Specific Antileukemic Activity of PD0332991, a CDK4/6 Inhibitor, against Philadelphia Chromosome–Positive Lymphoid Leukemia

Abstract The occurrence of acute bilineage leukemia is thought to be the malignant transformation of a myeloid or lymphoid leukemic progenitor with the potential to differentiate into the other lineages; however, the mechanisms of this lineage switch are not well understood. Here, we show the extremely rare case of adult Philadelphia chromosome positive acute bilineage leukemia, characterized by T-cell acute lymphoblastic leukemia, CD7+CD5+CD14−, and acute myelomonocytic leukemia, CD7−CD5−CD14+. Chromosome analysis showed 46,XY,del(7)(p11.2),t(9;22)(q34;q11.2) in all metaphase and leukemic cells expressed a minor BCR/ABL chimeric gene. When the CD5+CD14− and CD5−CD14+ cells were sorted, a fusion gene of BCR/ABL and a same clonal rearranged band of a T-cell receptor (TCR) gene were detected in both populations. Nucleotide sequencing of the TCRg gene revealed the clonal rearrangement of the V8-JGT2 complex in both populations. Over-expression of PU.1, which plays a fundamental role in myelomonocyte development was found in the sorted CD34+CD7+ and CD5−CD14+, but not CD5+CD14− cells. These results suggest that leukemic progenitor cells in the T-lineage with del(7),t(9;22) chromosome have the potential to differentiate into myeloid lineage and enforced PU.1 expression may contribute in part of this phenomenon. Studies of bilineage leukemia will be important for the understanding of lineage commitment and switch in hematopoietic cells.

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

Blood ◽

10.1182/blood.v116.21.1807.1807 ◽

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.

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BCR-ABL fusion transcript types and levels and their interaction with secondary genetic changes in determining the phenotype of Philadelphia chromosome–positive leukemias

Blood ◽

10.1182/blood-2008-04-148791 ◽

2008 ◽

Vol 112 (13) ◽

pp. 5190-5192 ◽

Cited By ~ 21

Author(s):

Dan Jones ◽

Rajyalakshmi Luthra ◽

Jorge Cortes ◽

Deborah Thomas ◽

Susan O'Brien ◽

...

Keyword(s):

De Novo ◽

Philadelphia Chromosome ◽

Fusion Transcript ◽

Kinase Domain ◽

Blast Transformation ◽

Genomic Amplification ◽

Lymphoid Leukemia ◽

Genetic Changes ◽

Or Gene ◽

Philadelphia Chromosome Positive

Abstract It remains unresolved how different BCR-ABL transcripts differentially drive lymphoid and myeloid proliferation in Philadelphia chromosome–positive (Ph+) leukemias. We compared BCR-ABL transcript type and level with kinase domain (KD) mutation status, genotype, and phenotype in 1855 Ph+ leukemias. Compared with e1a2/p190 BCR-ABL cases, de novo e13-e14a2/p210 Ph+ lymphoid leukemia more frequently showed CML-type background, had higher blast-normalized BCR-ABL transcript levels, and more frequent persistent BCR-ABL transcript in the absence of detectable lymphoblasts. Secondary lymphoid blast transformation of CML was exclusively due to e13/e14a2/p210 BCR-ABL but was associated, at a much higher level than p210 myeloid transformation, with acquisition of new KD mutations and/or Ph genomic amplification. In contrast, myeloid blast transformation was more frequently accompanied by new acquisition of acute myeloid leukemia-type chromosomal aberrations, particularly involving the EVI1 and RUNX1 loci. Therefore, higher kinase activity by mutation, transcriptional up-regulation or gene amplification appears required for lymphoid transformation by p210 BCR-ABL.

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