Safety and efficacy of imatinib in chronic eosinophilic leukaemia and hypereosinophilic syndrome – a phase‐II study

Metzgeroth, Georgia; Walz, Christoph; Erben, Philipp; Popp, Helena; Schmitt‐Graeff, Annette; Haferlach, Claudia; Fabarius, Alice; Schnittger, Susanne; Grimwade, David; Cross, Nicholas C. P.; Hehlmann, R; Hochhaus, Andreas; Reiter, Andreas

doi:10.1111/j.1365-2141.2008.07294.x

Cited by 125 publications

(100 citation statements)

References 23 publications

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“…These findings were consistent with the results reported for F/P-positive CEL patients [8,9]. We attempted to compare the results of blood tests, which have been reported for F/P-positive CEL patients by two large European groups [8,10] with those provided in this study. We demonstrated almost threefold higher number of median leukocyte and eosinophil counts at diagnosis in the latter cohort.…”

supporting

confidence: 90%

Chronic eosinophilic leukemia‐not otherwise specified has a poor prognosis with unresponsiveness to conventional treatment and high risk of acute transformation

et al. 2012

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Chronic eosinophilic leukemia-not otherwise specified (CEL-NOS) is a rare disorder with hypereosinophilia and an increased number of blood or marrow blast (<20%) or an evidence of eosinophil clonality. We evaluated the clinical outcome of 10 patients with CEL-NOS. Seven males and three females at a median age of 62 years (range, 23-73) were included. The median leukocyte count at diagnosis was 33.4 3 10 9 /l (range, 9.3-175.0) with a median eosinophil count of 15.6 3 10 9 /l (range, 1.5-136.0). Median hemoglobin and platelets were 11.0 g/dl (range, 8.3-13.3) and 158 3 10 9 /l (range, 31.0-891.0), respectively. Clinical manifestations included splenomegaly (n 5 7), hepatomegaly (n 5 6), cardiac failure (n 5 2), and lung infiltrations (n 5 1). Median survival from diagnosis to death for entire cohort was 22.2 months (range, 2.2-186.2). Five of the 10 studied patients developed acute transformation (AT) after median of 20 months from diagnosis (range, 1.6-41.9). None of patients with AT is alive at the time of last follow-up. Median time from AT to death was 2 months (range, 1.0-6.1). Among five patients who did not develop AT, three died in active disease. Two patients are alive in complete remission; first underwent allogeneic stem-cell transplantation preceding by intensive induction chemotherapy; the second remains on imatinib with hydroxyurea. Except the latter patient, imatinib was ineffective in our study population. CEL-NOS is a rare and aggressive disease with high rate of AT and resistance to conventional treatment.Chronic eosinophilic leukemia-not otherwise specified (CEL-NOS) is a rare Philadelphia-negative myeloproliferative neoplasm, which is due to clonal proliferation of eosinophil precursors. Peripheral blood hypereosinophilia (>1.5 3 10 9 /l), an increased number of myeloblasts in blood or marrow (<20%) or an evidence of eosinophil clonality, are required for diagnosis. The cases of myeloid and lymphoid neoplasms with abnormalities of platelet-derived growth factor alpha (PDGFRA), platelet-derived growth factor beta (PDGFRB), and fibroblast growth factor receptor 1 (FGFR1) must be also excluded [1]. In a new WHO classification, CEL-NOS is listed in the category of myeloproliferative neoplasms [2], whereas it was incorporated under the heading of myeloproliferative forms of hypereosinophilic syndromes according to the classification of the Eosinophilic Working Group [3]. Regardless of the classification used, CEL-NOS remains an extremely rare entity with variable prognosis [1,4]. The efficacy of currently used therapeutic agents is limited, and the hematological responses are usually short-lived [5].Ten patients (seven males and three females) at a median age of 62 years (range, 23-73) were included in this study. The median leukocyte count at diagnosis was 33.4 3 10 9 /l with a median eosinophil count of 15.6 3 10 9 /l. Blood smear was dominated by mature eosinophils with a small number of younger forms, for example, eosinophilic myelocytes and promyelocytes. Single eosinophils had dysplastic fe...

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confidence: 90%

Chronic eosinophilic leukemia‐not otherwise specified has a poor prognosis with unresponsiveness to conventional treatment and high risk of acute transformation

et al. 2012

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“…16 Unfortunately, many patients show only a transient or partial response and require treatment with additional agents. Although reported imatinib response rates in PDGFRA-negative HES vary widely (9-60%) depending on the series, 16,[78][79][80] recent data from our center suggest that the presence of myeloproliferative features (presumed clonal eosinophilic involvement) is an important predictor of imatinib response in patients with FIP1L1-PDGFRA-negative HES. Of note, PDGFR-negative patients often require higher doses of imatinib and appear to respond more slowly.…”

Section: Pdgfr-negative M-hesmentioning

confidence: 76%

“…Of note, PDGFR-negative patients often require higher doses of imatinib and appear to respond more slowly. 79,81 Consequently, imatinib (400 mg daily for $4 weeks) is recommended. Patients experiencing a suboptimal or partial response should undergo repeat bone marrow examination, because unmasking of pre-B-cell acute lymphocytic leukemia has been reported in $1 patient with a partial response to imatinib.…”

Section: Pdgfr-negative M-hesmentioning

confidence: 99%

How I treat hypereosinophilic syndromes

Klion

2015

Blood

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126

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Hypereosinophilic syndromes (HESs) are a group of rare disorders characterized by peripheral blood eosinophilia of 1.5 × 109/L or higher and evidence of end organ manifestations attributable to the eosinophilia and not otherwise explained in the clinical setting. HESs are pleomorphic in clinical presentation and can be idiopathic or associated with a variety of underlying conditions, including allergic, rheumatologic, infectious, and neoplastic disorders. Moreover, the etiology of the eosinophilia in HESs can be primary (myeloid), secondary (lymphocyte-driven), or unknown. Although corticosteroids remain the first-line therapy for most forms of HESs, the availability of an increasing number of novel therapeutic agents, including tyrosine kinase inhibitors and monoclonal antibodies, has necessarily altered the approach to treatment of HESs. This review presents an updated treatment-based approach to the classification of patients with presumed HES and discusses the roles of conventional and novel agents in the management of these patients.

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“…4,5 Importantly, the presence of the FIP1L1-PDGFRA fusion gene predicts a favourable response to the small molecule inhibitor imatinib and most positive patients show dramatic responses to therapy with rapid normalization of peripheral eosinophil counts and achievement of nested or real-time quantitative reverse transcription polymerase chain reaction (RQ-PCR) negativity. [6][7][8][9][10] Identification of patients who are positive for FIP1L1-PDGFRA is therefore critical to appropriate clinical management. 11,12 Exclusion of FIP1L1-PDGFRA is also important as some patients may benefit from alternative therapies such as mepolizumab.…”

Section: Introductionmentioning

confidence: 99%

Detection and molecular monitoring of FIP1L1-PDGFRA-positive disease by analysis of patient-specific genomic DNA fusion junctions

et al. 2008

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To evaluate current detection methods for FIP1L1-PDGFRA in hypereosinophilic syndrome (HES), we developed a means to rapidly amplify genomic break points. We screened 202 cases and detected genomic junctions in all samples previously identified as RT-PCR positive (n ¼ 43). Genomic fusions were amplified by single step PCR in all cases whereas only 22 (51%) were single step RT-PCR positive. Importantly, FIP1L1-PDGFRA was detected in two cases that initially tested negative by RT-PCR or fluorescence in situ hybridization. Absolute quantitation of the fusion by real-time PCR from genomic DNA (gDNA) using patient-specific primer/probe combinations at presentation (n ¼ 13) revealed a 40-fold variation between patients (range, 0.027-1.1 FIP1L1-PDGFRA copies/haploid genome). In follow up samples, quantitative analysis of gDNA gave 1-2 log greater sensitivity than RQ-PCR of cDNA. Minimal residual disease assessment using gDNA showed that 11 of 13 patients achieved complete molecular response to imatinib within a median of 9 months (range, 3-17) of starting treatment, with a sensitivity of detection of up to 1 in 10 5 . One case relapsed with an acquired D842V mutation. We conclude that detection of FIP1L1-PDGFRA from gDNA is a useful adjunct to standard diagnostic procedures and enables more sensitive follow up of positive cases after treatment.

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Safety and efficacy of imatinib in chronic eosinophilic leukaemia and hypereosinophilic syndrome – a phase‐II study

Cited by 125 publications

References 23 publications

Chronic eosinophilic leukemia‐not otherwise specified has a poor prognosis with unresponsiveness to conventional treatment and high risk of acute transformation

Chronic eosinophilic leukemia‐not otherwise specified has a poor prognosis with unresponsiveness to conventional treatment and high risk of acute transformation

How I treat hypereosinophilic syndromes

Detection and molecular monitoring of FIP1L1-PDGFRA-positive disease by analysis of patient-specific genomic DNA fusion junctions

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