Role of HLA match on results of hematopoietic stem cell transplantations from unrelated donors in children with acute leukemia and bone marrow failure syndromes

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Original research article/Praca oryginalna

Role of HLA match on results of hematopoietic stem cell transplantations from unrelated donors in

children with acute leukemia and bone marrow failure syndromes

Znaczenie zgodno ści HLA na wyniki transplantacji komórek hematopoetycznych od dawców niespokrewnionych u dzieci z ostrymi bia łaczkami i niewydolno ściami szpiku

Jan Styczy ński

^1,

*, Robert D ębski

¹

, Anna Krenska

¹

, Krzysztof Czy żewski

¹

, Natalia Bartoszewicz

¹

, Ewa Demidowicz

¹

, Ninela Irga-Jaworska

²

,

El żbieta Dro żyńska

²

, Marcin P łonowski

³

, Maryna Krawczuk-Rybak

³

, Tomasz Ociepa

⁴

, Tomasz Urasiński

⁴

, Mariusz Wysocki

¹

1KatedraiKlinikaPediatrii,HematologiiiOnkologii,CollegiumMedicumim.L.RydygierawBydgoszczy,Uniwersytet MikołajaKopernika,SzpitalUniwersyteckinr1im.JuraszawBydgoszczy,Kierownik:prof.drhab.n.med.Mariusz Wysocki,Poland

2KatedraiKlinikaPediatrii,HematologiiiOnkologii,UniwersytetMedyczny,Kierownik:prof.drhab.n.med.Elżbieta Adamkiewicz-Drożyńska,Gdańsk,Poland

3KlinikaOnkologiiDziecięcej,UniwersytetMedyczny,Kierownik:prof.dr hab.n.med.MarynaKrawczuk-Rybak, Białystok,Poland

4KatedraiKlinikaPediatrii,HematologiiiOnkologii,PomorskiUniwersytetMedyczny,Kierownik:

prof.drhab.n.med.TomaszUrasiński,Szczecin,Poland

article info Articlehistory:

Received:09.08.2016 Accepted:16.01.2017 Availableonline:28.02.2017

Keywords:

Hematopoieticstemcells

High-dosetherapy

Stemcelltransplantation

abstract

Background:Incaseofthelackofmatchedfamilydonors(MFD),hematopoieticstemcell transplantation(HSCT)fromunrelateddonor(UD)isanestablishedprocedureformany acquiredandcongenitaldisordersofthehematopoieticsystem,includingmalignancies and bone marrow failure (BMF) syndromes. Objective: The analysis of the results of HSCT in patients with acute leukemia or BMF syndromes from UDs with respect to humanleukocyteantigen(HLA) match.Patientsand methods:Atotalnumber of97of HSCTfromUDsperformedinsinglecenterbetween2007and2015inchildrenandado- lescentswithacutelymphoblastic(ALL)ormyeloblasticleukemia(AML)andBMFsyndro- mes were included into this analysis. HLA match between donor and recipient was

*Correspondingauthorat:KatedraPediatrii,HematologiiiOnkologii,CollegiumMedicumim.L.RydygierawBydgoszczy,Uniwersytet MikołajaKopernika,ul.Skłodowskiej-Curie9,85-094Bydgoszcz,Poland.

E-mailaddress:jstyczynski@cm.umk.pl(J.Styczyński).

ContentslistsavailableatScienceDirect

Acta Haematologica Polonica

journal homepage:www.elsevier.com/locate/achaem

http://dx.doi.org/10.1016/j.achaem.2017.01.002

zo.o.Allrightsreserved.

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Introduction

By the end of 2012, more than 1 million transplants has been done at 1516 transplantcenters in total 75 countries performing HSCTs [1]. The number of allogeneic transplantations performed in Poland in 2015 was 605 including 411 from unrelated donors (UD), 169 from (MFD), and 25 haploidentical transplants [2]. In our Department we had started transplant program with MFD allogeneic HSCT in 2003, autologous HSCT in 2004 and UD-HSCT in 2007 [3].

Allogeneic hematopoietic stem cell transplantation (HSCT)remainsacurativeoptionforchildrenwithhighrisk and advanced acute lymphoblastic (ALL) and myeloblastic leukemia(AML)andbonemarrowfailuresyndromes(BMF).

For patients who lack a human leukocyte antigen (HLA) matched family donor (MFD), a transplant from an alter- nativedonorremainsthebesttherapeuticoptions.Overlast decade HSCT from UD hasbecome an established method of treatmentfor refractory blood diseases, withthe aimof achievinglong-termsurvival.

HLAmatchbetweendonorandrecipientisamajorfactor contributingtosuccessofHSCTandtheuseofanHLA10of 10 allele-matched UD is obviously recommend worldwide.

High-resolution HLA-matching signiﬁcantly impacts outcome and also may predict for non-relapse mortality and overallsurvival(OS).

This is however not possible in all UD-HSCT. If such adonorisnotavailable, anysingle-alleleormultiple-allele (HLA-C,-DRB1,-DQB1)mismatcheddonoroutof10HLAsis acceptable as an UD for patients with severe aplastic anemia[4].InpatientswithALL,AML,andmyelodysplastic syndromes (MDS) matching for HLA-A, -B, -C, and -DRB1 alleles (8/8 match) was associated with better survival at 1year compared with7/8HLA-matchedpairs [5,6]. HLA-C antigen mismatch was associated with worse outcome in UDperipheralbloodstemcelltransplantation,howeverHLA mismatchwasnotassociatedwithrelapseorchronicgraft- versus-hostdisease(GVHD)[5].

Theobjectiveofthisstudywastheanalysisoftheresults ofstemcelltransplantationinpatientswithacuteleukemia orBMF syndromes fromUD withrespect toHLA match in singlepediatriccenter.

Methods

Patients

Between 2003 and 2015 a total number of 318 transplants were performedinourDepartment,including186allo-HSCT and132auto-HSCT.ProgramofHSCTsfromUDhasbegunin 2007. All transplantsperformed forpatients withALL, AML, MDS or BMF/SAA from UD between 2007 and 2015 in our Department were included in this analysis. Transplants performedwithcordbloodwereexcludedfromthisanalysis.

Demographics

The number of UD-HSCT performed for ALL, AML/MDS or BMF/SAA was 97, including 43 for ALL (25 in complete remissionCR1,18CR2),40forAML/MDS(AML:13CR1,18 CR2, 3 secondary AML; MDS: 3 JMML, 2 RCMD, 1RAEB) and 14 for BMF/SAA (11 acquired SAA, 1 PRCA, 1 Fanconi anemia, 1 Schwachman-Diamond syndrome). A second or subsequent transplant was performed in 12 cases (3/18 AML-CR2,8/18ALL-CR2,1/2MDS-RCMD).Therecipients of transplantsweremalesin67transplantsandfemalesin 30 cases.Themedianage of transplantrecipientswas10.5 years (range: 0.8–22 years). The source of hematopoietic stem cells was peripheral blood in 75 patients (77%), and bone marrow in 22 patients (23%). The median follow-up was1.4years(range:0.1–7.6years).

Transplantprocedures

Patients underwentHSCT according toprocedures described previously [3]andstandardinfectiousprophylaxiswereused [7–9]. Cyclosporinemethotrexate wereused for GVHDpro- phylaxis.InallpatientsinvivoT-celldepletionwasperformed before UD-HSCT with rabbit ATG (Genzyme) in total dose 8mg/kgfor9/10HLA matchandindose12mg/kgfor8/10 HLAmatch.Thefollow-upwascensoredat29February2016.

HLAtyping

High-resolutionDNA-based4-digittypingwasperformedfor 5pairsofloci:HLA-A,-B,-Cw,-DRB1and-DQB1.HLAmatch

Children

Adolescentsandyoungadults

Słowakluczowe:

terapiawysokodawkowa

komórkihematopoetyczne

przeszczepianiekomórek macierzystych

dzieci

młodzieżimłodzidorośli

analyzedattheallelelevelandclassiﬁedas10/10,9/10or8/10.Datawerecomparedto resultsof56MFD-HSCTs. Probabilityofoverallsurvival(pOS)wasgivenfor 3-yearand 1-year(asrequired byJACIEstandards)timeperiods.Results: Themeansurvivalfor all patientsestimated by Kaplan–Meier methodwas 4.8 years (95%CI=4.1–5.5 years). The 3-yearpOS afterallUD-HSCTwas0,600,05,andwithrespectto10/10,9/10and8/10 HLA match: 0,610,06; 0,590,09 and 0,600,22, respectively (ns). In patients with AML,3-yearpOSreached52%,60%and60%,respectively.InpatientswithALL,3-yearpOS was73%and62%(ns)for10/10and9/10HLAmatch,respectively,whileforBMFsyndromes 86%and57%(ns), respectively.Conclusion:Current datasuggest thatresultsofmismat- chedandmatchedUD-HSCTinchildrenwithacuteleukemiamightbecomparable.

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betweendonorandrecipientwasanalyzedattheallelelevel andclassiﬁedas10/10,9/10or8/10.

Endpoints

OS was set as the primary end point. OS was deﬁned as timefrom transplantationto death or last follow-up. Neu- trophil recovery was deﬁned as an absolute neutrophil count (ANC) of at least0,5G/Lfor three consecutive days.

Plateletrecovery was deﬁned asa count of at least 20G/L withoutplatelettransfusionsupportfor7days.AcuteGVHD (aGVHD) was deﬁned inaccordance with standard criteria.

ChronicGVHD(cGVHD)wasevaluatedinpatientssurviving formorethan100daysafterallo-HCTandwasclassiﬁedas limitedorextensivetype.

Statisticalanalysis

Probability of overall survival (pOS) and probability of event-freesurvival(pEFS)wascalculatedusingthe Kaplan– Meiermethodandcompared withthelog-ranktests.Mean survival was also determined by Kaplan–Meier method, with 95% conﬁdence interval (CI). Rate of survivors in analyzedtime periods was compared with chi-square test.

Allp-values are 2-tailedand consideredstatisticallysigniﬁ- cant if the values were less than 0,05. All statistical analyses were performed using the SPSS23 software (SPSS Inc,Chicago,IL,USA).

Results

Engraftment

The cumulative probabilities of neutrophil and platelet recovery were 91.6% and 78.5%, respectively. The median timetoneutrophilrecovery(ANC>500)was19days(range, 10–29), while the median time to platelet engraftment (plateletcount>20G/L)was15days(range,10–65).

Graft-versus-hostdisease

The cumulative probabilities of aGVHD and extensive cGVHD were 17.7% and 5.4%, respectively: 19/97 (19.6%) patients developedaGVHD grade II or higher, including11 (11.3%) with grade III or IV, while 4/72 (5.5%) evaluable patientsdevelopedextensivecGVHD.

Mortality

Atotalof63/97(64.9%)transplantswerenotassociatedwith mortality atthetimeofthisanalysis.Athirty-fourpatients (35.1%) had died due to transplant-related complications (n=26) or disease relapse/progression (n=8). The cumulative probability of transplant related mortality (TRM) was 24.7%(24/97)atoneyear:18patients(18.5%)diedwithinthe ﬁrst 100 days post-HCT, including 1patient (1%) who died beforeday30.

OSandevent-freesurvival

The mean survival for all patients estimated by Kaplan– Meiermethodwas4.8year(95%CI=4.1–5.5years).pOSafter all transplantswas0,600,05. Takingallpatientstogether, pOS after allo-HSCT with 10/10, 9/10 and 8/10 HLA match was 0,610,06; 0,590,09 and 0,600,21, respectively (p=0,912) (Table I). In patients with AML, 3-year OS reached 52%, 60% and 60%, respectively. In patients with ALL 3-year OS was 73% and 62% for 10/10 and 9/10 HLA match,respectively, and for BMFsyndromes 86% and 57%, respectively. No differences were observed in OS between patients transplanted beforethe end of 2012 and afterwards(Fig.1).RespectivevaluesforpEFSarepresented inTableII.

Transplant-relatedmortality

Out oftotalnumberof97transplants,in34(35%)casesthe treatment was unsuccessful. Treatment-related deaths occurred in 22 (22.7%) cases, including 2/5 (40%) patients with 8/10 HLA-matched HSCT, 8/30 (26.7%) patients with 9/10 HLA-matched HSCT, and 12/62 (19.3%) patients with 10/10 HLA-matched HSCT. The number of progression- related deaths in patients with acute leukemia was 12/83 (14.5%),including 4/43withALL(2/13 in9/10HLA-matched HSCT;2/30in10/10HLA-matchedHSCT)and8/40withAML (0/5 in 8/10HLA-matched HSCT; 2/10in 9/10HLA-matched HSCT; 6/25 in 10/10 HLA-matched HSCT). The causes of treatment-related deaths2patientswith8/10HLA-matched HSCT included: PTLD (n=1) and sepsis with multi-organ failure(MOF)afterprimarygraftfailure(n=1).Thecausesof treatment-related deaths8patientswith9/10HLA-matched HSCT included: septic shock with MOF (n=3), pneumonia (n=3) with CMV or fungal infection, post-transplant lym- phoproliferative disorder (PTLD) (n=1), and brain-stem

TableI–ResultsofHSCTwithrespecttoHLAmatch

Diagnosis Probabilityof3-yearoverallsurvival p

HLA8/10 HLA9/10 HLA10/10

Acutelymphoblasticleukemia – 0,620,13(8/13) 0,730,08(22/30) 0,562

Acutemyeloidleukemia 0,600,22(3/5) 0,600,15(6/10) 0,520,18(14/25) 0,975

Bonemarrowfailuresyndromes – 0,570,19(4/7) 0,860,13(6/7) 0,258

Total 0,600,22(3/5) 0,590,09(18/30) 0,610,06(42/62) 0,912

Numberofsurvivingandallpatientswithrespectivediagnosesareprovidedinparentheses.

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ischemic stroke (n=1). The causes of treatment-related deaths12patientswith10/10HLA-matchedHSCTincluded:

septic shockwith MOF(n=3),pneumonia (n=4) withCMV orfungalinfection,PTLD withMOF(n=2),GVHDwithMOF (n=2), sinusoid obstructive syndrome (SOS) with MOF (n=1).

One-yearOSandevent-freesurvival:comparisontoothertypes oftransplant.AccordingtorecentversionofJACIE standards requirements, one-year survival rates were calculated and compared to other types of transplants performed in our center.One-yearsurvivalforall318patientstransplantedin

our center between 2003 and 2015 was 0,7680,024; for allo-HSCT 0,7100,034, and for auto-HSCT 0,8500,032.

Estimated5-yearpOSafterallallo-HSCTperformedbetween 2003 and 2015 in our Department was 0,620,04. With respect to HLA donor match in HSCT from UD, 1-year survivalwas0,7090,052;0,6290,094and0,6000,219for 10/10, 9/10, and 8/10 HLA match, respectively. Results of probabilityof1-yearOSandprobabilityof 1-yearevent-free survival for patients with ALL, AML/MDS and BMF/SAA transplanted either from MFD or from UD are shown in TablesIIIandIV.

Fig.1–ResultsofHSCTwithrespecttoHLAmatch:(A)inAML,(B)inALL,(C)inallpatientstogether,(D)inallpatientstogether withrespecttoperiodoftransplantation

TableII–ResultsofEFSwithrespecttoHLAmatch

Diagnosis Probabilityof3-yearevent-freesurvival p

HLA8/10 HLA9/10 HLA10/10

Acutelymphoblasticleukemia – 0,620,13(n=13) 0,730,08(n=30) 0,562

Acutemyeloidleukemia 0,600,22(n=5) 0,400,16(n=10) 0,330,11(n=25) 0,826

Bonemarrowfailuresyndromes – 0,570,19(n=7) 0,860,13(n=7) 0,258

Total 0,600,22(n=5) 0,520,09(n=30) 0,570,06(n=62) 0,716

Numberofallpatientswithrespectivediagnosesareprovidedinparentheses.

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Discussion

In this study we analyzed results of transplants from UD performed in our center in children and adolescents with acute leukemia or BMF syndromes with respect to HLA match.Inthis smallseriesof childrenwehaveshown that OSmightnotsigniﬁcantlydifferwiththerespecttothelevel ofHLAmatch,howevercurrentliteraturedatademonstrate that still the level of HLA mismatchesmay, together with other factors, demonstrate impact on results of UD-HSCT.

The UD-HSCT results could also be compared with those performed from MFD-HSCT. Probability of 3-year overall survival(pOS) after all transplantsfrom UDshown inthis studywas0,610,06,while 3-yearpOS afterall MSD-HSCT performed between 2003 and 2015 inour Department was 0,730,04(p=0,044,datanotshown).Applicationoftrans- plantsfromUDinourcenterin2007hasenlargedtherapeu- ticpossibilitiesfor ourpatients.Sincepediatricpatientsare expected tolivefor a longtime after HSCTand the recent data have not shown any positive correlation between cGVHD and relapse in a landmark analysis of long-term survivors with the exception of chronic myeloid leukemia (CML)[10],the lowrateof cGVHDinourseriesshouldalso benoted.

Over this period of time we faced alsoan international trendinincreaseofthenumberofHSCTsfrom UDexceed- ing number of transplants from sibling donors. With the increase inthe number of donorsin Polish registries over 1millioninApril2016,nowadaysmostofourUDarefrom Poland. However, even withhigh resolution typing of HLA andbetterdonormatch,theriskof GVHDishigherincase oftransplantsperformed fromUDthan siblingdonors;this mightleadtoanincreaseintheriskofothercomplications such as life-threatening infections. Thus, it is difﬁcult to indicate if transplantsfrom UDimprove the resultsof OS.

Still,thenumberofpatientswithtransplant-relatedmortality is too high, and there is an international need in improvingsupportivetherapyfortransplantedpatients.

Report fromthe leadingSwedishcenterindicatedthree- year OSin2003–2013 forchildrenwithmalignantdisorders tobe68%andfornonmalignantdisorders87%[11],whilein French center overall 5-year OS was 64% for children transplantedbetween2000 and2010[12].Theimprovement in outcomewas alsoobserved in ourDepartment overthe analyzed period of 12 years, as the 5-year OS of patients undergoing allo-HSCT before the year 2007 was 43%, what shows growing experience and abilities of our transplant team, both doctors and nurses [13]. Probability of OS of HSCT patients in our transplant center showed results comparable with EBMT centers. This is valuable achieve- ment since nowadays more and more patients with more complex diagnoses are being qualiﬁed for transplantation, such asmultiple-relapsed patientsor those withadvanced disease or co-existing comorbidities. It is an international trendthatmoreandmorepatientsare qualiﬁed forsecond andsubsequenttransplant.

In summary, the presented resultsof HSCTobtained in our center are comparablewiththose from major international centers. One HLA mismatch between donor and recipient is not an obstacle to perform transplant for childrenwithacuteleukemiaintermsofOSafterallogeneic transplant. Current improvement in HSCT outcome is dependent not only on very good donor match but also multidirectionalandinterdisciplinarysupportivecare.

Authors’ contributions/Wkład autorów

JS had primary responsibility for study design and manu- script preparation. All authors participated in the project andcontributedtodatacollectionandinterpretation.

Conﬂict of interest/Konﬂikt interesu

Nonedeclared.

TableIII–One-yearsurvival

Diagnosis MFD-HSCT UD-HSCT Total

Acutelymphoblasticleukemia 0,680,10(n=23) 0,720,07(n=43) 0,710,06(n=66)

Acutemyeloidleukemia 0,840,08(n=19) 0,610,08(n=40) 0,680,06(n=59)

Bonemarrowfailuresyndromes 0,920,07(n=14) 0,660,13(n=14) 0,780,08(n=28)

Total 0,790,05(n=56) 0,670,05(n=97) 0,710,04(n=153)

Numberofpatientswithrespectivediagnosesisprovidedinparentheses.

TableIV–One-yearevent-freesurvival

Diagnosis MFD-HSCT UD-HSCT Total

Acutelymphoblasticleukemia 0,540,11(n=23) 0,700,07(n=43) 0,640,08(n=66)

Acutemyeloidleukemia 0,790,09(n=19) 0,560,08(n=40) 0,630,07(n=59)

Bonemarrowfailuresyndromes 0,920,07(n=14) 0,660,13(n=14) 0,780,08(n=28)

Total 0,750,06(n=56) 0,650,06(n=97) 0,660,06(n=153)

Numberofpatientswithrespectivediagnosesisprovidedinparentheses.

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Financial support/Finansowanie

Nonedeclared.

Ethics/Etyka

Thework describedin this article has been carriedout in accordance with TheCode of Ethics of the World Medical Association(Declaration of Helsinki)for experimentsinvol- ving humans; EU Directive 2010/63/EU for animal experi- ments;UniformRequirementsformanuscriptssubmittedto Biomedicaljournals.

Acknowledgements/Podziękowania

Wethankthenursingstaff(chairedbyEwaDembna)ofthe PediatricBMTTeam fortheir outstandingsupport andcare of our patients, and physicians from the Department of PediatricHematology andOncology at theCollegium Medi- cum of Bydgoszcz for their continuous support for trans- plantcenter.

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