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| CASE REPORT |
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| Year : 2015 | Volume
: 6
| Issue : 3 | Page : 125-129 |
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Chronic eosinophilic leukemia-not otherwise specified transformation into acute myeloid leukemia
Kshitija Kasturi1, Sana Vanajakshi2
1 Department of Pathology, Apollo Institute of Medical Sciences and Research, Apollo Hospitals, Hyderabad, Telangana, India
2 Department of Hematology and Clinical Pathology, Apollo Hospitals, Hyderabad, Telangana, India
| Date of Web Publication | 18-Sep-2015 |
Correspondence Address:
Kshitija Kasturi
Department of Pathology, Apollo Institute of Medical Sciences and Research, Apollo Health City Campus, Jubilee Hills, Hyderabad - 500 096, Telangana
India
 Source of Support: Nil., Conflict of Interest: There are no conflicts of interest.  | Check |
DOI: 10.4103/1658-5127.162580
Chronic eosinophilic leukemia-not otherwise specified (CEL-NOS) is a rare disorder with hypereosinophilia and an increase number of blood or marrow blasts (<20%) or an evidence of eosinophilic clonality. It is an aggressive disorder with a high rate of acute transformation and resistant to conventional treatment. Its clinical and pathological picture vaguely overlap and adds to diagnostic confusion with idiopathic hypereosinophilic syndrome (IHES) which is characterized by sustained overproduction of eosinophils over a period of 6 months with multiple organ damage. Due to the difficulty in distinguishing CEL from IHES, the true incidence of this disease is rare. We report a case of CEL-NOS, which was preceded by IHES and terminated in acute myeloid leukemia with maturation (M2) in a 38-year-old male. Keywords: Acute myeloid leukemia with maturation, chronic eosinophilic leukemia-not otherwise specified, idiopathic hypereosinophilic syndrome
How to cite this article:
Kasturi K, Vanajakshi S. Chronic eosinophilic leukemia-not otherwise specified transformation into acute myeloid leukemia. J Appl Hematol 2015;6:125-9 |
How to cite this URL:
Kasturi K, Vanajakshi S. Chronic eosinophilic leukemia-not otherwise specified transformation into acute myeloid leukemia. J Appl Hematol [serial online] 2015 [cited 2023 Sep 27];6:125-9. Available from: https://www.jahjournal.org/text.asp?2015/6/3/125/162580 |
| Introduction | |  |
Chronic eosinophilic leukemia-not otherwise specified (CEL-NOS) constitute a new entity within WHO classification.[1] It seems to be a rare disorder, and its true incidence is unknown. Recently reported study using Surveillance, Epidemiology and End results data from 2001 to 2005 an incidence of 0.036/100,000 person-years, but this calculation comprised patients with hypereosinophilic syndrome.[2] The rarity of CEL-NOS is further compounded by a variety of other disease process accompanied by chronically persistent eosinophilia. Patients with idiopathic hypereosinophilic syndrome (IHES) at presentation in whom a diagnosis of CEL becomes possible in retrospect when transformation to acute myeloid leukemia (AML) provides direct evidence that the condition was likely to have been a clonal, neoplastic, myeloproliferative disorder from the beginning. Here, we intent to present this rare entity who presented with IHES which progressively was transformed to CEL-NOS and finally terminated into AML-M2.
| Case Report | | |
In April 2009, a previously healthy 34-year-old man presented with fever, insidious onset of macular skin rash all over the body, shortness of breath, and cough. The patient was not taking any medications, had no reported allergies, no history of an infectious process, no family history consistent with the symptoms, and no other significant history in his past medical history. Computed tomography of chest and abdomen showed subtle thickening in both the lungs and mild splenomegaly, respectively. Echocardiogram showed trivial mitral regurgitation. The complete blood picture showed hemoglobin of 10.7 g/dl (11–16 g/dl), white blood cell count of 17.8 × 103/mm 3 (4–11 × 103/mm 3), and platelet count of 140 × 103/mm 3 ( 140–440 × 103/mm 3). Mean corpuscular volume (MCV) was 78 fl (80–100 fl), mean corpuscular hemoglobin (MCH) was 26.1 pg (27–34 pg) and MCH concentration (MCHC) was 33.5 g/dL (32–36 g/dl). The differential count indicated 70% eosinophils, 11% neutrophils, 11% lymphocytes, 3% monocytes, 3% basophils, and 2% myelocytes [Figure 1]. Urine and stool were negative for parasites. Bone marrow aspiration revealed normal erythropoiesis, megakaryopoiesis, and increased granulopoiesis with myelogram showing 29% neutrophils, 20% normoblasts, 25% eosinophils, 15% eosinophilic myelocytes, 4% eosinophilic metamyelocytes, 3% myelocytes, 1% band form, 2% basophils, 1% lymphocyte [Figure 2]. Bone marrow biopsy showed similar findings with prominence of eosinophils and eosinophilic myelocytes [Figure 3]. Interstitium showed increased fibrosis with reticulin grade 3 fibrosis [Figure 4]. A diagnoses suggestive of IHES was given, and the patient was put on prednisone 60 mg. On regular follow-up, every month his shortness of breath continued with persistent eosinophilia. In January 2010 he had an episode of fever and moderate splenomegaly on abdominal palpation. His complete blood picture showed hemoglobin of 10 g/dl, white blood cell count of 26.7 × 103/mm 3 and platelet count of 101 × 103/mm 3. MCV was 84 fl, MCH was 28.2 pg and the MCHC was 33.5 g/dl. The differential count indicated 63% eosinophils, 3% blast, 25% neutrophils, 8% lymphocytes, and 1% myelocytes. On blood smear dyspoietic eosinophils showing both basophilic and eosinophilic granulation and cytoplasmic vacuolation seen [Figure 1]. Bone marrow aspiration revealed decreased erythropoiesis and megakaryopoiesis with increased granulopoiesis showing dyspoietic eosinophilopoiesis with trilobed nuclei [Figure 2]. Myelogram revealed 28% neutrophils, 16% normoblast, 14% eosinophils, 2% lymphocytes, 1% basophil, 6% blasts, 15% eosinophilic metamyelocytes, 14% myelocytes, 1% metamyelocyte, and 3% band form. The biopsy showed similar findings with grade 3 fibrosis [Figure 3] and [Figure 4]. Cytogenetic abnormalities were not detected by conventional karyotyping, BCR/ABL rearrangement, Fip 1–like 1 platelet-derived growth factor receptor alpha (FIP1L1-PDGFRα) fusion gene and JAK2V617F mutations were negative. Correlating with the above findings a diagnosis of CEL-NOS was given. Patient was put on prednisone 60 mg, 1000 mg hydroxyurea and 80 mg febuxostat. Hydroxyurea is a myelosuppressive drug used to lower the eosinophil count whereas febuxostat is a xanthine oxidase inhibitor used to bring down the uric acid levels in the blood. He was on regular follow-up till mid of 2012 and had persistent eosinophilia, so he resorted to ayurvedic medicine, the details of which were not known. In December 2013 patient condition deteriorated with dyspnea, decrease urine output, drowsiness, hepatomegaly, and massive splenomegaly on palpation. His biochemical parameters showed deranged hepatorenal dysfunction with alkaline phosphatase - 288 U/L (50–136 U/L), gamma glutamyl transpeptidase - 316 U/L (15–85 U/L), total bilirubin - 1.8 mg/dl (≤1 mg/dL), plasma ammonia - 120 µmol/L (11–32 µmol), lactate dehydrogenase - 2406 U/L (85–227 U/L), urea - 58 mg/dL (15–38 mg/dL), urea nitrogen - 27 mg/dL (7–18 mg/dL), creatinine - 1.5 mg/dL (0.8–1.3 mg/dL), and uric acid - 13.8 mg/dL (3.5–7.2 mg/dL). His complete blood picture showed hemoglobin of 9.6 g/dL, white blood cell count of 15.4 × 103/mm 3 and platelet count of 15 × 103/mm 3. MCV was 89 fl, MCH was 28.4 pg and the MCHC was 32.5 g/dL. The differential count indicated 63% eosinophils, 9% blasts, 15% neutrophils, 12% lymphocytes, and 1% myelocyte [Figure 1]. Bone marrow aspiration revealed decreased erythropoiesis and megakaryopoiesis with increased granulopoiesis showing prominence of blasts with dyspoietic eosinophilopoiesis. Myelogram revealed 28% neutrophils, 15% normoblast, 13% eosinophils, 14% lymphocytes, 20% blasts, 4% metamyelocytes, 6% myelocytes [Figure 2]. The biopsy also showed similar findings with grade 3 fibrosis [Figure 3] and [Figure 4]. Cytogenetic abnormalities were not detected. Immunophenotyping by flow cytometry on bone marrow aspiration revealed CD45/side scatter gated population of 38.7% blasts (dim expression). These blasts showed positivity for CD45, CD34, CD13, CD15, CD33, CD117, and cMPO. Monocyte lineage marker (CD64), B and T lineage markers were negative [Figure 5]. Correlating with above findings, a diagnosis of AML with maturation was given. In 2 weeks, time patient died of cardiopulmonary arrest, septic shock with multiorgan damage. | Figure 1: Blood smear shows chronic eosinophilic leukemia with dyspoietic eosinophilic metamyelocte and a blast. Top inset shows human embryonic stem with prominence of eosinophils and a myelocyte. Down inset shows acute myeloid leukemia M2 showing 2 blasts and a dyspoietic eosinophil (leishman stain, ×100)
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 | Figure 2: Bone marrow aspiration cytology shows chronic eosinophilic leukemia with dyspoietic eosinophils with its precursors and a blast. Top inset shows human embryonic stem with prominence of eosinophils and its precursors. Down inset shows acute myeloid leukemia M2 with a predominance of blasts (giemsa stain, ×100)
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 | Figure 3: Bone marrow biopsy shows chronic eosinophilic leukemia with dyspoietic eosinophil and a blast. Up inset shows human embryonic stem with prominence of eosinophils and its precursors. Down inset shows acute myeloid leukemia M2 with a predominance of blasts (H and E, ×100)
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 | Figure 4: Bone marrow biopsy shows interstitium with increased fibrosis, grade 3 on a scale of 0-3 (reticulin, ×100)
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 | Figure 5: Flow cytometric analysis of diagnostic markers in acute myelocytic leukemia (M2). (a) Blasts are identified by CD45/SSC gating, showing 38.7% expression (dim expression). These blast showed (b) 99.9% CD45 (dim expression), 38.9% CD34 (dim to moderate expression), with following lineage markers as follows (c) 53.8% CD13 (dim expression), 1% CD14, (d) 56.7% CD15 (dim to moderate expression), 80.7% CD33 (dim expression), (e) cMPO (dim expression, 1% CD79a, (f) 19.8% CD117 (dim expression), (g) 0.7% cCD3, (h) 0.2% CD7, 0.8% CD19, (i) 15.2% CD64 monocyte lineage marker CD64 (dim expression)
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| Discussion | | |
Acquired eosinophilia is operationally categorized into secondary, clonal, and idiopathic types. Causes of the secondary eosinophilia include parasite infections, allergic or vasculitis conditions, drugs, and lymphoma. IHES is a myeloproliferative disorder characterized by persistent eosinophilia with damage to multiple organs. In 1975, Chusid et al. defined 3 features required for a diagnosis of hypereosinophilic syndrome.[3] A sustained absolute eosinophil count >1500/µl is present, which persists for longer than 6 months. No identifiable etiology for eosinophilia is present. Patients must have signs and symptoms of organ involvement. The tissue damage is due to eosinophil granules containing toxic cationic protein which includes major basic protein, eosinophil peroxidase, eosinophil-derived neurotoxin, and cationic protein. Free radicals produced by the eosinophilic peroxidase and the respiratory burst oxidative pathway of the infiltrating eosinophils further enhance the damage. The median age at hypereosinophilic syndrome diagnosis is 52.5 years with a male to female ratio ranging from 1.47 to 9, and a reported 10 years survival rate is <50%.[2] Our patient was male and was 34 years at the initial presentation of hypereosinophilic syndrome and died within 5 years of time. While HES and CEL are both characterized by unexplained, persistent hypereosinophilia, there are important differences. Idiopathic HES is a diagnosis of exclusion, whereas CEL requires positive identification of features indicative of leukemia, such as increased blast cells or evidence of clonality. The two disorders are mutually exclusive. CEL-NOS constitutes a rare entity within the WHO 2008 classification with following criteria.[1],[4],[5] Unexplained eosinophilia >1.5 × 109/L. No BCR-ABL fusion gene or myeloproliferative neoplasm (polycythemia vera, essential thrombocythemia, primary myelofibrosis) or myelodysplastic syndrome/myeloproliferative neoplasm. No t (5,12)(q31–35;p13) or rearrangement PDGFRB. No FIP1L1-PDGFRA fusion gene or FGFR1 rearrangements. No inv (16)(p13.1q22) or t (16;16)(p13.1;q22) or features of AML. The presence of >2% or 5% blasts (but <20%) in the peripheral blood or bone marrow, respectively [Figure 6]. Our case was diagnosed as CEL-NOS after 9 months of presenting as IHES with absolute eosinophilic count of 16,821/uL, 3% and 6% blasts in peripheral blood and bone marrow, respectively, with no abnormal molecular cytogenetics. FIP1L1-PDGFRα is present in only 10–20% of all patients with suspected nonreactive eosinophilia and is associated with increased disease severity due to constitutive tyrosine kinase activity of PDGFRα.[2] Recently, several activating mutations in PDGFRα have been identified in FIP1L1-PDGFRα-negative patients.[2] This set of activating mutations induces clonogenic growth, growth factor-independent cell proliferation and constitutive phosphorylation of PDGFRα and signal transducer and activator of transcription 5 and is thought to play a role in the pathogenesis of CEL. CEL is a rare Philadelphia negative myeloproliferative neoplasm, the incidence is highest in the fourth decade of life and the disease most commonly affects males.[6] Unlike clonal eosinophilic disorders secondary to PDGFRA and PDGFRB translocations, the WHO-defined CEL-NOS entity is not responsive to imatinib mesylate monotherapy. Furthermore, its prognosis is poor as it is characterized by an aggressive clinical course that is usually unresponsive to conventional chemotherapy and frequently transforms to acute leukemia.[7] In a trial consisting a cohort of 10 patients, the median survival was 22 months, five of whom developed acute transformation to leukemia after a median of 20 months from diagnosis.[8] One of the five patients who did not develop acute myeloid underwent an allogeneic stem-cell transplant and maintained a long-term remission.[8] Median time from acute transformation to death is 2 months (range, 1.0–6.1).[8] Our patient did not respond to steroid or hydroxyurea, nor bone marrow transplantation was planned and transformed to AML-M2 with progressive splenomegaly within a 4 years time from the diagnosis of CEL-NOS. Death occurred in 2 weeks of time after the onset of acute transformation. Although imatinib displays high rates of response in patients with FIP1L1-PDGFRα mutations, the response is less robust in patients without this abnormality, as seen in our case. Because of small number of reported cases and variable clinical course, which can range from cases with decades of stable disease to those with rapid progression to acute leukemia, it is extremely difficult to propose therapeutic scheme. Single case reports showed encouraging responses to interferon α in terms of diseases control and some patients even experienced cytogenetic remission.[8],[9] The role of allogenic stem-cell transplantation remains only curative option for younger and fit patients with CEL-NOS, though not well-established but appears to be the only curative option available.[8] Unfortunately, most patients with CEL-NOS are at advanced age and have significant comorbidities. This case highlights the occurrence of CEL-NOS in a patient who presented with IHES not responded to prednisone or hydroxyurea and finally terminated and died due to AML-M2 in 4 years duration. | Figure 6: Algorithmic approach to arriving at diagnosis of chronic eosinophilic leukemia, not otherwise specified
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Acknowledgment
The authors acknowledge the patient for sharing the clinical information and samples. And also technical support from Mr. Suresh for flow cytometry.
Financial Support and Sponsorship
Nil.
Conflicts of Interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
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