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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Cold Spring Harbor Laboratory Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002926/ https://www.ncbi.nlm.nih.gov/pubmed/27626069 http://dx.doi.org/10.1101/mcs.a001123 |
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author | Bochtler, Tilmann Fröhling, Stefan Weichert, Wilko Endris, Volker Thiede, Christian Hutter, Barbara Hundemer, Michael Ho, Anthony D. Krämer, Alwin |
author_facet | Bochtler, Tilmann Fröhling, Stefan Weichert, Wilko Endris, Volker Thiede, Christian Hutter, Barbara Hundemer, Michael Ho, Anthony D. Krämer, Alwin |
author_sort | Bochtler, Tilmann |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5002926 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-50029262016-09-13 Evolution of a FLT3-TKD mutated subclone at meningeal relapse in acute promyelocytic leukemia Bochtler, Tilmann Fröhling, Stefan Weichert, Wilko Endris, Volker Thiede, Christian Hutter, Barbara Hundemer, Michael Ho, Anthony D. Krämer, Alwin Cold Spring Harb Mol Case Stud Research Report 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. Cold Spring Harbor Laboratory Press 2016-09 /pmc/articles/PMC5002926/ /pubmed/27626069 http://dx.doi.org/10.1101/mcs.a001123 Text en © 2016 Bochtler et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited. |
spellingShingle | Research Report Bochtler, Tilmann Fröhling, Stefan Weichert, Wilko Endris, Volker Thiede, Christian Hutter, Barbara Hundemer, Michael Ho, Anthony D. Krämer, Alwin Evolution of a FLT3-TKD mutated subclone at meningeal relapse in acute promyelocytic leukemia |
title | Evolution of a FLT3-TKD mutated subclone at meningeal relapse in acute promyelocytic leukemia |
title_full | Evolution of a FLT3-TKD mutated subclone at meningeal relapse in acute promyelocytic leukemia |
title_fullStr | Evolution of a FLT3-TKD mutated subclone at meningeal relapse in acute promyelocytic leukemia |
title_full_unstemmed | Evolution of a FLT3-TKD mutated subclone at meningeal relapse in acute promyelocytic leukemia |
title_short | Evolution of a FLT3-TKD mutated subclone at meningeal relapse in acute promyelocytic leukemia |
title_sort | evolution of a flt3-tkd mutated subclone at meningeal relapse in acute promyelocytic leukemia |
topic | Research Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002926/ https://www.ncbi.nlm.nih.gov/pubmed/27626069 http://dx.doi.org/10.1101/mcs.a001123 |
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