Cytarabine, Aclarubicin, and G-CSF Effective Treatment Regimen for Relapsed/Refractory AML

Cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CAG)—used to treat neutropenia—generates a positive effect for patients with acute myeloid leukemia (AML) by decreasing the number of immunosuppressive cell types and their associated cytokines, while also downregulating SDF-1α levels, based on the results of a recent study.

AML is a hematologic cancer of the blood and bone marrow that is associated with increased immature white blood cells and an immunosuppressed state. For the past 30 years, patients with AML have been treated with the “3 + 7” regimen of 3 days anthracycline and 7 days of cytarabine. However, some patients, particularly the elderly, will relapse while on this treatment, highlighting the need for additional treatment regimens. CAG has been a regimen used for relapsed AML since 1995. In the study, mice given CAG were compared with mice given daunorubicin and cytarabine or nothing based on the alteration of the immunosuppressive bone marrow microenvironment.

Twenty-one mice were randomly divided into 3 groups: CAG, daunorubicin and cytarabine, or nothing (control group). In the CAG and daunorubicin and cytarabine treatment regimens, the levels of T regulatory cells and myeloid-derived suppressor cells decreased significantly. From the decreased levels of these cell types, anti-inflammatory and immunosuppressive cytokines associated with these cells also dropped. The CAG group exhibited the lowest cytokine TGF-β1, IL-10, and Arg-1 concentrations compared with the other 2 groups. The decrease in immunosuppressive cytokines suggests that CAG has the same potential as daunorubicin and cytarabine to modulate immune suppression from AML.

In addition, CAG treatment regimens downregulated SDF-1α levels in the bone marrow and peripheral blood, causing leukemia cells to be released from the bone marrow and inducing an antileukemic effect. The concentration of SDF-1α in the bone marrow and peripheral blood, however, did not vary significantly between the 3 groups. When comparing the histopathology of AML, CAG, and daunorubicin and cytarabine mice, the control group mice had swollen liver and spleens compared to the treated groups. Mice in both treated groups had decreased liver and spleen sizes as well as recovered hematopoietic systems.

However, in mice treated with CAG, leukemic cells infiltrated into the hepatic portal and central veins, potentially due to the lowered dose of chemotherapy given.

From this study, investigators found that CAG exerts a beneficial effect to counter the immunosuppressive nature that AML creates. The decreased levels of immunosuppressive cells and cytokines, as well as the downregulation of SDF-1α helps to restore the functions of the immune system. Also, because of the lower doses of the chemotherapeutic agents, CAG may reduce the harmful adverse effects of these agents, making it more useable in elderly patients. Although CAG results in more residual leukemic cells, it is a regimen worth considering in select populations for patients with relapsed/refractory AML.

Reference:

Chen J, Yang N, Liu H, et al. Immunological effects of a low-dose cytarabine, aclarubicin and granulocyte-colony stimulating factor priming regimen on a mouse leukemia model. Oncol Lett. 2018;16(3):3022-3028. doi: 10.3892/ol.2018.9018.