Myeloid blast crisis evolving during imatinib treatment of an FIP1L1-PDGFR alpha-positive chronic myeloproliferative disease with prominent eosinophilia [1]

Indications:1 patient with chronic myeloproliferative disorder and eosinophilia.

Patients:One 67-year-old male patient.

TypeofStudy:This case report described a patient with FIP1Ll- platelet derived growth factor receptor alpha (PDGFRalpha)-positive myeloproliferative disease with prominent eosinophilia who achieved a complete hematologic remission while receiving Glivec. This patient, however, subsequently progressed to myeloid blast crisis then harboring a kinase domain mutation in PDGFRalpha causing Glivec resistance. Letters to the editor.

DosageDuration:Initially, 100 mg daily then reduced to 100 mg every other day. After 5 months, dose was increased to 200 mg and subsequently to 400 mg daily. Duration: at least 6 months.

Results:After few days on Glivec, 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. Because of the occurrence of grade 4 neutropenia, the dose of Glivec had to be reduced temporarily to 100 mg every other day. Clinical condition and blood cell counts remained stable for a period of 5 months. Subsequently, the WBC increased to 29400/mm³, the platelet count was 139000/mm³ and hemoglobin 14.8 g/dl. Glivec was increased to 200 mg and subsequently to 400 mg per day. The WBC remained stable for only a short period. 3 weeks later, 6 months after Glivec 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 13600/mm³ with 29% eosinophils and hemoglobin was 11.6 g/dl. 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 demonstrated an aberrant karyotype with a gain of chromosome 8 that was detected in 17/25 mitoses. The FlPlL1-PDGFRalpha fusion mRNA was still present in bone marrow mononuclear cells. However, sequence analysis revealed a change of nucleotide 2417 of PDGFRalpha from cytosine to threonine, causing an exchange of threonine at amino acid position 674 to isoleucine. Mitoxantrone and high dose cytarabine chemotherapy failed. The diagnosis of a myeloid blast crisis was made. The patient died 2 months after transformation of his chronic myeloproliferative disease.

AuthorsConclusions: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 F1P1L1-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 FlP1Ll-PDGFRalpha, a situation that resembles Ph+ [Philadelphia chromosome-positive] leukemia where point mutations within the kinase domain of Bcr-Abl constitute the major cause of acquired resistance in patients treated with imatinib. Thus, it can be foreseen that an array of different mutations will emerge as the number of patients with FlP1Ll-PDGFRalpha-positive disorders treated with imatinib increases. It will be important to determine whether treatment of FIP1Ll-PDGFRalpha-positive myeloproliferative disease with imatinib doses higher than 100 mg per day translates in a higher proportion of haematologic [sic], cytogenetic and molecular remissions and lower rates of acquired resistance. In HES [hypereosinophilic syndrome]/CEL [chronic eosinophilic leukemia] suboptimal dosing as in the case reported may affect response rate, accelerate the emergence of resistance and thus facilitate transformation to blast crisis.

AdverseEffects:The patient developed grade 4 neutropenia.

FreeText:Patients were switched to Exelon following deterioration in their cognitive performance during donepezil treatment. The patient presented with asymptomatic eosinophilia of 1652/mm³. White blood count (WBC) was 5700/mm³, hemoglobin 15.6 g/dl and the platelet count 179000/mm³. Causes for secondary or reactive eosinophilia were excluded. Blood count remained unchanged over a period of 2 years when the eosinophil count increased to 6754/mm³. The platelet count was 121000/mm3, and the patient had back pain and fatigue. Bone marrow specimen revealed a hyperplastic marrow with an increased number of mature eosinophils and fibrosis. Cytogenetic studies revealed a normal karyotype and Bcr-Abl was negative. The diagnosis of a chronic myeloproliferative disorder with eosinophilia was made. After 6 months, the patient presented with severe back pain and fatigue. WBC was 52700/mm³, hemoglobin 12.9 g/dl and the platelet count 136000/mm³. Testing for Bcr-Abl was negative. However, reverse-transcription polymerase chain reaction from bone marrow mononuclear cells indicated a fusion of FlP1L1 exon 9 to PDGFRalpha exon 12. Glivec therapy at a dose of 100 mg daily was started. Other tests: chest radiography, blood smear, flow cytometry, and cytogenetics (metaphase chromosome analysis and sequence analysis).