Alexandra M. Stevens and colleagues from the Baylor College of Medicine, Houston, Texas, investigated the role of Interleukin-6 (IL-6) levels in the Bone Marrow (BM) microenvironment and its association with the clinical response to cytotoxic chemotherapy in pediatric Acute Myeloid Leukemia (AML) patients. The results of the study were published in Blood Advances on 8th August 2017.
BM samples from pediatric AML patients (AML cohort; n = 45) who were treated with chemotherapy at the Texas Children’s Cancer and Hematology Center between 2007–2016 and healthy sibling donors (NBM cohort; n = 7) were analyzed for their IL-6 levels. The median levels of IL-6 were significantly higher in AML patients (11.79 pg/ml) compared to the healthy controls (1.7 pg/ml). Patients were grouped into high (n = 21) and low (n = 24) levels of IL-6 using a cut-point of 12 pg/ml.
The key results of the study were:
- 5-year Event Free Survival (EFS) for patients with low and high levels of IL-6 at diagnosis; 43.4% ± 12% vs 20.6% ± 10%, P = 0.036
- 5-year EFS in low-risk patients with low (n = 14) and high (n = 13) levels of IL-6; 82.5% ± 11% vs 17.3% ± 11%, P = 0.0003
- Median IL-6 levels significantly decreased at remission (2.8 pg/ml) compared to diagnosis (11.2 pg/ml); P = 0.0004
- Exogenous IL-6 protected AML blasts from mitoxantrone-induced apoptosis in AML cell lines and patient samples
- IL-6 induced pY-STAT3 (frequently increases at relapse) increased significantly in Leukemia Stem Cells (LSCs)
In summary, pediatric AML patients with increased levels of IL-6 have poorer EFS, which may be as a result of IL-6-induced chemoresistance.
The authors concluded their study by noting that “IL-6 levels at diagnosis could be used to help identify children at high risk of relapse, particularly those who are otherwise classified as low risk by current algorithms”. They further proposed that targeting the “IL-6 signaling pathway can potentially eradicate chemoresistant LSCs and prevent relapse” in pediatric AML patients.
The tumor microenvironment can protect cancer cells from conventional anticancer therapies. Thus, targeting these protective mechanisms could eradicate therapy-resistant cancer cells and improve outcomes. Interleukin-6 (IL-6) provides extrinsic protection for several solid tumors and multiple myeloma. In pediatric acute myeloid leukemia (AML), IL-6–induced STAT3 signaling frequently becomes stronger at relapse, and increases in IL-6–induced STAT3 activity are associated with inferior survival after relapse. These findings suggested that the IL-6–induced STAT3 pathway may promote chemotherapy resistance and disease progression. Thus, we investigated the dysregulation of IL-6 levels in the bone marrow niche in pediatric patients with AML and the association between IL-6 levels and outcome. We measured levels of over 40 cytokines and growth factors in plasma from diagnostic bone marrow aspirates of 45 pediatric AML patients and 7 healthy sibling controls. Of the measured cytokines, only IL-6 levels were associated with event-free survival. Importantly, the effect of elevated IL-6 was most striking among children classified as having a low risk of relapse. In these patients, 5-year event-free survival was 82.5% ± 11% for patients with low IL-6 levels at diagnosis (n = 14) compared with 17.3% ± 11% for patients with elevated IL-6 (n = 13, log-rank P = .0003). In vitro, exogenous IL-6 reduced mitoxantrone-induced apoptosis in cell lines and primary pediatric AML samples. These results suggest that IL-6 levels at diagnosis could be used to help identify children at high risk of relapse, particularly those who are otherwise classified as low risk by current algorithms. Moreover, the IL-6 pathway could represent a target for overcoming environment-mediated chemotherapy resistance.