Rev. Bras. Hematol. Hemoter. vol.39 número1

rev bras hematol hemoter. 2017;39(1):57–59

w w w . r b h h . o r g

Revista

Brasileira

de

Hematologia

e

Hemoterapia

Brazilian

Journal

of

Hematology

and

Hemotherapy

Case

Report

Myelodysplasia

and

acute

myeloid

leukemia

fifteen

years

after

high-dose

cyclophosphamide

in

a

child

with

severe

aplastic

anemia

José

Carlos

Jaime-Pérez

_,

_Liliana

_Nataly

_Guerra-Leal,

_Olga

_Graciela

_{Cantú-Rodríguez,}

David

Gómez-Almaguer

UniversidadAutónomadeNuevoLeón,FacultaddeMedicina,HospitalUniversitarioDr.JoséE.González,Monterrey,Mexico

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Articlehistory:

Received26May2016 Accepted16June2016 Availableonline12July2016

Introduction

Aplasticanemia(AA)isararedisordercharacterizedby sup-pression of bone marrow function. It can develop as the resultofcongenitalmarrowdiseaseandchemicalexposure; however,mostcasesareidiopathic.1_{Treatmentwith} immuno-suppressive therapy(IST) forpatientswho do nothave an humanleukocyte antigen(HLA)-compatibledonorrelieson the evidence that a deregulated immune system drives T lymphocytestocytokine-mediated destructionoftheirown hematopoietic stem cells.1 _{The majority of these patients} respondwelltoup-frontadministrationofIST,including anti-thymocyte globulin(ATG) and cyclosporine (CsA), which is successfulinaround80%.2 _{Unfortunately,ATGandCsAcan} leadtoclonal disorders,inparticularmyelodysplastic syn-drome(MDS)andparoxysmalnocturnalhemoglobinuria.3_On theotherhand,highdosesofcyclophosphamide(HDCY)have been administered as a sole immunosuppressive agent in severeaplasticanemia (SAA),principallyinadults,withno

∗ _{Correspondingauthorat:HospitalUniversitario“Dr.JoséE.González”,Edificio“Dr.RodrigoBarragán”,2Piso,Ave.MaderoyGonzalitos}

S/N,ColoniaMitrasCentro,Monterrey,N.L.,C.P.64460,Mexico. E-mailaddress:carjaime@hotmail.com(J.C.Jaime-Pérez).

lateclonaldisordersreportedafteruptotenyearsoffollow up.4_{However,latecomplicationsfollowingHDCY,including} lastingneutropeniaandsevere fungalinfections havebeen reportedmainlyinadults,butnosimilarlatecomplications havebeenreportedforpatientswhoreceivedHDCYduring childhood.

Wereport thefirst caseofa boywithSAA treated suc-cessfullywithHDCYwhoafter15yearsdevelopedMDSthat rapidlyevolvedintoacutemyeloidleukemia(AML),andwho was treatedunsuccessfully withahematopoietic stem cell transplant(HSCT).

Case

report

Afive-year-oldboywasdiagnosedin1997withSAAaftera shortclinicalperiodoffatigue,anemicsyndromeand muco-cutaneousbleeding,andfindingsconsistentwithSAAinhis completebloodcount(Table1).1_{Bonemarrowaspirate(BMA)}

and biopsy examinations showed a hypoplastic specimen

http://dx.doi.org/10.1016/j.bjhh.2016.06.003

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Table1–Completebloodcountatdiagnosis,during myelodysplasiaandafterprogressiontoacutemyeloid leukemia(AML)ofasevereaplasticanemiapatient treatedwithhigh-dosecyclophosphamidewhosuffered lateclonalevolutionafter15yearsoffollow-up.

SAA MDS AML

Hemoglobin(g/dL) 4.00 7.4 4.88

Hematocrit(%) 11.9 20.8 14.5

MCV(fL) 101 84.6 84.5

RDW(%) 16.2 13.5 11.4

Plateletcount(×109/L) 15.0 22.4 6.36

WBC(×109/L) 1.52 2.12 5.47a

Neutrophils(×109/L) 0.36 0.45 0.361

Neutrophils(%) 23.7 21.24 6.60

Lymphocytes(×109/L) 1.05 1.4 1.39

Lymphocytes(%) 69.3 66.01 25.4

SAA: severe aplastic anemia; MDS: myelodysplastic syndrome; AML:acute myeloidleukemia;MCV:meancorpuscularvolume; RDW:redcelldistributionwidth;WBC:whitebloodcellcount. a _{96%myeloidblasts.}

withoutmegakaryocytes,withlessthan15%cellularityand nodysplasticchanges;cytogeneticstudieswerenotavailable inourcenteratdiagnosis.Atestforhypersensitivityof Fan-conianemia(FA)cellstodiepoxybutane,thediepoxybutane (DEB)test,which helpsearlydiagnosis ofFA5 _wasnot per-formed.ThepatienthadnoHLA-compatibledonorand,atthat time,therapywithATGplusCSwasnotavailableinour coun-try.ThepatientwaspartofagroupoffivechildrenwithSAA treated withHDCY under these circumstances; the results ofthat trial havebeen published.6 _{Thetreatment protocol} consistedofcyclophosphamide(CY)at50mg/kg/day adminis-teredintravenously(IV)over1honfourconsecutivedayswith atotaldoseof200mg/kg,plusgranulocytecolony stimulat-ingfactor(G-CSF)at5␮g/kg/day,administeredsubcutaneously fromDay +1post-HDCYuntilanabsoluteneutrophilcount (ANC)>1×109/Lwasreached.Thepatientachievedcomplete hematological remission, and remained freeoftransfusion requirements with no infections. No dysplastic or clonal hematologicaldisordersdevelopedover15yearsoffollow-up. FifteenyearsafterHDCY,thispatientpresentedwithsevere anemiaandhewastreatedwithpackedredbloodcell trans-fusions,folicacid(5mg/day)anddanazol(200mgb.i.d.).Three monthslater,classicalfindingsofmyelodysplasiawere doc-umented in peripheral blood and bone marrow, including hypercellularbonemarrowwithasignificantincreaseinthe numberofmicromegakaryocytesandreticulinfibrosisGrade 3.Fivemonthslater,theMDSprogressedtoalpha-naphthyl butyrateesterase-positiveacutemyeloblasticleukemia (AML-M5).Thebonemarrowimmunophenotypedemonstratedcells withCD4,CD11b,CD16,CD36,CD56,CD64,andHLA-DR anti-genicspecificities.

Importanthematologicdataatthetimeofmyelodysplasia andafterAMLareshowninTable1.

StandardAMLchemotherapywasstarted,including cytara-bineforsevendaysplusmitoxantroneforthreedays.Itwas decidedtoperformhaploidenticalstemcelltransplantation fourteendaysafterthediagnosisofAMLbecauseofthe per-sistence of blasts in the peripheral blood and due to the

backgroundand poorprognosis. Areduced-intensity condi-tioning(RIC)regimenwasadministered45daysaftertheend ofinductionconsistingofcyclophosphamide,fludarabine,and busulfan.HaploidenticalHSCTwasperformedonDay+6of conditioning usinghismotherasdonor. Hepresented neu-tropenia and fever onthe same dayasthe procedure, and antibioticswereadministeredwithnoimprovement. Hema-turiaand melenadevelopedrequiringintensivetransfusion support.Pneumoniaunresponsivetotreatmentwasfollowed bycardiopulmonaryarrest and deathtwodaysafter trans-plant.

Discussion

The treatment of choice for SAA patients who have a

matched sibling donor is HSCT with survival rates of up to90%.1 _{Front-linematchedunrelateddonorappearstobe} a viable option in children, with similar overall survival and event-freesurvivaltotransplantswithmatchedsibling donors. A matched unrelated donor HSCT after failure of IST has proved to be a very good rescue strategy.7 _{As in} our case, mostSAA patients lacka suitable donor and,in the absenceofIST, mortalityis75%.8_{Currently,aresponse} rate of44–80%witha three-tofive-year survivalrate

ran-ging from 81 to 93% for SAA patients immunosuppressed

withATGplusCsAand granulocyte-colonystimulating fac-tor (G-CSF) has been reported.2 _{AA patients, however, can} have apartialresponse,failtorespond,relapse, or remain

dependent of CsA. In order to circumvent these

short-comings, alternative IST, such asalemtuzumab,as well as promisingagents,includingeltrombopag,arecurrentlybeing investigated.

Successful immunosuppressive treatment of SAA with

ATG and CsA has been associated with late clonal disor-ders, including paroxysmal nocturnal hemoglobinuria and MDS.3_{Highdosecyclophosphamidehasalsobeen} success-fully administered inSAA, mostly in adults, withno such late clonaldisorders reportedafteradecade offollow up.4 There is however, evidence for late complications follow-ing HDCY, including lastingneutropenia and severe fungal infections.4 _{These adverse long-termeventshave notbeen} reportedforpatientswhoreceivedHDCYduringchildhood.A recentstudyfocusingontheoutcomesofpediatricpatients withAA foundclonalevolutionand diseaseprogressionto MDS in five patients out of 149 (3%) that had moderate AA.2 _{Our patienthad a stablecourse withgood qualityof} life for15 years aftersuccessful treatmentwith HDCY; he thenevolvedtosevereMDSshortlyfollowedbyAML,treated unsuccessfullywithchemotherapyandfollowedbyamatched relateddonorHSCTthatwascomplicatedbysepsisleadingto death.

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Acknowledgement

WethankSergioLozano-Rodriguez,M.D.forhisreviewofthe manuscript.

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