A single course of all‐trans retinoic acid plus arsenic trioxide reached a long‐term survival in a patient with newly diagnosed acute promyelocytic leukemia: a suggestion for reduction of treatment courses?
A single course of all‐trans retinoic acid plus arsenic trioxide reached a long‐term survival in a patient with newly diagnosed acute promyelocytic leukemia: a suggestion for reduction of treatment courses?
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DOI：
10.1111/ejh.12177
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发表时间：
2013-08
影响因子：
3.1
通讯作者：
Jinsong Yan;Xueyu Chen;Jing Shao
中科院分区：
文献类型：
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作者：
Jinsong Yan;Xueyu Chen;Jing Shao
致编辑：急性早幼粒细胞白血病（Acute promyelocytic leukemia，APL）是急性髓细胞性白血病的一个独特亚型，其特征为PML/RAR α融合基因，该基因由t（15：17）（q22;q21）染色体相互易位形成，在高达98%的APL患者中存在。已知异常融合基因的产物PML/RAR α融合蛋白是APL白血病发生的基础（1）。从历史上看，接受常规化疗的PML/RAR α阳性APL患者早期死亡率较高，主要是由于危及生命的血栓出血性并发症加重，完全缓解（CR）率较低（2，3）。由于引入了包括全反式维甲酸（ATRA）和三氧化二砷（As 2 O3）在内的分化剂，疗效大大提高（4）。治疗方案包括全反式维甲酸、三氧化二砷、蒽环类药物和阿糖胞苷的各种组合和持续时间，疗效可能多种多样。如单药ATRA诱导治疗CR率达95%以上（5），ATRA联合依达拉奉的APML 3试验4年无复发生存率达71%（6），ATRA联合依达拉奉和As 2 O3的APML 4试验2年无复发生存率达97.5%（7）;基于ATRA/As 2 O3联合治疗方案的5年无复发生存率达到94.8%（4）;而As 2 O3单药治疗方案的3年总生存率为74.8-87.6%，5年无病生存率为80%（8-10）。值得注意的是，含有As 2 O3的方案具有良好的结果（7），这表明需要优化APL的治疗方案。本文报告1例PML/RARa阳性APL患者，经单疗程ATRA加As_2O_3治疗32 d，存活7年以上。本例进一步证实As 2 O3在APL治疗中的重要作用，并提示应优化APL的个体化治疗方案，缩短疗程。在2006年3月，一名14岁男孩主诉疲劳，呼吸急促，下午晚些时候不明原因的低烧，和皮肤瘀伤超过1周，被提交给我们的部门。实验室检查显示外周全血细胞减少2.1 9 10/L，Hb 92 g/L，PLT 21 9 10/L，骨髓细胞过多，含异常早幼粒细胞（85%），46 XY，t（15：17）（q22;q21）易位，通过骨髓细胞巢式PCR检测发现长型PML/RAR α融合基因，并发重度凝血病（2）。因此，患者被诊断为APL，并立即给予口服ATRA（25 mg/m/d）和静脉注射As 2 O3（10 mg/d）作为诱导治疗。一周后，每天添加1 g的羟基脲，以防止白细胞增多。诱导治疗开始后32天，他的症状逐渐消退，并在骨髓中达到形态学CR。在这一点上，他的父母拒绝进一步治疗，我们完全失去了与病人的联系。五年后的2011年，我们收到了这个男孩的意外来访，他在没有任何进一步的APL相关治疗的情况下存活了5年，也没有使用中国传统药物，这让我们感到惊讶。仔细检查发现骨髓形态正常，染色体核型正常，PML/RAR α融合转录阴性，表明他可能仅用一个疗程的ATRA加As 2 O3就治愈了APL。从那以后，我们一直密切关注他。迄今为止，他已在健康状况下存活了7年。在中国，APL的ATRA/As 2 O3联合化疗和维持方案在约2年的治疗时间内实现了较高的CR率和长期生存率（4，11）。已知ATRA通过上调AQP 9蛋白（As 2 O3的转运蛋白）增强As 2 O3的功效。随着ATRA的存在，更多的As 2 O3可以被转运到APL细胞中，导致增强的分化和细胞毒性（4）。As_2O_3能降解PML/RAR α融合蛋白，而且As_2O_3能在体内清除APL干细胞，而ATRA不能。因此，ATRA可增强As 2 O3对干细胞的耗竭，As 2 O3可消除APL白血病发生的基础（12）。因此，良好的疗效主要归因于As 2 O3的存在，它可以长时间维持分子缓解（13）。虽然As_2O_3单用或与ATRA联合应用对APL有显著疗效并可长期生存，但ATRA联合As_2O_3单疗程治疗APL可达7年长期缓解的病例很少。PML/RAR α转录物仍然不可检测，表明APL干细胞可能已被完全根除（14）。
To the Editor: Acute promyelocytic leukemia (APL), a distinct subtype of acute myelogenous leukemia, is characterized by PML/ RARa fusion gene, which is formed by a reciprocal chromosomal translocation of t(15:17)(q22;q21), in up to 98% of all patients with APL. PML/RARa fusion protein, the product of the aberrant fusion gene, has been known to underlie APL leukemogenesis (1). Historically, PML/RARa-positive APL patients, treated with conventional chemotherapy, had presented with higher early deaths, mainly due to exacerbated life-threatening thrombohemorrhagic complication, and a lower complete remission (CR) rate (2, 3). Because differentiation agents including all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) were introduced, the efficacy had greatly improved (4). The treatment protocols include ATRA, As2O3, anthracycline agents, and cytarabine at various combinations and time durations, and the efficacy can be diverse. For instance, one single-agent ATRA for induction therapy markedly improved the CR rate of over 95% (5), APML3 trial incorporating ATRA and idarubicin obtained 71% 4-yr relapse-free survival rate (6); APML4 trial containing ATRA, idarubicin, and As2O3 gained 97.5% 2-yr failure-free survival rate (7); an ATRA/As2O3 combination-based protocol reached 5-yr relapse-free survival of 94.8% (4); and a single-agent As2O3 protocol attained 3-yr overall survival of 74.8–87.6% and 5-yr disease-free survival of 80% (8–10). Notably, the protocols containing As2O3 are accompanied with excellent outcomes (7), suggesting a need to optimize the treatment protocol for APL. Here, we report a case of PML/RARa-positive APL patient who has survived for more than 7 yr after being treated with only a single course of ATRA plus As2O3 for 32 d. This case may provide further evidence that As2O3 plays a pivotal role in APL treatment, and it might be the time to optimize the individualized APL treatment protocols and thereby shorten the overall treatment course. In March, 2006, a 14-yr-old boy with complaints of fatigue, shortness of breath, unexplained late afternoon lowgrade fever, and skin bruising for over 1 wk was presented to our department. The laboratory examinations showed peripheral pancytopenia with 2.1 9 10/L, Hb 92 g/L, and PLT 21 9 10/L, bone marrow hypercellularity containing abnormal promyelocytes (85%), a 46XY, t(15:17) (q22;q21) translocation, and a long-form PML/RARa fusion gene by nested PCR assay with bone marrow cells, and complicated with a severe coagulopathy (2). Therefore, the patient was diagnosed with APL and was immediately given oral ATRA (25 mg/m/d) and intravenous As2O3 (10 mg/d) simultaneously as induction therapy. One wk later, 1 g of hydroxycarbamide was added daily to prevent hyperleukocytosis. Thirty-two d after initiation of induction therapy, his symptoms gradually retreated and achieved morphological CR in bone marrow. At this point, his parents refused further treatments and we completely lost contact with the patient. Five yr later in 2011, we received unexpected visit from the boy, who surprised us by his survival for 5 yr without any further APL-related treatment and not Chinese traditional medicine either. The careful examination revealed normal bone marrow morphology, normal chromosomal karyotype, and negative PML/RARa fusion transcript, indicating he may have achieved an APL cure with only one single course of ATRA plus As2O3. From then on, we have closely followed up with him. Up to date, he has survived for 7 yr under a healthy condition. In China, ATRA/As2O3 combination-based chemotherapy and maintenance protocol for APL have achieved higher CR rate and long-term survival within about 2-yr treatment duration (4, 11). ATRA is known to enhance the efficacy of As2O3 by up-regulating AQP9 protein (a transporter of As2O3). With the presence of ATRA, more As2O3 can be transported into APL cells, leading to enhanced differentiation and cytotoxicity (4). PML/RARa fusion protein can be degraded by As2O3, and most importantly, APL stem cells can be depleted in vivo by As2O3 not ATRA. Hence, ATRA may enhance the depletion of stem cell by As2O3, and the basis for leukemogenesis of APL may be abolished by As2O3 (12). Therefore, the good efficacy was mainly attributable to the existence of As2O3, which can maintain molecular remission for a long time (13). Although As2O3 alone, or used with ATRA together, has been proven to promote efficacy and reached a long-term survival in APL, it is very unusual that a single course of ATRA plus As2O3 reached a long-term remission for 7 yr. The PML/RARa transcript remained undetectable, suggesting APL stem cells might have been completely eradicated (14).