Successful Treatment for Chronic Eosinophilic Leukemia ( CEL ) with Imatinib Mesylate

We report a case of a patient with Chronic Eosinophilic Leukemia (CEL) with mutation in alfa PDGFR gene exhibiting a satisfactory response to treatment with imatinib mesylate. A 25-year-old man presented in a hematology service with a persistent cough and hemogram alterations. His blood count showed a hemoglobin level of 12.5 g/dL and a white blood cell count of 94,030/mm3, eosinophils were 68% of all cells. Bone marrow aspiration and biopsy showed hypercellularity with marked eosinophilia (77%) and erythroid differentiation series was hypocellular with normoblast maturation. The immunohistochemically of the bone biopsy was positive for myeloperoxidase and negative for CD34/CD99, consistent with CEL. Fluorescence in situ hybridization (FISH) for the beta-fraction of platelet-derived growth factor (PDGFRβ) and Philadelphia chromosome (Ph 1) were negative and the alfa PDGFR (Platelet-Derived Growth Factor) was positive and showed heterozygosis in c.2531T>C on 18 Exon and homozygous in C.2562+1G>A at the region of the splicing site at the 18 intron. Treatment was initiated and maintained by administering 400mg/day imatinib mesylate. Laboratory findings returned to normal ranges, with clinical improvement and a hematological response observed after the second month of therapy. Currently, the patient’s blood count shows the white blood cell count (5,400 total leukocytes), eosinophils (8.6/mm3), hemoglobin (15.5 g/dl), hematocrit (45.4%) and platelets (298,000/mm3) within normal ranges. The mutation search was negative in in peripheral blood one year after the initial treatment. Our work corroborates other studies on the efficacy of imatinib mesylate in the treatment of paSuccessful Treatment for Chronic Eosinophilic Leukemia (CEL) with Imatinib Mesylate CASE REPORT


Introduction
Blood and tissue eosinophilia is associated with several conditions.Elevation of eosinophil levels may have different origins, such as helminthic parasitic infection, inflammation, hypersensitive drug reaction, adrenal insufficiency, and collagen diseases, in which cases the eosinophilia is classified as reactive [1,2,3].In reactive eosinophilia, the primary mechanism consists of an increase in interleukin production, especially that specific for eosinophil differentiation, interleukin-5 (IL-5).
Another cause of eosinophilia consists of a primary molecular failure involving hematopoietic stem cells and/or defects in signal transduction from eosinophilopoiesis-mediating receptors, which can cause clonal proliferation; these mechanisms underlie tumor-induced eosinophilia and in these cases eosinophilia is classified as a primary disease [4,5].
Diagnostic evaluation of primary eosinophilia is based on a combination of morphological analysis of the blood and marrow, cytogenetic evaluation, fluorescence in situ hybridization, flow immunocytometry, and evaluation of T cell clonally to detect histopathological or clonal evidence of an acute myeloid or lymphoproliferative disease or chronic.Screening for structural changes to primary eosinophilia should begin with peripheral blood analysis for fusion of the FIP1L1-PDGFRα gene.The absence of FIP1L1-PDGFRα fusion should stimulate the evaluation of other primary eosinophilia associated with recurrent molecular abnormalities [7].
In the absence of the Philadelphia chromosome, the rearrangement involving PDGFRα-FGFR1/ PDGFRβ/TEL, and no identification of other acute or chronic marrow neoplasias that present with eosinophilia, we are facing a CEL NOS [7,8].Patients with mutations in the platelet-derived growth factor receptor (PDGFR) genes respond well to imatinib mesylate therapy [9].This drug is a potent inhibitor of alpha and beta growth factors, which stimulate kinase activity [10].These structural alterations tend to occur predominantly in men, between the second and fifth decade of life [11].
In view of the above, the objective of our study was the diagnostic elucidation of a patient who was admitted with eosinophilic leukemia hypothesis to be clarified.Therefore, we report a case of pacient with mutacion in gene PDGFR alfa exhibiting a satisfactory response to treatment with imatinib mesylate.
tients with CEL PDGFR alpha positive.We emphasize the importance of molecular studies, considering its relevance for the correct staging of the disease.Since CEL is a rare disease, it is important to define its etiology and anticipate its treatment, thus minimizing the damage induced by the disease.

Case report
A 25-year-old man was referred to the hematology service of Napoleão Laureano Hospital for diagnosis of a persistent cough and blood count alterations.Physical examination did not show adenomegaly or visceromegaly.On admission, the patient presented with a hemoglobin level of 12.5 g/dL, and a white blood cell count of 94,030/mm 3 , 68% of which were eosinophils.Data from laboratory monitoring of the patient, from the time of admission, are described in Figure 1, 2.
Laboratory assays testing for human lymphotropic T virus (HTLV), human immunodeficiency virus (HIV), Venereal Disease Research Laboratory (VDRL test), virus hepatitis C and B (HCV and HBsAg B), serum antigen antinuclear factor, C-reactive protein, anti-DNA antibody, and mucoprotein were negative.Protein electrophoresis exhibited a polyclonal hypergammaglobulinemia pattern.Biochemical tests for kidney and liver functions revealed no changes; an echocardiogram revealed discrete right atrial hypertrophy.Computed tomography scans of the chest and abdomen were normal.Parasitic diseases were excluded by laboratory analysis and prophylactic treatment.
The myelogram and bone marrow biopsy (BMB) showed hypercellular bone marrow with eosinophilic proliferation, respectively, 73% and 95% immature cells, and an absence of fibrosis, suggesting eosinophilic leukemia, as shown in Figure 3, A.   Source: Image captured by authors.
The immunohistochemical study was positive for myeloperoxidase and negative for CD34/CD99, consistent with eosinophilic leukemia, as shown in Figure 3B.Bone marrow aspiration and biopsy showed hypercellularity with marked eosinophilia (77%).An erythroid differentiation series was hypocellular with normoblast maturation.Fluorescence in situ hybridization (FISH) for the beta-fraction of platelet-derived growth factor (PDGFRβ) and Philadelphia chromosome (Ph 1) were negative.
Genetic analysis of PDGFR alpha was performed using the PCR-DNA technique, with material obtained from the bone marrow, followed by bidirectional sequencing and analysis of exons 10, 12, 14 and 18.The mutations identified were heterozygosis in c.2531T>C on 18 exon and homozygous in C.2562+1G>A at the region of the splicing site at the 18 intron.
Treatment was initiated and maintained by administering 400 mg/day imatinib mesylate.The patient became asymptomatic and the laboratory findings returned to normal ranges, with clinical improvement and a hematological response observed after the second month of therapy.Currently, the patient's hemogram shows the white blood cell count (5,400 total leukocytes), eosinophils (8.6/ mm 3 ), hemoglobin (15.5 g/dl), hematocrit (45.4%) and platelets (298,000/mm 3 ) within normal ranges.
Under various conditions, eosinophils can produce and release a variety of biologically active substances that can invade target organs and cause dysfunction and/or damage.The harmful role of eosinophils results from their inflammatory, fibrotic, and thrombotic properties [12].
The diagnosis may be incidental due to laboratory findings or clinical manifestations such as pruritus, constitutional symptoms, and symptoms related to multisystem injury [13].Tissue infiltration occurs in several organs and systems, especially the heart, lungs, skin, central and peripheral nervous system, and gastrointestinal tract.The main mechanism promoting injury is the release of cytokines and the impact of the cytokines on several targets [4,14].
While patients are commonly referred to the competent services with complaints of the respiratory tract, heart disease is the leading cause of morbidity and mortality, occurring in up to 50% of cases [15].Endomyocardial fibrosis progresses into restrictive cardiomyopathy, apart from the thickening and fibrosis of the atrioventricular valves, with valve regurgitation and formation of intracardiac thrombi [13,14].
Specific therapies may potentially prevent morbidity and mortality, if started early.When investigating cytogenetic causes involved in the etiology of eosinophilia, the identification of PDGFRα or PDGFRβ rearrangements is critical because of the good response to treatment with imatinib mesylate [6].Among the available therapies, imatinib mesylate is consider the first choice in the treatment of CEL positive for when these mutations are positive [1,9,10,12].The drug is also used as therapy for the treatment of chronic myeloid leukemia and patients who are treated with the standard dose have favorable outcomes [16].
The first report of treatment with imatinib mesylate for Idiopathic Hypereosinophilia was in 20 January 2017.Cases of hypereosinophilic syndrome patients were published, highlighting rapid and complete hematological responses to imatinib mesylate 100-400 mg per day [18,19].
The identification of FIP1L1-PDGFRA translocation as a therapeutic target of this drug redefined such cases as a form of chronic eosinophilic leukemia, WHO category of "Myeloid and lymphoid neoplasms with eosinophilia and Abnormalities of PDGFRα, PDGFRβ or FGFR1 [17].
Cytogenetic differences have an impact on the response to treatment with imatinib mesylate when PDGFRA and PDGFRB are compared.The starting dose recommended by the FDA for patients with the FIP1L1-PDGFRA rearrangement is 100 mg per day.Cumulative data with long-term follow-up indicate that this dose is sufficient to cause complete and long-lasting hematological remissions.For patients with rearranged eosinophilia and PDGFRB myeloid neoplasms, the recommended dose is 400 mg per day [7].
There have been reports of patients with CEL NOS or Hypereosinophilic Syndrome who benefited from imatinib mesylate when given at doses higher than 400 mg per day [20].In our patient, four months elapsed between the diagnosis and the start of treatment; complete hematologic response occurred in the second month of treatment with a dosage of 400 mg/day, In agreement with the results found in the literature when referring to similar cases [21].
It is consensus in the literature on the satisfactory response of CEL with PDGFRα ou PDGFRβ B e FGFR1 positive's for mesylate imatinib [16,17,19].Thus, our patient has been undergoing treatment for 25 months and is clinically and laboratory stably in outpatient follow-up.

Conclusion
In our study, the efficacy of imatinib mesylate in the treatment of patients with CEL PDGFR alpha positive, in which we were successful in the treatment was verified.We recommend molecular screening using the PCR technique for future studies and we consider it essential for the correct staging of our case, since the FISH technique did not allow the diagnostic elucidation of the case under study.We highlight that since CEL is a rare disease, it is important to define its etiology and anticipate its treatment, thus minimizing the damage induced by the disease.The main contribution of our work is because it is a rare form of CEL and is the first case of eosinophilic leukemia with mutations in the PD-GFR alpha reported in northeastern Brazil.

Informed Consent
Informed consent was obtained from the patient included in the study

Figure 1 :
Figure 1: Evolution of the patient's white blood cell count during treatment with imatinib mesylate.

Figure 2 :
Figure 2: Evolution of the patient's eosinophil percentage during treatment with imatinib mesylate.