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Multicenter Study
. 2023 Apr 29;16(1):43.
doi: 10.1186/s13045-023-01440-6.

Elevated plasma levels of IL-6 and MCP-1 selectively identify CML patients who better sustain molecular remission after TKI withdrawal

Carolina Pavlovsky #  1 , Bianca Vasconcelos Cordoba #  2 , María Belén Sanchez  2 , Beatriz Moiraghi  3 , Ana Varela  3 , Rosario Custidiano  4 , Isolda Fernandez  1 , Maria Josefina Freitas  5 , Maria Verónica Ventriglia  5 , Georgina Bendek  6 , Romina Mariano  7 , María José Mela Osorio  1 , Miguel Angel Pavlovsky  1 , Ana García de Labanca  8 , Cecilia Foncuberta  4 , Isabel Giere  1 , Masiel Vera  4 , Mariana Juni  1 , Jose Mordoh  2 , Julio Cesar Sanchez Avalos  4 , Gerardo Cueto  9 , Silvia Miranda  10 , Estrella Mariel Levy  2 , Michele Bianchini  11
Affiliations
Multicenter Study

Elevated plasma levels of IL-6 and MCP-1 selectively identify CML patients who better sustain molecular remission after TKI withdrawal

Carolina Pavlovsky et al. J Hematol Oncol. .

Abstract

Treatment-free remission (TFR) in chronic myeloid leukemia (CML) is safe under adequate molecular monitoring, but questions remain regarding which factors may be considered predictive for TFR. Argentina Stop Trial (AST) is a multicenter TFR trial showing that 65% of patients sustain molecular remission, and the prior time in deep molecular response (DMR) was associated with successful TFR. Luminex technology was used to characterize cytokines in plasma samples. Using machine learning algorithms, MCP-1 and IL-6 were identified as novel biomarkers and MCP-1low/IL-6low patients showed eightfold higher risk of relapse. These findings support the feasibility of TFR for patients in DMR and MCP-1/IL-6 plasma levels are strong predictive biomarkers.

Keywords: Chronic myeloid leukemia; Cytokines; Predictive factors; Treatment free remission.

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Conflict of interest statement

CP provided services as a speaker to Novartis, BMS, Pfizer and Pint Pharma and is part of the advisory board of Novartis, Pfizer and Pint Pharma. MAP provided services as a speaker to Janssen, Abbvie, Astra Zeneca, Varifarma and Pint Pharma and is part of the advisory board of Janssen, Abbvie, Astra Zeneca, Merck and Ascentage Pharma. AV has provided services as a speaker to Novartis and Bristol. The remaining authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Treatment-free remission according to several variables of clinical relevance. A Molecular recurrence-free survival after TKI discontinuation (N = 46). The median molecular follow-up after TKI discontinuation was 31 months (range 2–38 months) overall and 34 months (range, 27 to 38 months) for the 30 patients in molecular remission without treatment. B Duration in months of DMR before stopping TKI in relapsed vs non-relapsed patients. C Molecular recurrence-free survival according to duration of stable DMR prior to TKI discontinuation (< 40 vs. > 40 months): Log-rank [Mantel-Cox] test: p = 0.004 HR = 4.29 CI: 0.64 to 28.59. D Molecular recurrence-free survival according to prior TKI duration (< 5.8 vs. > 5.8 years): Log-rank [Mantel-Cox] test: p = 0.039 HR = 2.80 CI 0.68–11.51)
Fig. 2
Fig. 2
Predictive model for discontinuation. A Data from 30 patients on TFR who did not relapse and 15 patients who relapsed during TFR were included in a decision tree analysis by incorporating MCP-1 and IL-6 levels. This recursive partitioning showed that all patients were divided into groups according to the relapse condition. In the first partition, MCP-1 was considered the criterion; in a terminal node, MCP-1hi group (> 265 pg/mL) included 25 patients, of which only 2 relapsed, while MCP-1low group (< 265 pg/mL) was further split by incorporating IL-6 measurement. When MCP-1low and IL-6 were combined, a relatively small percentage of patients (3/20) who did not relapse could be captured in the MCP-1low/IL-6hi group (> 4.5 pg/mL); on the other hand, the double low group (MCP-1low/IL-6low) selectively captured those patients who lost molecular response (13 out of 17 (76%)). B Confusion matrix used to define the performance of a decision tree model. To estimate the power of the model, an F1-score was calculated and a value of 0.81 was determined, suggesting a very high prediction power. C Molecular recurrence-free survival for the MCP-1high, MCP-1low/IL-6high and the MCP-1low/IL-6low groups at the time of discontinuation. D Multivariate Cox proportional hazard analysis including the most relevant clinical and biological variables and IL-6/MCP-1 cytokines levels combined
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