Azacitidine effectively reduces TP53-mutant leukemic cell burden in secondary acute myeloid leukemia after cord blood transplantation
Azacitidine effectively reduces TP53-mutant leukemic cell burden in secondary acute myeloid leukemia after cord blood transplantation
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阿扎胞苷有效降低脐带血移植后继发性急性髓系白血病的TP53突变白血病细胞负荷
DOI：
10.1080/10428194.2018.1443335
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发表时间：
2018
影响因子：
2.6
通讯作者：
Tojo Arinobu
中科院分区：
文献类型：
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作者：
Takei Tomomi;Yokoyama Kazuaki;Shimizu Eigo;Konuma Takaaki;Takahashi Satoshi;Yamaguchi Rui;Imoto Seiya;Miyano Satoru;Tojo Arinobu
同种异体干细胞移植（alloc - sct）后，TP53突变（mTP53）的急性髓系白血病（AML）预后不利，主要原因是复发率较高[1,2]。在这里，我们描述了一个mTP53的继发性AML （sAML）患者的病例，他在脐带血移植（CBT）后早期复发，随后是单周期的阿扎胞苷治疗和成功的第二次CBT。65岁男性，骨髓增生异常综合征（MDS）病史9年，表现为双氧体减少（血红蛋白8.4 g/dL；血小板计数51 x109/L）和细胞计数升高（15 x10/L）。骨髓检查显示62%的细胞，细胞遗传学分析显示复杂的核型。一组54个基因的靶向深度测序[TruSight Myeloid panel (Illumina, San Diego， CA), MiSeq (Illumina)]鉴定出纯合子TP53突变，p. R158G和p. E11Q。这些突变也被液滴数字PCR （ddPCR）证实[QX200 (Bio-Rad, Hercules， CA)]。变异等位基因频率（VAF）分别为92%和84%。荧光原位杂交和g波段检测未发现17p缺失。患者被诊断为sAML。在给予低剂量阿糖胞苷后，他接受了CBT治疗。调理方案为全身照射4Gy， busulfan 9.6 mg/kg，氟达拉滨180mg/m2，阿糖胞苷12g/m2。预防移植物抗宿主病（GVHD）包括环孢素和霉酚酸酯。外周细胞在调理后消失，但在第40天再次增加。骨髓检查显示36%的母细胞和58.4%的受体嵌合。因此，我们停用环孢素并给予阿扎胞苷（75mg/m2, 7天）。令人惊讶的是，在单周期阿扎胞苷治疗后，外周细胞再次被清除，每个mTP53的VAF（通过ddPCR测定）从约35-0%下降。患者在第一次CBT后的第125天接受了第二次CBT。这一次的调理方案包括4gy TBI，氟达拉滨200mg/m2和阿糖胞苷24g/m2。GVHD的预防包括环孢素，由于第二次CBT后第9天出现急性肾功能衰竭，将其改为甲基强的松龙。他在第二次CBT后的第21天实现了完全的供体嵌合。在第二次CBT治疗后的第119天，患者的外周血mTP53 VAF未检测到，病情仍处于缓解期。
The prognosis for acute myeloid leukemia (AML) with TP53 mutations (mTP53) after an allogeneic stem cell transplantation (allo-SCT) is unfavorable mainly due to a higher incidence of relapse [1, 2]. Here, we describe the case of a patient with secondary AML (sAML) with mTP53 who had an early relapse after cord blood transplantation (CBT), followed by a single cycle of azacitidine therapy and a successful second CBT. A 65-year-old man with a 9 year history of myelodysplastic syndrome (MDS) presented with bicytopenia (hemoglobin 8.4 g/dL; platelet count 51 x109/L) and elevation of blast count (15 x10/L). Bone marrow examination showed 62% blasts and a cytogenetic analysis showed a complex karyotype. Targeted deep sequencing of a panel of 54 genes [TruSight Myeloid Panel (Illumina, San Diego, CA), MiSeq (Illumina)] identified homozygous TP53 mutaitons, p. R158G and p. E11Q. These mutations were also confirmed by droplet digital PCR (ddPCR)[QX200 (Bio-Rad, Hercules, CA)]. Variant allele frequency (VAF) was 92% and 84%, respectively. 17p deletion was not detected by fluorescence in situ hybridization and G-band. The patient was diagnosed with sAML. After administration of low-dose cytarabine, he underwent CBT. The conditioning regimen consisted of 4Gy of total body irradiation (TBI), busulfan 9.6 mg/kg, fludarabine 180mg/m2 and cytarabine 12g/m2. Prophylaxis for graft-versushost disease (GVHD) consisted of cyclosporine and mycophenolate mofetil. Peripheral blasts cleared after conditioning but showed an increase again at day 40. Bone marrow examination showed 36% blasts and 58.4% recipient chimerism. Hence, we stopped cyclosporine and administered azacitidine (75mg/m2, 7 days). Surprisingly, after a single cycle of azacitidine therapy, peripheral blasts cleared again and the VAF of each mTP53, determined by ddPCR, had decreased from about 35-0%. The patient underwent a second CBT on day 125 after the first CBT. This time the conditioning regimen consisted of4Gy of TBI, fludarabine 200mg/m2, and cytarabine 24g/m2. Prophylaxis for GVHD consisted of cyclosporine, which was changed to methylprednisolone because of acute renal failure on day 9 after the second CBT. He achieved complete donor chimerism on day 21 after the second CBT. He remained in remission with an undetectable VAF of mTP53 in the peripheral blood on day 119 after the second CBT.