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CASE REPORT
Year : 2020  |  Volume : 23  |  Issue : 1  |  Page : 116-119

Hypereosinophilia (HE) in acute myeloid leukemia (AML) with normal karyotype: A report of two cases


1 Department of Hematology, Affiliated Changzhou Second Hospital of Nanjing Medical University, Changzhou, Jiangsu, China
2 Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, China
3 Department of Hematology, The First Affiliated Hospital of Suzhou University, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, Jiangsu, China

Date of Submission19-Nov-2018
Date of Acceptance26-Jun-2019
Date of Web Publication10-Jan-2020

Correspondence Address:
Dr. H Chao
Affiliated Changzhou Second Hospital of Nanjing Medical University, Changzhou 213003
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_585_18

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   Abstract 


We present two rare cases of hypereosinophilia (HE) in acute myeloid leukemia with normal karyotype (NK-AML) at diagnosis. The first case is a 29-year-old female who presented with HE. On evaluation, she was found to have NK-AML. She failed to achieve complete remission (CR) after the first induction therapy with standard idarubicin and cytarabine (IA). She achieved CR after two cycles of reinduction chemotherapy with cytarabine, aclarubicin, and granulocyte colony-stimulating factor (G-CSF) (CAG) but had early relapsed. Reinduction chemotherapy with fludarabine, Ara-C, and G-CSF (FLAG) led to her second remission, followed by unrelated umbilical cord hematopoietic stem cell transplantation (HSCT). Unfortunately, she died of thrombotic thrombocytopenic purpura. The second case is a 23-year-old male who was diagnosed as NK-AML with HE. IA regimen was successively used in two cycles treatment achieving CR. He underwent haploidentical HSCT but had a relapse after 17 months of sustained remission and died 4 months later. The presence of HE may be a poor prognostic feature in NK-AML.

Keywords: Acute myeloid leukemia, China, hematopoietic stem cell transplantation, hypereosinophilia


How to cite this article:
Zhang X, Wang B, Zhang R, Chai X, Chao H. Hypereosinophilia (HE) in acute myeloid leukemia (AML) with normal karyotype: A report of two cases. Niger J Clin Pract 2020;23:116-9

How to cite this URL:
Zhang X, Wang B, Zhang R, Chai X, Chao H. Hypereosinophilia (HE) in acute myeloid leukemia (AML) with normal karyotype: A report of two cases. Niger J Clin Pract [serial online] 2020 [cited 2020 Jan 25];23:116-9. Available from: http://www.njcponline.com/text.asp?2020/23/1/116/275628




   Introduction Top


Hypereosinophilia (HE) is characterized by a persistent elevated eosinophil count of ≥1.5 × 109/L in peripheral blood (PB) and is considered a heterogeneous disorder.[1] Clonal hematopoietic neoplasms can be categorized into three large groups: (1) myeloid/lymphoid neoplasms with eosinophilia and rearrangements of PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2; (2) HE associated with other well-defined myeloid neoplasm, such as chronic myeloid leukemia (CML), chronic myelomonocytic leukemia, or acute myeloid leukemia (AML) with inv (16) or t (16;16)/CBFβ-MYH11; and (3) chronic eosinophilic leukemia not otherwise specified.[2],[3] However, HE is extremely rare in normal karyotype (NK) AML. We report two cases of HE in adults at diagnosis of NK-AML, presenting to our institution. The case report was approved by the Institution Ethics Committee at May 21, 2014.


   Case 1 Top


A 29-year old female presented with a history of fatigue and low-grade fever for 10 days in May 2011. Physical examination revealed hepatosplenomegaly. There was no lymphadenopathy. The full blood count showed hemoglobin of 73 g/L and platelet count of 24 × 109/L. The total leukocyte count was 34.55 × 109/L with 49.0% eosinophils and lactate dehydrogenase (LDH) of 589 U/L (normal, <240 U/L). An extensive workup for drug use, parasitic infection, allergies, and autoimmune disease was all negative. Bone marrow (BM) examination revealed a markedly hypercellular marrow comprising blasts (23.5%) and eosinophils (31.5%) [Figure 1]a, 1b]. The immunophenotyping revealed HLA-DR, CD3, CD13, CD117, and CD7-positive blasts of myeloid lineage, with normal 46, XX karyotype in cytogenetic analysis.
Figure 1: Morphologic changes in bone marrow smear. Bone marrow aspirate smears showing hypercellular (Wright Giemsa, ×100), markedly abnormal myeloblasts with increased eosinophils (Wright Giemsa, ×1000) in case 1 (a/b) and 2 (c/d) at diagnosis, respectively

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Fluorescence in situ hybridization (FISH) analysis was negative for rearrangements of PDGFRA, PDGFRB, FGFR1, CBFB, and BCR-ABL transcripts. We retrospectively detected the molecular alterations in the patient using next-generation sequencing (NGS) and DNA-based polymerase chain reaction (PCR) Sanger sequencing of 51 genes known or suspected to have a role in myeloid malignancies. However, only two mutations, CSF3RT618I and WT1A382fs, were identified in BM samples at diagnosis.

Final diagnosis of AML with HE was made. Induction chemotherapy was started with idarubicin and cytarabine (IA) regimen. Eighteen (18) days after chemotherapy, the BM revealed 11.0% blasts and 9.0% eosinophils. She was managed conservatively and commenced on CAG regimen consisting of low-dose cytarabine (Ara-C), aclarubicin, and granulocyte colony-stimulating factor (G-CSF). Complete remission (CR) was achieved after two cycles of reinduction chemotherapy, but leukemia relapsed after 4 weeks. Reinduction chemotherapy with fludarabine, Ara-C, and G-CSF (FLAG) led to her second remission. The patient subsequently received unrelated umbilical cord hematopoietic stem cell transplantation (HSCT) because of the lack of a HLA-matched related or unrelated donor.

She developed rashes and systemic edema on day 15 after transplant, which were relieved by the administration of dexamethasone. Sadly, she had a sudden seizure and fell into a coma on day 19. Laboratory investigations indicated elevated levels of indirect bilirubin, LDH, serum creatinine, and red cell fragmentation. Based on these findings, thrombotic thrombocytopenic purpura (TTP) was considered and plasma exchanges therapy was performed. Unfortunately, the patient died 3 days later.


   Case 2 Top


A 23-year-old man presented with low-grade fever and dizziness (? Duration) in July 2014. His white blood cell count was 28.5 × 109/L, with 47% eosinophils. The hemoglobin concentration was 124 g/L, and the platelet count was 156 × 109/L. Physical examination revealed hepatosplenomegaly. Reactive causes of eosinophilia such as parasite infestation, autoimmune disease, and drugs were ruled out. A high level of LDH at 729 U/L (normal, <240 U/L) was observed. BM aspiration showed hypercellular marrow with 25% myeloblasts and 39.0% eosinophils [Figure 1]c, 1d]. Cytogenetic analysis revealed a karyotype of 46, XY in 20/20 of the metaphases examined. FISH analysis for rearrangements of PDGFRA, PDGFRB, FGFR1, CBFB, and BCR-ABL transcripts was negative. In the immune-phenotype showed, leukemic blasts were positive for CD13, CD33, CD34, and CD117. We also retrospectively detected the molecular alterations by NGS and PCR Sanger sequencing. Double CEBPA mutations were observed on BM genomic DNA.

The patient was diagnosed as a case of AML with HE and underwent induction chemotherapy with standard IA, but failed to achieve CR. The BM aspiration showed 10.0% blasts and 22.0% eosinophils. CR was achieved after the second cycle of IA reinduction. In the absence of a matched sibling donor, he received haploidentical stem cell transplantation (haplo-SCT) from his mother. Unfortunately, leukemia relapsed after 17 months of remission. The BM showed 29.5% blasts and 4.0% eosinophils without any complaints. He received another two rounds reinduction chemotherapy but died of the disease progression 4 months later.


   Discussion Top


Although the prognostic importance of tissue and blood eosinophilia in solid tumors,[4] acute lymphoblastic leukemia,[5] Hodgkin's lymphoma,[6] and myeloproliferative neoplasms[7] is well-described, its significance in NK-AML is unknown. The two cases we report illustrate marked PB and BM HE in the setting of NK-AML at initial presentation. The absence of inversion 16 and other recurrent abnormalities associated with eosinophilia was a paradox.

During literature search, we found only one similar case reported by Rashidi.[8] The patient was diagnosed as NK-AML with abnormal eosinophil precursors. FISH was negative for inversion 16, as well as for PDGFRA and PDGFRB rearrangement. The patient achieved CR after induction chemotherapy with IA and was referred for evaluation for allogeneic (allo) HSCT. Our review of the published cases has shown that eosinophilic folliculitis in NK-AML patients usually appeared after allo-HSCT.[9]

To the best of our knowledge, this is the second report that the NK-AML associated with HE at diagnosis without any other obvious symptoms. Both cases had similar characteristics, such as low-grade fever, hepatosplenomegaly, a high level of LDH, and resistance to conventional chemotherapy with IA.

We have performed unrelated umbilical cord HSCT and haplo-SCT in cases 1 and 2, respectively. However, case 1 died of TTP, a relatively frequent complication of HSCT. Both cases had a short remission period with chemotherapy or allo-HSCT. This may suggest that the presence of HE is a poor prognostic maker in NK-AML.

Notably, we identified coexisting of CSF3RT618I with WT1A382fs mutations in case 1 and double CEBPA mutations in case 2. CSF3R mutations, most frequently CSF3RT618I, were described in chronic neutrophilic leukemia (CNL), atypical CML,[10] idiopathic HE,[11] myelodysplastic syndromes,[12] and AML.[13] Some reports revealed that CSF3RT618I induced JAK inhibitor-sensitive activation of JAK-STAT and CNL-like disease in mice.[14] Recurrent somatic mutations in WT1 appear to occur in approximately 6%–15% of de novo AML. Multivariate analysis of 470 de novo AML patients demonstrated that WT1 mutations were associated with worsened overall survival and relapse-free survival.[15]

However, it is unclear whether the two mutations can lead to an unfavorable chemo-response and short CR in both cases. Similarly the disease relapsed after allo-HSCT, although CEBPA double mutation is considered as a favorable biomarker for clinical outcome.


   Conclusion Top


These cases highlight the fact that HE can occur in NK-AML at diagnosis and the presence of HE may be a poor prognostic feature that may failed induction and early relapse even after allo-HSCT.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgment

Xiuwen Zhang and Biao Wang contributed equally to this work.

Financial support and sponsorship

This work was supported by a grant from the National Natural Science funds (No. 81500103), natural science foundation of Jiangsu province (BK-20160283), and Changzhou Sci Tech Program(Grant NO. 20180033).

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Wang SA. The diagnostic work-up of hypereosinophilia. Pathobiology 2019;86:39-52.  Back to cited text no. 1
    
2.
Hu Z, Boddu PC, Loghavi S, Miranda RN, Goswami M, Jeffrey ML, et al. A multimodality work-up of patients with hypereosinophilia. Am J Hematol 2018;93:1337-46.  Back to cited text no. 2
    
3.
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le BMM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391-405.  Back to cited text no. 3
    
4.
Kolobovnikova YV, Dmitrieva AI, Yankovich KI, Vasil'eva OA, Purlik IL, Poletika VS, et al. Expression of galectins-1 and galectin-3 in stomach and colorectal cancer with tissue eosinophilia. Bull Exp Biol Med 2018;165:256-8.  Back to cited text no. 4
    
5.
Sahu KK, Malhotra P, Khadwal A, Sachdeva MS, Sharma P, Varma N, et al. Hypereosinophilia in acute lymphoblastic leukemia: Two cases with review of literature. Indian J Hematol Blood Transfus 2015;31:460-5.  Back to cited text no. 5
    
6.
Küpeli S, Kara F, Akyüz C, Büyükpamukçu M. Eosinophilia and multifocal vertebral involvement with Hodgkin lymphoma. Pediatr Blood Cancer 2010;55:560-1.  Back to cited text no. 6
    
7.
Reiter A, Gotlib J. Myeloid neoplasms with eosinophilia. Blood 2017;129:704-14.  Back to cited text no. 7
    
8.
Rashidi A, Roullet MR. Acute myeloid leukaemia with abnormal eosinophil precursors without inversion 16. Br J Haematol 2012;158:561.  Back to cited text no. 8
    
9.
Chew E, Mason KD, Juneja S. Marked eosinophilia with abnormal basophilic granules in acute graft-versus-host disease post-allogeneic haemopoietic stem cell transplant for acute myeloid leukaemia without CBFB-MYH11 mutation. Eur J Haematol 2013;90:175-6.  Back to cited text no. 9
    
10.
Dao KH, Solti MB, Maxson JE, Winton EF, Press RD, Druker BJ, et al. Significant clinical response to JAK1/2 inhibition in a patient with CSF3R-T618I-positive atypical chronic myeloid leukemia. Leuk Res Rep 2014;3:67-9.  Back to cited text no. 10
    
11.
Lee JS, Seo H, Im K, Park SN, Kim SM, Lee EK, et al. Idiopathic hypereosinophilia is clonal disorder? Clonality identified by targeted sequencing. PLoS One 2017;12:e0185602.  Back to cited text no. 11
    
12.
Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 2014;28:241-7.  Back to cited text no. 12
    
13.
Zhang Y, Wang F, Chen X, Zhang Y, Wang M, Liu H, et al. CSF3R Mutations are frequently associated with abnormalities of RUNX1, CBFB, CEBPA, and NPM1 genes in acute myeloid leukemia. Cancer 2018;124:3329-38.  Back to cited text no. 13
    
14.
Mehta HM, Glaubach T, Long A, Lu H, Przychodzen B, Makishima H, et al. Granulocyte colony-stimulating factor receptor T595I (T618I) mutation confers ligand independence and enhanced signaling. Leukemia 2013;27:2407-10.  Back to cited text no. 14
    
15.
Hou HA, Huang TC, Lin LI, Liu CY, Chen CY, Chou WC, et al. WT1 mutation in 470 adult patients with acute myeloid leukemia: stability during disease evolution and implication of its incorporation into a survival scoring system. Blood 2010;115:5222-31.  Back to cited text no. 15
    


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