Large granular lymphocytosis during dasatinib therapy

Qiu, Zhiyuan; Xu, Wei; Li, Jianyong

doi:10.4161/cbt.27310

Cited by 38 publications

(30 citation statements)

References 63 publications

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“…Treg reduction has been shown to be markedly enhanced in dasatinib-treated CML patients developing LGL lymphocytosis (109, 117). Balachandran et al (23) have found that the immune system contributes substantially to the antitumor effects of imatinib via the inhibition of indoleamine 2,3-dioxygenase (IDO), an important regulatory checkpoint influencing Treg expansion and activity (118).…”

Section: The Immunomodulatory Effects Of Tkimentioning

confidence: 99%

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

2017

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Chronic myeloid leukemia (CML) is a hematological cancer, characterized by a reciprocal chromosomal translocation between chromosomes 9 and 22 [t(9;22)], producing the Bcr-Abl oncogene. Tyrosine kinase inhibitors (TKIs) represent the standard of care for CML patients and exert a dual mode of action: direct oncokinase inhibition and restoration of effector-mediated immune surveillance, which is rendered dysfunctional in CML patients at diagnosis, prior to TKI therapy. TKIs such as imatinib, and more potent second-generation nilotinib and dasatinib induce a high rate of deep molecular response (DMR, BCR-ABL1 ≤ 0.01%) in CML patients. As a result, the more recent goal of therapy in CML treatment is to induce a durable DMR as a prelude to successful treatment-free remission (TFR), which occurs in approximately half of all CML patients who cease TKI therapy. The lack of overt relapse in such patients has been attributed to immunological control of CML. In this review, we discuss an immunological timeline to successful TFR, focusing on the immunology of CML during TKI treatment; an initial period of immune suppression, limiting antitumor immune effector responses in newly diagnosed CML patients, linked to an expansion of immature myeloid-derived suppressor cells and regulatory T cells and aberrant expression of immune checkpoint signaling pathways, including programmed death-1/programmed death ligand-1. Commencement of TKI treatment is associated with immune system re-activation and restoration of effector-mediated [natural killer (NK) cell and T cell] immune surveillance in CML patients, albeit with differing frequencies in concert with differing levels of molecular response achieved on TKI. DMR is associated with maximal restoration of immune recovery in CML patients on TKI. Current data suggest a net balance between both the effector and suppressor arms of the immune system, at a minimum involving mature, cytotoxic CD56dim NK cells may be important in mediating TFR success. However, a major goal remains in CML to identify the most effective pathways to target to maximize an advantageous immune response and promote TFR success.

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Section: The Immunomodulatory Effects Of Tkimentioning

confidence: 99%

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

2017

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“…1-15, 17, 18) but not in imatinib-or nilotinibtreated (no. [19][20][21][22][23][24][25][26][27][28][29] patients, suggesting that inhibition of signal transduction pathways is the major event occurring in dasatinib-treated patients. This phenomenon was common to NK cells and CTLs after consumption of dasatinib, but the detailed profiles slightly differed in each patient ( Fig.…”

Section: Change Of Signal Transduction Pathways In Cytotoxic Lymphocytesmentioning

confidence: 99%

Direct effect of dasatinib on signal transduction pathways associated with a rapid mobilization of cytotoxic lymphocytes

2016

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It has been shown that an increase in cytotoxic lymphocyte counts in the peripheral blood occurs rapidly after taking dasatinib, but the underlying mechanism is not yet elucidated. To investigate the influence of dasatinib on signal transduction pathways, we investigated the changes in JAK‐STAT, mitogen‐activated protein kinase (MAPK), and AKT in cytotoxic lymphocytes, including natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), before and after dasatinib treatment in chronic myeloid leukemia patients. Among a total of 30 patients, 18 were treated with dasatinib, nine with imatinib, and three with nilotinib. At constitutive levels, the expression of phosphorylated proteins, pSTAT1, pSTAT3, and pERK in NK cells and pSTAT3 in CTLs, was significantly higher in dasatinib‐treated patients. Among the patients evaluated, only dasatinib‐treated patients showed inhibition of multiple signaling pathways after taking a tyrosine kinase inhibitor. The magnitude of pERK and pAKT inhibition was closely associated with an increase in NK cells and CTLs, respectively, after taking a tyrosine kinase inhibitor. Those responses were more evident in patients with cytomegalovirus IgG positivity. In this study, we demonstrated for the first time, the influence of dasatinib on cell events in cytotoxic lymphocytes in vivo and explained the possible underlying mechanism that results in lymphocyte mobilization after dasatinib treatment.

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“…The mechanism underlying haemorrhage can be divided into three categories: 1) excessive anticoagulant therapy, 2) type 3 or 4 allergy, and 3) cytotoxicity (15). The suggested cause of pulmonary complications induced by dasatinib, such as pleural effusion and interstitial pneumonia, is the inhibition of platelet-derived growth factor (16) and participation of large granular lymphocytes (17,18); however, the exact mechanism is unknown. KL-6 and SP-D levels were elevated in our case, possibly suggesting at least the involvement of alveolar epithelial and interstitial damage.…”

Section: Discussionmentioning

confidence: 99%

A Suspected Case of an Alveolar Haemorrhage Caused by Dasatinib

et al. 2017

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A 39-year-old man treated with dasatinib for chronic myelogenous leukaemia presented to our hospital with haemoptysis, coughing, and dyspnoea. Chest radiography and computed tomography revealed ground-glass opacities and a crazy-paving pattern. Bronchoalveolar lavage was not performed due to serious hypoxemia and bleeding. Significant bleeding from the peripheral bronchi led to a diagnosis of an alveolar haemorrhage. Dasatinib-induced alveolar haemorrhaging was suspected based on the clinical findings. His condition improved immediately after dasatinib withdrawal and initiation of steroid therapy. Reports of alveolar haemorrhaging induced by dasatinib are rare. As such, this is considered an important case.

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Large granular lymphocytosis during dasatinib therapy

Cited by 38 publications

References 63 publications

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

Direct effect of dasatinib on signal transduction pathways associated with a rapid mobilization of cytotoxic lymphocytes

A Suspected Case of an Alveolar Haemorrhage Caused by Dasatinib

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