Therapeutic Effect of Bortezomib Combined with Dag Regimen in Hyperleukocytic Acute Myeloid Leukemia

AbstractIntroduction: Hyperleukocytic acute myeloid leukemia(HAML) is a high-risk type of acute myeloid leukemia (AML), with white blood cell counts exceeding 100 x 10 ^ 9/L in peripheral blood, accounting for approximately 5%-20% of AML.Bortezomib is the first proteasome inhibitor approved by the US FDA for clinical use.The efficacy of either single agent or in combination with other agents for acute myeloid leukemia is inconclusive. DAG is commonly used as a classical chemotherapy regimen for acute myeloid leukemia.We have found that bortezomib has a therapeutic effect on acute myeloid leukemia in clinical empirical medication, so we investigated the therapeutic effect of bortezomib combined with DAG regimen on HAML.

Methods:Primary hyperleukocytic leukemia cells were isolated from bone marrow of hyperleukocytic acute myeloid leukemia patients using ficoll liquid, then the primary hyperleukocytic leukemia cells were treated with bortezomib (0 nm, 5 nm, 10 nm, 20 nm, 50 nm), DAG, and bortezomib combined with DAG regimens at different concentration gradients.Cell viability was detected by flow cytometry. The HAML patient-derived xenograft (PDX) model were used to evaluate the in vivo effect of bortezomib combined with DAG regimen using the same dosing regimen as the clinical medication regimen: bortezomib 1.3 mg/m2, subcutaneous injection, 4 times a course, d1, 4, 8, and 11; doxorubicin liposome injection 5 mg/m2, intravenous drip, every other day, 5 times in total; cytarabine 10 mg/m2, subcutaneous injection, d1-14 every 12 h; and G-CSF 200 μg/m2 per day, subcutaneous injection, d1-14 days.

Results: With the increase of concentration gradient, the apoptosis of HAML leukemia cells induced by bortezomib alone and DAG alone was gradually enhanced, while the viable cell count of bortezomib combined with DAG was much lower than that of bortezomib alone or DAG alone. In animal experiments, flow cytometry showed that the ratio of human leukaemia cells in bone marrow blood decreased revealed the most significant decrease in the bortezomib combined with DAG group, absolute counts of CD45 cells in the bone marrow cells of mice in each group also revealed the most significant decrease in the bortezomib combined with DAG group. Morphological examination of myelocyte smears revealed significantly fewer myeloblasts in the bortezomib combined with DAG group than in the other groups. The survival rate in the bortezomib combined with DAG group was better than in the bortezomib alone or DAG alonefor the HAML PDX model.

Conclusion:Bortezomib combined with DAG regimen has synergistic killing effect on HAML and may serve as a certain clinical prospect in the treatment of hyperleukocytic acute myeloid leukemia.

Disclosures No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.