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Updated: Mar 9, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Reduced CD62L Expression on T Cells and Increased Soluble CD62L Levels Predict Molecular Response to Tyrosine Kinase
Sieghart Sopper1, Satu Mustjoki1, Deborah White1
1Sieghart Sopper, Günther Gastl, Matthias Baldauf, Zlatko Trajanoski, and Dominik Wolf, Medical University Innsbruck; Sieghart Sopper and Dominik Wolf, Tyrolean Cancer Research Institute; Matthias Baldauf, Oncotyrol, Innsbruck; Peter Valent, Medical University of Vienna, Vienna, Austria; Satu Mustjoki and Kimmo Porkka, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland; Deborah White and Timothy Hughes, South Australian Health and Medical Research Institute and University of Adelaide School of Medicine, Adelaide, South Australia, Australia; Andreas Burchert, Universitätsklinikum Gießen und Marburg and Philipps Universität Marburg, Marburg; Andreas Hochhaus, Thomas Ernst, and Thomas Schenk, Universitätsklinikum Jena, Jena; Dominik Wolf, University Hospital of Bonn, Bonn, Germany; Bjørn T. Gjertsen, University of Bergen, Bergen, Norway; Frank Giles, Northwestern University, Chicago, IL; and Jeroen J.W.M. Janssen and Gert J. Ossenkoppele, Vrije Universiteit Medical Center, Amsterdam, the Netherlands.
Abstract:
Purpose Immunologic surveillance of minimal residual disease in chronic myelogenous leukemia (CML) may be relevant for long-term control or cure of CML. Little is known about immune-modulatory effects of nilotinib in vivo, potentially predicting response to therapy. Patients and Methods A prospective and comprehensive flow cytometry-based immunomonitoring program paralleled the ENEST1st clinical study, investigating 52 nilotinib-naïve patients with chronic-phase CML. Data were verified in independent validation cohorts. Results T cells of patients with CML at diagnosis expressed low l-selectin (CD62L) levels, which was not a result of proportional aberrations of T-cell subsets. Low numbers of CD62L-expressing CD4+ and CD8+ T cells correlated with higher Sokal score, increased spleen size, and high leukocyte and peripheral-blood blast counts. At month 6 during nilotinib therapy, CD62L expression returned to levels of healthy individuals. The level of CD62L loss on T cells directly correlated with the extent of soluble CD62L (sCD62L) elevation. In parallel, the proteolytic activity of tumor necrosis factor α-converting enzyme (TACE; ADAM17, CD156b), the metalloproteinase shedding CD62L, was increased at diagnosis and significantly decreased during nilotinib treatment. High CD62L+ expression on both CD4+ and CD8+ T cells and, vice versa, low sCD62L levels at CML diagnosis were linked to superior molecular responses. These findings were corroborated in independent validation cohorts. Conclusion We demonstrate the prognostic impact of CD62L shedding from T cells and increased sCD62L plasma levels at CML diagnosis on molecular response to tyrosine kinase inhibitor therapy in early chronic-phase CML. Functionally, decreased CD62L may be a consequence of increased TACE-mediated CD62L cleavage and potentially impairs immune-cell function. Larger prospective studies are ongoing to confirm the prognostic relevance of this finding.
Insights
In chronic myelogenous leukemia (CML), low T cell CD62L expression at diagnosis predicts poor response to tyrosine kinase inhibitors. Nilotinib therapy restores CD62L levels, indicating a potential prognostic marker for CML treatment.
Area of Science:
- Immunology
- Hematology
- Oncology
Background:
- Minimal residual disease surveillance is key for chronic myelogenous leukemia (CML) control.
- Immune-modulatory effects of nilotinib and their predictive value are not well understood.
Purpose of the Study:
- To investigate the immune-modulatory effects of nilotinib in CML patients.
- To assess the prognostic impact of T cell CD62L expression and soluble CD62L (sCD62L) levels on nilotinib therapy response.
Main Methods:
- Prospective immunomonitoring using flow cytometry in 52 nilotinib-naïve chronic-phase CML patients.
- Analysis of T cell CD62L expression, sCD62L levels, and TACE activity.
- Validation in independent patient cohorts.
Main Results:
- CML patients at diagnosis showed low T cell CD62L expression, correlating with disease severity.
- Nilotinib therapy restored CD62L levels to those of healthy individuals by 6 months.
- Increased TACE activity was observed at diagnosis and decreased with nilotinib treatment.
- High CD62L+ T cells and low sCD62L at diagnosis predicted superior molecular response.
Conclusions:
- CD62L shedding from T cells and elevated sCD62L are prognostic markers for molecular response in early chronic-phase CML treated with tyrosine kinase inhibitors.
- Decreased CD62L may result from increased TACE activity, potentially impairing immune function.
- Further studies are needed to confirm the prognostic relevance of these findings.
