TGF-α, IL-6 Levels Predict Responses and Outcomes in CML

Elevated levels of transforming growth factor-alpha (TGF-α) and interleukin-6 (IL-6) in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML) were strongly predictive of subsequent failure to achieve molecular response, and of transition to blast crisis (BC-CML) and survival outcomes, according to a new study.

Previous studies have shown that the failure to achieve an early molecular response (EMR; defined as BCR-ABL1 ≤ 10% at 3 months) has poorer survival outcomes; EMR is also predictive of treatment outcomes on second-generation tyrosine kinase inhibitors (TKIs) such as nilotinib and dasatinib, suggesting that those with EMR failure may have intrinsic TKI resistance.

“Thus, the identification of relevant biomarkers is required so that alternative therapeutic approaches, preferably at the time of diagnosis, may be implemented in patients at high risk of EMR failure and transformation,” wrote study authors led by Deborah White, PhD, of the South Australian Health and Medical Research Institute in Adelaide.

The study involved analysis of plasma samples from CP-CML patients enrolled in the TIDEL-II trial; the researchers included samples from 186 patients prior to starting imatinib treatment, and from 17 patients after 6 months on TKI therapy, and these were compared with 19 healthy donor samples. The results were published in Leukemia.

In total, the levels of 13 out of 39 different pro-inflammatory and angiogenesis-promoting cytokines, chemokines, and growth factors were significantly elevated in the newly diagnosed patients compared with the healthy donors. Most of these molecules, including epidermal growth factor (EGF), fibroblast growth factor 2 (FGF2), vascular endothelial growth factor (VEGF), TGF-α, and others normalized after 6 months of imatinib therapy. Several others, including TNF-α, soluble interleukin-2 receptor alpha (sIL-2Rα), interleukin-8 (IL-8), and others, remained elevated, which the authors wrote could reflect “persistent disease-induced alterations within the microenvironment.” A third group of molecules were only elevated following TKI therapy, suggesting the drug induced those changes.

An analysis found that TGF-α and IL-6 were the two most important molecules for EMR prediction. The median plasma concentration of TGF-α in those who achieved EMR was 16.6 pg/mL, compared with 4.9 pg/mL in those who did not (P < .001). For IL-6, the concentrations were 1.26 pg/mL vs 0.44 pg/mL (P = .004).

A group that had elevated concentrations of both these factors had a 55% rate of major molecular response at 24 months, compared with 68% among those with high TGF-α but low IL-6, and 83% in those with low TGF-α. The group with elevated levels of both also had significantly poorer progression-free survival (P < .0001), event-free survival (P = .028), and failure-free survival (P = .0007). Only three patients transformed to blast crisis in the first 12 months, and all three had elevated levels of both TGF-α and IL-6.

TGF-α alone was also predictive of a failure to achieve EMR, though less so than when combined with IL-6. The authors wrote that this could suggest a pathogenic role for TGF-α.

“With further validation this predictive tool incorporating relatively easy to adopt laboratory tests has the potential to guide clinical decisions in the future,” the authors concluded.