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

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

Abstract

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 (APL) clones leading to disease relapse. Among 45 relapse patients from the ATRA/chemotherapy(CT)-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 co-analyzed, 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 (ACA); all co-analyzed 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 post-relapse survival.

  • Submitted January 30, 2012.
  • Accepted June 12, 2012.