Case-report 诱导治疗期间伴有PML：：RARA融合转录物长和短亚型的急性早幼粒细胞白血

The introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has transformed the outcome of acute promyelocytic leukemia (APL) from a uniformly fatal disease to one of the most curable human malignancies in recent decades. However, early mortality caused by coagulopathy, infection, multi-organ failure, and differentiation syndrome (DS) during disease onset and induction treatment remains a major issue in APL, especially in elderly patients who may suffer from higher treatment-related mortality due to a higher vulnerability to treatment toxicities. Herein, we present a case of an elderly patient with APL with rare mixed long (L-) and short (S-) isoforms of PML::RARA fusion transcripts who had multiple complications at disease onset. In addition, the initiation of treatment with ATRA in combination with ATO led to the rapid onset of severe DS. In particular, this patient experienced a rare clinical feature of DS, acute edematous pancreatitis (AEP). Furthermore, due to the patient's refractory abdominal distension related to the dose of ATRA, ATO, and Realgar-Indigo Naturalis Formula (RIF), we have to repeatedly adjust the doses of these drugs that the patient can maximally tolerate. Nevertheless, the patient achieved complete remission (CR) even after receiving asubstandard dose of these drugs. However, the patient relapsed, acquired the FLT3-ITD mutation nine months later, and experienced abdominal distension again while receiving the standard doses of ATRA and RIF. Therefore, these drugs were adjusted to the maximum tolerated dose based on the experience with the initial induction treatment, and the patient achieved CR after four weeks of reinduction treatment. We report that this case may provide some clinical information for the diagnosis and treatment of similar patients with APL.近几十年来，全反式视黄酸（ATRA）和三氧化二砷（ATO）的引入将急性早幼粒细胞白血病（APL）从一种一致致命的疾病转变为最可治愈的人类恶性肿瘤之一。然而，在疾病发作和诱导治疗期间，由凝血病、感染、多器官衰竭和分化综合征（DS）引起的早期死亡率仍然是APL的一个主要问题，特别是在老年患者中，由于更容易受到治疗毒性的影响，他们可能会遭受更高的治疗相关死亡率。在此，我们介绍了一例患有APL的老年患者，该患者具有罕见的PML：：RARA融合转录物的长（L-）和短（S-）混合亚型，在疾病发作时有多种并发症。此外，ATRA联合ATO治疗的开始导致严重DS的快速发作。特别是，该患者经历了DS的罕见临床特征，即急性水肿性胰腺炎（AEP）。再者，由于患者的难治性腹胀与ATRA、ATO和雄黄-靛蓝配方（RIF）的剂量有关，我们不得不反复调整患者最大耐受的这些药物的剂量。然而，即使在接受低于标准剂量的这些药物后，患者仍实现了完全缓解（CR）。然而，患者复发，9个月后获得了FLT3-ITD突变，并在接受标准剂量的ATRA和RIF治疗时再次出现腹胀。因此，根据初始诱导治疗的经验将这些药物调整到最大耐受剂量，患者在再次诱导治疗四周后达到CR。我们报告此病例可能为类似APL患者的诊断和治疗提供一些临床信息。

Acute Promyelocytic Leukemia【急性早幼粒细胞白血病APL】 

all-trans retinoic acid (ATRA) 【全反式视黄酸】

arsenic trioxide (ATO)【三氧化二砷】

coagulopathy【凝血病】

differentiation syndrome (DS）【分化综合症】

induction treatment【诱导治疗】

acute edematous pancreatitis (AEP)【急性水肿型胰腺炎】

refractory abdominal distension【难治性腹胀】

complete remission (CR)【完全缓解】

substandard dose【剂量不足】

relapse【复发】

Case Presentation 

A 70-year-old man was admitted to the hospital with a one-month history of fatigue and a two-day history of buccal mucosal purpura. We define the first day of admission as day 1 (D1). Table 1 shows the patient's most important test results at the time of initial admission.患者男，70岁，有1个月乏力史，2天颊粘膜紫癜病史入院。我们将入院的第一天定义为第1天（D1）。表1显示了患者初次入院时最重要的检查结果。

buccal mucosal purpura【口腔黏膜出血】

Based on the patient's clinical manifestations and laboratory test results, particularly fluorescent polymerase chain reaction (PCR) capillary electrophoresis fragment analysis and quantitative real-time PCR results indicating positive L- and S-isoform PML::RARA fusion transcripts, the patient was diagnosed with low-risk APL characterized by L- and S-isoform PML::RARA fusion transcripts (Figure 1). This condition was associated with cerebral hemorrhage, pulmonary infection, diabetes mellitus, and renal insufficiency (Figure 2A). Therapeutic intervention for the patient, according to the Chinese guidelines for diagnosis and treatment of APL (2018) [5], included ATRA (25 mg/m2/day; 40 mg/day) and ATO (0.16 mg/kg/day; 9 mg/day). Adjuvant therapy consisted of anti-infectives, glycemic control, and blood product transfusions. On D2, the patient rapidly developed generalized swelling, dyspnea, abdominal distension, weight gain of 4.3 kg, and oxygen saturation fluctuating between 82% and 85% after taking only one dose of ATRA (10 mg) on the evening of D1. Therefore, the diagnosis of DS is clear, and the dose of ATRA was reduced to 30 mg/day. The patient was immediately started on idarubicin hydrochloride (10 mg/day, D2, 4, 6) and dexamethasone (20 mg/day). On D4, the dose of ATRA was reduced to 20 mg/day as the WBC continued to rise to 20.60 × 109/L. Subsequently, the patient reported a rapid improvement in dyspnea. Laboratory parameters, including WBC, D-dimer, and FDP, gradually decreased, while FIB returned to normal. However, the patient's abdominal distension persisted despite the above treatment, concomitant albumin infusion, and diuretic therapy with furosemide. On the evening of D8, the patient experienced a sudden onset of abdominal pain. Clinical physical examination revealed tenderness throughout the abdomen but no abdominal rebound pain or tension; peristalsis sounds were noted one to two times per minute; and an abdominal CT scan revealed new bilateral pleural, abdominal, and pelvic effusions as well as subcutaneous exudation in the abdomen and pelvis (Figure 2B). The patient's sudden onset of abdominal pain was initially misdiagnosed as glucocorticoid-induced peptic ulcer disease, and empiric treatment with esomeprazole was initiated. However, the patient reported a significant worsening of abdominal pain and bloating after ten hours. Serum lipase and amylase levels were 1579 U/L (normal range, 23-300 U/L) and 557 U/L (normal range, 35-135 U/L), respectively. Albumin level was 32.4 g/L (normal range, 40-55 g/L), fasting glucose level was 8.79 mmol/L (normal range, 3.90-6.10 mmol/L), calcium ion level was 2.00 mmol/L (normal range, 2.112.52 mmol/L), creatinine level was 95.3 μmol/L (normal range, 57-111 μmol/L), and triglyceride level was 2.14 mmol/L (normal range, 0.56-1.70 mmol/L). The thoracoabdominal CT was re-evaluated on the afternoon of D9 and showed increased pulmonary interstitial exudate, bilateral pleural and abodominal effusion, pancreatic edema, subcutaneous effusion, and diffuse thickening of the abdominal and pelvic peritoneum (Figure 2C). These findings led to a diagnosis of acute edematous pancreatitis (AEP), scored as Grade 3 according to Common Terminology Criteria for Adverse Events (CTCAE) v.5.0.

基于患者的临床表现和实验室检测结果，特别是荧光聚合酶链反应（PCR）毛细管电泳片段分析和定量实时PCR结果表明L-和S-亚型PML：：RARA融合转录物阳性，该患者被诊断为以L-和S-亚型PML：：RARA融合转录物为特征的低风险APL（图1）。这种情况与脑出血、肺部感染、糖尿病和肾功能不全有关（图2A）。根据中国APL诊疗指南（2018）[5]，对患者的治疗干预包括ATRA（25 mg/m2/天；40毫克/天）和ATO（0.16毫克/千克/天；9毫克/天）。辅助治疗包括抗感染、血糖控制和血液制品输血。患者在D1晚仅服用1剂ATRA（10 mg）后，于D2迅速出现全身肿胀、呼吸困难、腹胀，体重增加4.3 kg，血氧饱和度在82%~85%之间波动。因此，DS的诊断是明确的，ATRA的剂量减少到30mg/天。患者立即开始服用盐酸伊达比星（10 mg/天，D2、4、6）和地塞米松（20 mg/天）。在第4天，随着WBC继续上升至20.60 × 109/L，ATRA的剂量减少至20mg/天。随后，患者报告呼吸困难迅速改善。实验室参数，包括WBC、D-二聚体和FDP逐渐降低，而FIB恢复正常。然而，尽管进行了上述治疗、伴随白蛋白输注和呋塞米利尿治疗，患者的腹胀持续存在。D8晚，患者突然出现腹痛。临床查体示全腹部压痛但无腹部反跳痛、紧张；每分钟记录一到两次蠕动声；腹部CT扫描显示新的双侧胸膜、腹部和盆腔积液以及腹部和盆腔皮下渗出（图2B）。患者突然发作的腹痛最初被误诊为糖皮质激素诱发的消化性溃疡病，开始用埃索美拉唑经验性治疗。然而，患者报告10小时后腹痛和腹胀显著恶化。血清脂肪酶和淀粉酶水平分别为1579 U/L（正常范围，23-300 U/L）和557 U/L（正常范围，35-135 U/L）。白蛋白水平为32.4 g/L（正常范围，40-55 g/L），空腹血糖水平为8.79 mmol/L（正常范围，3.90-6.10 mmol/L），钙离子水平为2.00 mmol/L（正常范围，2.112.52 mmol/L），肌酐水平为95.3 μ mol/L（正常范围，57-111 μ mol/L），甘油三酯水平为2.14 mmol/L（正常范围，0.56-1.70 mmol/L）。第9天下午再次评估胸腹部CT，显示肺间质渗出物增加，双侧胸腹腔积液，胰腺水肿，皮下积液，腹腔和盆腔腹膜弥漫性增厚（图2C）。这些发现导致了急性水肿性胰腺炎（AEP）的诊断，根据不良事件通用术语标准（CTCAE）v.5.0评分为3级。

fluorescent polymerase chain reaction (PCR) capillary electrophoresis fragment analysis 【荧光聚合酶链反应 (PCR) 毛细管电泳片段分析 】

cerebral hemorrhage【脑出血】

renal insufficiency 【肾功能不全】

Adjuvant therapy 【辅助治疗】

dyspnea【呼吸困难】

oxygen saturation【氧饱和】

idarubicin hydrochloride【盐酸伊达比星】

dexamethasone【DEX 地塞米松】

concomitant【伴随】 

albumin【蛋白】

furosemide【呋塞米】

peristalsis sounds【肠鸣音】

subcutaneous exudation【皮下渗出】

empiric treatment【经验性治疗】 

esomeprazole【艾司奥美拉唑】

abdominal pain and bloating 【腹痛和腹胀】

ATRA and ATO were paused on D9; dexamethasone (20 mg/day) was continued along with food and fluid restriction; intravenous nutritional support; and other therapeutic medications included ulinastatin, esomeprazole, and diuretics. Fortunately, the patient's abdominal distension and pain gradually relieved, and the amylase level decreased to 71 U/L on D12. ATO (9 mg/day) was restarted on the same day, but the patient again developed intolerable abdominal pain and bloating. Repeated cranial and abdominal CT on D13 showed that the hemorrhagic focus in the right centrum semiovalehad become less dense and the peripheral edema around the hemorrhagic focus had increased compared to D1 (Figure 2D), the peripancreatic fat space was blurred, the abdominopelvic and peripancreatic exudate was slightly absorbed, and there were bilateral pleural effusions consistent with the findings on D9 (Figure 2E). ATO had to be discontinued again, and Chinese herbal enema, abdominal massage, and acupuncture were used to relieve the patient's abdominal distension until the patient could tolerate D15. On the same day, we tried 75% of the standard dose of RIF (270 mg/tablet; 9 tablets/day) and reduced the dexamethasone to 5 mg/day. Unfortunately, the patient's abdominal distension worsened after only one dose of RIF (three tablets), but gradually improved after discontinuing RIF. We restarted ATRA (20 mg/day) on D18, but the patient experienced chest tightness and shortness of breath the next day, and the WBC increased to 10.63 × 10 9/L. Cytarabine (50 mg/day) was administered on D19. The patient's leukocytes gradually decreased, and the chest tightness and shortness of breath also gradually improved without stopping ATRA treatment. The patient's abdominal distension remained tolerable during this period. On D27, we again tried low-dose RIF (three tablets per day), and the patient did not experience any worsening of abdominal distension. A repeat thoracoabdominal CT on D28 showed that the patient's bilateral pleural effusions had resolved, the peripancreatic exudate had been absorbed, and the seroperitoneumhad decreased (Figure 2F). The doses of ATRA and RIF were gradually increased, as shown in Figure 3, on the premise that the patient could tolerate the abdominal distension. However, when the dose of RIF was increased to 9 tablets per day on D33, the patient experienced a significant worsening of abdominal pain and bloating. As a result, RIF had to be discontinued. Fortunately, the patient's amylase levels were normal, and no abnormal promyelocytes were found in the patient's bone marrow on D34. The patient achieved a CR after the first induction treatment.ATRA和ATO在D9暂停；继续使用地塞米松（20mg/天），同时限制食物和液体；静脉营养支持；其他治疗药物包括乌司他丁、埃索美拉唑和利尿剂。幸运的是，患者腹胀、疼痛逐渐缓解，淀粉酶水平在D12降至71 U/L。当天重新开始ATO（9 mg/天），但患者再次出现无法忍受的腹痛和腹胀。D13重复头颅和腹部CT显示，与D1相比，右侧半卵圆中心出血灶密度变小，出血灶周围周围水肿加重（图2D），胰周脂肪间隙模糊，腹盆腔和胰周渗出物轻度吸收，双侧胸腔积液与D9一致（图2E）。不得不再次停用ATO，并采用中药灌肠、腹部按摩、针灸等方法缓解患者腹胀，直至患者能够耐受D15。同一天，我们尝试了75%标准剂量的RIF（270 mg/片；9片/天），并将地塞米松降至5 mg/天。不幸的是，患者仅服用一剂RIF（三片）后腹胀加重，但停用RIF后逐渐好转。我们在第18天重新开始ATRA（20mg/天），但患者第二天出现胸闷气短，WBC升高至10.63 × 109/L。在D19给予阿糖胞苷(50mg/天)。患者白细胞逐渐下降，胸闷气短也逐渐好转，没有停止ATRA治疗。在此期间，患者的腹胀仍可耐受。在第27天，我们再次尝试低剂量RIF（每天三片），患者没有出现任何腹胀恶化。第28天重复胸腹部CT显示，患者双侧胸腔积液消退，胰周渗出物吸收，血清腹膜减少（图2F）。在患者能够耐受腹胀的前提下，逐渐增加ATRA和RIF的剂量，如图3所示。然而，当RIF的剂量在第33天增加到每天9片时，患者经历腹痛和腹胀的显著恶化。因此，RIF不得不停产。幸运的是，患者淀粉酶水平正常，D34时患者骨髓中未发现异常早幼粒细胞。患者在首次诱导治疗后达到CR。

ulinastatin【乌司他汀】

Chinese herbal enema【中药灌肠】

Cytarabine【胞磷胆碱】

seroperitoneum【腹水】

promyelocytes 【早幼粒细胞】

Nine months later, the patient experienced a recurrence of buccal mucosal purpura and weakness due to refusal of consolidation and maintenance therapy. The most important test results at the time of relapse are shown in Table 1. It's worth noting that genetic testing at the time of the relapse revealed a positive FLT3ITD mutation. We used a standard dose of ATRA (40 mg/day) in combination with RIF (12 tablets/day) as a reinduction regimen. However, the patient experienced intolerable abdominal pain and bloating after three days of reinduction therapy. The thoracoabdominal CT scan showed pulmonary exudation and abdominopelvic pleural effusions, as well as subcutaneous exudation, but the amylase level was normal. Based on the experience with the first induction treatment (Figure 3), a substandard but tolerable dose of ATRA (30 mg/day) in combination with RIF (six tablets per day) was selected for the reinduction treatment, and the patient achieved a second CR as no abnormal promyelocytes were found on bone marrow cytomorphology examinations after 28 days of treatment. The patient is currently undergoing consolidation and maintenance therapy according to Chinese guidelines. However, due to the patient's indelible fear of abdominal distension and pain, any treatment still requires constant explanation and persuasion.9个月后，由于拒绝巩固和维持治疗，患者出现了颊粘膜紫癜和虚弱的复发。复发时最重要的测试结果如表1所示。值得注意的是，复发时的基因检测显示FLT3ITD突变阳性。我们使用标准剂量的ATRA（40 mg/天）联合RIF（12片/天）作为再诱导方案。然而，患者在三天的再诱导治疗后出现无法忍受的腹痛和腹胀。胸腹部CT扫描显示肺渗出和腹盆腔胸腔积液，以及皮下渗出，但淀粉酶水平正常。根据首次诱导治疗的经验（图3），选择了低于标准但可耐受剂量的ATRA（30 mg/天）联合RIF（每天6片）进行再诱导治疗，患者获得第二次CR，因为治疗28天后骨髓细胞形态学检查未发现异常早幼粒细胞。患者目前正在根据中国指南接受巩固和维持治疗。但由于患者对腹胀、腹痛有着难以磨灭的恐惧，任何治疗仍需要不断的解释和劝说。