Severe Hemorrhagic Colitis Caused by Dasatinib in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Shimokaze, Tomoyuki; Mitsui, Tetsuo; Takeda, Hiroaki; Kawakami, Takako; Arai, Takehiro; Ito, Masafumi; Iwaba, Akiko; Izumino, Hiroko; Takahashi, Noriyuki; Kanno, Miyako; Sendo, Dai; Hayasaka, Kiyoshi

doi:10.1080/08880010903071295

Cited by 6 publications

(8 citation statements)

References 18 publications

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“…Until recently, the only evidence implicating a role for Lyn in intestinal disease had been clinical studies showing colitis as a side effect in cancer patients treated with the broad-spectrum tyrosine kinase inhibitor dasatinib (36)(37)(38). Although Dasatinib may affect a number of distinct tyrosine kinase families, including SFKs, of which Lyn is a member, these results nevertheless suggest a protective role for tyrosine kinase signaling pathways in the gut.…”

Section: Discussionmentioning

confidence: 81%

Lyn Deficiency Leads to Increased Microbiota-Dependent Intestinal Inflammation and Susceptibility to Enteric Pathogens

Roberts

Bishop

Fan

et al. 2014

The Journal of Immunology

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The Lyn tyrosine kinase governs the development and function of various immune cells, and its dysregulation has been linked to malignancy and autoimmunity. Using models of chemically induced colitis and enteric infection, we show that Lyn plays a critical role in regulating the intestinal microbiota and inflammatory responses as well as protection from enteric pathogens. Lyn−/− mice were highly susceptible to dextran sulfate sodium (DSS) colitis, characterized by significant wasting, rectal bleeding, colonic pathology, and enhanced barrier permeability. Increased DSS susceptibility in Lyn−/− mice required the presence of T but not B cells and correlated with dysbiosis and increased IFN-γ+ and/or IL-17+ colonic T cells. This dysbiosis was characterized by an expansion of segmented filamentous bacteria, associated with altered intestinal production of IL-22 and IgA, and was transmissible to wild-type mice, resulting in increased susceptibility to DSS. Lyn deficiency also resulted in an inability to control infection by the enteric pathogens Salmonella enterica serovar Typhimurium and Citrobacter rodentium. Lyn−/− mice exhibited profound cecal inflammation, bacterial dissemination, and morbidity following S. Typhimurium challenge and greater colonic inflammation throughout the course of C. rodentium infection. These results identify Lyn as a key regulator of the mucosal immune system, governing pathophysiology in multiple models of intestinal disease.

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Section: Discussionmentioning

confidence: 81%

Lyn Deficiency Leads to Increased Microbiota-Dependent Intestinal Inflammation and Susceptibility to Enteric Pathogens

Roberts

Bishop

Fan

et al. 2014

The Journal of Immunology

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“…By removing regulatory immunity while enhancing specific Type-1 T effector cell function using DAS, one may potentially promote autoimmune pathological responses (colitis, diabetes mellitus, rheumatoid arthritis, among others) as previously observed in clinical trials evaluating immunotherapeutic antibodies such as those targeting cytotoxic T-lymphocyte antigen 4 (CTLA4) or programmed cell death 1 (PD-1) 44 , 45 . Although there have been rare case reports of DAS-associated colitis in the setting of leukemia, 46 , 47 in extensive clinical trials so far DAS appears to be a reasonably well-tolerated agent for the treatment of solid tumors, including melanoma 17 , 48 . Indeed, to date, we have not observed any evidence of autoimmune pathology (including vitiligo) in our M05 murine melanoma model.…”

Section: Discussionmentioning

confidence: 99%

Dasatinib promotes the expansion of a therapeutically superior T-cell repertoire in response to dendritic cell vaccination against melanoma

et al. 2014

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Dasatinib (DAS) is a potent inhibitor of the BCR-ABL, SRC, c-KIT, PDGFR, and ephrin tyrosine kinases that has demonstrated only modest clinical efficacy in melanoma patients. Given reports suggesting that DAS enhances T cell infiltration into the tumor microenvironment, we analyzed whether therapy employing the combination of DAS plus dendritic cell (DC) vaccination would promote superior immunotherapeutic benefit against melanoma. Using a M05 (B16.OVA) melanoma mouse model, we observed that a 7-day course of orally-administered DAS (0.1 mg/day) combined with a DC-based vaccine (VAC) against the OVA257–264 peptide epitope more potently inhibited tumor growth and extended overall survival as compared with treatment with either single modality. The superior efficacy of the combinatorial treatment regimen included a reduction in hypoxic-signaling associated with reduced levels of immunosuppressive CD11b+Gr1+ myeloid-derived suppressor cells (MDSC) and CD4+Foxp3+ regulatory T (Treg) populations in the melanoma microenvironment. Furthermore, DAS + VAC combined therapy upregulated expression of Type-1 T cell recruiting CXCR3 ligand chemokines in the tumor stroma correlating with activation and recruitment of Type-1, vaccine-induced CXCR3+CD8+ tumor-infiltrating lymphocytes (TILs) and CD11c+ DC into the tumor microenvironment. The culmination of this bimodal approach was a profound “spreading” in the repertoire of tumor-associated antigens recognized by CD8+ TILs, in support of the therapeutic superiority of combined DAS + VAC immunotherapy in the melanoma setting.

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“…Therefore, its sequential clinical course is important for diagnosis that shows the occurrence of the symptoms after the drug administration, the recovery after the drug discontinuation and the recurrence after the drug re-administration. The occurrence of dasatinibinduced hemorrhagic colitis has been reported to be extremely rare worldwide [5][6][7]. This is likely to be due to the nondefinite establishment of the diagnostic criteria for it and to its low prevalence.…”

Section: Discussionmentioning

confidence: 99%

“…The possible adverse effects include hematologic toxicity such as thrombocytopenia and neutropenia as well as nonhematologic toxicity such as diarrhea, pleural effusion and gastrointestinal bleeding [2][3][4]. However, dasatinib-induced hemorrhagic colitis has been rarely reported worldwide [5][6][7] and none has been reported in Korea. The authors encountered dasatinib-induced hemorrhagic colitis in a CML patient who clinically resisted imatinib.…”

Section: Introductionmentioning

confidence: 99%

A Case of Dasatinib-Induced Hemorrhagic Colitis Diagnosed by the Lymphocyte Transformation Test in a Chronic Myeloid Leukemia Patient

Ahn

Kwon

Sohn

et al. 2015

Indian J Hematol Blood Transfus

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Dasatinib is an effective treatment option for patients diagnosed with Philadelphia chromosome positive chronic myeloid leukemia and who are non-responsive or intolerant to imatinib treatment. Dasatinib, however, is associated with various adverse effects and on rare occasions, may cause hemorrhagic colitis. We report the case of a 68-year-old male patient with dasatinib-induced hemorrhagic colitis, the first such case in Korea. Endoscopic biopsy of the transverse colon demonstrated non-specific inflammatory changes only. Cessation of dasatinib led to the resolution of symptoms, while reintroduction of the therapy led to the recurrence of his bloody diarrhea. To clarify the association between dasatinib and hemorrhagic colitis, the lymphocyte transformation test (LTT) was performed. The LTT result sustained a relatively high proliferation activity in the affected patient compared with almost no proliferation activity in normal control.

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Severe Hemorrhagic Colitis Caused by Dasatinib in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Cited by 6 publications

References 18 publications

Lyn Deficiency Leads to Increased Microbiota-Dependent Intestinal Inflammation and Susceptibility to Enteric Pathogens

Lyn Deficiency Leads to Increased Microbiota-Dependent Intestinal Inflammation and Susceptibility to Enteric Pathogens

Dasatinib promotes the expansion of a therapeutically superior T-cell repertoire in response to dendritic cell vaccination against melanoma

A Case of Dasatinib-Induced Hemorrhagic Colitis Diagnosed by the Lymphocyte Transformation Test in a Chronic Myeloid Leukemia Patient

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