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Myeloid blast crisis evolving during imatinib treatment of an FIP1L1-PDGFR alpha-positive chronic myeloproliferative disease with prominent eosinophilia


The idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL) are characterized by unexplained, persistent hypereosinophilia. Responses of HES/CEL to treatment with imatinib were reported.1, 2 Recently, FIP1L1-PDGFRalpha was identified as a novel oncogenic fusion tyrosine kinase in cases of HES/CEL2 and systemic mast cell disease with eosinophilia.3 We here report the case of an FIP1L1-PDGFRalpha-positive myeloproliferative disease with prominent eosinophilia with a complete haematologic remission receiving imatinib. This patient subsequently progressed to myeloid blast crisis then harbouring a kinase domain mutation in PDGFRalpha causing imatinib resistance.

Clinical case

A 67-year-old male patient presented with asymptomatic eosinophilia of 1652/mm3. The white blood count (WBC) was 5700/mm3, haemoglobin 15.6 g/dl and the platelet count was 179 000/mm3. Causes for secondary or reactive eosinophilia were excluded. The blood count remained unchanged over a period of 2 years when the eosinophil count increased to 6754/mm3. At that time, the platelet count was 121 000/mm3, and the patient reported back pain and fatigue. Microscopical examination of a bone marrow specimen revealed a hyperplastic marrow with an increased number of mature eosinophils and a modest fibrosis. Cytogenetic studies at that time revealed a normal karyotype and testing for Bcr-Abl was negative. The diagnosis of a chronic myeloproliferative disorder with prominent eosinophilia was made. The patient did not receive any treatment at that time. After 6 months, the patient presented with severe back pain and fatigue. The WBC was 52 700/mm3, haemoglobin was 12.9 g/dl and the platelet count 136 000/mm3. Again, testing for Bcr-Abl was negative. However, RT-PCR from bone marrow mononuclear cells using FIP1-like1 (FIP1L1) forward primers and platelet-derived growth factor receptor alpha (PDGFRalpha) reverse primers indicated a fusion of FIP1L1 exon 9 to PDGFRalpha exon 12. The resulting fusion transcript was identical to fusion sequences that were detected in cases of idiopathic HES.2

Imatinib mesylate 100 mg daily was started. Remarkably, after few days on imatinib, fatigue resolved to normal activity and the back pain disappeared. After 2 weeks of treatment the WBC had decreased to 4000/mm3 with 2% eosinophils. The dose of imatinib had to be reduced temporarily to 100 mg every other day due to grade 4 neutropenia. Clinical condition and blood cell counts remained stable for a period of 5 months. Subsequently, the WBC increased to 29 400/mm3, the platelet count was 139 000/mm3 and haemoglobin 14.8 g/dl. Imatinib was increased to 200 mg and subsequently to 400 mg per day. The WBC remained stable for only a short period. A period of 3 weeks later, 6 months after imatinib was started, the patient presented with fever, chills, and severe night sweats. Radiographic examination of the chest showed both sided pleural effusions. The WBC was 13 600/mm3 with 29% eosinophils and haemoglobin was 11.6 g/dl. A blood film showed eosinophilia and the presence of immature myeloid cells. Microscopic examination of the pleural effusions showed numerous myeloid blasts. Flow cytometric analysis of peripheral blood mononuclear cells displayed a population of myeloid precursors that stained positive for CD34, CD13, CD33, CD117 and CD15. Cytogenetic analysis of bone marrow mononuclear cells now demonstrated an aberrant karyotype with a gain of chromosome 8 that was detected in 17 out of 25 mitoses. The FIP1L1-PDGFRalpha fusion mRNA was still present in bone marrow mononuclear cells. However, sequence analysis at this time revealed a change of nucleotide 2417 of PDGFRalpha from cytosine to thymine, causing an exchange of threonine at amino-acid position 674 to isoleucine. This mutation was identical to the mutation described by Cools and co-workers, and is known to give rise to resistance toward imatinib when the corresponding position (threonine 315) is mutated in Bcr-Abl.4 The diagnosis of a myeloid blast crisis was made. Chemotherapy with mitoxantrone and high-dose cytarabine failed. The patient died 2 months after transformation of his chronic myeloproliferative disease.

The initial disease presentation of the patient under discussion may be classified as an FIP1L1-PDGFRalpha-positive myeloproliferative disease with eosinophilia or CEL that initially presented as HES. To date, no case of progression to blast crisis in patients with HES treated with imatinib has been reported. We here show that FIP1L1-PDGFRalpha gave rise to a myeloproliferative disease that progressed to myeloid blast crisis during continued therapy with imatinib.

The finding of a point mutation in a patient with a blast phase myeloproliferative disease with acquired resistance to imatinib strongly supports the concept of FIP1L1-PDGFRalpha being a potent oncogeneic tyrosine kinase that is sufficient to cause and to maintain a clonal proliferation of myeloid cells. Genetic instability of the malignant clone may lead to point mutations that inhibit binding of imatinib and thus reconstitute active FIP1L1-PDGFRalpha, a situation that resembles Ph+ leukemia where point mutations within the kinase domain of Bcr-Abl constitute the major cause of acquired resistance in patients treated with imatinib.5, 6 Thus, it can be foreseen that an array of different mutations will emerge as the number of patients with FIP1L1-PDGFRalpha-positive disorders treated with imatinib increases.

No dose finding studies for imatinib in HES or myeloproliferative disorders associated with fusions of PDGFRalpha have been carried out until now. Most HES/CEL patients reported so far responded to imatinib doses of 100 mg per day. FIP1L1-PDGFRalpha was found to be much more sensitive to inhibition by imatinib than Bcr-Abl: The IC50 values that have been reported were 3.2 nM for FIP1L1-PDGFRalpha and 250 nM for Bcr-Abl, respectively.2, 5 In previously untreated, chronic phase CML it has been reported that imatinib at 800 mg per day resulted in higher rates of complete cytogenetic and molecular remissions when compared to standard doses of 400 mg daily.7 In HES/CEL, suboptimal dosing as in the case reported may affect response rates, accelerate the emergence of resistance and thus facilitate transformation to blast crisis. It will be important to determine whether treatment of FIP1L1-PDGFRalpha-positive myeloproliferative disease with imatinib doses higher than 100 mg per day translates in a higher proportion of haematologic, cytogenetic and molecular remissions and lower rates of acquired resistance.


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Correspondence to J Duyster.

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von Bubnoff, N., Sandherr, M., Schlimok, G. et al. Myeloid blast crisis evolving during imatinib treatment of an FIP1L1-PDGFR alpha-positive chronic myeloproliferative disease with prominent eosinophilia. Leukemia 19, 286–287 (2005).

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