Abstract:
:For most children who relapse with acute lymphoblastic leukemia (ALL), the prognosis is poor, and there is a need for novel therapies to improve outcome. We screened samples from children with B-lineage ALL entered into the ALL-REZ BFM 2002 clinical trial (www.clinicaltrials.gov, #NCT00114348) for somatic mutations activating the Ras pathway (KRAS, NRAS, FLT3, and PTPN11) and showed mutation to be highly prevalent (76 from 206). Clinically, they were associated with high-risk features including early relapse, central nervous system (CNS) involvement, and specifically for NRAS/KRAS mutations, chemoresistance. KRAS mutations were associated with a reduced overall survival. Mutation screening of the matched diagnostic samples found many to be wild type (WT); however, by using more sensitive allelic-specific assays, low-level mutated subpopulations were found in many cases, suggesting that they survived up-front therapy and subsequently emerged at relapse. Preclinical evaluation of the mitogen-activated protein kinase kinase 1/2 inhibitor selumetinib (AZD6244, ARRY-142886) showed significant differential sensitivity in Ras pathway-mutated ALL compared with WT cells both in vitro and in an orthotopic xenograft model engrafted with primary ALL; in the latter, reduced RAS-mutated CNS leukemia. Given these data, clinical evaluation of selumetinib may be warranted for Ras pathway-mutated relapsed ALL.
journal_name
Bloodjournal_title
Bloodauthors
Irving J,Matheson E,Minto L,Blair H,Case M,Halsey C,Swidenbank I,Ponthan F,Kirschner-Schwabe R,Groeneveld-Krentz S,Hof J,Allan J,Harrison C,Vormoor J,von Stackelberg A,Eckert Cdoi
10.1182/blood-2014-04-531871subject
Has Abstractpub_date
2014-11-27 00:00:00pages
3420-30issue
23eissn
0006-4971issn
1528-0020pii
blood-2014-04-531871journal_volume
124pub_type
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