Survival and treatment response in adults with acute promyelocytic leukemia treated with a modified International Consortium on Acute Promyelocytic Leukemia protocol

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

Revista

Brasileira

de

Hematologia

e

Hemoterapia

Brazilian

Journal

of

Hematology

and

Hemotherapy

Original

article

Survival

and

treatment

response

in

adults

with

acute

promyelocytic

leukemia

treated

with

a

modified

International

Consortium

on

Acute

Promyelocytic

Leukemia

protocol

Erick

Crespo-Solis

∗

,

Jorge

Contreras-Cisneros,

Roberta

Demichelis-Gómez,

Adriana

Rosas-López,

Juan

Mauricio

Vera-Zertuche,

Alvaro

Aguayo,

Xavier

López-Karpovitch

InstitutoNacionaldeCienciasMédicasyNutriciónSalvadorZubirán(INCMNSZ),CiudaddeMéxico,Mexico

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Articlehistory:

Received3June2015 Accepted24August2016

Availableonline21September2016

Keywords:

Acutepromyelocyticleukemia IC-APLprotocol

Developingcountries Survival

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Acutepromyelocyticleukemiahasgoodprognosisinviewofthehighcompleteremission andsurvivalratesachievedwiththerapiescontainingall-transretinoicacidorarsenic tri-oxide.However,thereisasignificantriskofdeathduringinductionduetohemorrhage secondarytodisseminatedintravascularcoagulation.Thishascontributedtoagapinthe prognosisofpatientsbetweendevelopedanddevelopingcountries.TheInternational Con-sortiumonAcutePromyelocyticLeukemiawascreatedin2005andproposedatreatment protocolbasedondaunorubicinandall-transretinoicacidstratifiedbyriskgearedtoward developingcountries.Hereinarepresentedtheresultsfromthefirstpatientcohorttreated inasingledevelopingcountryhospitalemployingaslightlymodifiedversionofthe Interna-tionalConsortiumprotocolinareallifesetting.Twentypatientswithacutepromyelocytic leukemiawereenrolled:27.8%hadlow-risk,55.6%intermediateriskand16.7%high-risk. Thecompleteremissionratewas94.4%afteramedianof42days.Bothrelapseratesand deathrateswereonepatient(5.5%)each.Nodeathswereobservedduringconsolidation. Afteramedianfollow-upof29months,theoverallsurvivalratewas89.1%.Efficacyand safetyoftheInternationalConsortiumonAcutePromyelocyticLeukemiaprotocolhasbeen reproducedinacutepromyelocyticleukemiapatientsfromadevelopingcountry.

©2016Associac¸ ˜aoBrasileiradeHematologia,HemoterapiaeTerapiaCelular.Published byElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense (http://creativecommons.org/licenses/by-nc-nd/4.0/).

∗ _{Correspondingauthorat:InstitutoNacionaldeCienciasMédicasyNutriciónSalvadorZubirán(INCMNSZ),VascodeQuiroga15,col.} BelisarioDomínguez,Tlalpan,CP14000MexicoCity,DF,Mexico.

E-mailaddress:erick.crespo.solis@gmail.com(E.Crespo-Solis). http://dx.doi.org/10.1016/j.bjhh.2016.08.002

1516-8484/©2016Associac¸ ˜aoBrasileiradeHematologia,HemoterapiaeTerapiaCelular.PublishedbyElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Acutepromyelocyticleukemia(APL)isaclinicaland biolog-icalvariantofacutemyeloid leukemia (AML)characterized byapredominanceofabnormalpromyelocytes.Accordingto theWorldHealthOrganization(WHO),itiscurrentlyclassified amongtheAMLwithrecurrentcytogeneticabnormalities[APL andt(15;17)(q22;q12);PML-RARA].1_{Untreated,APListhemost} aggressiveformofAML,withamediansurvivalofunderone month.2_{Itismainlydiagnosedinyoungadultsagedbetween} 20and 59.Somestudieshavesuggestedanincreased inci-denceinLatinos(24.3%vs.8.3%innon-Latinopopulations) but this appears to reflect a selection and referral bias.3,4 Werecentlyreportedthatthistypeofleukemiaaccountsfor 10.5%ofallacuteleukemiasand21%ofAMLattheInstituto NacionaldeCienciasMédicasyNutriciónSalvadorZubirán (INCMNSZ).5

Sincetheintroductionofall-transretinoicacid(ATRA)in 1988byHuanginShangai,completeremission(CR)ratesof 85% changedthe naturalhistory ofthisdisease.6 _The Ital-ianGroupforAdultHematologicDiseases(GIMEMA)reported their experience with regimens including ATRA in combi-nation with anthracyclines, obtaining high CR rates and encouragingdisease-freesurvival(DFS)andoverall survival rates(OS).7,8

In 1999, Sanz et al. designed a risk-adapted strategy afterobservingthat patientswithhigh white blood counts (>10×109_{/L)andlowplateletcounts(<40×10}9_{/L)wereathigh}

riskofdeathduringinductionandrelapse.9_{Theirstudyadded} ATRAtotheconsolidationregimensinintermediateand high-riskpatients.Improvementsintreatmenthavetransformed thisleukemiaintotheonewiththebestsurvivalratesinadults today.

Indevelopedcountries,CRratesinAPLpatientsareclose to95%withDFScurvesattwoyearsbetween87%and97%.9,10 However,somestudiesindevelopingcountriesreportedCR ratesof67.9%,deathduringinductionin32%ofcasesandan OSbelow60%in2005.11_{Themaincauseofdeathduring} induc-tionwashemorrhagefollowedbydifferentiationsyndrome.

ThecurrentbasisoftherapyofAPLpatientshingesonthe useofspecificagentsthatinducedifferentiation,suchasATRA and arsenictrioxide(ATO) inconjunction with chemother-apeutic agentssuchasanthracyclines.12 _{ATRA and arsenic} trioxidearedrugswhosecostsareprohibitivetoalargegroup ofpatientsindevelopingcountries.

The International Consortium on Acute Promyelocytic Leukemia (IC-APL) was created in 2005in order tonarrow the gap betweenthe response rates reportedin developed countriesand those insomedeveloping countries. Its pur-pose was to integrate an inter-institutional web designed programto generate and implementdiagnostic and thera-peutic strategies for APL patients in developing countries. This endeavor was supported by expert North American andEuropeanworkgroups.Thetargetedcountriesincluded Brazil,Mexico,ChileandUruguay.TheIC-APLimplemented the regimen designed bythe Programa para el Estudiode la Terapéutica en Hemopatía Maligna (PETHEMA)/Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) LPA 2005, in which idarubicin was replaced by daunorubicin

(equivalence:daunorubicin5mg=idarubicin1mg) in induc-tionandconsolidationtherapy.Thissubstitutionwasmainly duetoeconomiclimitations.Theregimenanditsresultswere recentlypublished.13_{CRrateswere85%witha15%mortality} duringinductionand5%duringconsolidation.Median follow-upwas28monthswitharelapserateof4.5%,OS80%andDFS 91%.13

The Department of Hematology and Oncology of the INCMNSZparticipatedintheConsortium’soriginalserieswith theinclusionoftwopatients.Becauseoflogisticaspects,we couldnotincludemorepatients.Duetotheencouraging pre-liminarydataatthetime,thisregimenwaslateradoptedas first-linetherapyinAPLpatientstreatedattheINCMNSZasof January2007.ByJune2013,18morepatientshadbeentreated withthisregimen,butnotincludedintotheoriginal Consor-tiumstudy.Patientcharacteristics,responsetotreatmentand survivalaredescribedinthisretrospectivestudyofareal-life scenario.

Methods

Aretrospectivecohortstudywascarriedoutofadultpatients with APL t(15;17)(q22;q12);PML-RARA, treated in the Acute LeukemiaClinic,DepartmentofHematologyandOncologyof the INCMNSZ, betweenJanuary2007and June1,2013.The diagnosis of APL t(15;17) was established according to the WHO criteria.1 _{Morphological andcytogenetic studies were} conductedinallpatients(conventionalkaryotype andFISH withaprobeforPML/RARA)inabonemarrowsampleobtained at diagnosis. Disseminated intravascular coagulation (DIC) wasdefinedinaccordancewiththeInternationalSocietyfor Thrombosisand Hemostasiscriteria(ISTH)ifscoreswere5 orabove.14_{Coagulopathywasdefinedastheprolongationof} coagulationtimes(PTorPTT)oradecreaseinfibrinogenthat didnotfulfillDICcriteria(Table1).

Theinduction,consolidationandmaintenanceregimens werethesameasthoseusedbytheIC-APL200613_;theywere appliedwithoutanymodification(Figure1).

Table1–Baselinecharacteristicsofthepatients.

Median(range)

Age(years) 40(21–74)

Hemoglobin(g/dL) 8.2(3.2–13.1) Whitebloodcells(×109_{/L) 1.75(0.2–15.90)}

Absoluteneutrophilcount(×109_{/L) 0.079(0–13,880)}

Promyelocytes(%) 17.5(0–96) Platelets(×109_{/L) 43.5(9–108)} PT(s) 11.9(9.2–14.7) aPTT(s) 27.1(22–38.4) TT(s) 16.9(13.8–23.1) Fibrinogen(mg/dL) 263(88–901) D-dimer(␮g/L) 3467(682–6570) Promyelocytesinbonemarrow(%) 81.5(3–96) Blastsinbonemarrow(%) (0–80)a

PT:prothrombintime;aPTT:activatedpartialthromboplastintime; TT:thrombintime.

a _{80%myeloidblastcountwasreportedintheinitialbonemarrow}

Induction

DNR 60mg/m2_/d (days 2,4,6,8) ∗ ATRA 45mg/m2_/d (from day 1 to CR) Low risk DNR: 25mg/m2_{/d (1-4)} ATRA 45mg/m2_{/d (1-15)} DNR: 35mg/m2_{/d (1-4)} ATRA 45mg/m2_{/d (1-15)} DNR: 25mg/m2_{/d (1-4)} Ara-C 1000mg/m2_{/d (1-4)} ATRA 45mg/m2_{/d (1-15)} DNR: 60mg/m2_{/d (1)} Ara-C 150mg/m2_{/8hrs (1-5)} ATRA 45mg/m2_{/d (days 1-15)}

ATRA: 45mg/m

2

_{/d (days 1 to 15) every 3 months +}

methotrexate: 15mg/m

2

_{/d, weekly + 6-mercaptopurine: 50mg/m}

2

_/d

DNR: 25mg/m2_{/d (1,2)} ATRA 45mg/m2_{/d (1-15)} DNR: 25mg/m2_{/d (1)} ATRA 45mg/m2_{/d (1-15)} MTZ 10mg/m/d (1-5) ATRA 45mg/m2_{/d (1-15)} MTZ 10mg/m/d (1-3) ATRA 45mg/m2_{/d (1-15)} MTZ 10mg/m/d (1-3) ATRA 45mg/m2_{/d (1-15)}

Intermediate risk High risk ±

Consolidation

Maintenance (2 years)

Figure1–Induction,consolidationandmaintenanceregimens.

During induction, differentiation syndrome prophylaxis was administered with dexamethasone 2.5mg/m2_{q 12h}

for two weeks, in patients with a white blood cell count ≥5×109_{/L.Patientsathigh-riskandoverage60weretreatedas}

intermediate-riskpatients.Maintenancewasinitiatedwhen hematologicalrecoverywasachieved,usuallyonemonthafter the last consolidation. Support measures during induction andconsolidationstrictlyadheredtotherecommendations oftheEuropeanLeukemiaNet.15

ToxicitywasevaluatedaccordingtotheNationalCancer Institutecommontoxicitycriteriascale(version4.03).16_The onlymodificationtotheoriginalprotocol wasthe adminis-trationofprophylacticintrathecalchemotherapytopatients considered tobe athigh-risk; it consistedof methotrexate (12.5mg)and cytarabine (60mg),every month,sixdosages, onceallthreesystemicconsolidationshadbeenconcluded. Modificationswere madein monitoringduringfollow-up – evaluationofminimalresidualdiseasewasnotperformed.At thattime,PML/RARAbreakpointswerenotidentifiedinour center.

Statisticsandethics

This study was approved by our local Ethics Committee, governed by the principles established in the Declaration of Helsinki for research in humans. Due to the retrospec-tivenatureofthis report,aconsentformwasnotrequired; howeveratourcenter,weroutinelyrequestwritten autho-rizationforchemotherapyadministrationandthepatientis informedontherisksandbenefits.Continuousvariablesare describedasmediansandintervalswhilecategoricalvariables arepresentedasfrequenciesandproportions.Between-group differences were establishedwith Mann–Whitney Uor Chi squaretestsfornumericalandcategoricalvariables, respec-tively. Survivalcurveswere createdusingtheKaplan–Meier method.TheSPSSv15.0statisticalpackagewasused.

Results

Twentypatientswere includedbut tworequestedtransfers tootherhospitalsduringthediagnosticstage,so18patients

APL: n=20

Transfered to other institutions: n=2

Induction with modified IC-APL: n=18 Induction mortality: n=1 Consolidations (3): n=17 Maintenance: n=17

Relapse and death in progresion: n=1 Lost to follow-up: n=1 Alive in CR: n=15

Figure2–Studydesign.

underwentinductiontherapywiththemodifiedIC-APL proto-col(Figure2).

Elevenofthe18evaluatedpatients(61.1%)werefemaleand seven(38.9%)weremale,aratioof1.6:1.Medianageat diagno-siswas40witharangeof21–74years;notethatthreepatients (16.6%)were over65 yearsofageatdiagnosis.Ofthetotal numberofpatients,five(27.8%)wereclassifiedaslow-risk,10 (55.6%)wereintermediateandthree(16.6%)werehigh-risk.

Atdiagnosis,fivepatients(27.8%)fulfilledDICcriteriaand 38.9%fulfilledthose forcoagulopathy.None ofthepatients hadabnormalliverorkidneyfunctiontestresults.Ofthe18 analyzedpatients,nine(50%)hadoneormorecomorbidities: four(22%)hadhypothyroidism,two(11%)hadtype2diabetes mellitus,two(11%)wereobese,two(11%)hadahistoryof can-cer(onepatienthadhadbreastandbasalcellcarcinomaand theotherbreastcancer),two(11%)hadcardiovasculardisease (onehadsystemichypertensionandtheotherhadatrial fibril-lation),one(5.5%)hadrheumatoid arthritis,one(5.5%)had chronicobstructivepulmonarydisease(COPD)andone(5.5%) hadrelapsingAPLandwasadmittedtotheprotocol.Oneof thepatientshadmultiplecomorbiditiesatthetimeof diag-nosis:COPD,obesity,pulmonarytuberculosis,pastbreastand basalcellcarcinoma,post-radiationpulmonaryfibrosis,type 2diabetesmellitusandhypothyroidism;thiswasthepatient thatdiedduringinduction.

The morphologic characteristics of the bone marrow aspirate were analyzed in 17 cases: 16 (94.1%) had a clas-sic morphology and one case (5.9%) was considered a

variant. The diagnosis of AML was initially established in this patient because the variant promyelocytes were countedasblasts. Immunophenotypes wereobtainedin16 patients: 100% had a classic immunophenotype: CD34(−), HLA-DR(−), CD13(+), CD33(+), and myeloperoxidase(+). The t(15;17)(q22;q21) translocation was found by karyotype or FISHin17patients(94.4%)andonlyinonecase(5.5%)was thedemonstrationofthePML/RARArearrangementby poly-merasechainreactionnecessary.

Ofthe18patientstreatedwiththemodifiedIC-APL2006 regimen,17(94.4%)achievedCRinamedianof42days(range: 34–158 days).Onepatientdied (5.5%)duringinduction, the aforementionedpatientwithmultiplecomorbidities.Twelve patients (66.7%) developed grade 3–4 infectious complica-tionsandtwo(11.1%)developedgrade3–4non-hematological complications(subarachnoidhemorrhageand leukocytoclas-ticvasculitis).Therateofseverefebrile neutropeniaduring inductionwas61.1%(11/18)andwasmorefrequentinpatients overtheageof65:100%vs.53.3%,althoughthisdifferencewas notstatisticallysignificant(p-value=0.2).Differentiation syn-dromewasidentifiedinfourpatients(22.2%).Interestingly,a groupoffourpatients(22%)didnotdevelopsevere complica-tionsduringinduction.

Among the 17 patients in hematologic CR, cytogenetic remissionwascorroboratedbyfluorescenceinsitu hybridiza-tion(FISH)in15;ofthese,100%wereincompletecytogenetic remission.Molecularremissionswerenotanalyzed.

Ofthe 17 patientsthatachieved CR,14 (82.3%)received threeprogrammedconsolidationsandthreepatients(17.6%) receivedoneconsolidationonemonthlate;inonecaseitwas due toeconomichardship and intwocases, asaresultof severe treatment-related complications(severe febrile neu-tropeniaandlivertoxicityduringthesecondconsolidation). Therateofsevere febrileneutropeniaduringconsolidation was29.4%(5/17).Onepatientwaslosttofollow-upafterthe thirdconsolidationbutwecorroboratedthathewasaliveand inremissionafterwhichwewereunabletocontacthim.

During follow-up, one bone marrow relapse was doc-umented (5.9%). The patient was administered rescue chemotherapy and underwent autologous hematopoietic stem cell transplantation;however, the disease progressed and led toherdeath.Ofall the studiedpatients, two died (11.1%):one,duetopost-chemotherapyaplasiaduring induc-tion(5.5%)andtheotherasaresultofgraftversushostdisease (5.5%).Atthetimeofanalysis,thetreatmentprotocolhadbeen completedby10ofthe16patientsinremission(62.5%)andthe medianoverallsurvivalhadyettobereached(Figure3).After afollow-upof29months,OSwas89.1%andonlyonepatient hadrelapsed(5.8%).

Discussion

Todate,this isthefirstseries ofAPL patientstreatedwith the IC-APL protocol after its publication in 2013.Although the cohortissmall,weconfirmedthepreviouslypublished responseratesandsurvival.

As in the IC-APL and European reports, patients at an intermediate-risk prevail (55.5% in the current cohort vs. 52–52.9%)buttherewasalowerincidenceofhigh-riskpatients

0.0 0.0 25.0 50.0 75.0 Time in months 100.0 125.0 0.2 0.4 0.6 0.8 1.0

Figure3–Overallsurvival.

(16.7%inthiscohortvs.28.17–32%)andagreaterincidenceof low-riskpatients(37.8%inthiscohortvs.16–19.1%).13,17

Ourdatacannotformallybecomparedwiththeprevious reportoftheIC-APLinterms ofsuperiorityorinferiorityof resultsbecausethisstudywasnotdesignedwiththatgoal. Moreover,thisstudyhadsomelimitationssuchasthesmall samplesizeandshortfollow-up.However,wethinkthatsafety aspectsand responsetotreatmentwere reproduced.Thus, someinterestingnumbersareworthnoting:theCRratewas 94.5%andthosedescribedbytheoriginalConsortiumwere 85%andEuropeancenters91–94.3%.Intermsofoverall sur-vival,itisslightlyabovethatreportedbytheconsortium(89.1% vs. 80% attwo years); both were determined after a short follow-up when compared with other reports.13,18,19 _Death ratesduringinductionandconsolidationwere5.5%and0%, respectivelycomparedtoratesof15%and5%reportedbythe originalConsortium.13Theseratesaresuperiortothose pre-sented byaBrazilianreportbeforethe IC-APL initiative, in whichdeathratesduringinductionandconsolidationwere 32%and10%,respectively.11_{Also,incomparisonwith} devel-opedcountries,themortalityinthecurrentstudyiswithinthe previouslydescribedrange:mortalityduringinduction5–10% and<5%duringconsolidation.9,10,17–19

Hemorrhageisthemaincauseofdeathdescribedinthe literaturefollowedbydeathduetocoagulopathy.13,19 _Inthis study,theratesforbothDIC(27.8%)andcoagulopathy(38.9%) were low; there were no deathsdirectly related to hemor-rhages.

TherearepeculiaritiestoclottingabnormalitiesandDICin patientswithAPL.TheincidenceofDICmaybepossibly over-estimatedifthediagnosisisestablishedaccordingtotheISTH criteria,sincethrombocytopeniaand increasesinD-dimers scoremanypointsinthisclassificationsystemandtheyare alsocommonfindingsinleukemiapatientswithnoother clot-tingabnormalities.5,14,20_{Thepathophysiologyoffibrinolysisin} patientswithAPLisalsodifferenttothatofotherDICcauses, sothesecriteriashouldnotnecessarilybeappliedtopatients withAPL.20_{Webelievethatthevalueofserumfibrinogenis} perhapsthemostrelevantparameterwhendefiningDICand

fortherapeuticdecision-makinginAPLpatients;inanycase, closedynamicmonitoringofthesepatientsisveryimportant duringinduction.

To date,nocentral nervous system(CNS) relapses have beenobserved;however, wecannotreachanysolid conclu-sionsonprophylactictreatmentofthesepatientssincethe samplesizewassmall.CNSprophylaxiswithchemotherapy iscurrentlyrecommendedinpatientsathigh-riskofrelapse.21 TherearemanyreportsonthepresenceoftheFLT3-ITD mutation in APL patients. The frequency of the mutation isvariable(12–38%)anditsprognosticvalueisquestionable sinceit has notaffected survivalcurves in all reports.22–25 Arecentmeta-analysiscorroboratedthatAPLpatientswith the FLT3-ITDmutationhavesimilarCRrates;however, this mutationdoesleadtoshortenedOSandDFSduetoagreater incidenceofrelapse.25_{TheFLT3-ITDmutationhasalsobeen} correlatedtoCNSrelapse.26_{However,todatethepresenceof} theFLT3-ITDmutationhasnotbeenincorporatedinto thera-peuticalgorithmsnorshoulditbeconsideredintherapeutic decision-makingunlessitisinthecontextofaclinicaltrial.

Althoughthenumberofover65-year-oldpatientsinthis cohortissmall,theyallareneverthelessaliveandinCRwhich coincideswiththedatareportedbyothergroupsthathave describedlongOSintheelderly.27_{Itisimportanttomention} thattheover65-yearoldsinthisstudyhadsevereneutropenia and infectiouscomplicationsduringinduction. This under-scores the importance of supportive care in this group of patients withAPL and inwhom curativetreatment should alwaysbethegoal.

PatientswithAPLmustbetreatedinspecializedcenters. Mortalityrisks,particularlyduringinduction,makethemvery vulnerable. Althoughno deathsoccurred during consolida-tion,strictsurveillanceisalsomandatoryduringthisphase. Effortsshouldfocusonthetimelypreventionandtreatment ofcomplicationsduringchemotherapyfollowingthe recom-mendationsofexpertgroups.15

Conclusions

ThisisthefirstcohortofadultpatientswithAPLtreatedin onecenterthatreproducestheresultsoftheoriginalIC-APL protocol.TheCRratesandsurvivalcurvesobservedinthis reportconfirmtheeffectivenessandsafetyofthistreatment protocolinareal-lifescenario.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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