Successful treatment of a patient with acute promyelocytic leukemia with a STAT5B/RARA fusion gene using decitabine
Successful treatment of a patient with acute promyelocytic leukemia with a STAT5B/RARA fusion gene using decitabine
复制标题
DOI：
10.1080/10428194.2017.1357176
复制
发表时间：
2018-03
影响因子：
2.6
通讯作者：
Anyou Wang;Xiaoyan Cai;P. Qiang;Q. Duan
中科院分区：
文献类型：
--
作者：
Anyou Wang;Xiaoyan Cai;P. Qiang;Q. Duan
急性早幼粒细胞白血病（APL）的典型特征是染色体重排，t（15;17）（q22;q12），其在PML和RARA中具有断点（也称为RARa）基因导致PML-RARA融合转录物的产生;然而，在大约1-2%的典型形态学定义的APL患者中，t（15;17）（q22; q12）重排和PMLRARA转录本不能通过荧光原位杂交（FISH）或逆转录-聚合酶链反应（RT-PCR）检测[1]。这些患者通常携带涉及RARA基因的罕见变异易位，包括STAT 5 B/RARA、ZBTB 16/RARA、NMP 1/RARA、BCOR/ RARA、NUMA 1/RARA、FIP 1 L1/RARA和PRKAR 1A/RARA。通常，全反式维甲酸（ATRA）和三氧化二砷（ATO）的联合治疗可获得良好的治疗效果，并延长APL患者的无病生存期;然而，一些APL患者，特别是那些具有STAT 5 B/RARA融合转录物的患者，似乎对ATRA和ATO的联合治疗具有耐药性。到目前为止，只有10例携带STAT 5 B/ RARA融合转录本的APL病例已在文献中发表，据报道，他们对ATRA和ATO治疗无反应。在目前的研究中，我们报告了一例携带STAT 5 B/RARA融合转录本的APL病例，该病例使用地西他滨成功治疗并实现了分子缓解。一位47岁的男性患者，因发烧和皮肤瘀斑数日而就诊，没有任何其他白血病的临床证据，并进行了常规血液检查。全血细胞计数结果为WBC 17.18 10 /L，HGB 77 g/L，PLT 78 10 /L。肝肾功能指标正常。在外周血（4%）和骨髓（48.5%）中检测到具有APL形态和突出的奥尔杆的原始细胞。骨髓原始细胞的免疫表型表明CD 13 + CD 33 + CD 117+的分布。虽然临床上不明显，但凝血试验结果表明纤维蛋白原异常（56 mg/dL）。细胞遗传学分析显示核型为46，XY，t（5;7）（q22;q31）[5]/46，XY，der（11）[3]/46，XY[2]，而RT-PCR检测典型PML/RARA融合和双色探针检测t（15;17）易位均为阴性。由于白血病融合基因检测结果滞后，且骨髓原始细胞具有APL形态，患者接受标准双诱导治疗，ATRA和ATO联合治疗（ATRA，25 mg/m2/d，持续2周; ATO，10 mg/d，持续28天）。每日分析显示凝血功能无改善。随后，白血病融合基因检测表明STAT 5 B/ RARA融合转录物阳性;因此，立即停止ATRA治疗，并替换为米托蒽醌（2 mg/天，持续10天）联合ATO诱导化疗;然而，化疗后由于骨髓抑制发生严重脓毒症和肺部疾病。为了控制感染，使用美罗培南、替考拉宁和伏立康唑联合治疗加强和刺激造血支持治疗。症状改善后，患者出院。骨髓分析表明，诱导治疗后1个月，原始细胞和早期未成熟粒细胞占细胞的11.5%，STAT 5 B/RARA融合转录本的定量检查表明，它以每10，000个ABL 1转录本拷贝4897个拷贝存在。凝血试验结果在74 mg/dL纤维蛋白原时仍异常。患者随后接受了由伊达洛酮（15 mg/天，持续3天）和阿糖胞苷（190 mg/天，持续7天）组成的IA联合治疗。重复骨髓分析表明，原始细胞和早期未成熟粒细胞占41%的细胞后，IA治疗。在第一阶段治疗失败后，患者被转诊到我们中心。骨髓检查在我们的中心使用RARA特异性FISH探针试剂盒和实时PCR进行。结果表明，在44%的骨髓细胞中存在RARA缺失，并且STAT 5 B/RARA融合转录物以每10，000个ABL 1转录物拷贝10，900个拷贝存在。STAT 5 B/RARA特异性引物设计如下
Acute promyelocytic leukemia (APL) is typically characterized by the chromosomal rearrangement, t(15;17)(q22;q12), which has breakpoints in the PML and RARA (also known as RARa) genes leading to generation of the PML-RARA fusion transcript; however, in approximately 1–2% of typical morphologically defined APL patients, the t(15;17)(q22;q12) rearrangement and PMLRARA transcript cannot be detected by fluorescence in situ hybridization (FISH) or reverse transcription-polymerase chain reaction (RT-PCR) [1]. These patients generally carry rare variant translocations involving the RARA gene, including STAT5B/RARA, ZBTB16/RARA, NMP1/RARA, BCOR/ RARA, NUMA1/RARA, FIP1L1/RARA, and PRKAR1A/RARA. Typically, combination treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) lead to good therapeutic results and prolong disease-free survival for APL patients; however, some APL patients, particularly those with the STAT5B/RARA fusion transcript, appear to be resistant to combination treatment with ATRA and ATO. To date, only 10 APL cases harboring the STAT5B/ RARA fusion transcript have been published in the literature, and they were reported not to respond to treatment with ATRA and ATO. In the current study, we report an APL case with a STAT5B/RARA fusion transcript, who was successfully treated and achieved molecular remission using decitabine. A 47-year-old male patient presented with fever and skin ecchymosis for several days, without any other clinical evidence of leukemia, and underwent a routine blood test. The full blood count test results were WBC 17.18 10 /L, HGB 77 g/L, and PLT 78 10 /L. Liver and kidney function indices were normal. Blast cells with APL morphology and prominent Auer rods were detected in the peripheral blood (4%) and bone marrow (48.5%). Immunophenotyping of myeloid blast cells indicated a profile of CD13þCD33þCD117þ. Although it was not apparent clinically, a coagulation test result indicated abnormal fibrinogen (56mg/dL). Cytogenetic analysis indicated a 46,XY,t(5;7)(q22;q31)[5]/46,XY,der(11)[3]/46, XY[2] karyotype, while RT-PCR to detect the typical PML/RARA fusion, and dual color probe analysis to detect the t(15;17) translocation both produced negative results. Due to the hysteresis of leukemia fusion gene detection results, and bone marrow blast cells with APL morphology, the patient was administered with standard double induction therapy, combining ATRA and ATO (ATRA, 25mg/m per day for two weeks; ATO, 10mg per day for 28 days). Daily analysis indicated no improvement in blood coagulation function. Subsequently, leukemia fusion gene detection indicated positivity for the STAT5B/ RARA fusion transcript; therefore, treatment with ATRA was immediately stopped and replaced with induction chemotherapy with mitoxantrone (2mg per day for 10 days), in combination with ATO; however, severe sepsis and pulmonary disease occurred after chemotherapy as a result of bone marrow suppression. To control the infection, hematopoietic support therapy was strengthened and stimulated using a combination of meropenem, teicoplanin, and voriconazole. After his symptoms improved, the patient was discharged from hospital. Bone marrow analysis indicated that blast cells and early immature granulocytes accounted for 11.5% of cells one month after induction treatment, and quantitative examination of the STAT5B/RARA fusion transcript indicated it was present at 4897 copies per 10,000 ABL1 transcript copies. Coagulation assay results remained abnormal at 74mg/dL fibrinogen. The patient then received IA combination treatment consisting of idarubicin (15mg per day for three days) plus cytarabine (190mg per day for seven days). Repeat bone marrow analysis indicated that blast cells and early immature granulocytes accounted for 41% of cells after 15 days of IA treatment. After this first stage of unsuccessful treatment, the patient was referred to our center. Bone marrow examination was performed in our center using a RARA-specific FISH probe kit and real-time PCR. The results demonstrated a deletion of RARA in 44% of bone marrow cells, and the STAT5B/RARA fusion transcript was present at 10,900 copies per 10,000 ABL1 transcript copies. STAT5B/ RARA-specific primers were designed with the following