lable at ScienceDirect

Journal of Cancer Research and Practice 3 (2016) 23e27

Contents lists avai

Journal of Cancer Research and Practicejournal homepage: http : / /www.journals .e lsevier .com/journal-of-cancer-

research-and-pract ice

Case report

Salvage therapy of imatinib-resistant hypereosinophilic syndromewith PDGFRB rearrangement

Miao-Erh Chang a, b, *, Hao-Wei Teng a, b

a Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwanb School of Medicine, National Yang-Ming University, Taipei, Taiwan

a r t i c l e i n f o

Article history:Received 27 April 2015Accepted 6 August 2015Available online 17 November 2015

Keywords:Hypereosinophilic syndrome (HES)ImatinibPDGFRAPDGFRB

* Corresponding author. Division of Hematology anMedicine, Taipei Veterans General Hospital, No. 20111217, Taiwan.

E-mail address: miawerl@hotmail.com (M.-E. ChanPeer review under responsibility of The Chinese O

http://dx.doi.org/10.1016/j.jcrpr.2015.10.0032311-3006/Copyright © 2016, The Chinese Oncologycreativecommons.org/licenses/by-nc-nd/4.0/).

a b s t r a c t

Hypereosinophilic syndrome (HES) has generally been defined as a peripheral blood eosinophil countgreater than 1500/mm3 and may be associated with tissue damage. Imatinib is customarily used as thefirst-line therapy for HES with gene abnormalities, such as PDGFRA or PDGFRB. We presented a casewhere the patient was diagnosed with HES, with PDGFRB rearrangement. The patient began animatinib regimen after diagnosis and then developed resistance to imatinib. The combination ofdasatinib, methylprednisolone and hydroxyurea was administered to the patient as the salvagetherapy.Copyright © 2016, The Chinese Oncology Society. Production and hosting by Elsevier B.V. This is an open

access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

The eosinophilias encompass a broad range of nonhematologic(secondary or reactive) and hematologic (primary, clonal) disorderswith potential for end-organ damage.1 Hypereosinophilic syn-drome (HES) has generally been defined as a peripheral bloodeosinophil count greater than 1500/mm3 and may be associatedwith tissue damage.1 Overall, HES is a rare disease with an inci-dence of approximately 0.036 per 100,000.2

After exclusion of secondary causes of eosinophilia, diagnosticevaluation of primary eosinophilias relies on a combination ofmorphologic review of the blood and marrow, standard cytoge-netics, fluorescent in situ hybridization, flow immunocytometry,and T-cell clonality assessment to detect histopathologic or clonalevidence for an acute or chronic myeloid or lymphoproliferativedisorder.1

The classification of eosinophilic diseases was revised in the2008 World Health Organization categorization of myeloid neo-plasms. In recognition of the growing list of recurrent, molecularlydefined primary eosinophilias, a new major category was created,“Myeloid and lymphoid neoplasms with eosinophilia and

d Oncology, Department ofShipai Road, Sec. 2, Taipei,

g).ncology Society.

Society. Production and hosting by

abnormalities of platelet-derived growth factor receptor alpha(PDGFRA), platelet-derived growth factor receptor beta (PDGFRB),or fibroblast growth factor receptor 1 (FGFR1)” (Table 1).1

The success of imatinib in cases of chronic myelogenous leu-kemia (CML) led to its empirical use in patients with HES whoexhibited signs suggestive of a myeloproliferative disorder since2001. However, the effect of imatinib varied with gene abnormal-ities in treating HES.3,4

As we know, some patients with CML develop resistance toimatinib. In prospective cohorts, imatinib-treated FIP1L1-PDGFRA-positive myeloid neoplasms were evaluated and resistance ofimatinib was rarely reported.5,6 Herein we have presented a casediagnosed as HES with PDGFRB rearrangement that subsequentlydeveloped resistance to imatinib.

2. Case presentation

Initially, the 39-year-old woman presented to our facility withfever, skin rash, and pneumonitis in February 2005 (Fig. 1). Herhemogram showed a WBC of 30,100/mm3, Hb 13.7 g/dl, PLT303000/mm3, seg 61%, lym 21%, mono 10%, and eos 8%. Her pul-monary function test displayed normal ventilator function andmoderate reduction of gas exchange in May 2005. We hadadministered pulse therapy (steroid) for 3e4 months but hereosinophil counts remained persistently high. Then, she had beennoted as persistent hypereosinophilia (absolute eosinophil count>1500/mm3) for more than 6 months. She received a lung biopsy

Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://

Table 12008 World Health Organization (WHO) classification of myeloid malignancies.

1 Acute myeloid leukemia and related disorders2 Myeloproliferative neoplasms (MPN)

� Chronic myelogenous leukemia, BCR-ABL1 positive� Chronic neutrophilic leukemia� Polycythemia vera� Primary myelofibrosis� Essential thrombocythemia� Chronic eosinophilic leukemia, not otherwise specified� Mastocytosis� Myeloproliferative neoplasms, unclassifiable

3 Myelodysplastic syndromes� Refractory cytopenia with uni-lineage dysplasia

- Refractory anemia- Refractory neutropenia- Refractory thrombocytopenia

� Refractory anemia with ring sideroblasts� Refractory cytopenia with uni-lineage dysplasia� Refractory anemia with excess blasts (RAEB)

- RAEB-1- RAEB-2

� Myelodysplastic syndrome with isolated del(5q)� Myelodysplastic syndrome, unclassifiable

4 MDS/MPNChronic myelomonocytic leukemia- CMML-1- CMML-2Atypical chronic myeloid leukemia, BCR-ABL1 negativeJuvenile myelomonocytic leukemiaMDS/MPN, unclassifiable- Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T)Myeloid and lymphoid neoplasms associated with eosinophila andabnormalities of PDGFRA, PDGFRB and FGFR1

5 Myeloid and lymphoid neoplasms associated with PDGFRA rearrangementMyeloid neoplasms associated with PDGFRB rearrangementMyeloid and lymphoid neoplasms associated with FGFR! abnormalities

Fig. 1. A chest X-ray showing mild infiltration with ground glass opacities in bothlower lungs in February, 2005 (Initial presentation).

M.-E. Chang, H.-W. Teng / Journal of Cancer Research and Practice 3 (2016) 23e2724

in January 2006, wherein the pathology revealed increased eo-sinophils in the capillaries of the alveolar walls. She received bothbone marrow examination and bone marrow cytology, whichshowed hypercellularity of approximately 80%, an M/E ratio of 4/1,no excess blasts, no dysplastic changes, and eosinophilia of about8% in November 2007. Subsequent to review of gastrointestinalstromal tumors, her fusion gene was detected as t (5; 14)KIAA1509-PDGFRB by PCR and the karyotype was t (3; 16) (p13;q24), �16, þmar. Lab data were noted normal-range ESR 8 mm/hand high-level IgE 1168 kU/L. Her abdominal sonogram detectedsplenomegaly with long axis of about 12.8 cm. At that time, wesearched associated journals about HES for diagnosis.7 In the nextyear, according to the 2008 World Health Organization (WHO)Classification of Myeloid Malignancies, the diagnosis of this pa-tient was revised as “myeloid neoplasms associated with PDGFRBrearrangement”. Besides, pneumonitis may be recognized as end-organ damage (Fig. 2).

After diagnosis, the patient still complained of shortnessof breath and started to take imatinib 200 mg per day andmethylprednisolone 8 mg per day in November 2007 (Fig. 3).This combination had lasted for 4 months, after which she thenkept using imatinib. Subsequent computer tomography (CT)of the chest revealed gradual regression after imatinib use(Fig. 4). Prior to admission to our facility, her disease had been

stable for 6 years (2008e2013). During this period, the fusiongene PDGFRB had not been detected (from May 2008 throughAugust 2012).

Unfortunately, she suffered from progressive dyspnea and a CTof her chest also revealed progressive pneumonitis in October 2013(Fig. 5). Her WBC count was elevated to 13,400/mm3 (AEC 817/mm3). However, her fusion gene PDGFRBwas still not detected. Weincreased the dose of imatinib to 400 mg per day in November2013. However, the symptoms did not improve. We arranged for are-biopsy of her lung lesion to investigate other possible etiology inApril 2014. The pathology still revealed “eosinophilic pneumoniawith cellular interstitial lymphoid cells infiltration”. Due to thelimitation of our laboratory, we could not detect the T674I muta-tion. Then, we prescribed nilotinib 300 mg per day exclusively toreplace imatinib in June 2014. However, this change of drugregimen still only produced a poor result. Her lung lesions weregetting worse and WBC count also increased to 21,400/mm3 (AEC2268/mm3). We rechecked the fusion gene PDGFRB and the resultwas negative. Dasatinib 70 mg per day was administered to replacenilotinib in September 2014. After 2months, the disease activity didnot subside. Due to the patient's economy and choice, we decidedto use the combination of dasatinib 50 mg per day, methylpred-nisolone 8 mg per day, and hydroxyurea 1000 mg per day. There-after, her symptoms improved and AEC also decreased. A successiveCT of the chest was also consistent with clinical improvement(Fig. 6).

Fig. 2. A CT of the chest showing ground glass opacities at the peripheral regions of RLL (B6), left lingual lobe and posterior basal segments of bilateral lower lobes with minimalatoll sign at anterior basal segment of RLL in January, 2006. (Before imatinib 200 mg/day).

Fig. 3. A chest X-ray showing increased infiltration over bilateral lower lungs inNovember, 2007 (Just before imatinib 200 mg/day).

M.-E. Chang, H.-W. Teng / Journal of Cancer Research and Practice 3 (2016) 23e27 25

3. Discussion

Clinically, HES may be separated into two subgroups: HES with,and HES without gene abnormality such as PDGFRA, PDGFRB, or

FGFR1.1 The standard therapy of HES without gene abnormality issteroid; by contrast, the first-line therapy of HES with gene ab-normality is imatinib.8

Although in-depth and durable molecular responses occur withimatinib, discontinuation of the drug can lead to relapse.6,9 In theFrench series, imatinib was stopped in 11 patients - 6 of those pa-tients subsequently relapsed.10 According to these studies, we maypresume that imatinib could suppress abnormal clones, but notclear them out. In contrast to CML, very few cases of acquiredimatinib resistance have been reported with almost 10 years ofexperience in treating FIP1L1-PDGFRA-positive disease. Most of thecases have involved the T674I mutation within the ATP-bindingdomain.9,11,12 The T674I mutation is analogous to the T315I BCR-ABL mutation in CML which confers resistance to the tyrosine ki-nase inhibitors imatinib, dasatinib, and nilotinib.13,14

The salvage therapy of imatinib-resistant HES has remainedunclear so far.

In this case, our laboratory could not provide the testdetecting the T674I mutation. According to the study of David M.et al, imatinib with 400 mg per day could elicit durable hema-tologic and cytogenetic remissions.15 However, this patientdeveloped resistance to imatinib 400 mg per day. Then, dasatinib70 mg per day was prescribed but her symptoms did notimproved. Following the patient's insistence of dasatinib 50 mgper day, we tried the combination therapy with dasatinib, ste-roid, and hydroxyurea. Fortunately, this regimen was effective asto this patient. We did not answer the mechanism of this salvagetherapy and just provided a feasible regimen in treatingimatinib-resistant HES.

Fig. 4. A successive CT of the chest showing regressive changes in September 2008 (After imatinib 200 mg/day by 1 year).

Fig. 5. A CT of the chest showing patchy ground glass opacities at lingual segment of LUL and LLL of lung, increased infiltration in the RLL of the lung when the disease deterioratedin October 2013. (After imatinib 200 mg/day for 6 years and before imatinib 400 mg/day).

M.-E. Chang, H.-W. Teng / Journal of Cancer Research and Practice 3 (2016) 23e2726

Fig. 6. A successive CT showing. regressive changes in May 2015 (after the salvage therapy of 4 months).

M.-E. Chang, H.-W. Teng / Journal of Cancer Research and Practice 3 (2016) 23e27 27

References

1. Gotlib J. World Health Organization-defined eosinophilic disorders: 2014 up-date on diagnosis, risk stratification, and management. Am J Hematol. 2014;89:325e337.

2. Crane MM, Chang CM, Kobayashi MG, et al. Incidence of myeloproliferativehypereosinophilic syndrome in the United States and an estimate of allhypereosinophilic syndrome incidence. J Allergy Clin Immunol. 2010;126:179e181.

3. Cogan E, Roufosse F. Clinical management of the hypereosinophilic syndromes.Expert Rev Hematol. 2012;5:275e289. quiz 90.

4. Sekkach Y, Mekouar F, Jira M, et al. Durable efficacity and remission aftertreatment with imatinib mesylate for FIP1L1-PDGFRA transcript negativeassociated eosinophilic cardiomyopathy. Ann Pharm Fr. 2011;69:277e281.

5. Baccarani M, Cilloni D, Rondoni M, et al. The efficacy of imatinib mesylate inpatients with FIP1L1-PDGFRalpha-positive hypereosinophilic syndrome. Re-sults of a multicenter prospective study. Haematologica. 2007;92:1173e1179.

6. Jovanovic JV, Score J, Waghorn K, et al. Low-dose imatinib mesylate leads torapid induction of major molecular responses and achievement of completemolecular remission in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia.Blood. 2007;109:4635e4640.

7. Nutman TB. Evaluation and differential diagnosis of marked, persistent eosin-ophilia. Immunol Allergy Clin N Am. 2007;27:529e549.

8. Arefi M, Garcia JL, Briz MM, et al. Response to imatinib mesylate in patientswith hypereosinophilic syndrome. Int J Hematol. 2012;96:320e326.

9. Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of thePDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathichypereosinophilic syndrome. N Engl J Med. 2003;348:1201e1214.

10. Legrand F, Renneville A, Macintyre E, et al. The Spectrum of FIP1L1-pdgfra-associated chronic Eosinophilic Leukemia: New Insights Based on a Survey of44 cases. Medicine. 2013. Baltimore.

11. Ohnishi H, Kandabashi K, Maeda Y, et al. Chronic eosinophilic leukaemia withFIP1L1-PDGFRA fusion and T6741 mutation that evolved from Langerhans cellhistiocytosis with eosinophilia after chemotherapy. Br J Haematol. 2006;134:547e549.

12. Lierman E, Michaux L, Beullens E, et al. FIP1L1-PDGFRalpha D842V, a novelpanresistant mutant, emerging after treatment of FIP1L1-PDGFRalpha T674Ieosinophilic leukemia with single agent sorafenib. Leukemia. 2009;23:845e851.

13. Bradeen HA, Eide CA, O'Hare T, et al. Comparison of imatinib mesylate, dasa-tinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea(ENU)-based mutagenesis screen: high efficacy of drug combinations. Blood.2006;108:2332e2338.

14. Ikezoe T, Togitani K, Tasaka T, et al. Successful treatment of imatinib-resistanthypereosinophilic syndrome with nilotinib. Leuk Res. 2010;34:e200e1.

15. David M, Cross NC, Burgstaller S, et al. Durable responses to imatinib in pa-tients with PDGFRB fusion gene-positive and BCR-ABL-negative chronicmyeloproliferative disorders. Blood. 2007;109:61e64.