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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 Cold Spring Harbor molecular case studies
Vol 2
Issue 5
Date 2016 Sep
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 - 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
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 (tretinoid), which was found to be due to a FLT3 D835Y variant (PMID: 27626069). 27626069