Pleural Effusion in Patients With Chronic Myelogenous Leukemia Treated With Dasatinib After Imatinib Failure

Quintás‐Cardama, Alfonso; Kantarjian, Hagop M.; O’Brien, Susan; Borthakur, G.; Bruzzi, John F.; Munden, Reginald F.; Cortes, Jorge

doi:10.1200/jco.2007.12.0329

Cited by 355 publications

(383 citation statements)

References 31 publications

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“…17 Interestingly, recent studies have suggested that dasatinib induced pleural effusions may be immune mediated. [18][19][20] These observations are concordant with our results, as almost all our patients with LGL proliferation had pleural effusions or pneumonitis. Analysis of lymphocytes from pleural fluid showed a similar phenotype (CD3 þ CD8 þ CD57 þ ) and genotype (identical T-cell clone) as simultaneously observed in peripheral blood.…”

Section: Discussionsupporting

confidence: 92%

Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy

et al. 2009

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Dasatinib, a broad-spectrum tyrosine kinase inhibitor (TKI), predominantly targets BCR-ABL and SRC oncoproteins and also inhibits off-target kinases, which may result in unexpected drug responses. We identified 22 patients with marked lymphoproliferation in blood while on dasatinib therapy. Clonality and immunophenotype were analyzed and related clinical information was collected. An abrupt lymphocytosis (peak count range 4-20 Â 10 9 /l) with large granular lymphocyte (LGL) morphology was observed after a median of 3 months from the start of therapy and it persisted throughout the therapy. Fifteen patients had a cytotoxic T-cell and seven patients had an NK-cell phenotype. All T-cell expansions were clonal. Adverse effects, such as colitis and pleuritis, were common (18 of 22 patients) and were preceded by LGL lymphocytosis. Accumulation of identical cytotoxic T cells was also detected in pleural effusion and colon biopsy samples. Responses to dasatinib were good and included complete, unexpectedly long-lasting remissions in patients with advanced leukemia. In a phase II clinical study on 46 Philadelphia chromosome-positive acute lymphoblastic leukemia, patients with lymphocytosis had superior survival compared with patients without lymphocytosis. By inhibiting immunoregulatory kinases, dasatinib may induce a reversible state of aberrant immune reactivity associated with good clinical responses and a distinct adverse effect profile.

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Section: Discussionsupporting

confidence: 92%

Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy

et al. 2009

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“…28,32 The use of high concentrations raises the concern of drug toxicity, as pleural effusion is a welldocumented side effect of dasatinib. 33 In the current study, we define sensitivity as IC 50 less than 128 nM. Using this criterion, five cell lines including LY1, LY7, LY8, LY10 and VAL are considered sensitive.…”

Section: Discussionmentioning

confidence: 99%

Tyrosine kinase inhibition in diffuse large B-cell lymphoma: molecular basis for antitumor activity and drug resistance of dasatinib

et al. 2008

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Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Although some patients can be cured by current therapies, novel agents are needed to further improve outcomes. We hypothesized that Src tyrosine kinase inhibition by dasatinib may have antilymphoma effects. Here, we demonstrate that dasatinib inhibits cell growth through G 1 -S blockage in five of seven DLBCL cell lines at clinically achievable concentrations. Compared to resting B cells, DLBCL has increased tyrosine phosphorylation activities. As expected, dasatinib inhibits phosphorylation of several Src family kinase members. However, this inhibition occurs in all cell lines regardless of their proliferative response to the drug. In contrast, the activity of two downstream signaling molecules, Syk and phospholipase Cc2 (PLCc2), are well correlated with cell line sensitivity to dasatinib, suggesting that these molecules are crucial in mediating the proliferation of activated lymphoma cells. Furthermore, dasatinib inhibits B-cell receptor signaling in primary lymphoma cells. Together, our findings not only show dasatinib as a potentially useful therapy for DLBCL but also provide insights into the pathogenesis of the lymphoma. The results further suggest the possibility of using Syk and PLCc2 as biomarkers to predict dasatinib therapeutic response in prospective clinical trials.

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“…1,2 Most recently, an increase in the right ventricular systolic pressure, a non invasive surrogate marker of PAP, was detected at the onset of PE in a subset of CML patients treated with dasatinib, suggesting the possibility of drugrelated PAH and subsequent subclinical heart failure. 3 Notably, the left ventricular ejection fraction remained unchanged in all patients at the time of PE. Discontinuation of dasatinib resulted in resolution of PE and a significant decrease in the right ventricular systolic pressure.…”

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confidence: 87%

Reversible dasatinib-induced pulmonary arterial hypertension and right ventricle failure in a previously allografted CML patient

Mattei

Feola

Orzan

et al. 2008

Bone Marrow Transplant

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Pleural Effusion in Patients With Chronic Myelogenous Leukemia Treated With Dasatinib After Imatinib Failure

Abstract: Pleural effusions occur during dasatinib therapy, particularly among patients in AP or BP. A twice-daily schedule may result in a higher incidence of pleural effusion. Close monitoring and timely intervention may allow patients to continue therapy and achieve the desired clinical benefit.

Cited by 355 publications

References 31 publications

Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy

Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy

Tyrosine kinase inhibition in diffuse large B-cell lymphoma: molecular basis for antitumor activity and drug resistance of dasatinib

Reversible dasatinib-induced pulmonary arterial hypertension and right ventricle failure in a previously allografted CML patient

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