Chronic Eosinophilic Leukemia-not Otherwise Specified Research Articles

Clinical Profile and Treatment in Hypereosinophilic Syndrome Variants: A Pragmatic Review

Hypereosinophilic syndrome (HES) is a group of rare hematologic disorders leading to eosinophil-driven tissue damage and dysfunction. Better understanding of HES variants may facilitate improved patient management. To describe disease characteristics, treatment, and outcomes of patients with idiopathic (I-HES), myeloproliferative (M-HES), lymphocytic (L-HES), and chronic eosinophilic leukemia, not otherwise specified (CEL-NOS) among HES case reports and aggregate data where available. Relevant articles published between January 1, 2000, and March 20, 2020, were retrieved via PubMed; those reporting secondary, associated/reactive, overlap/single-organ, or familial HES were excluded. Of 188 articles included, 171 contained data on 347 separate HES cases (152 I-HES, 121 M-HES, 62 L-HES, 12 CEL-NOS). Based on individual data, mean age at diagnosis was 43 to 48 years for patients with all HES variants. Males accounted for 90% to 91% of M-HES/CEL-NOS and 55% to 65% of I-HES/L-HES cases. Cardiac symptoms were frequently observed for all HES variants (13%-22% of patients). Respiratory symptoms (I-HES), splenomegaly (M-HES and CEL-NOS), and skin conditions (L-HES) were also frequently observed. Bone marrow, heart, lung, spleen, liver, skin, and lymph nodes were commonly involved. Most patients with I-HES, L-HES, and CEL-NOS received corticosteroids (65%-85%), whereas most with M-HES received imatinib (81%); those with CEL-NOS also received interferon alpha (42%). Collective analysis of HES case reports supports and extends current understanding of HES variants, highlighting differences in signs and symptoms, organ involvement, and treatment approaches. Improved characterization of HES variants may facilitate the development of novel treatments.

Gene therapy in a murine model of chronic eosinophilic leukemia-not otherwise specified (CEL-NOS).

Chronic eosinophilic leukemia-not otherwise specified (CEL-NOS) is a rare, aggressive, fatal disease characterized by blood eosinophilia and dysfunction of organs infiltrated with eosinophils. Clinically, the disease manifests with weight loss, cough, weakness, diarrhea, and multi-organ dysfunction that is unresponsive to therapy. We developed a one-time gene therapy for CEL-NOS using an adeno-associated virus (AAV) expressing an anti-eosinophil monoclonal antibody (AAVrh.10mAnti-Eos) to provide sustained suppression of eosinophil numbers in blood, thus reducing eosinophil tissue invasion and organ dysfunction. A novel CEL-NOS model was developed in NOD-scid IL2rγnull (NSG) mice by administration of AAV expressing the cytokine IL5 (AAVrh.10mIL5), resulting in marked peripheral and tissue eosinophilia of the heart, lung, liver, and spleen, and eventually death. Mice were administered AAVrh.10mAnti-Eos (1011 genome copies) 4 wk after administration of AAVrh.10mIL5 and evaluated for anti-eosinophil antibody expression, blood eosinophil counts, organ eosinophil invasion, and survival. AAVrh.10mAnti-Eos expressed persistent levels of the anti-eosinophil antibody for >24 wk. Strikingly, CEL-NOS treated mice had markedly lower blood eosinophil levels and reduced mortality when compared with control treated mice. These results suggest that a single treatment with AAVrh.10mAnti-Eos has the potential to provide substantial therapeutic benefit to patients with CEL-NOS, a fatal malignant disorder.

Update on CML-Like Disorders

Chronic myeloid leukemia (CML) is defined for many years as BCR-ABL1 positive disease, but older publications refer to a poor prognosis, clinically heterogeneous entity termed ‘BCR-ABL1 negative CML’ constituting about 5% of CML cases. Apart from very rare CML cases with cytogenetically cryptic, atypical variant BCR-ABL1 fusions that had been inadvertently missed during the diagnostic work up, most of these cases would now be classified as a subtype of myelodysplastic/myeloproliferative neoplasm (MDS/MPN), such as atypical CML (aCML), chronic myelomonocytic leukemia (CMML), or chronic neutrophilic leukemia (CNL). A minority would be classified as systemic mastocytosis with associated hematological neoplasm (SM-AHN), myeloid/lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, FGFR1 or with PCM1-JAK2 (MLN-eo), or chronic eosinophilic leukemia not otherwise specified (CEL-NOS).1

Recurrent activating STAT5B N642H mutation in myeloid neoplasms with eosinophilia

Determining the underlying cause of persistent eosinophilia is important for effective clinical management but remains a diagnostic challenge in many cases. We identified STAT5B N642H, an established oncogenic mutation, in 27/1715 (1.6%) cases referred for investigation of eosinophilia. Of the 27 mutated cases, a working diagnosis of hypereosinophilic syndrome (HES; n = 7) or a myeloid neoplasm with eosinophilia (n = 20) had been made prior to the detection of STAT5B N642H. Myeloid panel analysis identified a median of 2 additional mutated genes (range 0–4) with 4 cases having STAT5B N642H as a sole abnormality. STAT5B N642H was absent in cultured T cells of 4/4 positive cases. Individuals with SF3B1 mutations (9/27; 33%) or STAT5B N642H as a sole abnormality had a markedly better overall survival compared to cases with other additional mutations (median 65 months vs. 14 months; hazard ratio = 8.1; P < 0.001). The overall survival of STAT5B-mutated HES cases was only 30 months, suggesting that these cases should be reclassified as chronic eosinophilic leukemia, not otherwise specified (CEL-NOS). The finding of STAT5B N642H as a recurrent mutation in myeloid neoplasia with eosinophilia provides a new diagnostic and prognostic marker as well as a potential target for therapy.

A Fatal Case of Chronic Eosinophilic Leukemia Not Otherwise Specified (CEL-NOS) in a 19-Year-Old Male with Acute Transformation into Blast Crisis

Chronic eosinophilic leukemia (CEL) is a rare disorder that is characterized by hypereosinophilia with increased number of blood or marrow blasts (>5% and <20%). CEL is distinguished from hypereosinophilic syndrome (HES) by the presence of eosinophilic clonality. Chronic eosinophilic leukemia not otherwise specified (CEL-NOS) diagnosis is made when no fusion genes are detected by most modern molecular testing, particularly the most common fusion gene FIP1L-1/PDGFRA (Factor Interacting with PAP like-1/Platelet-Derived Growth Factor Receptor Alpha). This disease is very rare, and its description in the literature is not well characterized. We report a fetal case of severe CEL-NOS in a 19-year-old male who presented with a plethora of clinical features consists of constitutional symptoms, pancytopenia, intravascular thrombosis, acute stroke and endomyocardial infiltrates. The course of his disease was aggressive and resistant to conventional treatment. After a short period of improvement, an acute transformation into blast crisis (BC) had occurred. The diagnosis was confirmed by morphology and immunophenotyping of bone marrow biopsy. The patient eventually died of heart failure and sepsis. To our knowledge this is the first case report of fatal CEL-NOS transforming into severe blast crisis.

Tyrosine Kinase Inhibitors and Therapeutic Antibodies in Advanced Eosinophilic Disorders and Systemic Mastocytosis

World Health Organization-defined myeloproliferative neoplasms share a common pathobiologic theme of constitutive activation of tyrosine kinases (TKs). While myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA or PDGFRB exhibit exquisite responsiveness to imatinib, other eosinophilic disorders such as chronic eosinophilic leukemia--not otherwise specified (CEL-NOS) and idiopathic hypereosinophilic syndrome (HES) lack recurrent gene mutations or known druggable targets. In systemic mastocytosis (SM), KIT D816V is identified in ∼ 90% of patients, but demonstrates imatinib resistance. Recently, the multikinase/KIT inhibitor midostaurin (PKC412) has demonstrated encouraging activity in patients with advanced SM, and selective KIT D816V inhibitors are entering clinical development. Pre-clinical rationale also exists for use of small molecule inhibitors of TK-linked pathways (e.g., BTK, JAK-STAT, PI3K/AKT, and FGFR1) that are implicated in normal or dysregulated signaling in eosinophils or mast cells. A complementary therapeutic approach is the use of naked antibody (e.g., mepolizumab and alemtuzumab) or antibody-based drug immunoconjugates (brentuximab vedotin) against targets expressed on the surface of eosinophils or mastocytes that can block proliferation and/or induce apoptosis of these cells. Ultimately, biologic and molecular characterization of eosinophilia and SM cases will help to optimize selection of TK inhibitors or therapeutic antibodies for individual patients.

Chronic eosinophilic leukemia with a FIP1L1-PDGFRA rearrangement: Two case reports and a review of Korean cases.

TO THE EDITOR: According to the 2008 World Health Organization (WHO) guidelines, eosinophilia is associated with hematologic diseases such as chronic eosinophilic leukemia-not otherwise specified (CEL-NOS); idiopathic hypereosinophilic syndrome (HES) or idiopathic hypereosinophilia; and myeloid and lymphoid neoplasms with eosinophilia, and abnormalities of PDGFRA, PDGFRB or FGFR1 [1]. CEL is diagnosed in cases with increased blasts or cytogenetic/clonal abnormalities. We report 2 cases of myeloid and lymphoid neoplasms (CEL) with the FIP1L1-PDGFRA rearrangement.

Chronic eosinophilic leukemia-not otherwise specified transformation into acute myeloid leukemia

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.

Jak-2 Positive Myeloproliferative Neoplasms

Originally described by Dameshek in 1951, myeloproliferative disorders are today classified as myeloproliferative Neoplasms (MPNs) in WHO's Classification of Tumors of Hematopoietic and Lymphoid Tissues. The term includes a range of conditions, [ie, BCR-ABL-positive chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), polycythemia vera (PV), primary myelofibrosis (PMF), essential thromobocythemia (ET), chronic eosinophilic leukemia not otherwise specified (CEL-NOS), mastocytosis, and unclassifiable myeloproliferative neoplasm]. In the specific case of CML, a better understanding of the pathogenesis and pathophysiology of the disease has led to a targeted therapy. The presence of chromosome Philadelphia, t(9;22)(q34;11) results in the oncogene BCR-ABL, which characterizes the disease; this molecular rearrangement gives rise to a tyrosine-kinase, which in turn triggers the proliferation of the myeloid line through the activation of the signaling pathways downstream. Tyrosine-kinase inhibitors (TKIs) have altered the therapy and monitoring of CML patients and improved both their prognosis and quality of life. In 2005, various groups of investigators described a new point mutation of the gene JAK2 associated to MPNs. Although the presence of this mutation has led to a modification in the diagnostic criteria of these conditions, the impact of the use of JAK2 inhibitors on the prognosis and course of the disease continues to be controversial.

Long-Term Follow-Up of Patients With Hypereosinophilic Syndrome Treated With Alemtuzumab, an Anti-CD52 Antibody

Relapsing, refractory patients with idiopathic hypereosinophilic syndrome (I-HES) and chronic eosinophilic leukemia-not otherwise specified (CEL-NOS) do not have many effective, durable therapeutic options. Alemtuzumab, an anti-CD52 antibody, has been reported to be an effective therapy due to inherent expression of CD52 on eosinophils. A retrospective chart review of 12 patients treated with alemtuzumab at our center until 2012. Ten (83%) of 12 patients achieved complete hematologic response (CHR) after a median of 1 week for a median duration of 66 weeks, with the elimination of disease-related symptoms; 2 patients achieved partial hematologic remission hematologic remission (PHR). Patients with CHR who received alemtuzumab maintenance (n = 5) had a significantly longer time to progression than those patients who were only observed (n = 5) (P = .01). Eleven patients relapsed (only one while on maintenance), and 6 were rechallenged with alemtuzumab. Five (83%) achieved second CHR after a median of 3.5 weeks, for a median duration of 123 weeks. Again, those given maintenance (n = 3) had a longer time to progression than those who were only observed (P = .04). Adverse effects were mostly related to infusion reactions and lymphopenia-related viral infections (despite antibiotic prophylaxis). One patient developed Epstein-Barr virus-related lymphoma. Alemtuzumab is an effective treatment for patients with relapsed, refractory idiopathic hypereosinophilic syndrome and chronic eosinophilic leukemia-not otherwise specified, in terms of both CHR achievement (even after repeated rechallenges) and duration (particularly if provided as a maintenance therapy). Common adverse effects are related to infusion reactions and immunosuppression.

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 (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 3109/l (range, 9.3–175.0) with a median eosinophil count of 15.6 3 109/l (range, 1.5–136.0). Median hemoglobin and platelets were 11.0 g/dl (range, 8.3–13.3) and 158 3 109/l (range, 31.0–891.0), respectively. Clinical manifestations included splenomegaly (n 5 7), hepatomegaly (n 56), 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.

Myeloproliferative Neoplasms: An Overview

1. Kathleen Finnegan, MS, MT(ASCP)SHCM[⇑][1] 1. Stony Brook University Health Science Center, School of Health Technology and Management, Stony Brook, NY <!-- --> 1. Address for Correspondence: Kathleen Finnegan, MS, MT(ASCP)SHCM, Chair, Department of Clinical Laboratory Sciences, Stony Brook University Health Science Center, School of Health Technology and Management, Level 2, Room 442, Stony Brook, NY 11794-8205, 631-444-3224, Kathleen.finnegan{at}stonybrook.edu INTRODUCTION The myleproliferative neoplasms (MPNs) are a closely related group of clonal stem cell hematologic blood disorders characterized by an increase in one or more cell lines of the bone marrow. The proliferation of red blood cells (RBCs), white blood cells (WBCs) or platelets is usually mature in morphology. The MPNs have overlapping clinical features but different etiologies. The original name of these disorders was the myeloid proliferative disorders or MPDs proposed by William Damashek in 1951;1 they were renamed by the World Health Organization (WHO) in 2008 to “myeloproliferative neoplasms”2 due to new findings. The 2008 WHO classification of MPNs has added new entities, including chronic myelogenous leukemia, Philadelphia chromosome-positive (CML); chronic neutrophilic leukemia (CNL); polycythemia vera (PV); primary myelofibrosis (PMF); essential thrombocythemia (ET); chronic eosinophilic leukemia, not otherwise specified (CEL/NOS); mastocytosis; and myeloproliferative neoplasm, unclassifiable (MPN-U). The identification of numerous molecular mutations such as the “breakpoint cluster region/Abelson fusion 1 ( BCR/ABL1 ) mutation, Janus kinase 2 ( JAK2 ) mutation, ( JAK2 ), myeloproliferative leukemia virus oncogene homolog ( MPL ) and others,, has contributed to the further understanding of the genetic complexity of the MPNs. The current classification of the MPNs is based on clinical presentation, pathologic descriptions, histological information, and genetic mutations. The genetic mutations or molecular markers have become essential for diagnosis, prognosis and treatment of these disorders. The MPNs are characterized by a hypercellular bone marrow due to unregulated cell proliferation. Usually one cell line is increased, but all may be elevated. The classification is based on which cell line is… [1]: #corresp-1