<scp>WHO</scp> defined chronic eosinophilic leukemia, not otherwise specified ( <scp>CEL</scp> , <scp>NOS</scp> ): A contemporary series from the Mayo Clinic
Authors: Erika Morsia, Kaaren Reichard, Animesh Pardanani, Ayalew Tefferi, Naseema Gangat
Journal: American Journal of Hematology (2020)

Chronic eosinophilic leukemia, not otherwise specified (CEL, NOS) is an extremely rare and aggressive form of break point cluster (BCR)/abelson negative myeloproliferative neoplasm (MPN), with a genetic signature characterized by absence of PDGFRA, PDGFRB, or FGFR1 rearrangements and PCM1-JAK2, ETV6-JAK2, or BCR-JAK2 fusion genes.1-3 Diagnostic features include sustained proliferation of eosinophilic precursors with marked eosinophilia in the peripheral blood (eosinophils >1.5 × 109/L) and bone marrow. Importantly, two elements distinguish CEL, NOS from hyper eosinophilic syndromes (HES); (a) evidence of clonality determined by karyotype analysis or molecular testing, and/or (b) presence of excess myeloblasts (<20%) in the peripheral blood (>2%) or bone marrow (>5%).1, 4 Moreover, non-myeloid malignancies and myeloid neoplasms with associated eosinophilia (acute myeloid leukemia [AML] with inv16, chronic myeloid leukemia, MPNs, and myelodysplastic syndrome) require systematic exclusion.5 Given the challenges associated with diagnostic confirmation coupled with its rarity, comprehensive analyses of World Health Organization (WHO)-2016 defined CEL, NOS patients have been limited. The objective of our report is to outline the clinical characteristics, treatment patterns with response evaluation, and long-term survival in patients with CEL, NOS. Furthermore, we seek to identify determinants of inferior survival and leukemic transformation. At our institution, 1416 patients with peripheral blood eosinophilia were evaluated between 2008 and 2019 of which 17 patients (1.2%) fulfilled the WHO-2016 criteria for CEL, NOS.6 After institutional review board (IRB) approval, clinical and laboratory data was retrieved from the medical records. Bone marrow morphological review was performed by our hematopathologist (K.R.) to ensure exclusion of other WHO-defined clinicopathological entities and myeloid neoplasms with a recurring genetic abnormality. Conventional cytogenetic analysis was performed in all cases with a minimum of twenty metaphases analyzed and reported using the International System for Human Cytogenetic Nomenclature. Additionally, targeted next generation sequencing (NGS) of myeloid relevant genes (30 or 41 gene-panel) was obtained in seven patients. JMP Pro 13.0.0 software from SAS Institute, Cary, NC, USA, was used for statistical analysis. Seventeen patients of median age 63 years (range; 25-92 years) with WHO-2016 defined CEL, NOS were studied. A male preponderance was noted with the vast majority of patients (88%) presenting with systemic symptoms; fatigue (n = 9), gastrointestinal symptoms (n = 6), weight loss (n = 4), persistent cough (n = 3), night sweats (n = 2), dyspnea (n = 2), rash (n = 2), fever and chest pain in one patient each. Organ involvement was a prominent feature; spleen (n = 5), cardiac (n = 3), pulmonary (n = 2), distal esophagus (n = 2), liver (n = 1), and peritoneum (n = 1). Notable laboratory abnormalities included anemia with median hemoglobin of 11.9 g/dL and leukocytosis (median 15.6 × 109/L) with eosinophilia of 6.4 × 109/L (range; 2.0-53.1 × 109/L). Further details regarding clinical and laboratory findings at presentation are provided in Table 1. The peripheral blood demonstrated hypereosinophilia (absolute eosinophil count ≥1.5 × 109/L) in all cases. Bone marrow eosinophilia also occurred in all cases, accounting for 43.0% (range, 9.0%-65.0%) of cells; in half (9/17, 52.9%) of which, bone marrow was hyper cellular. The most common bone marrow abnormalities included abnormal eosinophils (8/17, 47.1%), abnormal megakaryocytes (7/17, 41.2%), increased megakaryocytes (3/17, 17.6%), fibrosis (3/17, 17.6%), and increased M:E ratio ≥5:1 (8/17, 47.1%) due predominantly to the increase in eosinophils. Dysplasia in erythroid and granulocytic precursors was distinctly unusual, as was increased blasts in either the peripheral blood or bone marrow. In fact, only one patient had excess bone marrow blasts (≥5%) at diagnosis. The spectrum of peripheral blood eosinophilic abnormalities (n = 9) included sparse granulation in the cytoplasm (n = 6) and abnormal nuclear segmentation either hypersegmentation or hyposegmentation in two patients each; likewise abnormal bone marrow eosinophils (n = 8) depicted atypical forms (n = 5), abnormal nuclear segmentation (n = 2), and atypical eo myelocytes (n = 1). The principal megakaryocytic changes were monolobated, hypolobated or hyperlobated forms. Cytogenetic abnormalities occurred in 15 of 17 (88.2%) patients; trisomy 8 (n = 4), complex karyotype (n = 3), two patients each with 13q, 20 q deletion, and chromosome 1 abnormalities, and one patient each with monosomy 7 and 3q deletion. All seven patients with NGS studies harbored one or more mutations; ASXL1 (3/7, 42.9%); IDH1 (2/7, 28.6%), and one each (1/7, 14.3%) with TP53, SRSF2, SH2B3, STAT5B, KDM6A and NF1 mutations. All but one patient received therapy after diagnosis. The most frequently utilized first line agents were hydroxyurea as a single agent (n = 5) or in combination with steroids (n = 3), and steroids as a single agent (n = 3), or in combination (n = 5). Half of patients treated with hydroxyurea based regimens responded with a persistent decline in eosinophil count for a median duration of 17.5 months. Meanwhile, approximately one third of patients demonstrated response to steroids for a median duration of 13 months. Three patients were treated with imatinib of which two had normalization of eosinophil count. Overall response to first line therapy was assessed in 15 patients of which seven (46.6%) demonstrated a response. Six patients went on to receive further therapies, of which only one patient responded to a combination of hydroxyurea and interferon used as third line, first and second agents administered were steroids and imatinib respectively. Further specifics regarding therapy are outlined in Table S1. At a median follow up of 13 months (range, 1-49 months), nine patients are deceased secondary to infection, disease related organ failure, or leukemic transformation. Three patients underwent leukemic transformation. Patient one was a 55-year-old male, who evolved to AML, with complex monosomal karyotype, P53 mutated, 3.5 months after CEL, NOS diagnosis. Disease was refractory to induction with cytarabine/anthracycline, followed by salvage therapies with CLAG-M, clofarabine/dasatinib, tretinoin and ibrutinib and succumbed to the disease 7 months post evolution. Patient 2 was a 25-year-old female with myeloid sarcoma involving the peritoneum/omentum 3 months post CEL, NOS. At CEL diagnosis, she had a complex karyotype, with IDH1/KDM6A mutations, and received imatinib, steroids, tocilizumab and cladribine. At disease evolution, AML FISH, and NGS (spleen) were without abnormalities. She received cytarabine/anthracycline induction therapy followed by a matched unrelated donor allogeneic transplant and remains disease free 1 month post-transplant. Patient 3 was a 62-year-old gentleman treated with hydroxyurea, transformed to AML with monosomy 7, 11 months following CEL-NOS. He had a favorable response to cytarabine/anthracycline induction therapy but passed away secondary to injuries from a fall. In our 17 patients with WHO-2016 defined CEL, NOS, all patients showed bone marrow morphological abnormalities, with clonality determined by abnormal karyotype in 15 patients, and ASXL1 mutation on NGS in two patients. Somatic mutations associated with myeloid neoplasms have been reported in up to 30% of cases of eosinophilia that otherwise would be classified as HES.4, 5, 7 With increasing utilization of NGS studies in practice, identification of additional cases of CEL, NOS is possible, provided mutational data is interpreted cautiously in conjunction with clinicopathological findings. Prognosis in patients with CEL, NOS is uniformly unfavorable with median overall survival of 16 months (range, 1-49 months) in our cohort which is consistent with a prior report.8 On univariate survival analysis, predictors of inferior survival included megakaryocytic atypia (P = .01), peripheral blood eosinophilic atypia (P = .024), LDH (P = .046) and abnormal karyotype (P = .020). In regards to leukemic transformation, on univariate analysis, peripheral blood eosinophilic atypia (P = .018), bone marrow eosinophilic atypia (P = .026), marked fibrosis (P = .002), complex karyotype (P = .009) and lack of response to therapy (P = .021) emerged prognostic for leukemic evolution. However, independent prognostic significance could not be established in a multivariable model due to limitations of sample size underscoring the dire need for collaborative endeavors. A noteworthy recent observation suggests a putative pathogenic role for recurrent activating STAT5B N642H mutations in myeloid neoplasms with eosinophilia.9 Future investigations focused on delineating the genetic landscape of CEL, NOS are essential for refining diagnosis and prognosis of this unique entity. The authors declare no potential conflict of interest. E.M., N.G. and A.T. designed the study, contributed patients, helped abstract patient information, performed statistical analysis, and wrote the paper. K.R. performed pathological review. A.P. contributed patients. Table S1. Treatment details with response rate in 17 patients with CEL, NOS. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.