Comparison of Two Leukocytapheresis Protocols in a Case of Idiopathic

Home , Eosinophil, Leukostasis, Volume expander

Page 1of26 between this versionandtheVersionrecord. Pleasecitethis articleasdoi:10.1002/jca.21435. through thecopyediting, typesetting, paginationandproofreadingprocess, whichmayleadtodifferences This istheauthormanuscript acceptedforpublicationandhasundergone full peerreviewbuthasnotbeen B A C

Figure1. blood). and peripheral ma 1000X at images All taken after nea discharge months 8 at was marrow (F) core (F), smear blood Peripheral blood). and peripheral hypereos showing marked presentation initial at(C)

Accepted Article aspirate s marrow bone smear (A), blood Peripheral

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bone marrow aspirate smear (E), and bone (E), aspiratesmear marrow bone inophilia (>90 % eosinophils in bone marrow bone in (>90 % eosinophils inophilia r normal (<5 % eosinophils in bone marrow bone in eosinophils (<5 % rnormal gnification. gnification. mear (B), and bone marrow core core marrow bone and (B), mear

medications. medications. count neutrophil peripherally inser PICC: deep DVT: thrombosis, vein Figure2. Timelinera eosinophil of and peripheral count WBC

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This article isprotected by copyright. All rights reserved. Journal ofClinicalApheresis John Wiley& Sons ted central catheter, ANC: absolute absolute ANC: catheter, central ted tio with leukocytapheresis and leukocytapheresis with tio

Page 2of26 Page 3of26 • • • • • • • • • • other and Molecular, Cytogenetic, • • Labs SelectAdmission 1. Table EBV:E cytomegalovirus, CMV: Ova O&P: and parasite, • Studies Marrow Bone • panel Cytokine • disease Infectious • • • • • • • • • • • • • • • • • • Normal TNFa, IL1B, 2, 4, 5, 6, 8, 12 12 8, 6, 5, 4, IL1B, 2, TNFa, Normal Negative for BCR/ABL1 or FIP1L1/PDGFRA gene fusions gene or FIP1L1/PDGFRA BCR/ABL1 Negativefor Negative transcriptome and whole genome sequencing sequencing genome whole and Negativetranscriptome Negative for CEBPA, NPM1, FLT3 D835, JAK2 V617F, KI JAK2 FLT3 D835, NPM1, CEBPA, Negativefor Negative for BCR/ABL1 and indeterminate forPML/RAR and indeterminate BCR/ABL1 Negativefor (Bone mar with % cellularity 70-80 up follow month 8 At afterdays 3 discharge Hospital day 9 (Bone marrow: 81 t 81 (Bone marrow: day Hospital 9 D-Dimer 1.73 mg/L D-Dimer1.73 mg/dL 4.4 protein ng/mL,C-Reactive 680 Ferritin Chromosomal microarray analysis – normal female pro female microarray normal – analysis Chromosomal K/ 216 eosinophil %,Absolute 96.0 ratio Eosinophil 136 %,Plt 27.4 g/dL, Hct K/µL,10.1 Hgb 225 WBC Hospital day 1 95% cellularity wi cellularity 95% day Hospital 1 gam Interferon IL IL10,13, IL2R , ElevatedSoluble negative all – Histoplasmosis Blastomycos Aspergillus, Respiratory panel, zoster, P O&P, difficile, C. cultures, culture,Urine Blood Troponin 5.06 ng/mL, Lactate dehydrogenase 877 IU/L 877 Lactatedehydrogenase ng/mL, 5.06 Troponin Mycoplasma IgM positive prior to admission per prim per admission to prior IgM positive Mycoplasma Whole genome sequencing – normal normal – genome sequencing Whole normal – sequencing Transcriptome normal Tryptase – normal – TCR-Vbeta gene rearrangements, and MDS FISH Panel FISH Panel MDS and generearrangements, mutations mutations Accepted Article workup. Summarydiagnostic of

Journal ofClinicalApheresis John Wiley& Sons row: 4.4 %, Peripheral blood: 4.5 %) 4.5 blood: %,Peripheral 4.4 row:

th marked eosinophilia eosinophilia marked th o 70 %, Peripheral blood: 92.5 to 80 %) 80 to 92.5 %,Peripheral blood: 70 o arvovirus B19, CMV, EBV, Varicella Varicella EBV, B19, arvovirus CMV, slightly increased eosinophils eosinophils slightly increased is, Coccidioidomycosis, and Coccidioidomycosis, is, µL µL ma ma pstein-Barr virus virus pstein-Barr arycare physician file file

A transcripts Atranscripts , PDGFRA, PDGFRB or FGFR1 FGFR1 or PDGFRB PDGFRA, , T D816V, IDH1, and IDH2IDH1,and D816V, T

60 59 58 57 hemoglobin, platelet and count fluid balance. rcdr 1 3 4 3 Pre: Pre-procedure, Post-procedure Post: 2 Fluid balance (mL) Platelet (K/ Hemoglobin (g/dL) 1 (%)Eosinophil (K/Eosinophil WBC (K/ Procedure # Protocol Table 2. Pre- and post-procedureeach values of leukocytaph µ L) L) µ Accepted L) Article µ L)

02 06 . 89 02 +14.6 10.2 8.9 3.9 % 10.6 10.2 5 18 -31.6 % 108 158 0 17 -23.0 % 157 204 4 9 -33.2 % 96 144 r Ps Change Post Pre 1 9 22% 1 5 44% 4 4 8 8 -6.8 % 82 88 0 % 84 84 +4.4 % 95 91 -2.2 % 89 91

Journal ofClinicalApheresis 0 8 -22.9 % 84 Change 109 Post Pre 3 13 -18.1 % 113 138 -20.0 % 80 100 John Wiley &Sons eresis for count, absoluteWBC eosinophil count, eo %

4 16 -27.9 % 106 Change 147 Post Pre 9 16 -46.2 % 156 290 -31.0 % 89 129 8.3 8.1 -2.4 % 8.3 7.8 -6 % -6 % 7.8 8.3 -2.4 % 8.1 8.3 MNC

sinophil percentage,sinophil 7 8 -52.3 % 82 172 -33.7 % 69 Change 104 Post Pre 1 7 -37.4 % 57 91 Page 4of26

60 59 58 57 Page 5of26 processed. EBV: estimated blood volume Fluid Balance/EBVEnd (mL) Platelet Change/EBV (%) RBC Change/EBV (%) PercentageEosinophil Change/EBV (%) Absolute Change/EBV Eosinophil (%) Absolute Change/EBV Eosinophil (K/µL) WBC Change/EBV (%) WBC Change/EBV (K/µL) Number Processed of Bolume Blood (x EBV) Procedure # Protocol 3.Table

Accepted ArticleComparison of effects of using leukocytapheresis PM

This article is protected by copyright. All rights reserved. Journal ofClinicalApheresis 1. -. -04 1. -61 -13.4 -14.2 -16.1 -12.0 -14.7 -10.7 -14.6 -14.5 -13.7 -10.4 -15.1 -9.6 -13.3 -14.1 -7.8 -10.7 -7.8 -14.9 -13.0 -9.0 -18.8 -9.8 -12.4 -19.5 15 12 19 8 8 -47 -87 -8 -129 -132 -125 22 73 48 03 20 -0.9 -2.0 +0.3 +4.8 +7.3 +2.2 .6 .6 .6 .1 .2 2.61 2.32 2.91 2.56 2.56 2.56 90 71 80 1. -26 -19.2 -1.5 -22.6 -2.9 -15.9 -8.0 0 -7.1 +0.4 -9.0 +1.7 -0.9 2 en 2 Mean 2 1 Mean 2 1 John Wiley &Sons N and MNC protocols, normalized eachto estimated b M MNC PMN lood volume

E-mail: E-mail: 734-936-6888 Fax: 734-936-6776 Telephone: Arbor, Ann 48109-5054 MI 2F225UH 5054, SPC Dr. CenterMedical E. 1500 Departmentof Pathology Medicine Transfusion / Bank Blood Michigan Universityof Yamada, M.D. Chisa correspondence for Address System Health Michigan Universityof performed the was at which work Institution Arbor, Ann MI Michigan Universityof Departmentof Pathology 1 Ph.D. L.M.D., Wang, Michael Syndrome a in Protocols Leukocytapheresis Two of Comparison Hypereosinophilia for Leukocytapheresis title form of Short

Division of Transfusion Medicine Medicine of Transfusion Division

[email protected] Article

John Wiley& Sons 1 Case of Idiopathic Hypereosinophilic Idiopathic Hypereosinophilic Caseof 1 , Chisa Yamada, M.D. Chisa , 1

Page 6of26 Page 7of26 polymorphonuclear cell (PMN) protocol, followed by followed protocol, cell(PMN) polymorphonuclear percentage continued to decrease, and were 6.4 K/µL 6.4 andwere decrease, to percentagecontinued methylprednisolone and hydroxyurea. She received tw received hydroxyurea. She and methylprednisolone Leukocytapheresiswas s % eosinophils. 96 K/µLwith an cardiac with presented female A4-year-old Case: using t procedures four leukocytapheresis with HEOS succ the here We report unclear. is context this in ra is syndrome (HEOS) Hypereosinophilic Background: Abstract under stable condition with WBC of 22 K/µL with 86 86 K/µL of 22 with WBC with condition under stable % eosinophils. 82 K/µL 69 with to decreased herWBC proto cell(MNC) mononuclear with leukocytapheresis Syndrome Hypereosinophilic Leukocytapheresis, KeyWords res protocol andMNC balancefluid negativegreater reductions. similar achieving protocols and MNC PMN decr in effective Leukocytapheresis was Conclusion: bal %,and fluid -19.2 and -8.1 by %, platelet 13.4 byWBC - average, changed, on protocols and MNC PMN t respectively. Normalized % perleukocytapheresis, (aEO) counts eosinophil absolute and Findings:WBC respectively. discharge, after % bymonths 3

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This article isprotected by copyright. All rights reserved. Journal ofClinicalApheresis John Wiley& Sons 2 essful treatment of a patient with idiopathic idiopathic with of a treatment patient essful ance by -129 and -47 mL, respectively. respectively. andmL, -47 ance -129 by o estimated blood volume, procedures with with procedures volume, blood estimated o d respiratory dysfunction, and WBC of 225 of 225 and WBC dysfunction, respiratory d ulted in greater platelet loss. loss. greater platelet in ulted easing WBC and aEO counts in HEOS, with with HEOS, in counts and aEO WBC easing and 52 % by 2 weeks and 3.9K/µL and 4.9 and4.9 and 3.9K/µL weeks 2 % by and52 wo protocols. protocols. wo % eosinophils. WBC count and eosinophil and eosinophil count WBC %eosinophils. initiation of imatinib therapy, then two two therapy, then of imatinib initiation tarted after initiation of initiation tartedafter decreased by an average of 29.0 and 30.4 and30.4 averageof 29.0 decreasedan by o leukocytapheresis with with leukocytapheresis o col. After the fourth leukocytapheresis, leukocytapheresis, fourth After col. the She was discharged on hospital day hospital 21 on was discharged She However, PMN protocol resulted in in resulted However, protocol PMN re, and the efficacy of leukocytapheresis ofleukocytapheresis efficacy andthe re, 10.7 and -12.1 %, aEO by -10.4 and- %, aEO -10.4 by and-12.1 10.7

protocols as part of her treatment with favorable o favorable with treatment as partof her protocols polyclonal, driven by increased eosinophilopoietic eosinophilopoietic increased by polyclonal,driven per 100,000 (1). Hypereosinophilia is defined as bl is Hypereosinophilia (1). per 100,000 Methods leukocytaphere two the compared and each procedure neoplastic and monoclonal, often with increased bla increased oftenwith and monoclonal, neoplastic secondar It be primary, can (2). damage/dysfunction associa is hypereosinophilia when diagnosed is HEOS marked and/or depositi byeosinophils, infiltration %eosin defined as >20 is turn in hypereosinophilia one mont bytime least at separated in examinations idiopathic HEOS who received a total of fourleukoc of a received who total HEOS idiopathic unc remain setting ofthe HEOS in leukocytapheresis apheresis regarding optimal the Therefore,details leukocytapheresis with of HEOS reportsof treatment Hypereosinophilic syndrome (HEOS) is a rare entity entity a rare (HEOS) is syndrome Hypereosinophilic Introduction All leukocytapheresis procedures were performed usi performed were procedures leukocytapheresis All mL/min/liter of total blood volume. The inlet: ACD The inlet: volume. blood of total mL/min/liter m height,to and weight sex, on calculated is based usi machine apheresis by the wascalculated (ACD-A) of amount The Lakewood, CO). BCT, (Spectra,Terumo

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This article isprotected by copyright. All rights reserved. Journal ofClinicalApheresis John Wiley& Sons 3 utcome. We analyzed the patient’s response to response to patient’s analyzed We the utcome. on of eosinophil granule proteins in tissue (2). tissue in proteins granule of eosinophil on procedure or the effectiveness of effectiveness or the procedure eet the set infusion rate of 0.8-1.1 of 0.8-1.1 rate infusion eet set the ood eosinophils > 1.5 K/µL on two K/µLtwo > on 1.5 eosinophils ood signaling (2). Due to rarity of the disease, rarity disease, of Duethe to (2). signaling ophils in the bone marrow, extensive tissue tissue extensive marrow, bone the in ophils h and/or tissue hypereosinophilia (2). Tissue (2). Tissue hypereosinophilia tissue and/or h sts. Secondary HEOS is reactive and reactive is Secondary HEOS sts. y, or idiopathic (2). Primary HEOS is is HEOS y,Primary (2). or idiopathic -A ratio for the polymorphonuclear cell polymorphonuclear -Afor ratio the ytapheresis procedures using two different different using two procedures ytapheresis lear. We encountered a patient with with a patient encountered lear.We are limited to a handful of cases (3-8).of cases a handful to are limited with an estimated prevalence at 0.36-6.3 0.36-6.3 at prevalence an estimated with ng the COBE Spectra ngCOBE the ng the patient’s total blood volume, which which volume, blood ngtotal patient’s the ted with eosinophil-mediated organ eosinophil-mediated with ted sis protocols. protocols. sis anticoagulant citrate dextrose solution A solution dextrose citrate anticoagulant ® apheresis system system apheresis Page 8of26 Page 9of26 prior (differential) for the third procedure, and 9 procedure, third forthe (differential) prior an first the right before drawn were labs procedure polymorphonuclear cells, eosinophils, and basophils eosinophils, cells, polymorphonuclear gra for ofremoval mature the optimized is protocol bloo estimated small patient’s the to performeddue eosinophil percentage, and absolute eosinophil (aEO eosinophil absolute percentage,and eosinophil count cell(WBC) blood andwhite each the procedure j right patient’s internal the in French) 10 placed a non-t performed proceduresthrough All were size. ba fluid negative large of relatively consideration protocol MNC using performed were leukocytapheresis cardiac had signs of patient sinceourwas held HES were procedures and second leukocytapheresis first andsimi are segmented eosinophils Since disorders. (DIC coagulation intravascular as disseminated such car to contraindicated due is when used HES also is o cells of mononuclear for removal the optimized is agent sedimenting a RBC (HES), hydroxyethylstarch tol if volumes blood three to total up allowanceof and protocols) and MNC (PMN Spectra guidelinefrom for Our leukocyt protocol protocol. comparedPMN to wou protocol MNC in used ACD-A relativein increase set are protocols cell(MNC) and mononuclear (PMN)

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This article isprotected by copyright. All rights reserved. Journal ofClinicalApheresis John Wiley& Sons hours prior to the fourth procedure. Post- procedure. fourth the to prior hours 4 ugular vein. Blood was drawn before and after after and before drawn was Blood ugularvein. lance with PMN protocol in her small bodyher small in protocol PMN with lance erated by the patient. RBC prime was prime RBC erated patient. the by d second procedures, right before and 9 hours hours and9 before right second d procedures, nulocytes (segmented cells including cells (segmented nulocytes d volume and rinse back was held. The PMN The PMN was held. and rinse back volume d diac or renal dysfunction, coagulopathies coagulopathies dysfunction, renal diacor r immature cells (lymphocytes and blasts); it it and blasts); (lymphocytes cells rimmature dysfunction. The third and fourth and fourth The third dysfunction. performed using PMN protocol. However, However, protocol. PMN using performed lar to polymorphonuclear cells in size, the the size, in cells polymorphonuclear larto ), and should be performed with the use ofuse the with be performed ),and should unneled double-lumen catheter (Sorenson, (Sorenson, catheter double-lumen unneled ), or certain hereditary coagulation coagulation hereditary certain ),or ) count were recorded. Of pre- note, recorded. were )count , hemoglobin (Hgb), platelet count, count, (Hgb), hemoglobin platelet , apheresis is based on the procedure procedure the basedon is apheresis and volume expander. The MNC protocol protocol The MNC expander. andvolume as13:1 and 12:1, respectively. The slight The slight respectively. and 12:1, as13:1 ld result in a less negative fluid balance balance fluid negative a less in result ld due to contraindication of HES and of HES contraindication due to processes two total blood volumes, with with volumes, blood total two processes

presented to an outside hospital emergency departme hospital an presentedoutside to procedure labs were drawn right afterright procedure the drawn were labs procedure blood volume processed in each procedure was also c also was each in procedure processed volume blood At our institution, she wasshe febrile (39.4 institution, our At institution. our transferredto ha to found and an enema.was later She amoxicillin an infection aurinary tract with was diagnosed She of intermitte as one week as well and legs herhips 20.2 weight and cm 115 height female, A4-year-old Case these laboratory data and the patient’s clinical re clinical patient’s the and theselaboratory data leukocyt two and the was analyzed leukocytapheresis mach apheresis byused the balance and fluid volume f the after hours and13 after procedure, third the

(Figure 1A). She was admitted to the pediatricinte the to admitted was She (Figure1A). witho and platelets cells blood red normal revealed eosino % 96 K/µL with of 225 (WBC hypereosinophilia count A blood ischemia). for concerning depression (tropon cardiacdysfunction revealed Initial workup dehydrate andBPM), appeared (139 air),tachycardic PMN and MNC effects was not performed due to only h due to performed was effects not and MNC PMN

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This article isprotected by copyright. All rights reserved. Journal ofClinicalApheresis John Wiley& Sons o C), mildly hypoxic (93% oxygen saturation on room room on saturation (93% oxygen hypoxic mildly C), 5 sponse. The laboratory data normalized to one to normalized data The laboratory sponse. ourth procedure. The calculated processed blood blood processed calculated The procedure. ourth nt fevers, abdominal pain, and constipation. and constipation. pain, fevers, nt abdominal nsive care unit for further management. The management. for further care unit nsive ut blast cells or evidence of myelodysplasia of myelodysplasia or evidence cells blast ut d constipation, and treated accordingly with with accordingly and treated constipation, d in I up to 6.13 ng/mL and ECG showing ST showing ST ECG Iand ng/mL in 6.13 to up for the first and second procedures, 6 hours hours 6 procedures, and second first for the ve a WBC count of > 200 K/µL and was K/µL and was >200 of count vea WBC revealed leukocytosis with with revealed leukocytosis nt after several weeks of malaise and pain in in and pain ofmalaise weeks after nt several kg, with no significant past medical history medical past significant kg,no with d. She continued to have malaise and pain. and pain. malaise have to continued She d. ine were also recorded. The effect of each each The effect of recorded. also were ine apheresis protocols are compared based on basedon compared are protocols apheresis ompared. Statistical analysis comparing comparing analysis ompared.Statistical phils). A peripheral blood smear blood A peripheral phils). aving 2 data points for each parameter. for parameter. each points data 2 aving

Page 10of26 Page 11of26 back down to 109 K/µL, and she received a second le asecond and received she K/µL, 109 backto down physician (Table 1). Chest X-ray showed bilateral i X-ray bilateral showed Chest (Table1). physician r was IgMadmission to prior mycoplasma testing but processes. As her extensive diagnostic workup did n did workup diagnostic extensive processes.her As bone marrow studies during admission showed marked marked showed admission during marrow bone studies excluded (Table 1). Microbiology testing during her testing during (Table 1).Microbiology excluded a negative all were tests andmolecular Cytogenetic eosinophil percentage from 91 to 89 % (Table 2). He % (Table 89 2). to 91 percentagefrom eosinophil 96 to 144 decreased from count K/µL and aEO 108 to cardiacdysfu patient’s the due to used was not HES eosinoph as was favored protocol PMN available, the caused leukostasis. by dysfunction andrespiratory s required andstill she ng/mL) (1.51 remainedhigh a her day WBC since hospital 4 on leukocytapheresis o K/µL and180 between 144 andstabilized decreased (25mg dayand hydroxyurea 2) on hours 6 mg/kgevery t (2 mg/kgx1 methylprednisolone was on started She syndrome. hypereosinophilic havingidiopathic her hype explain to process infectious attributable ultrasound did not identify lymphadenopathy or mass identify lymphadenopathy not did ultrasound and spleno colon, sigmoid distal of the compression ora edema pulmonary bilateral revealed andabdomen

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This article isprotected by copyright. All rights reserved. Journal ofClinicalApheresis John Wiley& Sons 6 reosinophilia, she was clinically diagnosed as diagnosed wasshe clinically reosinophilia, Between the two leukocytapheresis protocols protocols leukocytapheresis Betweentwo the nterstitial infiltrates. CT scans of the chest scans chest of the CT infiltrates. nterstitial nd chronic eosinophilic leukemia was leukemia eosinophilic chronic nd upplemental oxygen, suggestive of cardiac of suggestive oxygen, upplemental megaly. Chest X-rays, CT scans, and CT X-rays, megaly. Chest nction. Her WBC count decreased from 158 158 decreased from count Her WBC nction. admission showed no evidence of infection, infection, evidenceof no showed admission ot reveal either a clonal process or an processor a reveal clonal ot either r WBC increased subsequently to 122 then then 122 to subsequently increased rWBC nd eosinophil counts and troponin I and troponin counts eosinophil nd hen 1 mg/kg x1 on hospital day 1 and 0.5 and0.5 day hospital 1 on mg/kgx1 hen1 eported to be positive from primary care primary from beeported positive to ukocytapheresis with the PMN protocol protocol PMN the with ukocytapheresis However, granulocytes. were ils mature es to suggest lymphoma or other neoplastic or otherneoplastic lymphoma suggest esto n hospital days 2 and 3, she received received she 3, and 2 days hospital n typical infection, pleural effusions, pleuraleffusions, infection, typical K/µL with only slight decrease of only K/µLslight with /kg on day 2). Although her WBC count count WBC Althoughher day 2). on /kg eosinophilia (Table 1 and Figure 2). and Figure 1 (Table eosinophilia

breaths/min) and she was clinically doing well with well clinically doing and was she breaths/min) months after discharge showed a normocellular bone bone a normocellular after showed discharge months d after % by4.9 months 3 at reference range within K/µL 0.5 b at range reference was within weeks,aEO was Herwithi WBC eosinophils. % 86 K/µL of22 with hos on wasshe discharged and decrease to continued % eosinophils, 82 K/µL and 69 with % eosinophils 84 leukocyta and fourth balance.third the fluid After shou protocol anduse MNC HES avoid wanted to still leukocytaphe and fourth third For her leukostasis. hospital on moreleukocytapheresis two received she abdo K/µL and 147 to again increasing count herWBC therapy, currently imatinib on started was also She respiratory distress, O2 saturation 94-99 % on room % on 94-99 saturation O2 respiratorydistress, milrinon off weaned leukocytapheresis, aftersecond resolv were dysfunction and respiratory Hercardiac baseline), mg/dL,~2x (0.33 secondleukocytapheresis tachyca intermittent of >2 second, capillaryrefill suggest and symptoms showing signs mL. was 1400 She s body givensmall her concern a average,was which resulte %.These procedures 95 to 91 from increased b K/µL, 80 to 100 from decreased aEO count K/µLand day 5. day hospital on again HES next the without

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This article isprotected by copyright. All rights reserved. Journal ofClinicalApheresis John Wiley& Sons 7 rdia, transient increase in creatinine after the aftercreatininethe in increase transient rdia, pheresis, her WBC decreased to 106 K/µL with K/µL with 106 to decreased her pheresis, WBC resis, the MNC protocol was used because we was because used protocol MNC the resis, a first line therapy for HEOS. However, with with However, HEOS. for therapy line first a ischarge. Follow-up bone marrow study at 8 8 at marrow study bone Follow-up ischarge. Her WBC count decreased from 109 to 84 84 to 109 from decreased count HerWBC only mild constipation and abdominal pain. pain. and abdominal constipation only mild air, though intermittently tachypneic to ~40 ~40 to tachypneic air, though intermittently I, ng/mL 1.19 Troponin ingtrending (down e without tachycardia, hypotension, or hypotension, tachycardia, ewithout d in a negative fluid balance of 329 mL on on mL 329 balanceof a negativefluid in d days 12 and 14 to prevent further prevent to and14 days 12 pital day 21 in stable condition with WBC WBC with condition day stable pital in 21 ize with an estimated total blood volume of volume blood total an estimated with ize marrow with trilineage hematopoiesis and trilineage with hematopoiesis marrow y 2 months, and eosinophil percentagewas yand eosinophil months, 2 as well as a mild headache. headache. as a mild as well respectively (Table 2). Her WBC count count 2).Her WBC respectively (Table ld theoretically result in a less negative a less in result theoretically ld minal pain possibly due to leukostasis, leukostasis, dueto possibly pain minal ut her eosinophil percentage slightly percentageslightly eosinophil her ut n reference range at 6.4 K/µL by 2 K/µL2 6.4 by at reference range n ive of dehydration, including prolonged including prolonged dehydration, of ive Page 12of26 Page 13of26 percentage, hemoglobin, platelet count, and fluid b and fluid count, platelet percentage,hemoglobin, associa line catheter central peripherallyinserted Findings during and micafungin, sulfamexazole-trimethroprim, therapie antibiotic day and various 5 to hospital 1 Ot Figure in 1. summarized percentageis eosinophil proced leukocytapheresis and the treatments various and K/µL 5.7 at reference ranges, and within stable whenher after months 6 discharge, discontinuation neutrophil absolute low due to and off on imatinib 2 weeks after discharge; hydroxyurea from hospital hospital from hydroxyurea weeks discharge; 2 after and prednisol (methylprednisolone steroids included cour clinical her leukocytapheresis, to Inaddition since. well remained dysplasia.has She aspirate % (4.4 on s eosinophils slightlyincreased an average of 30.8 and 34.2 %, respectively (Table (Table %,respectively and 34.2 30.8 anaverage of %,respectively; and 26.7 of 27.3 aEOan average by Leukocytapheresiswith %. and30.4 % average29.0 one l by and aEO counts WBC decrease of Theoverall 9 (between the 2 (between 9 the af day weeks 2 to 5 hospital from artery subclavian

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and 3 rd This article isprotected by copyright. All rights reserved. leukocytapheresis) until 2 weeks after discharge. weeks discharge. 2 after leukocytapheresis) until Journal ofClinicalApheresis John Wiley& Sons 8 ted deep vein thrombosis (DVT) in the left left the in (DVT) deep thrombosis vein ted s, including cefepime, azithromycin, azithromycin, cefepime, including s, se involved multiple medications. Treatments Treatments medications. multiple involved se mears) and no morphologic evidence of evidence morphologic mears)and no alance with the PMN and MNC protocols protocols and MNC PMN the with alance count and mild hepatic toxicity until hepaticuntil toxicity and mild count ter discharge; and imatinib from hospital day hospital from andimatinib terdischarge; 1.4 %, respectively. The duration of these duration The %,respectively. 1.4 2). The mean change in eosinophil eosinophil in change 2).The mean WBC and percent eosinophil were both eosinophil and percent WBC day 2 to day 19; enoxaparin for a enoxaparin day 19; to day2 ures in relation to her WBC and peripheral and peripheral WBC her to relation uresin her treatments include milrinone from milrinone include hertreatments one) from hospital day 1 and weaned off and weaned 1 by day one)hospital from MNC protocol decreased WBC and aEO by WBC decreased protocol MNC the PMN protocol decreased WBC and decreased WBC protocol PMN the the first week of admission. admission. week first of the eukocytapheresis procedure was on wason procedure eukocytapheresis Thereafter, she was Thereafter, she

processed, on average, the PMN and MNC protocols de protocols and MNC PMN average,the processed, on based on American Society for Apheresis guidelines, Apheresis for Society American basedon later, while on prednisone 20 mg BID, her WBC incre BID,WBC mg 20 her prednisone on later,while (70% eos eosinophils 82% with K/µL was 13.6 herWBC was who trea reaction drug a hypereosinophilic with E Insyndrome. 1974, of hypereosinophilic treatment literat the ofarticles in area Therehandful only K/µL. was100-150 WBC while pain andleg a K/µL,>200 and developed WBC with course clinical r and experiencedcardiac Our patient organdamage. increa of the morphology magnitudeof leukocytosis, disease,of the leukocy rarity the availabledue to resultin counts WBC typical Since respectively(9). andmonoblas ALL, AML, <50K/µL for and >400, >100, is of hyperleukocytosis setting the in Leukostasis Discussion +0.4 and -1.5 %, +4.8 and -0.9 %, -8.0 and -19.2 %, -19.2 and%, -8.0 -0.9 +4.8and +0.4and%, -1.5 percentage eosinophil in change (Tablemean the 3); 14 and 13.3 andaEO by count %) K/µLand 12.1 (10.7 When the change of each laboratory result was norma laboratory result each change the of When and-4 and%, -20.6 -4.2 %,+9.3 +1.1and -3.4 were

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This article isprotected by copyright. All rights reserved. Journal ofClinicalApheresis John Wiley& Sons ure regarding the use of apheresis in the the in apheresis ofuse the regarding ure 9 tapheresis is currently applied based on basedon applied currently is tapheresis a category I indication for leukocytapheresis leukocytapheresis Ifor indication category a g in leukostasis for hypereosinophilia is not not is for hypereosinophilia gleukostasis in and -129 and -47 mL, respectively. mL, -47 andand -129 9.3 %, and -329 and -113 mL, respectively. mL, respectively. -113 %,andand -329 9.3 ted with leukocytapheresis. At presentation, presentation, At leukocytapheresis. with ted , RBC, platelet count, and fluid balance were were balance andfluid count, platelet RBC, , llman et al reported a 25-year-old female female 25-year-old a reportedalet llman earlier her in complications espiratory sed cells, and signs and symptoms of end symptoms and and signs cells, sed and typically occurs at WBC counts of counts WBC at occurs and typically lized to one estimated blood volume volume blood one estimated to lized ased to ~116 K/µL with ~85% eosinophils. eosinophils. ~85% with K/µL ~116 to ased .2 K/dL (10.4 and 13.4 %), respectively %), respectively and13.4 K/dL .2 (10.4 line associated DVT and had abdominal and had abdominal DVT associated line creased WBC count by and 14.6 14.9 count creasedWBC inophils in bone marrow). Two weeks weeks marrow). bone in Two inophils tic/monocytic variants of AML, variants tic/monocytic

Page 14of26 Page 15of26 7-18 hours post-procedure, and none showed clinical andshowed none post-procedure, hours 7-18 eosinoph the patients, Inall reducingeosinophils. indicating patients, same3 the in decrease and 35% count, eosinophil in decrease and 35% 83, a 90, in packed mL removed 200 of leukocytapheresis andeach Each plas hypereosinophilia. with treating patients pl between a comparison Davies reported alet 1982, splenomegaly, in reduction decreasecreatinine, in improve clinical also was K/µL. 2.5 to There months t count eosinophil blood in a resultingdecrease in

four times. The mean yield of eosinophils was 1.3 x was 1.3 of eosinophils yield The mean fourtimes. were who eosinophilia moderate with seven patients fo during well subsequent remained She eosinophils. month 6 at marrow bone Arepeat byofECG months. 2 o week; and disappearance 1 in lacticdehydrogenase of her ser normalization and cutaneousmicroinfarts days; 2 within well-being sense of tenderness,and with responded well She days. successive two of the was performed, removing a total of 1.38 X10 of 1.38 a total removing was performed, leukocytapheresis with was treated that eosinophils pr who male an18-year-old reported alet Blacklock or symptoms eosinophilia in significantimprovement She received leukocytapheresis and 22 x 10 x and 22 leukocytapheresis received She

Accepted Article

This article isprotected by copyright. All rights reserved. Journal ofClinicalApheresis John Wiley& Sons 10 and 9.6 x 10 and x 9.6 12 eosinophils (11.5 X10 (11.5 eosinophils 10 il count returned to the previous high level afterhigh level previous returned the count to il hat continued to decrease over the next 6 6 overnext the hatdecrease to continued ma exchange processed 2.5 to 4.0 L 4.0 to of plasma 2.5 processed exchange ma weight gain, and loss of night sweats (5). In(5). nightsweats of and loss gain, weight resolution of her subungual petechiae and petechiae of her subungual resolution while leukocytapheresis resulted in a 38, 27, 27, a 38, in resulted leukocytapheresis while . In a one-month period, 12 leukocytapheresis leukocytapheresis 12 In period, a. one-month that plasmapheresis was more effective at moreeffective was plasmapheresis that um aldolase, creatine phosphokinase, and phosphokinase, creatine aldolase, um 10 esented with a WBC of 257 K/µL with 95% 95% K/µL with 257 of a WBC esentedwith improvement in her dyspnea, muscle muscle her dyspnea, in improvement asmapheresis and leukocytapheresis in in asmapheresisand leukocytapheresis llow-up (3). In 1977, Pineda et al reported reported alet Pineda In (3). 1977, llow-up ment with reduction in ischemic attacks, ischemic in reduction with ment improvement (6). In 1990, Chambers et alet Chambers In1990, (6). improvement f S3 and S4 heart sounds and normalization and normalization heart sounds and S4 fS3 treated with leukocytapheresis from one to to one from leukocytapheresis with treated in any of the patients (4). In (4). 1979, any in of patients the 10 buffy coat cells. Plasmapheresis resulted resulted Plasmapheresis cells. coat buffy s after discharge showed 16% 16% after showed s discharge per procedure, and there was no perand procedure, 10 eosinophils were removed on each each wereon eosinophils removed 10 per procedure),

published case reports or series in the last 40 yea 40 last the seriesin or case reports published r failure, and circulatory progressive bronchospasm between 1.0 x 10 betweenx 1.0 leukocytapheresis, respectively. respectively. leukocytapheresis, decre and 37.4% 31.0, for 20.0, a 33.3, eosinophils

similar reductions in eosinophils. Inrepo previous eosinophils. in reductions similar Comparingt hypereosinophilia. specific to is that of h treatment the in efficacyof leukocytapheresis plausib most be the to hypothesized celltrauma was t with through contact eosinophils of degranulation leukocytapheresis and required intensive care thera intensive and required leukocytapheresis res procedure The first leukocytapheresis. received a 42- in complications reportedal life-threatening stabil a of degree provided and acuteexacerbations in leukoplasmapheresis Combined period. duringthis months. On average, each procedure processed betwee processed procedure average, On each months. atwice we and later as periods treatment intensive exa clinical duestarted to was leukoplasmapheresis drug-indu due to wasdiscontinued Afterhydroxyurea fact or differentiating growth etiologiceosinophil th greaterfor and plasmapheresis leukocytapheresis hypereosinophilia with male a26-year-old described reductions were achieved per leukocytapheresis. We We perleukocytapheresis. achieved were reductions

Accepted Article

10 to 2.3 x 10 2.3 to x

This article isprotected by copyright. All rights reserved. 10 eosinophils. He also required vincristine on 2 sep 2 on He required also eosinophils. vincristine Journal ofClinicalApheresis John Wiley& Sons 11 rs provide conflicting data regarding the data conflicting provide rs or, but in the end required cytotoxic therapy. cytotoxic end required the in but or, year-old female with severe eosinophilia who who eosinophilia year-oldsevere with female o the previous reports above, we achieved we achieved above, reports previous the o rts, 1.0 to 22 x 10 x 22 to 1.0 rts, risk a potential and highlight ypereosinophilia, ekly therapy over a period of at least 17 17 of least at a period eklyover therapy ase for the first, second, third, and fourth and fourth second, third, first, asefor the ulted in status asthmaticus within 30 min of min 30 within asthmaticus status in ulted he extracorporeal surface and by mechanical mechanical and by surface heextracorporeal py. A second leukocytapheresis led to to led Asecond leukocytapheresis py. ization of his disease (7). In 2005, Gwinner et Indisease Gwinner of 2005, his (7). ization equiring artificial ventilation. Activation and Activation ventilation. artificial equiring cerbation and increasing WBC, first in short short in first WBC, and increasing cerbation an 1 year, to remove both the cells and any cells the year, both an 1 remove to le mechanism (8). In summary, the six Insummary, six the (8). mechanism le who was treated with both both with was who treated removed 6.7, 2.8, 5.6, and 4.8 x 10 x and 4.8 5.6, 2.8, removed6.7, this case contributed to the management of management the to case contributed this ced thrombocytopenia, cedthrombocytopenia, n 2.7 and 3.4 L of plasma, and removed and removed L plasma, of and 3.4 2.7 n 10 eosinophils and 27 to 38% 38% to and 27 eosinophils arate occasions occasions arate 10

Page 16of26 Page 17of26 because HES expands blood volume and interferes wit and interferes volume blood expands HES because contraindic is Ofofuse HES note, not. is protocol protocol without HES. However, the larger negative negative However, HES. larger the without protocol

of HES to allow for granulocyte harvest with minima with granulocyteharvest for allow to ofHES Firs ways. differthree in protocols The two cells. pro MNC the remove while granulocytes, to optimized PM the leukocytapheresis, for have protocols two We function, underlying coagulopathies such as DIC, or asDIC, such coagulopathies underlying function, WBC and eosinophil counts was slightly greater with greater was slightly counts and eosinophil WBC th Between (13). of hyperleukocytosis othercauses of leukoreduction extent The ofhypereosinophilia. red in was effective leukocytapheresis Incase, our a slightly negat in less result would theoretically respective are and 12:1, protocols 13:1 and MNC PMN protocol. for MNC the layer platelet the closerto for HES) ofuse (hence the RBCs the closer to depth S beused. not could HES cardiacfunction, impaired change in peripheral eosinophil percentage due to t percentagedue to eosinophil change peripheral in For p both as well. slightly affecteddata lab the ti the difference the in And effect. concentration post-pro a higher relatively in have might resulted

Accepted Article

This article isprotected by copyright. All rights reserved. Journal ofClinicalApheresis John Wiley& Sons 12 rotocols, the WBC reduction was without much much was without reduction WBC the rotocols, ive fluid balance. balance. fluid ive ming of the blood draws also might have might also draws mingof blood the t, the PMN protocol is optimized with the use the with optimized is protocol PMN the t, Third, the inlet: anticoagulant (AC) ratio for the for (AC) ratio the anticoagulant inlet: the Third, ated in patients with impaired cardiac or renal or renal cardiac impaired with patients atedin cedure WBC and eosinophil counts due to a due to counts and eosinophil cedureWBC ucing the WBC and aEO counts in the setting the in counts andaEO ucingWBC the he fact that nearly all WBCs were eosinophils eosinophils were WBCs all hefact nearly that was comparable to leukocytapheresis for leukocytapheresis to wascomparable e two protocols, the percent decrease in in decrease percent the protocols, etwo certain hereditary coagulation disorders, disorders, coagulation hereditary certain the PMN protocol, while it is shallower andshallower is it while protocol, PMN the econd, Spectra uses a deeper collection collection deepera econd,Spectra uses fluid balance seen with the PMN protocol protocol PMN the with seen balance fluid l red cell content (10), while the MNC MNC the while (10), red l cellcontent the MNC protocol compared to PMN comparedPMN to protocol MNC the N and MNC. The PMN protocol is is protocol The PMN andN MNC. h coagulation (11). Due to our patient’s our patient’s Dueto (11). coagulation h tocol is optimized to remove mononuclear to remove mononuclear optimized is tocol ly, and thus the MNC protocol protocol MNC the andthus ly,

patient had FIP1L1/PDGFRA-negative HEOS. For these For HEOS. had FIP1L1/PDGFRA-negative patient platelet-derived growth factor receptor alpha(PDGF receptor factor growth platelet-derived procedure. Again, this may be due to the negative f negative the due mayto be this Again, procedure. procedures. procedures.

FIP1L1/PDGFRA-positive HEOS, imatinib is currently is imatinib HEOS, FIP1L1/PDGFRA-positive remiss andmolecular hematologic, clinical, achieve HE FIP1L1-PDFGRA-positive with majorityof patients for used treating those than lower requiring doses FIP1L1-PDG The 15). (14, activities kinase (PDGFRB) treatment of CML. In addition, imatinib has also also has be imatinib In addition, of CML. treatment (CM leukemia myelogenous chronic in kinase BCR/ABL1 Imatinibwas desig our patient. in treatedHEOS the of medical combination a that of note is report,it o management medical of the a thorough review While each procedure, and was effective in maintaining a maintaining in effective was and each procedure, t the of priming mL), RBC (approximately1400 volume effect a concentration to value due highermeasured loss. However, hemoglobin (Hgb) levels remained the (Hgb) remained levels However, hemoglobin loss. ofuse HE the without andespecially layer, RBC the The collecti platelets. of a loss greater in result platel the andshallower nearer is protocol MNC the a non-selecti being procedure the nature andthe of

Accepted Article

This article isprotected by copyright. All rights reserved. Journal ofClinicalApheresis John Wiley& Sons on depth for the PMN protocol is deeper within within deeper is protocol for PMN depth the on 13 therapy that included imatinib successfully imatinib included that therapy CML to induce molecular remission, and the and the remission, molecular induce CMLto ve reduction of WBC. The collection depth for for depth collection The veof WBC. reduction luid balance after the procedure, resulting in a resultingin procedure, after balancethe luid steady hemoglobin level pre-and post- level hemoglobin steady en found to be a potent inhibitor of Abl, c-kit, c-kit, of Abl, inhibitor a potent be to en found ned to be a specific inhibitor to the aberrant the to inhibitor aspecific be nedto . Also, due to her low estimated total blood blood total estimated her duelow to Also, . ion (14,16-24). As such, for such, As (14,16-24). ion ets layer as discussed above, and did in fact in and did above, asdiscussed layer ets S, was expected to result in a greater RBC a greater in RBC result to was expected S, RA), and platelet-derived growth factor beta factor growth and platelet-derived RA), same or even increased after the the after increased sameor even f HEOS is outside the scope of this case case scope the of this outside is fHEOS FRA fusion is very sensitive to imatinib, imatinib, to sensitive very is FRAfusion ubing (285 mL) (12) was performed with with was performed (12) ubingmL) (285 the first line therapy. However, our therapy. However, line first the OS who are treated with imatinib imatinib with treated are who OS patients, glucocorticoids are first the glucocorticoids patients, L), and is most commonly used for the the for used commonly L),most andis Page 18of26 Page 19of26 been reported to respond to imatinib therapy, with imatinib to respond to beenreported beeff to known is imatinib that bearany mutations patients) of chronic eosinophilic leukemia without without leukemia eosinophilic of chronic patients) patient achieved remission and was without symptoms and was without remission achieved patient

continued to improve with only medical therapy. Aft therapy. only medical with improve to continued a added,was then and Imatinib leukostasis. improve required leukocy still but hydroxyurea, by followed in to respond did patient Our findings25-33). (14, recommended is or interferon-alpha andhydroxyurea or of PDGFRA havemutations of which (some features recommend is imatinib cells; T clonal haveabnormal interfero these patients, For beadded (25). should requ are glucocorticoids Ifexcessive therapy. line short, no known target for imatinib therapy was fou imatinib target for known no short, nex and generearrangement partners(by both fusion invo or othermutations disorder myeloproliferative (6 patients) or partial (4 patients) response in on response in patients) (4 or partial (6 patients) of imatinib therapy in combination with steroids, steroids, h with combination therapy in ofimatinib co clinical Our patient’s partner.fusion alternate anundete cases Itharbor bethese may our patient. may aberrations molecular known cases HEOS without remission hematological achieved complete imatinib 9 months after discharge. after discharge. months 9

Accepted Article

This article isprotected by copyright. All rights reserved. Journal ofClinicalApheresis John Wiley& Sons 14 e study (25). In another study, 40 % (6 of 15 (6of 15 In% study, 40 another study(25). e urse improved in the weeks following initiation following initiation weeks the in improved urse ired for a response, a second line therapy line a second aresponse, for ired n-alpha is recommended for those that also also that for those recommended n-alphais itial treatment with methylprednisolone methylprednisolone with treatment itial cted fusion of PDGFRA or PDGFRB with an with orPDGFRB of PDGFRA ctedfusion 23 % (10 of 43 patients) achieving complete complete achieving patients) % of(10 43 23 ydroxyurea, and leukocytapheresis. The ydroxyurea,andleukocytapheresis. known molecular aberration treated with treated with aberration molecular known ective against, nor did she show evidence of a of evidence show she did nor ectiveagainst, lving PDGFRA or PDGFRB with other with PDGFRB or lvingPDGFRA tapheresis to further reduce WBC counts and counts WBC reduce further to tapheresis nd. FIP1L1/PDGFRA-negative HEOS has HEOS FIP1L1/PDGFRA-negative nd. fter additional leukocytapheresis, our patient our patient leukocytapheresis, additional fter er extensive workup, our patient did not not did our patient workup, erextensive t-generation sequencing techniques). In t-generationtechniques). sequencing ed for those with myeloproliferative myeloproliferative edwith for those (34). These studies demonstrate some some demonstrate (34).These studies for those without either of the above of the either without for those or eosinophilia at her last follow-up visit visit follow-up herat last or eosinophilia PDGFRB with other fusion partners); partners); otherfusion with PDGFRB benefit from imatinib, as illustrated in in as illustrated imatinib, from benefit

patient. The choice of which leukocytapheresis pro leukocytapheresis of which The choice patient. prot both with was stable Hemoglobin loss. platelet balan fluid negative greater a in resulted protocol

in patients with various myeloid or lymphocytic leu myeloid or lymphocytic various with patients in ex the to comparable is procedure leukocytapheresis a reduction of eosinophil extent andThe aEO count. wer protocols leukocytapheresis and MNC HES without leukocyta with treated successfully femalewas that sy hypereosinophilic report of aidiopathic case We Conclusions c particular andthe differences of these knowledge

Accepted Article

This article isprotected by copyright. All rights reserved. Journal ofClinicalApheresis John Wiley& Sons 15 ce and the MNC protocol resulted in greater in resulted protocol MNC and the ce ontext of the patient. of patient. the ontext pheresis and medications. Both the PMN PMN Both the andpheresis medications. ocols with RBC prime in our pediatric in prime RBC with ocols healthy4-year-old a previously in ndrome tocol to use should be made with the the bemade with should use to tocol kemias, respectively. However, the PMN PMN the However, respectively. kemias, chieved by both protocols per protocols chieved both by tent of myelocyte and lymphocyte reduction reduction andlymphocyte of myelocyte tent e similarly effective in reducing WBC reducing WBC in effective esimilarly Page 20of26 Page 21of26

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Accepted LawM, Brown P, M, Noel C, Akin AD, Robyn J, Klion Article

This article isprotected by copyright. All rights reserved. Journal ofClinicalApheresis John Wiley& Sons 18 patients with a myeloproliferative a myeloproliferative with patients Wierda W, Rios MB, Letvak L, MB, Kaled Letvak Rios W, Wierda erative variant of hypereosinophilic of hypereosinophilic erativevariant the treatment of idiopathic of idiopathic treatment the sociated with tissue fibrosis, poor poor fibrosis, tissue with sociated ase created by fusion of the the of asefusion created by drome. Proc Natl Acad Sci U S A. US Sci Acad Natl Proc drome. ic syndrome and other eosinophilic eosinophilic andother syndromeic ewitz R. Discovery of a fusion kinase kinase afusion Discovery R. of ewitz ;101(12):4660. ;101(12):4660. HD, Baxter EJ, Witzig TE, Cross Cross TE, Witzig EJ, Baxter HD, di E, Metzgeroth G, Erben P, Popp Popp ErbenP, MetzgerothG, E, di imatinib in idiopathic in imatinib ofibrosis in response to imatinib imatinib to response in ofibrosis 4. 4. 13):1201. 13):1201. ls J, TB. Nutman MetcalfeJ, DD, ls Metcalfe DD, Dunbar C, C, Dunbar DD, Metcalfe darska I, Kantarjian H, Marynen I,Marynen H, darska Kantarjian e C, Solomon E, E, ApperleyJ, Solomon eC,

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NC, Reiter A, Grimwade D. Low-dose imatinib mesylat Low-doseD. imatinib Grimwade A, Reiter NC, blast crisis evolving during imatinib treatment of treatment imatinib evolving during crisis blast PDGFRA-positive chronic eosinophilic leukemia. Bloo leukemia. eosinophilic chronic PDGFRA-positive comple of and achievement responses molecular major Rondoni M, Ottaviani E, Martinelli G, Brito-Babapul G, Martinelli E, Ottaviani M, Rondoni (Baltimore). 2013 Aug 26. 26. Aug 2013 (Baltimore). Surv a Leukemia:on InsightsBased New Eosinophilic FIP1L1-P of The Spectrum Network. FrenchEosinophil Prin M, Capron C, Preudhomme Bletry O, S, Dubucquoi M, Hamidou V, Lefranc Cottin D, Sène D, P, Makhoul de Jaureguib M, Michel O, Fain A, Schmidt-Tanguy P, S, Mastrilli Macintyre E, A, F,Renneville Legrand Syndrome: a case of molecular remission. Leuk Res. remission. molecular caseof aSyndrome: Ima M. Petrini G, Carulli S, Galimberti G, Cervetti von Bubnoff N, Sandherr M, Schlimok G, Andreesen R, Andreesen G, Schlimok M, Sandherr N, Bubnoff von 2005;19(2):286. 2005;19(2):286. e prominent disease with chronicmyeloproliferative

Acceptedstud prospective of a multicenter syndrome.Results FIP1L1-PDGFRalph with mesylate patients in imatinib F, Pane RancatiG, C, F, Astolfi Rosti S, Soverini Giug A, de E, Vivo Gottardi N, F, Buccisano Testoni Mes E, Ottaviani M, Rondoni D, Cilloni M, Baccarani Article

This article isprotected by copyright. All rights reserved. Journal ofClinicalApheresis John Wiley& Sons 19 an FIP1L1-PDGFR alpha-positive alpha-positive anFIP1L1-PDGFR Saglio G, Martinelli G. The efficacy of efficacy of The G. SaglioMartinelli G, tinib therapy in Hypereosinophilic Hypereosinophilic therapy in tinib Ackermann F, Cayuela JM, Rousselot Rousselot JM, F,Cayuela Ackermann y. Haematologica. 2007;92(9):1173. y.2007;92(9):1173. Haematologica. osinophilia. Leukemia. osinophilia. liano E, Iacobucci I, Paolini S, S, I, Paolini Iacobucci E, liano 2005;29(9):1097. 2005;29(9):1097. le F, Saglio G, Hehlmann R, Cross Cross R, Hehlmann G, F,le Saglio sa F, Merante S, Tiribelli M, M, Tiribelli S, sa F, Merante ey of 44 Cases. Medicine Medicine eyCases. 44 of te molecular remission in FIP1L1- in remission molecularte erry JP, Hatron PY, Cony- Hatron PY, erryJP, a-positive hypereosinophilic hypereosinophilic a-positive d. 2007;109(11):4635. 2007;109(11):4635. d. Lidove O, Baruchel A, LidoveBaruchel O, e leads to rapid induction of induction rapid eleadsto DGFRA-Associated Chronic Chronic DGFRA-Associated Peschel C, Duyster J. Myeloid J. Duyster C, Peschel L, behalfon of the Kahn JE, Page 24of26 Page 25of26

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1995;96(1):131. 1995;96(1):131. sy for hypereosinophilic treatment alpha-interferon L, Corbetta C, Pronzato G, Passalacqua GW, Canonica status. Leuk Res. 2009;33(6):837. Leuk 2009;33(6):837. status. Res. or unknown with patients syndrome hypereosinophilic th Imatinib limited has S. Verstovsek KantarjianH, L T, Quintás-Cardama Cortes N, Manshouri A, J, Jain hypereosinophilic syndrome. Am J Hematol. 1994;45(3 Hematol. J Am syndrome. hypereosinophilic Bolling Alpha-Inte SF. JT, PL, Santinga Bockenstedt therapy. J Allergy Clin Immunol. 2009;124(6):1319. 2009;124(6):1319. Immunol. Allergy Clin therapy.J of analysis retrospective amulticenter, syndrome: PF, Weller A, HU, Stein ML, Wardlaw Simon D, Simon Roufo Rothenberg ME, Ring J, F, TB, Pfab Nutman KM, H GJ, Gleich ButterfieldBS, JH, Bochner Ogbogu PU, years. Semin Hematol. 2012 Apr;49(2):182-91. Apr;49(2):182-91. 2012 Hematol. years.Semin Treatment of hypereosino CR. Weiler ButterfieldJH, Br J Haematol. 1996;92(1):176. 1996;92(1):176. Haematol. BrJ wit a case in byinduced interferon-alpha remission hae syndrome: complete hypereosinophilic idiopathic evi Further ZachéeP. H, Bergh Van den ML, Malbrain

AcceptedIntern1994;12 Ann Med. syndrome. hypereosinophilic Interferon-alphatreatme GJ. Gleich ButterfieldJH, Article

This article isprotected by copyright. All rights reserved. Journal ofClinicalApheresis John Wiley& Sons 20 clinical characteristics and response to response to and characteristics clinical ndrome. J Allergy Clin Immunol. Immunol. Allergy Clin J ndrome. nt of six patients with the with idiopathic patients of six nt h a unique chromosomal abnormality. chromosomal a h unique erapeutic activity for activity erapeutic rferon treatment for idiopathic idiopathic for rferontreatment philic syndromes--the first 100 100 first syndromes--the philic matological and cytogenetic and matological uthra R, Garcia-Manero G, Garcia-Manero R, uthra negative PDGFRalpha mutation mutation negativePDGFRalpha Bagnasco M. Effective long-term long-term Effective M. Bagnasco dence for the clonal natureof the clonal for the dence uss-Marp J, Kahn JE, Leiferman Kahn JE, J, uss-Marp 1(9):648. 1(9):648. ):248. ):248. Klion AD. Hypereosinophilic AD. Hypereosinophilic Klion sse F, Sajous MH, Sheikh J, J, Sheikh MH, F, sse Sajous

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phase-II study. Br J Haematol. 2008;143(5):707. 2008;143(5):707. Haematol. BrJ study.phase-II imatinib. Blood. 2014 Jun;123(23):3574-7. Jun;123(23):3574-7. 2014 Blood. imatinib. du genes achieve fusion PDGFRB bearing malignancies P JF. Seymour NC, Cross A, Odenike Gimelfarb O, RC, Patton N, P, Rousselot P, Forrest DM, Genet D, Ross H JF, Apperley K, Burbury CY, Cheah 2006;20(5):827. wit patients in overexpression PDGFRA screeningfor KIF5B responsive imatinib of a novel Identification Jotterand M, Stalder K, C, Waghorn Curtis ScoreJ, eosinophilic leukaemia. Br J Haematol. 2007;138(1): Haematol. BrJ leukaemia. eosinophilic P imatinib-responsive novel Two NC. Cross A, Reiter Pe J, MurphyA, Clark P, Grand FH, CE, Musto Curtis

Acceptedleukae eosinophilic chronic in efficacyof imatinib Hoc R, Hehlmann NC, Cross D, Grimwade SchnittgerS, Schmitt-Grae H, Popp Erben P, C, Walz MetzgerothG, Article

This article isprotected by copyright. All rights reserved. Journal ofClinicalApheresis John Wiley& Sons 21 mia and hypereosinophilic syndrome: a syndrome: and hypereosinophilic mia -PDGFRA fusion genefollowing fusion -PDGFRA M, Grand FH, Cross NC. NC. Cross Grand M, FH, 77. 77. Smith G, Dunbar CE, Ito Aguiar Dunbar G, CE, S, Smith DGFRA fusion genes in chronic in genes DGFRAfusion h hypereosinophilia. Leukemia. Leukemia. hypereosinophilia. h rla G, Minervini MM, Stewart J, J, Stewart MM, rlaMinervini G, ff A, Haferlach C, Fabarius A, Fabarius C, ffHaferlach A, uguet F, Pitini V, GardembasV, M, F,uguetPitini rable long-term remissions with with remissions long-term rable atients with myeloid with atients hhaus A, Reiter A. Safety andSafety A. Reiter A, hhaus Page 26of