Novel Therapeutic Regimen Achieves Responses in Elderly Patients with AML/MDS

Elderly patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) who have not been treated can benefit from and tolerate a therapy regimen of granulocyte colony stimulating factor (G-CSF), ultra low–dose decitabine, and low-dose cytarabine, according to a new study.

The report, published in the journal Therapeutic Advances in Hematology, offers a potential new strategy for patients who are unfit for intensive chemotherapy and have few suitable treatment options.

Older patients with AML/MDS generally face a poor prognosis, especially if they have other comorbidities, organ dysfunction, or adverse cytogenetics, wrote the investigators who were led by Yun Ling, PhD, of the Third Affiliated Hospital of Soochow University in China. These patients’ inability to tolerate intense chemotherapy leads to poor outcomes, including higher early death rates and lower complete response (CR) rates, they added.

One strategy has been lower-intensity chemotherapy such as low-dose cytarabine and hypomethylating agents, including azacitidine and decitabine, they wrote. Hypomethylating agents appear to work by reactivating hypermethylated tumor suppressor genes.

“Decitabine, which has the double effect of inducing differentiation of neoplastic cells at low dosage and cytotoxicity at high dosage, has been regarded as the frontline treatment of older AML/MDS patients according to the National Cancer Center Network since 2016, especially those who are not suitable for standard intensive chemotherapy,” Ling and colleagues wrote.

Still, they said, many patients cannot tolerate the standard dose of decitabine. In such cases, a reduced intravenous dosage of 6 mg/m² for 7 to 10 days has led to improvement. They added that pairing decitabine with cytarabine has led to synergistic effects, augmenting the regulation of natural killer cells.

In the new study, Ling and colleagues sought to understand what might happen if ultra low–dose decitabine were combined with low-dose cytarabine and the glycoprotein granulocyte colony stimulating factor (G-CSF) in intensive-therapy ineligible older patients with AML/MDS. The investigators enrolled 28 patients who were over the age of 60, were newly diagnosed with AML/MDS, and were deemed unfit for standard intensive chemotherapy. The patients ranged in age from 60 to 83 years (median, 68) and most (n = 20; 71.4%) harbored AML. Each of the patients received therapy consisting of subcutaneous G-CSF at 300 μg per day for priming, daily decitabine at 5.15 to 7.62 mg/m² given intravenously, and twice daily subcutaneous cytarabine at 15 mg/m² for 10 consecutive days every 28 days. The primary outcome was overall response rate (ORR).

The regimen, Ling and colleagues found, was generally well tolerated. The observed response rate was 57.1% and the rate of hematologic improvement was 64.3%.

“The myeloid suppression was short-lived, with a median neutrophil recovery time of 14 days,” Ling and colleagues wrote. “The incidence of grade 3 or 4 non-hematological adverse events was 43.1%. There was zero 4- and 8-week mortality.”

Febrile neutropenia, infection, fatigue, and hemorrhage were the most common non-hematological adverse events, the investigators reported.

The authors cautioned that it was not possible to include a control arm in the study due to the patient population. They added that most patients in the study could not continue treatment past 4 cycles, either because of disease resistance, the high cost of treatment, or their inability to attend regular treatment.

Ling and colleagues said their intention in the study was to see if the novel treatment regimen would result in longer overall survival and improved quality of life. They recorded a median overall survival of 8.2 months (range, 3.5-29.6) with the patients in the study undergoing a variety of subsequent therapies following the study regimen. The investigators said further research is needed to verify these results and evaluate the significance of the treatment. However, they concluded that this early evidence suggests the regimen may provide a valuable option for some members of this hard-to-treat group.

Reference

Zhu H, Yang B, Liu J, et al. A novel treatment regimen of granulocyte colony-stimulating factor combined with ultra-low-dose decitabine and low-dose cytarabine in older patients with acute myeloid leukemia and myelodysplastic syndromes. Ther Adv Hematol. Published April 30, 2021. doi:10.1177/20406207211009334