Laboratory Assessment of Patients with Hypereosinophilic Syndrome

嗜酸性粒细胞增多综合征患者的实验室评估

• 批准号: 7733667
• 负责人: irina maric
• 金额: $ 2.38万
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7733667
• 关键词: Address; Biological Assay; Blood specimen; Bone Marrow; Cardiac; Chromosomes, Human, Pair 4; Chronic eosinophilic leukemia; Clinical; Count; Daily; Data; Diagnosis; Disease; Disease remission; Disseminated eosinophilic collagen disease; Dose; Elevation; Endomyocardial Fibrosis; Enrollment; Eosinophilia; Fibrosis; Idiopathic Hypereosinophilic Syndromes; Imatinib; Imatinib mesylate; Laboratories; Left; Legal patent; Methods; Molecular; Monitor; Myelofibrosis; Myeloproliferative disease; National Institute of Allergy and Infectious Disease; Patients; Peripheral Blood Eosinophilia; Peripheral Blood Mononuclear Cell; Population; Protein Tyrosine Kinase; Rate; Recurrence; Relapse; Reverse Transcriptase Polymerase Chain Reaction; Serum; Shapes; Subgroup; Symptoms; Testing; Time; Tissues; Tryptase; World Health Organization; disorder risk; eosinophil; experience; follow-up; fusion gene; interstitial; mast cell; mortality; novel; outcome forecast; peripheral blood; response; treatment duration

A subset of patients presenting with hypereosinophilic syndrome (HES) have clinical features consistent with a myeloproliferative disorder. These patients have aggressive disease characterized by tissue fibrosis, including endomyocardial fibrosis and myelofibrosis and a poor prognosis with 5 year mortality rates as high as 50%, if left untreated. The peripheral blood mononuclear cells of the overwhelming majority of these patients have an interstitial deletion in chromosome 4, leading to the formation of the imatinib-sensitive FIP1L1/PDGFRA fusion gene, thus fulfilling the WHO criteria for a diagnosis of chronic eosinophilic leukemia (CEL). We have established a novel RT-PCR assay to test for FIP1L1/PDGFRA fusion gene in peripheral blood samples of patents with eosinophilia. Positive patients are followed over time and treatment responses to imatinib are monitored using this novel RT-PCR assay. Although imatinib is clearly the treatment of choice for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia (CEL), little is known about optimal dosing, duration of treatment, and the possibility of cure in this disorder. To address these questions, 5 patients with FIP1L1/PDGFRA-positive CEL with documented clinical, hematologic, and molecular remission on imatinib (400 mg daily) and without evidence of cardiac involvement were enrolled in a dose de-escalation trial. The imatinib dose was tapered slowly with close follow-up for evidence of clinical, hematologic, and molecular relapse. Two patients with endomyocardial fibrosis were maintained on imatinib 300 to 400 mg daily and served as controls. All 5 patients who underwent dose de-escalation, but neither of the control patients, experienced molecular relapse (P < .05). None developed recurrent symptoms, and eosinophil counts, serum B12, and tryptase levels remained suppressed. Reinitiation of therapy at the prior effective dose led to molecular remission in all 5 patients, although 2 patients subsequently required increased dosing to maintain remission. These data are consistent with suppression rather than elimination of the clonal population in FIP1L1/PDGFRA-positive CEL and suggest that molecular monitoring may be the most useful method in determining optimal dosing without the risk of disease exacerbation.

一部分患有低粒细胞综合征（HES）的患者具有与骨髓增生性疾病一致的临床特征。这些患者患有组织纤维化为特征的侵袭性疾病，包括内膜纤维化和骨髓纤维化，预后不良，如果未治疗，则为5年死亡率高达50％。这些患者中绝大多数的外周血单核细胞在4染色体中具有间质缺失，导致形成了伊马替尼敏感的FIP1L1/PDGFRA融合基因，从而满足WHO标准以诊断出慢性嗜酸性嗜酸性白血病（Cel）。我们已经建立了一种新型的RT-PCR测定法，以测试嗜酸性粒细胞增强专利的外周血样品中的FIP1L1/PDGFRA融合基因。随着时间的流逝，阳性患者对伊马替尼的治疗反应使用这种新型的RT-PCR分析进行监测。 尽管伊马替尼显然是FIP1L1/PDGFRA阳性慢性嗜酸性白血病（CEL）的选择的治疗方法，但关于最佳给药，治疗持续时间以及这种疾病中治愈的可能性知之甚少。为了解决这些问题，有5例FIP1L1/PDGFRA阳性CEL患者在伊马替尼（每天400毫克）中具有证明是临床，血液学和分子缓解的患者，并且没有心脏参与的证据。伊马替尼剂量通过紧密随访缓慢地逐渐变细，以证明临床，血液学和分子复发。每天300至400毫克的伊马替尼维持两名患有内膜纤维化的患者，并用作对照。所有5例接受剂量降低但对照患者的患者均未出现分子复发（p <.05）。没有人会产生复发性症状，嗜酸性粒细胞计数，血清B12和胰蛋白酶水平仍然受到抑制。在先前的有效剂量下重新定期治疗导致所有5例患者的分子缓解，尽管随后有2例需要增加给药以维持缓解。这些数据与FIP1L1/PDGFRA阳性CEL中克隆人群的抑制是一致的，并表明分子监测可能是确定最佳剂量而不会加剧疾病风险的最佳剂量的最有用方法。