Combination reduces relapse incidence after allogeneic HSCT in high-risk AML subset
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Recombinant human granulocyte colony-stimulating factor combined with minimal-dose decitabine appeared to reduce relapse incidence after allogeneic transplant among patients with high-risk acute myeloid leukemia, study results showed.
The randomized phase 2 trial results, published in Journal of Clinical Oncology, also showed changes in the number of lymphocyte subtypes among patients who received the combination.
Although there have been many advances in allogeneic hematopoietic stem cell transplant over the last decade, the survival rate for patients with high-risk AML undergoing this procedure after achieving complete remission is only 55% and relapse remains common, according to Lei Gao, MD, PhD, clinical researcher in the Medical Center of Hematology at Xinqiao Hospital in China, and colleagues.
“Donor lymphocyte infusion (DLI) is one of the most common interventions for AML relapse because donor lymphocytes are expected to promote the graft-versus-leukemia effect,” they wrote. “However, DLI treatment success in AML relapse has been limited, and the reported OS rates at 3 years are only 10% to 20%.”
Previous studies have shown that decitabine, a hypomethylating agent currently approved to treat high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia and AML, can prevent AML relapse after allogeneic HSCT by increasing the number of T-regulatory cells. It also leads to induction of cytotoxic CD8-positive T-cell responsiveness to tumor antigens.
Studies also have shown that granulocyte colony-stimulating factor (G-CSF), a soluble growth factor that interacts with the G-CSF receptor to promote cell entry into the cell cycle, combined with decitabine promotes the production and function of cytotoxic CD8-positive T cells, as well as natural killer and T-regulatory cells.
Gao and colleagues studied the effect of the combination in preventing relapse among 204 patients with high-risk AML and no minimal residual disease who previously received allogeneic HSCT. Researchers randomly assigned 102 patients to 100 g/m2 recombinant human G-CSF on days 0 to 5 combined with minimal-dose (5 mg/m2) decitabine on days 1 to 5 every 6 to 8 weeks for as many as six courses. The other 102 patients received no intervention.
Relapse after transplant served as the primary outcome. Chronic graft-versus-host disease, safety and survival served as secondary outcomes.
Median follow-up was 28.2 months (range, 2.8-35.9) for the treatment group and 26.4 months (range, 2.9-35.7) for the nontreatment group.
Results showed an estimated 2-year cumulative incidence of relapse of 15% (95% CI, 8-22.1) among patients who received treatment compared with 38.3% (95% CI, 28.8-47.9) among patients who received no intervention (HR = 0.32; 95% CI, 0.18-0.57).
Thirty-four patients in the treatment group and 49 patients in the nontreatment group developed chronic GVHD. Researchers observed no significant differences between the groups in 2-year cumulative incidence of chronic GVHD without relapse (23% vs. 21.7%; HR = 1.07; 95% CI, 0.6-1.92).
Patients who received the combination demonstrated increases in the numbers of CD8-positive T cells, natural killer cells and T-regulatory cells by the second or third course of treatment. Increases in these cells significantly reduced the risk for relapse, a univariable competing model showed. A multivariable model revealed the number of natural killer cells to be an independent factor influencing relapse (HR = 0.96; 95% CI, 0.94-0.99).
Researchers reported leukemia-free survival rates of 81.9% in the treatment group and 60.7% in the nontreatment group (HR = 0.38; 95% CI, 0.22-0.66) and 2-year OS rates of 85.8% vs. 69.7% (HR = 0.45; 95% CI, 0.24-0.83).
Adverse events, most of which were grade 1 or grade 2, occurred among 93% of patients in the treatment group and 83.3% of patients in the nontreatment group.
“Our findings demonstrate that [recombinant human G-CSF] combined with minimal-dose decitabine after [allogeneic hematopoietic stem cell transplantation] could significantly reduce the incidence of high-risk AML relapse,” Gao and colleagues wrote. “Future studies are required to investigate combinations of other drugs or treatment regimens with minimal-dose decitabine for AML relapse prophylaxis in patients who are [minimal residual disease]-positive before transplantation.”
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