A single weekly dose of imatinib is sufficient to induce and maintain remission of chronic eosinophilic leukaemia in FIP1L1-PDGFRA-expressing patients

Hypereosinophilic syndrome (HES) is defined as chronic, unexplained hypereosinophilia with organ involvement. A subset of HES patients presents an interstitial deletion in chromosome 4q12, which leads to the expression of an imatinib-responsive fusion gene, FIP1L1-PDGFRA. These patients are diagnosed as chronic eosinophilic leukaemia (CEL). We treated seven CEL and HES patients, six of which expressed FIP1L1-PDGFRA , with imatinib using initial daily doses ranging from 100 to 400 mg. In a remission maintenance phase, the patients were treated with imatinib once weekly. All imatinib-treated patients achieved a complete haematological remission (CHR), and five of the six patients with FIP1L1-PDGFRA expression exhibited molecular remission. The decreased imatinib doses were as follows: 200 mg/week in three patients, 100 mg/week in two patients and 100 mg/d in the remaining two patients. For remission maintenance, imatinib doses were set at 100 mg/week in five patients and 200 mg/week in two patients. At a median follow-up of 30 months all patients remained in CHR and FIP1L1-PDGFRA expression was undetectable in five of the six FIP1L1-PDGFRA -expressing patients. These data suggest that a single weekly dose of imatinib is sufficient to maintain remission in FIP1L1-PDGFRA - positive CEL patients.     

Safety and efficacy of imatinib in chronic eosinophilic leukaemia and hypereosinophilic syndrome: a phase-II study

This study evaluated the efficacy and safety of imatinib in chronic eosinophilic leukaemia (CEL, n = 23) and hypereosinophilic syndrome (HES, n = 13). In CEL with FIP1L1-PDGFRA (n = 16) or various PDGFRB fusion genes (n = 5), complete haematological remission (CHR) was achieved in 95% (20/21) after 3 months. Complete molecular remission (CMR) was seen in 75% (12/16) of cases with FIP1L1-PDGFRA positive CEL by 6 months, and in 87% (13/15) after 12 months. CMR was achieved in three of five PDGFRB fusion positive patients after 3, 9 and 18 months respectively. All patients are currently on imatinib (100 mg; n = 13, 400 mg; n = 8) and no molecular relapse has yet been observed (median 26.7 months; range, 6.9-39.9). Imatinib was less effective in HES and CEL without known molecular aberration (n = 15); CHR was observed in 40% (6/15) of patients, two patients relapsed after 4.8 and 24.5 months. Three patients died due to imatinib-resistant progressive CEL (n = 2) or myocardial infarction (n = 1) unrelated to study treatment. Overall, imatinib was well tolerated with a low incidence of grade III/IV toxicities. These data confirmed the long-term efficacy of imatinib for PDGFR-rearranged CEL patients, and also showed that a minority of HES cases without known molecular aberrations may benefit from imatinib.     

The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management

Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL) comprise a spectrum of indolent to aggressive diseases characterized by unexplained, persistent hypereosinophilia. These disorders have eluded a unique molecular explanation, and therapy has primarily been oriented toward palliation of symptoms related to organ involvement. Recent reports indicate that HES and CEL are imatinib-responsive malignancies, with rapid and complete hematologic remissions observed at lower doses than used in chronic myelogenous leukemia (CML). These BCR-ABL-negative cases lack activating mutations or abnormal fusions involving other known target genes of imatinib, implicating a novel tyrosine kinase in their pathogenesis. A bedside-to-benchtop translational research effort led to the identification of a constitutively activated fusion tyrosine kinase on chromosome 4q12, derived from an interstitial deletion, that fuses the platelet-derived growth factor receptor-alpha gene (PDGFRA) to an uncharacterized human gene FIP1-like-1 (FIP1L1). However, not all HES and CEL patients respond to imatinib, suggesting disease heterogeneity. Furthermore, approximately 40% of responding patients lack the FIP1L1-PDGFRA fusion, suggesting genetic heterogeneity. This review examines the current state of knowledge of HES and CEL and the implications of the FIP1L1-PDGFRA discovery on their diagnosis, classification, and management.     

Successful treatment with low-dose dasatinib in a patient with chronic eosinophilic leukemia intolerant to imatinib

A 77-year-old man with cough and dyspnea was admitted to hospital. Chest X-ray demonstrated reticulated shadows in the bilateral inferior lung fields and marked eosinophilia was detected in peripheral blood. Although he received steroid pulse therapy, eosinophilia became more serious and he was referred to our hospital. Bone marrow examination demonstrated a hypercellular marrow that consisted predominantly of dysplastic eosinophils with differentiation. FISH analysis of bone marrow cells demonstrated 4q12 deletion and RT-PCR analysis detected FIP1L1-PDGFRA fusion gene, leading to the diagnosis of chronic eosinophilic leukemia (CEL). Treatment with low-dose imatinib was immediately initiated; however, drug-induced systemic edema was progressive and became intolerable. Therefore, we changed imatinib to low-dose dasatinib (20 mg/day), resulting in complete molecular response of CEL after 3 months without any severe adverse effects. This is the first report on the efficacy of low-dose dasatinib for the treatment of CEL. The peak level (Cmax) of dasatinib in this patient was 55.3 nM, which exceeded the concentration of dasatinib required to inhibit cells with FIP1L1-PDGFRA by 50%. Thus, low-dose dasatinib with therapeutic drug monitoring can be a useful therapy for imatinib-intolerant CEL even in elderly patients.     

Clinical Features of Hypereosinophilic Syndrome: FIP1L1-PDGFRA Fusion Gene—Positive Disease is a Distinct Clinical Entity with Myeloproliferative Features and a Poor Response to Corticosteroid

We conducted a retrospective analysis of the clinical features of 20 patients with severe eosinophilia at our institution, including 10 cases of hypereosinophilic syndrome (HES) (5 definite and 5 probable cases) and 10 cases of other eosinophilic disorders. Of the 20 patients, 14 initially received prednisolone treatment, which resulted in rapid improvement and normalization of eosinophilia within 8 weeks; however, 2 patients with splenomegaly showed poor control of eosinophilia in response to corticosteroid treatment. In addition, the FIP1L1-PDGFRA fusion gene was detected only in these 2 cases. One of the FIP1L1-PDGFRA - positive HES cases featured bone marrow fibrosis. Treatment of this patient with imatinib mesylate resulted in a dramatic improvement of eosinophilia, organomegaly, and the bone marrow fibrosis. Taken together, our data and previous reports suggest that FIP1L1-PDGFRA - positive HES is a distinct clinical entity with myeloproliferative features and showing a poor response to corticosteroid treatment.     

Sorafenib is a potent inhibitor of FIP1L1-PDGFRalpha and the imatinib-resistant FIP1L1-PDGFRalpha T674I mutant

The FIP1L1-PDGFRA oncogene is a common cause of chronic eosinophilic leukemia (CEL), and encodes an activated tyrosine kinase that is inhibited by imatinib. FIP1L1-PDGFRA-positive patients with CEL respond to low-dose imatinib therapy, but resistance due to acquired T674I mutation has been observed. We report here the identification of sorafenib as a potent inhibitor of the FIP1 like 1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRalpha) (T674I) mutant. Sorafenib inhibited the proliferation of FIP1L1-PDGFRalpha and FIP1L1-PDGFRalpha(T674I)-transformed Ba/F3 cells and induced apoptosis of the EOL-1 cell line at a low nanomolar concentration. Western blot analysis confirmed that these effects were due to a direct effect on FIP1L1-PDGFRalpha and FIP1L1-PDGFRalpha(T674I). Sorafenib was recently approved for the treatment of renal cell carcinoma. Our data suggest that low doses of sorafenib could be efficient for the treatment of FIP1L1-PDGFRA-positive CEL and could be used to overcome resistance to imatinib associated with the T674I mutation.     

高嗜酸性粒细胞综合征2例报告并文献复习

目的:探讨高嗜酸性粒细胞综合征的诊断及治疗。方法:选取高嗜酸性粒细胞综合征患者2例,对其FIP1L1-PDGFRA融合基因进行检测,结合临床资料进行分析,并复习相关文献。结果:2例中第1例FIP1L1-PDGFRA融合基因为阳性,确诊为慢性嗜酸性粒细胞白血病(CEL),应用甲磺酸伊马替尼治疗效果好,另1例FIP1L1-PDGFRA融合基因阴性,诊断为特发性嗜酸性粒细胞综合征,用糖皮质激素治疗有效。结论:对FIP1L1-PDGFRA融合基因的检测,并结合临床,有助于高嗜酸性粒细胞综合征的诊断及鉴别诊断,并对指导治疗有一定的意义。     

The idiopathic hypereosinophilic syndrome and chronic eosinophilic leukemia

Idiopathic hypereosinophilic syndrome is a heterogenous group of hematological disorders characterized by eosinophilia (> 1.5 x 10(9)/l) persistent for more than 6 months, exclusion of reactive eosinophilia from other causes, such as parasitic infections or allergy, and evidence of end-organ damage. According to World Health Organization the exclusion includes all neoplastic disorders in which eosinophils are part of the neoplastic clone. Excluded should be also T cell population with aberant phenotype and abnormal cytokine production, recently considert also as "lymphocytic" variants of the HES [42]. HES has to be reclassified as chronic eosinophilic leukemia (CEL) when there is evidence for clonality based on the presence of chromosomal abnormalities or inactivation of X-chromosome in female patients. The successful empiric treatment of patients with tyrosine kinase inhibitor imatinib (Glivec) suggested the presence of an imatinib-sensitive tyrosine kinase inhibitor. The identification of a specific intersticial chromosome deletion del(4)(q12;q12) creating the FIP1L1-PDGFRA fusion gene confirmed this hypothesis. Patients carrying this gene should be reclassified as CEL and detection of this gene is a positive predictor for response to imatinib therapy. Effective doses of imatinib are 100 mg/day. The side effects are minimal. The only exception is an acute left ventricular dysfunction which has been reported in three patients within the first week of treatment with imatinib. Imatinib has been successfully used also in some patients with the constitutively activated thyrosine kinase ETV6-PDGFRbeta [1] and in systemic mast cell disease associated with eosinophilia. Other therapeutical options for HES/CEL have been mentioned. The resistence to imatinib and the possibilities how to overcome it are discussed.     

The FIP1L1-PDGFRalpha kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia

PURPOSE OF REVIEW: The idiopathic hypereosinophilic syndrome is a rare hematologic disorder characterized by sustained unexplained eosinophilia with associated end-organ damage and by a striking male predominance. The first insights into the molecular etiology of this heterogeneous disease were obtained from a "bedside-to-bench" approach. Successful empiric treatment of patients with the hypereosinophilic syndrome with the selective tyrosine kinase inhibitor imatinib mesylate (Gleevec, Novartis) ultimately led to the discovery of the FIP1L1-PDGFRalpha fusion kinase in about half of the hypereosinophilic syndrome cases. RECENT FINDINGS: The FIP1L1-PDGFRA fusion gene is generated by a cryptic interstitial chromosomal deletion, del(4)(q12q12), which indicates that these cases are clonal hematopoietic malignancies and should be reclassified as chronic eosinophilic leukemias based on current World Health Organization recommendations. In addition, the FIP1L1-PDGFRA fusion gene was also identified in cases with systemic mast cell disease. In vitro and in vivo studies confirmed that FIP1L1-PDGFRalpha is a therapeutic target of imatinib, forming a rational basis for the treatment of FIP1L1-PDGFRA positive chronic eosinophilic leukemia and mastocytosis with imatinib. Similar to BCR-ABL-positive leukemias, resistance to imatinib due to point mutations in the PDGFRalpha kinase domain may develop. We have explored strategies to circumvent resistance to imatinib using alternative tyrosine kinase inhibitors such as PKC412. SUMMARY: The discovery of the FIP1L1-PDGFRA fusion gene in the hypereosinophilic syndrome is an example of the power of clinical translational research and identifies interstitial chromosomal deletion as a novel mechanism to generate oncogenic tyrosine kinase fusion genes.     

Response to imatinib mesylate in patients with hypereosinophilic syndrome

Idiopathic hypereosinophilic syndrome (HES) is a rare disorder characterized by unexplained, persistent hypereosinophilia associated with multiple organ dysfunctions. The cause of HES is unknown and shows clinical heterogeneity. FIP1L1-PDGFRA fusion is a clonal marker for the diagnosis and treatment of HES. We prospectively studied 78 patients with chronic eosinophilia. In all cases, the most salient clinical and biological characteristics as well as the response to the therapy were analyzed. In addition, we performed conventional cytogenetics and fluorescent in situ hybridization (FISH) with three BACs covering the FIP1-like-1 (FIP1L1)/platelet-derived growth factor receptor-α gene (PDGFRA) fusion. Nineteen of 78 patients (24?%) presented criteria of HES. The majority of patients were male (18) with median age of 49?years (range 19-84?years). FIP1L1-PDGFRA fusion was found in eight patients. Patients with FIP1L1-PDGFRA fusion presented with more bone marrow eosinophils and peripheral blood eosinophilia as well as anemia, leukocytosis and thrombocytopenia. Using of low-dose imatinib mesylate (100?mg/day) a hematological and molecular remission in all patients displaying the FIP1L1-PDGFRA fusion gene was observed. Therefore, imatinib may be effective for use in the treatment of chronic eosinophilic leukemia, and patients should be treated before tissue damage.     

Relapse following discontinuation of imatinib mesylate therapy for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia: implications for optimal dosing

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. This trial was registered at http://www.clinicaltrials.gov as no. NCT00044304.     

Cough and hypereosinophilia due to FIP1L1-PDGFRA fusion gene with tyrosine kinase activity.

Eosinophil-associated conditions, such as asthma and eosinophilic bronchitis, have been associated with chronic persistent cough, usually responding to corticosteroid therapy. This case study reports a case of persistent cough associated with gastro-oesophageal reflux (GOR) and hypereosinophilia. Treatment of GOR with proton pump inhibitors and fundoplication did not control the cough. However, high dose prednisolone, but not inhaled corticosteroids, did. The presence of the FIP1L1-PDGFRA fusion gene in myeloid cells was confirmed by fluorescence in situ hybridisation analysis using CHIC2 deletion as a surrogate marker. The cough and other disease features were subsequently suppressed by the tyrosine kinase inhibitor, imatinib. This is the first case of persistent cough caused by hypereosinophilic syndrome characterised by FIP1L1-PDGFRA fusion gene and aberrant tyrosine kinase activity.     

Response to Imatinib Mesylate in a Patient with Idiopathic Hypereosinophilic Syndrome Associated with Cyclic Eosinophil Oscillations

A 26-year-old man with idiopathic hypereosinophilic syndrome (HES) was treated with imatinib mesylate following a 5-year history of prednisolone therapy. The patient had hypereosinophilia (absolute eosinophil counts >1500/microL) occurring in cyclic oscillations as well as histologically diagnosed eosinophilic vasculitis, bursitis, and periodic soft-tissue swellings. Laboratory data revealed high levels of serum tryptase and increased numbers of mast cells in the bone marrow, but serum interleukin 5 levels were within the normal range. The disease initially responded well to 100 mg/day of imatinib mesylate but recurred 8 weeks later. Thereafter, a daily 200-mg dose was temporarily effective. Despite the response to imatinib, the FIP1L1-PDGFRA fusion gene was not detected by fluorescence in situ hybridization analysis. Additional molecular and cytogenetic studies showed neither translocations of platelet-derived growth factor receptor (PDGFR) genes nor mutations in the c-KIT or the PDGFR genes. Although imatinib mesylate is a choice of treatment for patients with HES, its precise molecular mechanism in individual cases remains to be clarified.     

Successful treatment of myeloid neoplasms associated with PDGFRA rearrangement with imatinib mesylate

Hypereosinophilic syndromes (HES) constitute a rare and heterogeneous group of disorders, defined as persistent and marked blood eosinophilia associated with evidence of eosinophil-induced organ damage. Cardiac dysfunction is the most frequent result of end-organ damage and is the major cause of morbidity and mortality among patients with HES. Despite patients with FIP1-like-1-platelet-derived growth factor alpha (FIP1L1-PDGFRA) associated HES (myeloid neoplasms associated with PDGFRA rearrangement) have been shown to respond to low-dose imatinib with a complete and durable hematological and cytogenetic remission, influences of imatinib on clinical manifestations related to hypereosinophilia heart involvement are variable. Here we describe the case of a young male patient with severe heart involvement who had a prompt, clinical and hematological complete remission following administration of imatinib. However, as endomyocardial fibrosis and related loss of function are deteriorated after initiation of imatinib therapy, valvular replacement and tricuspid annuloplasty had to perform to restore his heart function. Our finding concurs with recent reports that severe heart involvement was irreversible with imatinib treatment. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

伴t(5;12)(q31;p13),FIP1L1/PDGFRα阴性慢性嗜酸细胞白血病一例并文献复习

目的 提高对慢性嗜酸细胞白血病(CEL)的认识水平.方法 报告1例伴t(5;12)(q31;p13),FIP1样基因1(FIP1L1)血小板衍化生长因子(PDGFRα)(-)CEL的诊治过程.外周血及胸腔积液细胞的免疫表型采用流式细胞术(FCM)分析,染色体采用G显带分析,FIP1L1/PDGFRα融合基因表达采用RT-PCR技术检测,骨髓、肺及脾组织行常规病理学检查.结果 1例16岁女性患者严重贫血、发热、脾大、血小板减少、嗜酸细胞显著增高,持续22个月.骨髓嗜酸细胞浸润伴纤维化改变;肺和脾组织均呈嗜酸细胞浸润,伴脾栓塞.克隆性染色体异常为t(5;12)(q31;p13),不表达FIP1L1/PDGFRα融合基因.外周血及胸腔积液细胞中除大量嗜酸细胞外,CD3-、CD4-、CD8+异常T淋巴细胞分别占淋巴细胞总数的5.43%和1.66%.患者对羟基脲、泼尼松、干扰素和甲磺酸伊马替尼(400 ms/d共40 d)治疗无效,小剂量阿糖胞苷、米托蒽醌、长春新碱、环磷酰胺、甲氨蝶呤、泼尼松等联合化疗仅有短期效果.患者最终死于心、肺、肝、肾多脏器功能衰竭.结论 本例FIP1L1/PDGFRα(-)CEL符合WHO诊断标准,对多种药物及甲磺酸伊马替尼治疗无效,应在疾病早期尽早争取造血干细胞移植.CD3-、CD4-、CD8+克隆性T细胞异常与CEL发病的关系值得关注.