Potential clinical application of imatinib mesylate in patients with leukemic large granular lymphocytes

Tyrosine kinases (TKs), including receptor TKs and cellular TKs, are enzymes that catalyze the phosphorylation of tyrosine residues by transferring the terminal phosphate of adenosine triphosphate (ATP), and are activated by the signals that are closely related to the survival, proliferation, migration, and invasion of tumor cells. Constitutively activating mutations of the receptor tyrosine kinases (RTKs), such as c-Kit, platelet-derived growth factor receptor (PDGFR), and FMS-like tyrosine kinase 3 (FLT3), are often involved in the pathogenesis of various types of hematologic malignancies [1]. Tyrosine kinase inhibition is one of the most successful targeted therapeutic strategies in the clinical management of hematologic malignancies. In chronic myeloid leukemia (CML), targeting a fusion protein, BCR–ABL tyrosine kinase, with the tyrosine kinase inhibitors (TKIs) imatinib mesylate (IM) and nilotinib showed promising clinical results [2]. Similar to other synthetic drugs and chemical compounds, the off-target effects of TKIs are considered as a double-edged sword, with the possibilities of therapeutic efficacy as well as causing normal tissue damage.

In this issue of Leukemia and Lymphoma, Fedele and his colleagues report that cytotoxic T lymphocyte (CTL) expansion was observed in 10 of 12 allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients with the typical cell surface markers of T-cell large granular lymphocyte (LGL) leukemia and T-cell receptor (TCR) gene rearrangements. Two of the recipients received IM treatment, and this treatment led to significant clinical improvement and LGL clone clearance via the down-regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation [3]. Previously we had observed that high RTK activity played a decisive role in triggering and sustaining leukemic cell survival in patients with LGL leukemia [4]. Although TKIs have been used clinically in different hematological malignancies, the biological effects of TKIs in regulating the fate of LGL leukemia cells remain generally unknown, and further investigations are warranted.

Large granular lymphocytes including CD3+/CD8+/CD57+ T cells and natural killer (NK) cells make up about 10–15% of the total peripheral blood mononuclear cell (PBMC) population in healthy individuals. They are essential for the acquired immunity against viral infection and neoplasm development. Expanded clonal LGLs are known to be responsible for causing cytopenias and autoimmune disorders [5]. Ongoing efforts have focused on seeking strategies for the induction of leukemic cell death and/or restoration of the deregulated apoptotic pathways in leukemic LGLs. The ultimate goal of eliminating these pathologic CTL clones in patients with LGL leukemia remains unfulfilled, especially in patients with uncommon acute aggressive subtypes.

Importantly, Fedele and his colleagues report that constitutive ERK1/2 phosphorylation was also observed in the fibrocytes that were derived from the prolonged PBMC culture of the allo-HSCT recipients. IM treatment resulted in clinical improvement in cutaneous sclerosis via inactivation of the overall cellular ERK1/2 kinases. Pulmonary involvement, including the development of pulmonary arterial hypertension (PAH), has been reported in LGL leukemia. The etiology of primary pulmonary hypertension is unknown. Current theories on pathogenesis focus on abnormalities in interaction between endothelial and smooth-muscle cells. Endothelial cell injury may result in an imbalance in endothelium-derived mediators, favoring vasoconstriction [6]. Tajsic and Morrell documented that the PDGF-BB homodimer potently stimulates pulmonary arterial smooth muscle cell proliferation and remodeling, and that this effect is inhibited by PDGF RTK inhibitors, including imatinib [7]. We found elevated serum levels of PDGF-BB in leukemic LGLs of both T and NK subtypes [4]. PAH is also associated with lymphoproliferative diseases, and lung biopsies performed in some of these cases revealed infiltration of lung parenchyma with LGLs [8]. CD8+/CD28null T cells from patients with LGL leukemia have the ability to directly lyse pulmonary artery endothelial cells and human synovial cells. This acquired cytotoxicity is closely related to the constitutively up-regulated DAP10/DAP12 adpator levels, and downstream phosphatidylinositol 3-kinase (PI3K) and ERK1/2 activation [9]. Finally, Svegliati and his colleagues reported that stimulatory antibodies to the PDGFR were found selectively in all patients with extensive chronic graft-versus-host disease (cGVHD). These antibodies activated PDGF RTK and downstream Ha-Ras-ERK1/2-ROS (reactive oxygen species), which led to increased collagen gene expression and myofibroblast phenotype conversion of normal human primary fibroblosts [10]. To summarize, we predict that PDGF RTK constitutive activation may play an important role in contributing to the development of PAH in patients with LGL leukemia as well as the sclerodermatous lesions in patients with cGVHD. The biologic effectiveness of IM reported by Fedele et al. in allo-HSCT recipients provides a rational link between RTK activity and LGL leukemia-related pulmonary complications. However, it is of interest that oligoclonal/clonal expansion of LGLs has been observed in patients with CML treated with RTK inhibitors, particularly with second-generation agents such as dasatinib. Therefore, what role, if any, RTK inhibitors might play in the therapy of cytopenias associated with LGL leukemia is not certain.

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