treatment on average to achieve a complete response. In those with a complete response, average survival time was 14 months. For all study participants, average survival time was 7.7 months. Treatment-related adverse events included low blood counts (red cells, white cells, and platelets), infection, fever, and fatigue. Almost half of the study participants had at least one serious adverse event. Seven patients discontinued treatment, and three patients died as the result of adverse events.

In a different study, we looked back at our institution experience with decitabine as initial treatment for older patients with de novo AML and MDS-related AML and found that 45 patients met the criteria. About one-third of patients achieved complete response (CR/CRi) with maximum of 5 cycles of therapy and durable response of 13 months. The median overall survival for the whole cohort was about 9 months and for CR/CRi group was 19 months. Day 100 mortality was about 20%. The length of hospital stay averaged 20 days. Cytogenetics had no impact on response. No documented invasive infections were found, and only fatal bleed was reported.

Decitabine seems to have acceptable response rate, side-effect profile, and short hospital stay duration. At the same time, we have to wait for the results of further trials of decitabine to have a better estimate of the response rate and survival outcome compared to other low-intensity options for older adults.

This edition of Oncology Fellows is supported by Genentech, a member of the Roche Group.