Evolution of a FLT3-TKD mutated subclone at meningeal relapse in acute promyelocytic leukemia.
Evolution of a FLT3-TKD mutated subclone at meningeal relapse in acute promyelocytic leukemia.
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DOI：
10.1101/mcs.a001123
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发表时间：
2016-09
影响因子：
1.8
通讯作者：
Krämer A
中科院分区：
文献类型：
--
作者：
Bochtler T;Fröhling S;Weichert W;Endris V;Thiede C;Hutter B;Hundemer M;Ho AD;Krämer A
在这里，我们报告了一名急性早幼粒细胞白血病 (APL) 患者的病例，尽管诊断时 FLT3 突变呈阴性，但出现了孤立的 FLT3 酪氨酸激酶 II 结构域 (FLT3-TKD) 阳性脑膜复发，回想起来，这可以追溯到首次诊断时存在的微小骨髓亚克隆。最初，这位被诊断为高危 APL 的 48 岁女性，经过全反式维甲酸 (ATRA) 标准治疗和 AIDA（ATRA 加伊达比星）方案化疗后，获得了完全分子缓解。开始 ATRA 维持治疗 13 个月后，患者出现临床上明显的脑膜复发，并伴有骨髓中 PML/RARA（早幼粒细胞白血病/视黄酸受体 α）的微小分子痕迹。在接受三氧化二砷和 ATRA 联合鞘内注射阿糖胞苷和甲氨蝶呤治疗后，患者的脑脊液 (CSF) 和骨髓均达到完全分子缓解，目前这种缓解在治疗完成后可持续 2 年。全外显子组测序和随后的超深靶向重测序揭示了 CSF 白血病细胞中的杂合 FLT3-TKD 突变（p.D835Y，c.2503G>T，1000/1961 读数 [51%]），该突变在同时骨髓样本中无法检测到。有趣的是，FLT3-TKD 突变脑膜克隆起源于初始诊断时变异等位基因频率为 0.4%（6/1553 个读数）的小型骨髓亚克隆。该病例强调了克隆进化的概念，带有额外突变的亚克隆被选为“最适者”并导致脑膜复发。它还进一步支持了早期的建议，即 FLT3 突变可能在 CSF 避难所位点的迁移和克隆扩张中发挥作用。
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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影响因子：
6.5
作者：
Arrigoni, P;Beretta, C;Biondi, A
通讯作者：
Biondi, A
影响因子：
20.3
作者：
Lo-Coco, Francesco;Avvisati, Giuseppe;Mandelli, Franco
通讯作者：
Mandelli, Franco
影响因子：
11.4
作者：
Kordes, M.;Roering, M.;Froehling, S.
通讯作者：
Froehling, S.
影响因子：
11.4
作者：
Callens, C;Chevret, S;Dombret, H
通讯作者：
Dombret, H
DOI：
10.3324/haematol.2009.015073
发表时间：
2010-05-01
期刊：
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
影响因子：
--
作者：
Carmen Chillon, Maria;Santamaria, Carlos;Gonzalez, Marcos
通讯作者：
Gonzalez, Marcos