Details

Autor(en) / Beteiligte

• Gallagher, Robert E.
• Moser, Barry K.
• Racevskis, Janis
• Poiré, Xavier
• Bloomfield, Clara D.
• Carroll, Andrew J.
• Ketterling, Rhett P.
• Roulston, Diane
• Schachter-Tokarz, Esther
• Zhou, Da-cheng
• Chen, I-Ming L.
• Harvey, Richard
• Koval, Greg
• Sher, Dorie A.
• Feusner, James H.
• Tallman, Martin S.
• Larson, Richard A.
• Powell, Bayard L.
• Appelbaum, Frederick R.
• Paietta, Elisabeth
• Willman, Cheryl L.
• Stock, Wendy

Titel

Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia

Ist Teil von

• Blood, 2012-09, Vol.120 (10), p.2098-2108

Ort / Verlag

Washington, DC: Elsevier Inc

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• Mutations in the all-trans retinoic acid (ATRA)–targeted ligand binding domain of PML-RARα (PRα/LBD+) have been implicated in the passive selection of ATRA-resistant acute promyelocytic leukemia clones leading to disease relapse. Among 45 relapse patients from the ATRA/chemotherapy arm of intergroup protocol C9710, 18 patients harbored PRα/LBD+ (40%), 7 of whom (39%) relapsed Off-ATRA selection pressure, suggesting a possible active role of PRα/LBD+. Of 41 relapse patients coanalyzed, 15 (37%) had FMS-related tyrosine kinase 3 internal tandem duplication mutations (FLT3-ITD+), which were differentially associated with PRα/LBD+ depending on ATRA treatment status at relapse: positively, On-ATRA; negatively, Off-ATRA. Thirteen of 21 patients (62%) had additional chromosome abnormalities (ACAs); all coanalyzed PRα/LBD mutant patients who relapsed off-ATRA (n = 5) had associated ACA. After relapse Off-ATRA, ACA and FLT3-ITD+ were negatively associated and were oppositely associated with presenting white blood count and PML-RARα type: ACA, low, L-isoform; FLT3-ITD+, high, S-isoform. These exploratory results suggest that differing PRα/LBD+ activities may interact with FLT3-ITD+ or ACA, that FLT3-ITD+ and ACA are associated with different intrinsic disease progression pathways manifest at relapse Off-ATRA, and that these different pathways may be short-circuited by ATRA-selectable defects at relapse On-ATRA. ACA and certain PRα/LBD+ were also associated with reduced postrelapse survival.