Pre-TKI cytokine profiling predicts CP-CML outcome

Measuring levels of transforming growth factor (TGF)-α and interleukin (IL)-6 may help identify patients with newly diagnosed chronic phase-chronic myeloid leukaemia (CP-CML) at risk of a poor outcome from tyrosine kinase inhibitor (TKI) therapy, research suggests.

"These data highlight, for the first time, the predictive value of cytokine profiling in CML patients", report Deborah White, from South Australian Health and Medical Research Institute in Adelaide, Australia, and colleagues.

"The combination of TGF-α and IL-6 plasma levels at CML diagnosis is strongly predictive for early and late molecular response rates and survival."

Plasma concentrations for 13 of 39 cytokines, chemokines and growth factors were significantly higher in 186 participants of the TIDEL-II trial before imatinib initiation than in 19 healthy controls. And although most of the biomarker levels had normalised in 17 patients assessed after 6 months of treatment, five remained elevated, "possibly reflecting persistent disease-induced alterations within the microenvironment", the researchers say.

In all, 13% of 183 patients assessed after 3 months did not achieve early molecular response (EMR), defined as BCR-ABL1 of 10% or less on the International Scale.

These patients, compared with those who did achieve EMR, had significantly higher baseline levels of both TGF-α (16.6 vs 4.9 pg/mL) and IL-6 (1.26 vs 0.44 pg/mL). Indeed, just 40.0% of patients with high levels of both biomarkers achieved EMR compared with 94.4% of patients with low levels of TGF-α, and 84.2% of patients with high TGF-α and low IL-6.

There was a similar relationship between elevated baseline TGF-α and IL-6 and the likelihood of a major molecular response (MMR, BCR-ABL1 ≤0.1% on two occasions), with 55% of patients with high levels of both biomarkers achieving this outcome versus 83% and 68% of patients with low TGF-α and high TGF-α, low IL-6, respectively.

High levels of both biomarkers at baseline were also predictive of significantly poorer progression-free survival, event-free survival and failure-free survival, and a higher rate of developing BCR-ABL1 mutations. And all three of the patients who transformed within a year of TKI treatment had high levels of both TGF-α and IL-6, the researchers add.

Moreover, when assessing the two biomarkers as continuous variables within multivariate analysis, alongside Sokal score, age and gender, only TGF-α level and BCR-ABL1 halving time at 3 months were significant and independent predictors of EMR.

Measuring baseline levels of TGF-α alone revealed that high concentrations of the marker were significantly more common in patients who did not achieve EMR, and again associated with poorer progression-free and failure-free survival and an increased risk of BCR-ABL1 mutations.

Plasma samples were also taken from 70 patients who were treated upfront with nilotinib, all of whom achieved EMR. But patients with elevated TGF-α at baseline, defined as 43.0 pg/mL or above, had higher median BCR-ABL1 levels between 3 and 24 months than those with lower levels and none achieved MMR after 24 months compared with 28% of those with lower baseline TGF-α.

"Although TGF-α alone delineates a poor response group of patients, the addition of IL-6 provides additional power and strongly selects for high-risk patients who may benefit significantly from early proactive intervention", White et al summarise in Leukemia.

"Thus, incorporation of these simple measurements to the diagnostic work-up of CP-CML patients may enable therapy to be individualized according to the risk profile of the patient."

They add: "Further mechanistic studies are required to ascertain a biological role of TGF-α in CML and its potential involvement in TKI-resistance and progression, potentially leading to the discovery of novel therapeutic targets."

By Lynda Williams, Senior medwireNews Reporter

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