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 Table of Contents  
CASE REPORT
Year : 2020  |  Volume : 11  |  Issue : 2  |  Page : 80-83

Hypereosinophilic syndrome posttreatment with triple-negative breast cancer


Department of Medicine, King Saud University Medical City, King Saud University, Riyadh, Kingdom of Saudi Arabia

Date of Submission21-Apr-2020
Date of Decision26-Apr-2020
Date of Acceptance27-Apr-2020
Date of Web Publication28-Jul-2020

Correspondence Address:
Dr. Khalid A AlSaleh
Department of Medicine, King Saud University, Riyadh
Kingdom of Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_49_20

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  Abstract 

Therapy-related secondary hematological changes play a crucial role in determining the life span of an otherwise recovered cancer patient after successful treatment. Hypereosinophilic syndrome (HES) is a potentially life-threatening condition when left unmanaged. The exact etiology of HES, however, remains elusive. We report a case of an adequately treated triple-negative breast cancer patient in remission, who presented with a confirmed diagnosis of HES 2 years after her therapy. On presentation, the blood picture showed leukocytosis of 42.7 × 109/L, where 20% were eosinophils. FIP1-like-1-platelet-derived growth factor receptor-alpha fusion was observed by fluorescence in situ hybridization. The patient was treated with imatinib, according to the World Health Organization guidelines, and full remission was achieved. This is the first case of HES postchemotherapy in a solid malignancy.

Keywords: FIP1 like-1-platelet-derived growth factor receptor-alpha, hypereosinophilic syndrome, imatinib, leukocytosis, triple-negative breast cancer


How to cite this article:
AlSaleh KA. Hypereosinophilic syndrome posttreatment with triple-negative breast cancer. J Appl Hematol 2020;11:80-3

How to cite this URL:
AlSaleh KA. Hypereosinophilic syndrome posttreatment with triple-negative breast cancer. J Appl Hematol [serial online] 2020 [cited 2020 Aug 4];11:80-3. Available from: http://www.jahjournal.org/text.asp?2020/11/2/80/290962


  Introduction Top


Hypereosinophilic syndrome (HES) is defined as the presence of nonreactive blood eosinophilia with eosinophil count of >1.5 × 109/L persistent for more than 6 months accompanied by organ involvement.[1],[2] According to the World Health Organization (WHO) classification of hematopoietic tumors, there must be a distinction from eosinophilic disorders, and eosinophilia should not be associated with an abnormal and/or clonal lymphocytes.[3]

Chromosomal translocations are associated with morphologically distinct types of chronic myeloproliferative disorders and chronic eosinophilic leukemia, which are the most frequent associations of clonal eosinophilia.[4] Notably, two breakpoint clusters at 5q31-33[5] and 8p11[6] coding platelet-derived growth factor receptor (PDGFR) beta gene and the fibroblast growth factor receptor-1 gene have been identified as major culprits. Recently, a cytogenetic cryptic interstitial deletion at chromosome 4q12 of cysteine-rich hydrophobic domain 2 gene was determined in hypereosinophilic patients with normal karyotype suffering from chronic myeloproliferative disorders, causing fusion of PDGFR-alpha (PDGFRA) gene to an uncharacterized human gene called factor interacting with poly-A polymerase alpha and cleavage and polyadenylation specificity factor subunit 1 FIP1-like-1 (FIP1 L1).[7]

This FIP1 L1-PDGFRA fusion leads to the constitutive expression of active tyrosine kinase fusion proteins.[8] Pardanani et al. reported that imatinib mesylate is effective in treating such hypereosinophilic cases as it is active against PDGFR.[7] Cytogenetic and hematological remission was observed in response to imatinib, and in some cases, even molecular remission was achieved;[9] however, discontinuation has been found to cause a relapse.[10]

Nevertheless, therapeutic response to imatinib is not constant in all hypereosinophilic patients, due to heterogeneous attributes of disease pathology.[11] In addition, not all the patients responding to imatinib carry FIP1 L1-PDGFRA fusion; Gotlib et al. reported that ~ 40% of responding patients were tested negative for FIP1 L1-PDGFRA fusion, depicting heterogeneous nature of genetic etiology of the disease.[11]

More than a hundred reports of FIP1 L1-PDGFRA-positive eosinophilia-associated myeloproliferative neoplasms (MPNs) have been published to date; however, very few of them focused on the possibility of secondary cause due to chemotherapy of the primary origin.[12],[13],[14]

Here, we report a clinical case of a patient with a history of triple-negative breast cancer (TNBC) after 2 years of chemotherapy with three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), followed by three cycles of docetaxel (D).


  Case Report Top


A 53-year-old female, in 2015, presented with a left breast lump for 2 months with no skin changes. A biopsy confirmed the presence of TNBC, and a full-staging workup did not show any evidence of metastasis. Baseline blood work showed normal complete blood count (CBC) with no evidence of leukocytosis or hypereosinophilia. The patient underwent chemotherapy of three cycles of FEC, followed by three cycles of D.

She then underwent surgical resection, with the final staging confirming the presence of T1N1 disease postchemotherapy. One lymph node was positive for metastatic carcinoma out of four sentinel lymph nodes. Invasive ductal carcinoma was observed in pathological findings with Scarff-Bloom-Richardson (SBR) Grade III/III (tubular formation, nuclear grade mitosis). Tumor size was 5 mm in the greatest margin, and metastatic lymph node was 2 mm in the greatest dimension. Deep margins were free of tumor, whereas fibrocystic changes were observed in the background tissue.

She underwent radiotherapy and clinical follow-up for 2 years with routine blood work, which showed a normal CBC with no evidence of abnormality. However, in March 2017 – after being in complete remission post-FEC-D for her TNBC – she presented to us with complaints of body aches and itching. Blood picture showed leukocytosis of 42.7 × 109/L; 20% were eosinophils with no evidence of circulating blasts. CBC showed an absolute count of white blood cells (WBC) 42.7 × 109/L, neutrophils 20.9/mm3, eosinophils 12.8 × 109/L, lymphocytes 3 × 109/L, hemoglobin 106 g/L, red blood cell 4.1 × 1012 cells/L, and platelet 74 × 109/L.

Full evaluation workup looking for the possible TNBC relapse, including computed tomography scan and bone scan, turned out to be negative. However, bone marrow aspirate did show evidence of increased eosinophils typical of a primary HES. Megakaryocytes appeared marginally reduced mostly of unremarkable morphology with occasional hypolobation. Granulopoiesis (71%) was markedly left shifted with increased granulation, including 6% eosinophilic and 4% basophilic lineages. Erythropoiesis (24%) was observed with moderate dyserythropoiesis, mainly megaloblastoid changes. Lymphocytes and blasts accounted for 4% and 1%–2% of all bone marrow nucleated cells. No extrinsic abnormal cells were identified to infiltrate the bone marrow.

A cytogenetic study showed typical chromosomal analysis. Since the patient had significant hypereosinophilia, a workup for molecular testing for FIP1 L1-PDGFRA mutation came out to be positive by fluorescence in situ hybridization (FISH). No other chromosomal abnormality was found. A final diagnosis of HES due to F1P1 L-PDGFRA mutation was confirmed, and further evaluation did not show any evidence of end-organ damage.

We managed her with imatinib 100 mg OD, with an excellent hematological response and significant symptom improvement within 3 weeks. We repeated bone marrow aspiration after 3 months and 1 year, also checking for the translocation for FIP1 L1-PDGFRA mutation, and she turned out to be negative by FISH. The patient is compliant on imatinib 100 mg OD for more than 2 years now, showing a complete response.


  Discussion Top


Successful treatment and complete remission of primary solid tumors may be complicated by secondary malignancies.[12] Hematological malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are common therapy-related secondary malignancies, and ample literature is available concerning their molecular pathogenesis, prognosis, epidemiology, and therapeutic response. Secondary eosinophilia-associated MPNs are not rare, with an incidence ranging from 0.8% to 6.3% for t-MDS/AML at 20 years after conventional therapy.[15]

Here, we report the new case of a 53-year-old female who developed hypereosinophilia after 2 years of exposure to chemotherapy for TNBC. The patient underwent three cycles of FEC-D and radiotherapy for 2 years with routine blood work. There was no evidence of leukocytosis. However, blood work and bone marrow analysis confirmed hypereosinophilia after 2 years in the absence of any relapse. FISH confirmed the FIP1 L1-PDGFRA fusion.

Previously, the FIP1 L1-PDGFRA fusion gene was reported in only two cases, post combination chemotherapy in a non-Hodgkin's lymphoma and 3 years after cyclophosphamide therapy.[12] In the latter case, 1 year after multiagent chemotherapy for Langerhans cell histiocytosis, hypereosinophilia was reported.[14] Jin et al. reported chronic eosinophilic pneumonia after chemotherapy with trastuzumab and radiation therapy in a breast cancer patient, which might reflect radiation pneumonitis.[16] However, no case of HES after TNBC remission with chemo- and radiotherapy has been reported previously with characteristic FIP1 L1-PDGFRA mutation.

According to the WHO, based on the therapeutic cause, t-MDS/AML are categorized into two major types: topoisomerase II inhibitor-related and alkylating agent/radiation-related type.[17] In response to topoisomerase II inhibitors, AML often skips preceding myelodysplastic phase and manifests as acute leukemia, with a brief latency period of 2–3 years. Topoisomerase II inhibitor-induced t-AML is linked with balanced translocations involving 11q23 or 21q22.[18] However, the latency period for alkylating agent-related t-MDS/AML is usually 4–7 years with a high incidence of abnormalities involving 5del(5q) and 7del(7q).[19]

These abnormalities result from DNA damage caused by the metabolism of genotoxic agents. There are two major metabolic phases: first is the activation of the substrate into reactive electrophilic intermediates, which causes DNA damage, whereas in phase II, enzyme inactivation of genotoxic substrates is performed by NAD (P) H quinone oxidoreductase-1 and glutathione S-transferase. The imbalance between the two phases – due to the high activity of phase I enzyme and low activity of phase II enzyme – results in DNA damage, which eventually manifests as mutations.[15]

Nonetheless, an accurate distinction of t-MDS/AML is of paramount importance to decide intensive/nonintensive or no therapy.[20] In our case, we had a patient of HES – which is not classically reported under t-MDS/AML – whom we managed with traditional and approved course of therapy, i.e., imatinib, achieving full remission. Imatinib is a drug of choice not only for HES associated with FIP1 L1-PDGFRA mutation but also against other hematological malignancies such as chronic myeloid leukemia.[9]


  Conclusion Top


Chemo- and radiotherapy are designed to cause DNA damage, which may cause further undesired mutations resulting in secondary malignancies and syndromes. FIP1 L1-PDGFRA fusion was detected as a cause of HES in a TNBC patient of ours, after 2 years of a full remission with no evidence of a relapse. Imatinib was prescribed, resulting in remission of the disease. This case illustrates the presence of secondary causes for recurrent cytogenetic mutations causing HES due to the exposure to chemo- and radiotherapy. The patient was successfully managed by imatinib, though it still needs to be seen if it is able to eradicate the abnormal clone and the possibility of discontinuation of the drug.

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.

Financial support and sponsorship

Deanship of Scientific Research, King Saud University, Researcher Supporting Project Number RSP-2019/88 for Khalid AlSaleh.

Conflicts of interest

Nil.



 
  References Top

1.
Klion AD. How I treat hypereosinophilic syndromes. Blood 2015;126:1069-77.  Back to cited text no. 1
    
2.
Chusid MJ, Dale DC, West BC, Wolff SM. The hypereosinophilic syndrome: Analysis of fourteen cases with review of the literature. Medicine (Baltimore) 1975;54:1-27.  Back to cited text no. 2
    
3.
Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008;22:14-22.  Back to cited text no. 3
    
4.
Bain BJ. Cytogenetic and molecular genetic aspects of eosinophilic leukaemias. Br J Haematol 2003;122:173-9.  Back to cited text no. 4
    
5.
Steer EJ, Cross NC. Myeloproliferative disorders with translocations of chromosome 5q31-35: Role of the platelet-derived growth factor receptor Beta. Acta Haematol 2002;107:113-22.  Back to cited text no. 5
    
6.
Macdonald D, Reiter A, Cross NC. The 8p11 myeloproliferative syndrome: A distinct clinical entity caused by constitutive activation of FGFR1. Acta Haematol 2002;107:101-7.  Back to cited text no. 6
    
7.
Pardanani A, Ketterling RP, Brockman SR, Flynn HC, Paternoster SF, Shearer BM, et al. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood 2003;102:3093-6.  Back to cited text no. 7
    
8.
Vandenberghe P, Wlodarska I, Michaux L, Zachée P, Boogaerts M, Vanstraelen D, et al. Clinical and molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias. Leukemia 2004;18:734-42.  Back to cited text no. 8
    
9.
Razmkhah F, Razavi M, Zaker F, Kazemi A, Negari S, Rasighaemi P, et al. Hematologic and molecular responses to generic imatinib in patients with chronic myeloid leukemia. Lab Med 2010;41:547-50.  Back to cited text no. 9
    
10.
Mori S, Vagge E, le Coutre P, Abruzzese E, Martino B, Pungolino E, et al. The Risk of Relapse in CML Patients Who Discontinued Imatinib can be Predicted Based on Patients Age and the Results of dPCR Analysis. Washington, DC: American Society of Hematology; 2014.  Back to cited text no. 10
    
11.
Gotlib J, Cools J, Malone JM 3rd, Schrier SL, Gilliland DG, Coutré SE. The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: Implications for diagnosis, classification, and management. Blood 2004;103:2879-91.  Back to cited text no. 11
    
12.
Tanaka Y, Kurata M, Togami K, Fujita H, Watanabe N, Matsushita A, et al. Chronic eosinophilic leukemia with the FIP1L1-PDGFRalpha fusion gene in a patient with a history of combination chemotherapy. Int J Hematol 2006;83:152-5.  Back to cited text no. 12
    
13.
Ohnishi H, Kandabashi K, Maeda Y, Kawamura M, Watanabe T. Chronic eosinophilic leukaemia with FIP1L1–PDGFRA fusion and T674I mutation that evolved from Langerhans cell histiocytosis with eosinophilia after chemotherapy. Br J Haematol 2006;134:547-9.  Back to cited text no. 13
    
14.
Balatzenko G, Stoyanov N, Bekrieva E, Guenova M. Chronic eosinophilic leukemia with FIP1L1-PDGFRA transcripts after occupational and therapeutic exposure to radiation. Hematol Rep 2011;3:e17.  Back to cited text no. 14
    
15.
Bhatia S, Krailo MD, Chen Z, Burden L, Askin FB, Dickman PS, et al. Therapy-related myelodysplasia and acute myeloid leukemia after Ewing sarcoma and primitive neuroectodermal tumor of bone: A report from the Children's Oncology Group. Blood 2007;109:46-51.  Back to cited text no. 15
    
16.
Jin F, Wang ST. Chronic eosinophilic pneumonia after trastuzumab and radiation therapy for breast cancer: A case report. Medicine (Baltimore) 2019;98:e14017.   Back to cited text no. 16
    
17.
Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002;100:2292-302.  Back to cited text no. 17
    
18.
Pedersen-Bjergaard J, Philip P. Balanced translocations involving chromosome bands 11q23 and 21q22 are highly characteristic of myelodysplasia and leukemia following therapy with cytostatic agents targeting at DNA-topoisomerase II. Blood 1991;78:1147-8.  Back to cited text no. 18
    
19.
Le Beau MM, Albain KS, Larson RA, Vardiman JW, Davis EM, Blough RR, et al. Clinical and cytogenetic correlations in 63 patients with therapy-related myelodysplastic syndromes and acute nonlymphocytic leukemia: Further evidence for characteristic abnormalities of chromosomes no. 5 and 7. J Clin Oncol 1986;4:325-45.  Back to cited text no. 19
    
20.
Gale RP, Bennett JM, Hoffman FO. Who has therapy-related AML? Mediterr J Hematol Infect Dis 2017;9:e2017025.  Back to cited text no. 20
    




 

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