Reference Detail

Ref Type

Journal Article

PMID

(27626069)

Authors

Bochtler T, Fröhling S, Weichert W, Endris V, Thiede C, Hutter B, Hundemer M, Ho AD, Krämer A

Title

Evolution of a FLT3-TKD mutated subclone at meningeal relapse in acute promyelocytic leukemia.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cold Spring Harbor molecular case studies	2	5	2016 Sep	a001123	Cold Spring Harb Mol Case Stud

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 D835Y	acute promyelocytic leukemia	predicted - resistant	Tretinoin	Case Reports/Case Series	Actionable	In a clinical case study, a patient with acute promyelocytic leukemia developed meningeal relapse after maintenance therapy with Vesanoid (tretinoin), which was found to be due to a FLT3 D835Y variant (PMID: 27626069).	27626069
FLT3 D835Y	acute promyelocytic leukemia	predicted - sensitive	Arsenic trioxide + Cytarabine + Methotrexate + Tretinoin	Case Reports/Case Series	Actionable	In a clinical case study, a patient with acute promyelocytic leukemia harboring FLT3 D835Y demonstrated a complete molecular remission after treatment with Trisenox (arsenic trioxide) and Vesanoid (tretinoin) combined with Cytosar-U (cytarabine) and Methotrexate (PMID: 27626069).	27626069