Evolution of a FLT3-TKD mutated subclone at meningeal relapse in acute promyelocytic leukemia.
Here, we report the case of an acute promyelocytic leukemia (APL) patient who-although negative for FLT3 mutations at diagnosis-developed isolated FLT3 tyrosine kinase II domain (FLT3-TKD)-positive meningeal relapse, which, in retrospect, could be traced back to a minute bone marrow subclone present at first diagnosis. Initially, the 48-yr-old female diagnosed with high-risk APL had achieved complete molecular remission after standard treatment with all-trans retinoic acid (ATRA) and chemotherapy according to the AIDA (ATRA plus idarubicin) protocol. Thirteen months after the start of ATRA maintenance, the patient suffered clinically overt meningeal relapse along with minute molecular traces of PML/RARA (promyelocytic leukemia/retinoic acid receptor alpha) in the bone marrow. Following treatment with arsenic trioxide and ATRA in combination with intrathecal cytarabine and methotrexate, the patient achieved a complete molecular remission in both cerebrospinal fluid (CSF) and bone marrow, which currently lasts for 2 yr after completion of therapy. Whole-exome sequencing and subsequent ultradeep targeted resequencing revealed a heterozygous FLT3-TKD mutation in CSF leukemic cells (p.D835Y, c.2503G>T, 1000/1961 reads [51%]), which was undetectable in the concurrent bone marrow sample. Interestingly, the FLT3-TKD mutated meningeal clone originated from a small bone marrow subclone present in a variant allele frequency of 0.4% (6/1553 reads) at initial diagnosis. This case highlights the concept of clonal evolution with a subclone harboring an additional mutation being selected as the "fittest" and leading to meningeal relapse. It also further supports earlier suggestions that FLT3 mutations may play a role for migration and clonal expansion in the CSF sanctuary site.
Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany;; Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany;
Tilmann
T
Bochtler
Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;; Section for Personalized Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany;; DKFZ-Heidelberg Center for Personalized Oncology (HIPO), 69120 Heidelberg, Germany;
Stefan
S
Fröhling
Institute of Pathology, Technical University of Munich, 81675 Munich, Germany;; Institute of Pathology, University of Heidelberg, 69120 Heidelberg, Germany;
Wilko
W
Weichert
Institute of Pathology, University of Heidelberg, 69120 Heidelberg, Germany;
Volker
V
Endris
Department of Internal Medicine I, University of Dresden, 01307 Dresden, Germany;
Christian
C
Thiede
Division of Applied Bioinformatics, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Barbara
B
Hutter
Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany;
Michael
M
Hundemer
Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany;
Anthony D
AD
Ho
Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany;; Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany;
Alwin
A
Krämer
leukemia