Rev. Bras. Hematol. Hemoter. vol.38 número4

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

Revista

Brasileira

de

Hematologia

e

Hemoterapia

Brazilian

Journal

of

Hematology

and

Hemotherapy

Special

article

Guidelines

on

Beta-thalassemia

major

–

regular

blood

transfusion

therapy:

Associac¸ão

Brasileira

de

Hematologia,

Hemoterapia

e

Terapia

Celular:

project

guidelines:

Associac¸ão

Médica

Brasileira

–

2016

Dante

Langhi

Jr

_,

_Eugênia

_Maria

_Amorim

_Ubiali

,

José

Francisco

Comenalli

Marques

Jr

_,

_Mônica

_de

_Almeida

_Verissimo

_,

Sandra

Regina

Loggetto

_,

_Antonio

_Silvinato

_,

_Wanderley

_Marques

_Bernardo

b_{HemocentrodeRibeirãoPreto,RibeirãoPreto,SP,Brazil}

c_{UniversidadeEstadualdeCampinas(UNICAMP),Campinas,SP,Brazil} d_{CentroInfantilBoldrini,Campinas,SP,Brazil}

e_{CentrodeHematologiadeSãoPaulo(CHSP),SãoPaulo,SP,Brazil} f_{Associac¸ãoMédicaBrasileira(AMB),SãoPaulo,SP,Brazil}

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Articlehistory:

Received13September2016 Accepted13September2016 Availableonline22September2016

Introduction

Theguidelines projectisajoint initiative ofthe Associac¸ão MédicaBrasileiraandtheConselhoFederaldeMedicina.Itaims to bring together information in medicine to standardize conductinordertohelpdecision-makingduringtreatment. The data contained in this article were prepared by and arerecommendedbytheAssociac¸ãoBrasileiradeHematologia, HemoterapiaeTerapiaCelular(ABHH).Evenso,allpossible con-ductsshould beevaluatedbythephysicianresponsible for

∗ _{Correspondingauthorat:HemocentrodeRibeirãoPreto,RuaTenenteCatãoRoxo,2501,MonteAlegre,14051-140RibeirãoPreto,SP,Brazil.} E-mailaddress:eugenia@hemocentro.fmrp.usp.br(E.M.A.Ubiali).

treatmentdependingonthepatient’ssettingandclinical sta-tus.

Thisarticlepresents theguidelines onBeta-thalassemia major–regularbloodtransfusiontherapy.

Description

of

the

method

used

to

gather

evidence

Theseguidelinesusethetechniqueofsystematicreviewand informationrecoverybasedontheevidence-basedmedicine

http://dx.doi.org/10.1016/j.bjhh.2016.09.003

movement,in which clinical experience is integrated with thepossibilitytocriticallyanalyzeandrationallyapply sci-entificinformationtherebyimprovingthequalityofmedical care. Evidence-based medicine uses existing scientific evi-dencewithgoodinternalandexternalvalidityintheclinical practice.1,2

Today,systematicreviewsareconsideredthehighestlevel ofevidenceforanyclinical questionastheysystematically summarizeinformationonaparticulartopicusinga repro-ducible methodology to analyze primary studies (clinical trials,cohort,case–controlorcross-sectionalstudies),aswell as integrating information on efficiency, effectiveness and safety.1,2

Thequestions oftheseguidelines werestructuredusing thePatient/Problem,Intervention,ComparisonandOutcome (PICO) system, allowing the generation of evidence search strategiesinthekeyscientificdatabases(AnnexI).1,2

Degree

of

recommendation

and

level

of

evidence

A:Majorexperimentalandobservationalstudies

B:Minorexperimentalandobservationalstudies

C:Casereports(non-controlledstudies)

D:Opinionwithoutcriticalevaluationbasedonconsensus, physiologicalstudiesoranimalmodels

Background

Beta-thalassemiasyndromesareagroupofinherited disor-derscharacterizedbyageneticdeficiencyinthesynthesisof betaglobinchains.

Beta-thalassemia affects oneor bothof the beta-globin genes (chromosome11). These point or, morerarely, dele-tion mutations cause impropersynthesis of beta-globin, a componentofhemoglobin,resultinginanemia.3,4_Itis inher-itedasan autosomalrecessive disease;however dominant mutations have also been reported. The defect may be a completelackofthebeta-globinprotein(i.e.␤0-thalassemia) orgreatly reduced synthesisofbeta-globin protein(i.e.␤+ -thalassemia).5 _{Thereisadecreaseofapproximately50% in} thesynthesisofbeta-globinproteinintheheterozygousstate, that is, beta-thalassemia minor or beta-thalassemia trait whichcausesmildtomoderatemicrocyticanemia.In beta-thalassemia major (i.e.homozygous beta-thalassemia), the productionofbeta-globinchainsisgreatlyimpairedbecause bothbetaglobingenesaremutated.Theintenseimbalance ofglobinchainsynthesis(alpha≫beta)resultsinineffective erythropoiesisand severehypochromicmicrocyticanemia.6 Thereisalsotheintermediateformofbeta-thalassemia (beta-thalassemia intermedia), in which mutationsof both beta genesoccur(amildmutationinoneandaseveremutation in the other, or two mild mutations or a complex muta-tionthatmaybeassociatedwithalphathalassemia).Inthis condition, patients can have from mild anemia toanemia requiringred blood cell transfusions,sometimessimilar to beta-thalassemiamajor.7

Additional factors influence the clinical manifestations ofthedisease,i.e.,the samemutationsmayhavedifferent clinical manifestations in different patients. The follow-ing factors are known to influencethe clinical phenotype: intracellularfetalhemoglobinconcentrations,co-inheritance with alpha thalassemia and coexistence with sickle cell trait.6

Treatment of patients with beta-thalassemia major includeschronictransfusiontherapy,ironchelation, splenec-tomy, allogeneic hematopoietic stem cell transplantation andsupportmeasures.Regulartransfusiontherapyleadsto complicationsrelated toironoverload,includingendocrine manifestations(delayedgrowth,impairedsexualmaturation, diabetesmellitusandparathyroid,thyroid,pituitaryand,less commonly, adrenal insufficiency), dilated cardiomyopathy, liverfibrosisandcirrhosis.4,6

Objective

Thepurposeoftheseguidelinesistoprovide recommenda-tionsthatcanassistindecisionmakingaboutthetherapeutic roleandregimenofbloodtransfusionsinpatientswith beta-thalassemiamajor.

What

is

the

purpose

and

recommended

regimen

of

transfusions

in

the

treatment

of

beta-thalassemia

major?

The objectives of transfusion therapy is to correct ane-mia,suppresserythropoiesisandinhibitgastrointestinaliron absorptionthatoccursinuntransfusedpatientsasaresultof increased,albeitineffective,erythropoiesis.

Thedecisiontostarttransfusiontherapyinpatientswith confirmeddiagnosisofbeta-thalassemiashouldbebasedon the presence of severe anemia with hemoglobin (Hb) lev-els<7g/dL on two occasions at an interval of more than two weeks. All other possible contributingfactors such as infections, folicacid deficiency, coinheritanceof glucose-6-phosphate dehydrogenase(G6PD)deficiency andblood loss mustbediscarded.However,anyofthefollowingclinical crite-ria,regardlessoftheHblevel(>7g/dL)shouldbeconsidered: facialchanges,poorgrowth,spontaneousfracturesand clini-callysignificantextramedullaryhematopoiesis.Theneedfor transfusionscanstartasearlyassixmonthsold.5_(D)When possible,thedecisiontostartregulartransfusionsshouldnot be delayed untilafter the second tothird yearof life,due totheriskofdevelopingseveralanti-redbloodcell antibod-iesandsubsequentdifficultyinfindingcompatibleunitsfor transfusion.7–10_(D)(B)

patients and minimizes the accumulation oftransfusional iron.11,12_(B)

Apre-transfusionhemoglobinlevelbetween11and12g/dL maybeappropriateforpatientswithheartdisease,clinically significantextramedullaryhematopoiesisandsplenomegaly. Extramedullaryhematopoiesisoccursinpatientswhodonot achieveadequatesuppressionofbonemarrowactivitywith lowerhemoglobinlevels.Somepatientswithlowerbackpain nearthetimeoftransfusionmayneedtomaintainhigher pre-transfusionHblevelstoo.8_(D)

Themean target Hb should be12g/dL.Post-transfusion hemoglobinshouldbe maintainedatamaximum between 14and 15g/dL,becausethe higherthepost-transfusion Hb levelthegreaterthehyperviscositywhichincreasestherisk ofstroke.8_(D)

Patientsstartingregulartransfusion regimensshould be vaccinatedagainsthepatitisAandB(dependingontheage) andtheircytomegalovirusstatusshouldbeassessed.3_(D)

Thedevelopmentofoneormorespecificanti-redbloodcell antibodies(alloimmunization)isanimportantcomplicationof regulartransfusiontherapy.13–15_(B)

Beforestartingtransfusiontherapy,thepatient’sbloodtype mustbedeterminedaswellasredbloodcellphenotypingfor atleastthe C,c,D,E,e,andKell antigensinorder tohelp identifyandcharacterizeantibodiesinthecaseofsubsequent immunization.Preferably, extendedphenotypingshould be madeincludingantigensofotherbloodsystemssuchasDuffy andKiddandgenotyping.8_(D)

Baselinephenotypingandgenotypingisimportantto mon-itorpatientscarefullyforthedevelopmentofnewantibodies andtoavoidthetransfusionofpackedredbloodcellunitswith thecorrespondingantigens.8_(D)

The use of packed washed leukocyte depleted/filtered red blood cells is recommended for all patients to reduce allergic reactions and febrile non-hemolytic transfusion reactions, as well as cytomegalovirus infection.3 _{(D) The} washing of packed red blood cells is in fact indicated for patients with repeated allergic reactions and IgA-deficient patients.8_(D)

Theamountofredbloodcells tobetransfuseddepends on several factors, such as patient weight, target Hb level andhematocritofthebloodbag.Inclinicallystablepatients, approximately8–15mL/kgbodyweightofredbloodcellscan beinfusedoveraperiodof1–2h.3_(D)

Authors suggest that current recommendations lead to under-transfusionin men. As a result, they may be more likelytohaveextramedullaryhematopoiesisandthusmore likely torequire splenectomy or develop spinal cord com-pression, a rare, but serious complication ofparavertebral extramedullary hematopoiesis. In a study of 116 patients (51menand 65women)withbeta-thalassemiamajor, men received more packedred blood cell units per transfusion and had a higher annual transfusion volume. However, with the correction for weight, the women received a greater transfused volume per kg: 225mL/kg in women versus202mL/kginmen(p-value=0.028).Erythropoietin lev-els (EPO) were higher in men (72mIU/mL) compared to women(52mIU/mL;p-value=0.006).Theincidenceof splenec-tomy was alsohigher in men(61% versus 40% inwomen;

p-value=0.031).15_(B)

Theneedfortransfusioninnon-splenectomizedpatientsis generallyhigher(approximately30%)thaninsplenectomized patients.16_(B)

Recommendations

Inpatientswithbeta-thalassemiamajor:

- Patientsstartingregulartransfusionregimensshould bevaccinatedagainsthepatitisAandB(dependingon theage)and theircytomegalovirusstatusshouldbe assessed.

- Beforestartingtransfusiontherapy,thepatient’sblood typemustbedeterminedaswellasredbloodcell phen-otypingforatleasttheC,c,D,E,e,andKellantigens inorder tohelpidentifyandcharacterizeantibodies inthe caseofsubsequent immunization.Preferably, extendedphenotypingshouldbemadeincluding anti-gensofotherblood systemssuchasDuffyandKidd andgenotyping.

- Patientsshouldbemonitoredforthedevelopmentof newantibodiestoavoidthetransfusionofredblood cellunitswiththecorrespondingantigens.

- Theuseofpackedwashedleukocytedepleted/filtered redbloodcellsisrecommendedforallpatients.The washingofredbloodcellsisindicatedforpatientsat riskofallergicreactions.

- Transfuse every 2–5 weeks, maintaining the pre-transfusion hemoglobin level from 9–10.5g/dL or higher(11–12g/dL)forpatientswithcardiac complica-tions.Keeppost-transfusionhemoglobinlevelsbelow 15g/dL.

- Approximately8–15mL/kgbodyweightofpackedred bloodcellscanbeinfusedoveraperiodof1–2hin clin-icallystablepatients.

- The need for transfusion in non-splenectomized patients isgenerally higher than insplenectomized patients.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Annex

I.

1.Clinicaldoubt

Whatisthepurposeandrecommendedregimenof transfu-sionsinthetreatmentofbeta-thalassemiamajor?

2.Structuredquestion

P:Confirmeddiagnosisofbeta-thalassemiamajor I:Anytransfusionregimen

C:. . .. . .. . .. . .. . .. . .. . .. . .. . .. . .

3.EvidenceSearchStrategy

#1 – (beta-Thalassemia OR Thalassemia Major OR Anemia, Cooley* OR Mediterranean Anemia* OR Hemoglobin F Disease)

#2 - (Blood Transfusion* OR Erythrocyte Transfusion* OR Red Blood Cell Transfusion*)

#3 - “therapy/broad” [Filter])

Firstsearch:=#1AND#2AND#3=49

(Beta-Thalassemia OR Thalassemia MajorOR Anemia, Cooley* OR MediterraneanAnemia*ORHemoglobinFDisease)AND(Blood Trans-fusion*ORErythrocyteTransfusion*ORRedBloodCellTransfusion*) AND“therapy/broad”[Filter])−1150studiesfound(17/06/2016)

4.Worksfound

Obtainingtheevidencetobeusedtoanalyzetheeffectiveness anddangersoftheuseofregulartransfusionregimeninthe treatmentofbeta-thalassemiamajoremployedthefollowing steps:preparingtheclinical question,structuringthe ques-tion,searchforevidence,criticalevaluationandselectionof evidence,displayoftheresultsandrecommendations.

The electronic databases consulted were Medline via PubMed Central, Lilacs via BVS, EMBASE and CINAHL via EBSCO.Manualsearchesweremadeafterreviewingthe ref-erences(narrativeorsystematic),aswellasofselectedworks. Thenumberofarticlesfoundafterapplyingtheinclusion andexclusioncriteriawas14.

5.Criteriaforinclusionofselectedworks

The selection of studies, the evaluation of the titles and abstractsobtainedfromthe searchstrategy wasconducted bytwo independentand blinded researcherswith skills in preparing systematic reviews, strictly observing the estab-lishedinclusionandexclusioncriteriadescribedinthePICO components.Worksofpotentialrelevancewereseparated.

5.1Accordingtothestudydesign

Narrativereviews,case reports,caseseries and works pre-sentingpreliminaryresultswere,inprinciple,excludedfrom theselection. Systematicreviewswereused withthe prin-ciple offinding references that may have been overlooked onemployingtheinitialsearchstrategy.Comparative obser-vationalstudies, systematicreviews and narratives (in the absenceofsystematicreviews)wereincludedinthese guide-lines.

5.2Language

StudiesinPortuguese,EnglishandSpanishwereincluded.

5.3Accordingtothepublication

Onlyarticleswithavailablefulltextswereconsideredforthe criticalevaluation.

6.Criticalevaluation

Whentheselectedarticlewasdefinedasacomparativestudy (observational cohortsor non-randomizedclinicaltrials), it wassubjectedtoanappropriatechecklistofcritical evalua-tion,allowingtheclassificationofthestudyaccordingtothe NewcastleOttawaScale17_{;forcohortsstudies,scores≥6were}

consideredconsistentandscores<6wereconsidered incon-sistent.

7.Presentationofresults

Resultswithavailableevidencearedefinedinaspecificway, whereverpossible,inrespecttothepopulation,intervention, outcomes,thepresenceorabsenceofbenefitsanddangerand controversies.

8.Recommendations

Recommendationsweremadebytheauthorsofthereview, withtheinitialcharacteristicofthesynthesisofevidence.The evidencewasthenvalidatedbyallparticipatingauthorswho draftedtheguidelines.

The degree of recommendation used was directly from the power of the studies found according to the Oxford classification,18_{andusingtheGRADEsystem.}19

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