Stem cell transplantation offers the only cure for acute myeloid leukemia (AML), but the majority of patients with the disease are not candidates for the treatment because they cannot withstand the intensive chemotherapy needed to induce complete remission.
Patients might be considered ineligible for intensive chemotherapy because of poor performance status and multiple comorbidities. As a result, many elderly AML patients receive hypomethylating agents (HMAs).
Figure: Crystal structure of a short DNA helix with sequence "accgcCGgcgcc". (By Christoph Bock, Max Planck Institute for Informatics)
HMAs provide a promising option for older patients. A review of randomized clinical trials found that HMAs, particularly azacytidine, offer superior outcomes compared to conventional care regimens, including intensive chemotherapy, low dose cytarabine and best supportive care. Based on the analysis, HMAs had an overall response rate nearly double conventional care (23.7% vs. 13.4%) and provided a 12-month improvement in overall survival rates.
A study at the Mayo Clinic in Rochester published in the American Journal of Hematology in May 2017 found a higher response rate, 28%, and a median duration of response of 10 months among patients over age 59. For non-responders and those who relapse, however, the outcomes were worse than anticipated. Median overall survival after primary or secondary failure of HMAs was just 2 months.
The researchers reviewed the charts of 56 AML patients who received either azacytidine (27%) or decitabine (73%) as frontline therapy. Sixteen patients responded and 10 achieved complete remission. Of those, 13 relapsed.
The study analyzed outcomes for the 40 non-responders and the 13 who relapsed following response. Of those 53 patients, 12 received additional therapies. None of the patients responded to the first salvage therapy, treatment with the alternate HMA. This study joins previous work in finding no benefit to offering azacytidine to patients who failed decitabine or vice versa.
Five patients received a second salvage therapy and 2 of them achieved complete remission. Of the patients who received a second salvage therapy, 2 received low dose cytarabine and neither achieved complete remission nor an overall survival benefit compared to other patients who received any therapy after HMA failure. The 2 patients who participated in clinical trials to receive their subsequent lines of therapy also had no overall survival benefit, according to the authors.
The researchers stated that patients who received salvage therapies had much better outcomes than those who did not, with a median overall survival more than 4 times those who had no treatment after HMAs, 9.5 months versus just 2 months. They said the differences could be related to better care provided to these patients and improvements in supportive care or selection bias that favored more fit patients for subsequent therapies.
In a somber conclusion, the researchers wrote that “this patient population is in dire need of more treatment options…Our study found all traditional salvage therapies and clinical trials that our patients underwent to be ineffective.”