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Ibrutinib is not an effective drug in primografts of TCF3-PBX1.

Abstract：

AIM:The Bruton's tyrosine kinase (BTK) inhibitor Ibrutinib (PCI-32765) is effective in patients with multiple myeloma, non-Hodgkin lymphoma and chronic lymphoblastic leukemia. We previously showed that primary cells of children with TCF3-PBX1 positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL) express BTK and are sensitive to ibrutinib in vitro. However, preclinical studies in mice are lacking that justify clinical implementation. METHODS:Immunocompromised NSG mice were engrafted with a luciferase-positive TCF3-PBX1 leukemic cell line or primary leukemic cells and treated with ibrutinib or placebo. Additionally, primary cells were exposed in vitro to 4 main induction drugs as monotherapy and in combination with ibrutinib. RESULTS:Treatment with ibrutinib of mice engrafted with a TCF3-PBX1 cell line, TCF3-PBX1 positive or TCF3-PBX1 negative primary leukemic cells did not result in prolonged life span compared to placebo treated mice. In vitro sensitivity to ibrutinib was unaltered in leukemic cells obtained from engrafted mice compared to the original material. However, ibrutinib treatment did not affect leukemic cell viability and tumor outgrowth, nor could lymphocytosis be detected. Ibrutinib was biologically active, since hCD19+ cells harvested from ibrutinib treated mice had no detectable levels of phospho-BTK at tyrosine 223 (pBTK Y223), whereas pBTK Y223 was still detectable in placebo treated cases. In combination tests, we noticed an antagonistic effect of ibrutinib on vincristine sensitivity, which was not observed for prednisolone, L-asparaginase and daunorubicin. CONCLUSIONS:We conclude that ibrutinib is not the precision medicine of choice for TCF3-PBX1 positive BCP-ALL.

journal_name

Transl Oncol

journal_title

Translational oncology

authors

van de Ven C,Boeree A,Stalpers F,Zwaan CM,Den Boer ML

doi

10.1016/j.tranon.2020.100817

subject

Has Abstract

pub_date

2020-10-01 00:00:00

pages

100817

issue

10

issn

1936-5233

pii

S1936-5233(20)30309-0

journal_volume

13

pub_type

杂志文章

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