scholarly journals Ponatinib therapy in recurrent Philadelphia chromosome‐positive central nervous system leukemia with T315I mutation after Allo‐HSCT

2019 ◽  
Vol 147 (4) ◽  
pp. 1071-1077
Author(s):  
Jia‐Bao He ◽  
Xin Zhang ◽  
Zi‐Wen Guo ◽  
Miao‐Miao Liu ◽  
Na Xu ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Philadelphia Chromosome ◽  
T315i Mutation ◽  
Central Nervous System Leukemia ◽  
Philadelphia Chromosome Positive

Remission of Philadelphia chromosome-positive central nervous system leukemia after dasatinib therapy

2007 ◽  
Vol 48 (5) ◽  
pp. 1053-1056 ◽  
Author(s):  
Ahmed Abdelhalim ◽  
Maurice Barcos ◽  
Annemarie W. Block ◽  
Sheila N. J. Sait ◽  
Petr Starostik ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Philadelphia Chromosome ◽  
Central Nervous System Leukemia ◽  
Philadelphia Chromosome Positive

Dasatinib Cerebrospinal Fluid Concentration and Plasma Pharmacokinetics: Potential for Central Nervous System Prophylaxis In Philadelphia Chromosome-Positive Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1807-1807
Author(s):  
Naoto Takahashi ◽  
Masatomo Miura ◽  
Stuart Scott ◽  
Hirobumi Saitoh ◽  
Mutsuhito Motegi ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Conflicts Of Interest ◽  
Philadelphia Chromosome ◽  
T Test ◽  
Lymphoid Leukemia ◽  
Csf Levels ◽  
Philadelphia Chromosome Positive

Abstract Abstract 1807 Dasatinib (DA) is approved for use in imatinib-resistant or intolerant chronic myeloid leukemia (CML)/Philadelphia-positive acute lymphoid leukemia (Ph+ALL) and may also be useful for central nervous system (CNS) leukemia accompanied with CML/Ph+ALL; however, little is known about the relationship between DA pharmacokinetics and its ability to penetrate the blood-brain barrier. Consequently, we measured DA plasma and cerebrospinal fluid (CSF) levels by high-performance liquid chromatography in 20 samples obtained from 11 DA-treated patients (seven Ph+ALL and four lymphoid crisis CML). DA was detected in 10 CSF samples from five patients who were treated with 100 mg QD of DA (CSF C4h of detectable group; 3.526±2.604 ng/mL, 1.11–7.95 ng/mL), which was above the IC50 level for wild type BCR-ABL positive leukemia cells in vitro (0.8 nM = 0.39 ng/mL). However, DA was not detected in 10 CSF samples from 7 patients (CSF C4h of non-detectable group; <1.0 ng/mL). The concentration ratio of CSF to plasma was 3.90% (0.42-12.23%), which approached previously reported ratios for imatinib. There were significant differences in the AUC0-4 and the plasma C4h between the CSF detectable (D) and non-detectable (ND) patients (AUC0-4: 268.29±92.452 vs. 90.83±76.45, P=0.00019 by Student t-test, Figure 1; plasma C4h: 126.15±62.58 vs. 47.41±50.935, P=0.00637 by Student t-test). Moreover, there were significant correlations between CSF C4h and AUC0-4 (P<0.01, Figure 2) and between CSF C4h and plasma C2h (P<0.001), together suggesting that penetration of DA into the CSF may depend on DA plasma concentration. To investigate any influence of pharmacogenetic variation on CSF penetration, single nucleotide polymorphisms in genes involved in DA pharmacokinetics and transport (ABCB1, ABCG2, SLC22A1, SLC22A3, and CYP3A4/5) were interrogated; however, no significant correlation between CSF levels and genotype were observed. DA has a 325 fold greater potency than imatinib for inhibiting BCR-ABL tyrosine kinase, which undoubtedly influences the efficacy of DA for Philadelphia-chromosome positive CNS leukemia; however, our data suggest that clinical DA blood level monitoring may help estimate the penetration of DA to the CSF. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome–positive leukemia

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1005-1012 ◽  
Author(s):  
Kimmo Porkka ◽  
Perttu Koskenvesa ◽  
Tuija Lundán ◽  
Johanna Rimpiläinen ◽  
Satu Mustjoki ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Brain Barrier ◽  
Clinical Activity ◽  
Cns Relapse ◽  
Blood Brain ◽  
Philadelphia Chromosome Positive

Abstract Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome–positive (Ph+) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasa-tinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a preclinical mouse model of intracranial Ph+ leukemia. Clinical dasatinib treatment in patients with CNS Ph+ leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasa-tinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph+ leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL–mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials.gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097).

Systemic dasatinib fails to prevent development of central nervous system progression in a patient with BCR-ABL unmutated Philadelphia chromosome–positive leukemia

Blood ◽  
2009 ◽  
Vol 113 (20) ◽  
pp. 5028-5029 ◽  
Author(s):  
Ferdinando Frigeri ◽  
Manuela Arcamone ◽  
Luigia Luciano ◽  
Raffaele Di Francia ◽  
Fabrizio Pane ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Philadelphia Chromosome ◽  
Philadelphia Chromosome Positive
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