Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome–positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study

Ottmann, Oliver G.; Dombret, Hervé; Martinelli, Giovanni; Simonsson, Bengt; Guilhot, Joëlle; Larson, Richard A.; Rege‐Cambrin, Giovanna; Radich, Jerald P.; Hochhaus, Andreas; Apanovitch, Anne Marie; Gollerkeri, Ashwin; Coutre, Steven

doi:10.1182/blood-2007-02-073528

Cited by 341 publications

(243 citation statements)

References 36 publications

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“…No clonal LGL proliferation has been reported in the literature with colitis or pleuritis caused by other factors. Furthermore, the prevalence of grade III-IV diarrhea has been reported to be much lower (8%) in dasatinib clinical studies 17 and none of our eight control patients without LGL lymphocytosis during dasatinib treatment encountered colitis or pleuritis. This suggests that the adverse effects were causally related to LGL lymphoproliferation by virtue of autoimmune reactivity of the expanded cytotoxic LGL cells.…”

Section: Discussionmentioning

confidence: 99%

“…16 Pleural effusion is a common dasatinib-related adverse-effect, particularly in patients with advanced disease in whom incidence up to 20% has been reported. 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.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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“…5 Nilotinib monotherapy exhibits clinical activity in patients with relapsed/refractory Ph þ ALL with 26% achieving complete hematologic response (median treatment duration 1.8 months) 6 while 31% achieved complete hematologic response with dasatinib (follow-up 6 months). 7 A 36-year-old woman with Ph þ ALL, who was M-BCR-and m-BCR-positive and karyotype 46, XX, t(9;22) in 20/20 (100%) of metaphases analyzed without additional anomalies, received induction therapy according to the HyperCVAD regimen (hyperfractionated CY, VCR, doxorubicin and dexamethasone) in combination with imatinib mesylate 400 mg twice daily (BID). 2 The hematologic and clinical outcome is described in Table 1.…”

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confidence: 99%

Nilotinib restores long-term full-donor chimerism in Ph-positive acute lymphoblastic leukemia relapsed after allogeneic transplantation

Merante

Colombo

Calatroni

et al. 2009

Bone Marrow Transplant

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“…Second-generation TKIs have demonstrated increased inhibitory potency against BCR-ABL tyrosine kinase and have shown efficacy in treating patients with number of the BCR-ABL kinase domain mutations that develop on imatinib (Kantarjian et al, 2006(Kantarjian et al, , 2007Ottmann et al, 2007). Despite the significant clinical activity demonstrated in clinical trials, a number of patients do not show durable response (Garg et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Combined effects of novel heat shock protein 90 inhibitor NVP-AUY922 and nilotinib in a random mutagenesis screen

et al. 2011

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To overcome imatinib resistance, more potent ABL tyrosine kinase inhibitors (TKIs), such as nilotinib and dasatinib have been developed, with demonstrable preclinical activity against most imatinib-resistant BCR-ABL kinase domain mutations, with the exception of T315I. However, imatinib-resistant patients already harboring mutations have a higher likelihood of developing further mutations under the selective pressure of potent ABL TKIs. NVP-AUY922 (Novartis) is a novel 4,5-diaryloxazole adenosine triphosphate-binding site heat shock protein 90 (HSP90) inhibitor, which has been shown to inhibit the chaperone function of HSP90 and deplete the levels of HSP90 client protein including BCR-ABL. In this study, we investigated the combined effects of AUY922 and nilotinib on random mutagenesis for BCR-ABL mutation (Blood, 109; 5011, 2007). Compared with single agents, combination with AUY922 and nilotinib was more effective at reducing the outgrowth of resistant cell clones. No outgrowth was observed in the presence of 2 lM of nilotinib and 20 nM of AUY922. The observed data from the isobologram indicated the synergistic effect of simultaneous exposure to AUY922 and nilotinib even in BaF3 cells expressing BCR-ABL mutants including T315I. In vivo studies also demonstrated that the combination of AUY922 and nilotinib prolonged the survival of mice transplanted with mixture of BaF3 cells expressing wild-type BCR-ABL and mutant forms. Taken together, this study shows that the combination of AUY922 and nilotinib exhibits a desirable therapeutic index that can reduce the in vivo growth of mutant forms of BCR-ABL-expressing cells.

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Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome–positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study

Cited by 341 publications

References 36 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

Nilotinib restores long-term full-donor chimerism in Ph-positive acute lymphoblastic leukemia relapsed after allogeneic transplantation

Combined effects of novel heat shock protein 90 inhibitor NVP-AUY922 and nilotinib in a random mutagenesis screen

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