autoimmune (and other) cytopeniasin pids · 2017-04-02 · cytopeniasin...

Autoimmune(andother)Cytopenias inPIDs

MarkusGSeidelHeadOutpatientClinic PediatricHematology-Oncology

MedicalUniversityGraz,AustriaMarch2017

ResearchUnitPediatricHematology&Immunology

DisclosuresConsultancyfee(onetime)2016:Baxalta [Ig,Hyaluronidase],Novartis[TRA]Travelgrants2016:Jazz,Octapharma,BaxaltaLecturehonoraria2016:CSL Behring

©wikimedia,DanielSchwen

Cytopenias inprimary immunodeficiency: notions andconundrums

• FrenchCohort Study,2183PID patients(AlainFischeretal.,JACI 2017):

– 26%had autoimmunity or inflammation,occurs inallage groups

– relativerisk to develop autoimmunecytopenia inPID is 120x,AIHA 830x,ITP 60x

–mostly B&T-PIDs

– allergy is arisk factor,outcome is worse!

– 15%of AIcytopenias inchildren are estimatedto be based onaPID

Ø notallcytopenias are ALPS- or CVID-linkedØ 85%are not linked to aknown PID

March2017 CytopeniasinPID|CIS2017Seattle|MarkusSeidel 3

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after-H

SCT

AlainFischeretal.,JACI 2017,pii:S0091-6749(17)30226-9,(C)AAAAI,JAllergyClinImmunol

0 10 20 30

Immune-/AutoimmuneDisease

FanconiAnemia,MDS/RCC

Infection

Bi- orPancytopenia

Lymphoproliferation

GranulomatousInflammation

MPSIIISanfilippo

37,3%

%of cohortEvansSyndromeALPSCHAISLEAI-thyroiddiseaseMBL-deficiency

àmanyadditionalorotherdiagnosesinchildrenwithchronicITP

Immunecytopenia from the hematologist‘s view:pediatric cITP Austria(n=81)ba

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Sipurzynski etal.,Semin.Hematol.2016

Number of patients 4546232691424

Highly variableresponses to multiplelines of treatment inpediatric cITPba

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Sipurzynski etal.,Semin.Hematol.2016

479interventionsà differentunderlyingmechanisms?


02468 101214161820222426 years

EVANSSy.(cITP)

GLILD

MMF MMFTRASiro

DanChloro ?

CTLA4haploinsufficiency

Adolescent with EvansSyndromeandGLILDba

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orgranulomatouslunginfection?

+antibiotics

7

Infantwith invasiveCMVinfection andmany causes for thrombocytopenia...

March2017 CytopeniasinPID|CIS2017Seattle|MarkusSeidel

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2

4

6

8

10

12

0

50

100

150

200

250

300

24.01.15

31.01.15

07.02.15

14.02.15

21.02.15

28.02.15

07.03.15

14.03.15

21.03.15

28.03.15

04.04.15

11.04.15

18.04.15

25.04.15

02.05.15

Platelets(/nl) MPV(fl)

1,E+00

1,E+01

1,E+02

1,E+03

1,E+04

1,E+05

1,E+06

1,E+07

13 14 15 16 17 18 19 20 21 22

CMVplasmaCMVurineCMVCNSfluid

age(weeks)

123456789101112131415161718months

bron

chilolitis

CMVpneumonitis

recurringbloodydiarrhea

ganciclovir

DLI

DLI

DLI

PSC1

DLI

PSC2

volvulus

ilealne

crosis

IgGreplacement,PjP prophylaxis,TPN

PICU Ped.Hem.Onc.

gggKleb

s.oxyt.

sepsis

Pfajfer,Seideletal.,submitted

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ctives WIP deficiency

à notallcytopenias inPID are autoimmune

8

Two sisters with cytopenias,multiorgan autoimmunity,andinfections:1xcured by HSCT (12yrsFU),1ximproved onabatacept (2yrs,ongoing)

March2017 CytopeniasinPID|CIS2017Seattle|MarkusSeidel

cITP

02 4 68 10 121416 18 years

ENTinfections

IVIG

diarrhea,exoc.pancr.ins.growth retard.,maldigest.

pancreas enzymes

steroids

pancytopenia

airway infxLPD

1,CsA (4-6weeks post-SCT;two courses)2,MMF3,rapamycin4,Adenovirus viremia

IVIG

1 2

cITPMFD

-SCT

vitiligorec.UTI

hepatitis4

AZT3romiplostim

MFD-BMT (HLA-id.mother):5x30mg/m2fludarabin,3x20mg/kgATG-F2x70mg/m2melphalane5.5x10^6/kgCD34,4.2x10^7CD3

topic

01 2345678910111213

AIHA

years

enterocolitis NoroV,AdVgrowth retardation

RITU

XIMAB

UTI

hepatopathy

A,AIHA1,systemic steroids2,MMF3,vincristine (2x)4,androgens5,rapamycin6,gonarthritis

5

1

24

3

4x375mg/m2

IVIG/SCIG/IVIG

UTI

PEGtubeTPN

budesonide

malresorption

5

6

ABATAC

EPT

sinustachycardia

15mg/kg,q4wks

ABATAC

EPT

ABATAC

EPT

6 6

ABATAC

EPT

ABATAC

EPT

ABATAC

EPT

ABATAC

EPT

ABATAC

EPT

ABATAC

EPT

6

JACI 2015,135(5):1384-90.e1-8

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LRBA deficiency

Differentpathomechanisms requiredifferenttreatments

• primaryimmunodeficiencies1. whatcausesthecytopenia?2. whichPID isit?3. whichpathwayisinvolved

(phenotype,functional,&genetics)?4. isatargetedtreatmentavailable?

Ø identifycytopenia-relatedcommonfeatures:“biomarkers”withintheimmunephenotype,e.g.skewedlymphocytesubsets

Ø discoverepigenetictolerance-impedingfactors

• parallelstoGvHD?(amongtheworstimmunecytopenias!)1. whatcanwelearnfromGvHD?2. whatcanweusefromthetreatmentof

multiplemyeloma/CLL?

• “primary”immunecytopenias (85%)1. excludeunderlyingPID or

hematologicaldiseaseASAP2. identifyparallelpatternstoPID

Ø stratify treatmentmodalitytoavoidprolongedphasesoftry-and-errorandtoimprove therapy


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CytopeniasinPID

antibody-mediatedCVIDALPSSLE

CID*(LRBA,CTLA4,Pi3Kd)Good

[ITP,AIHA,AIN,ES]

XLP-1,2CD27/CD70

ITKALPS

FHL1-5Griscelli-2CHS,HPS-2

[secondary HLH]

cellular

CID*WAS,WIP [+ptl defect]22q11[SAA,MDS-RCC]

*incl.hypomorphic mutations inSCIDgenes,CD40,CD40L,etc.;#excl.primary defects ofphagocyte number or function

SDS,DKCCHH,Schimke

IKAROS deficiencyRD &other syndromes(virus)infection-mediated

drug-induced;nutritionalmalignomamyelokathexis,WHIM

MonoMac/GATA2SCN1

PNH/CD59

phagocytosis

hemo-

lympho-proliferation

BLOOD.2014Oct9;124(15):2337-2344

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IPEX(-like)

11

General:Mechanisms of Autoimmunity inPrimaryImmunodeficiencies1. Lymphopenia (RAG1/2,Artemis...)expansion of T&Bcells with autoreactive TCR/BCR

2. Apoptosis defects:ALPS,autoreactive Tand Bcells are noteliminated

3. Breakdownof central tolerance (DGS,APECED):impaired auto-Ag presentation,checkpoint editing,anddefective negativeselection

4. Breakdownof peripheral tolerance:lostTreg function (FoxP3,CD25,CTLA4,LRBA...)

5. Increased type1Interferonsignature:STAT1GOF,STAT3GOF

6. Defect ofearly complement components (C1q,C1r/s,C2,C4)– with SAA andCRP strongopsonins for ICandapoptotic material,if lostà nuclear antigens induce IFNαinplasmacytoid dendritic cells andbreakself-tolerance inautoreactive TandBcells

7. Impaired clearance of cell debris: variants of Fc𝛾RII/III,CRP,or ITGAM (CD11b),deficiency of coatomer protein (COPA;ERstress),tripeptidyl peptidase II(TPPII;post-proteasome cytosolic protein modification,amino acid homeostasis)

8. Hyperactivation oflymphocytes:PI3KδGOF,PLC𝛾2,PKCδ

9. Impairment of B-lymphocyte function/BCR production:e.g.AID

Grimbacher etal.,JACI 2016;137(1):3-17(C)AAAAI,JAllergyClinImmunol

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Lucasetal.,NatImmun 2014;15(1):88-97

CD8+backgrou

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...no suchfool likeanimmunosenescent fool...

Rensing-Ehl etl.,Blood.2014;124(6):851-860)

APDS

ALPS

March2017 CytopeniasinPID|CIS2017Seattle|MarkusSeidel 13Stepensky etal.,Blood2015;125(5):753-61

senescentCD8+Tcells

AgeassociatedBcells(ABC)

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e.g.:TEMRA &Senescence of CD8+&Bcells:TPP2deficiency

autoimmunecytopenia

TPPIIintracellular peptide

degradation

loss of naivity,premature senescence &apoptosis

of T&Blymphocytes,failing tolerance

Blood 2015;125:741-742©2015 by American Society of Hematology

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ß CHAIEvansSyndromeoligosymptomaticunderMMF


Gorkiewicz andSeidel,unpublisheddata

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Epigenetic regulators:Microbiome &cytopenias?prospective studies warranted

ß LRBA deficiencyoligosymptomatic,underabatacept

information

March2017 Cytopenias inPID |CIS2017Seattle|MarkusSeidel 16

Tcell

Bcell

9

5b687

complement

IVIGplasmapheresis

modulate:sirolimusIVIG

MMF,AZT,6-MPCY

CsAATGalemtuzumab

VP16alemtuzumabJAK1/2inhibitors(ruxolitinib,tofacitinib,baricitinib)

?tocilizumab

eculizumabTNT001/3

TPO-RA(eltrombopag,romiplostim)

[erythropoietin]GCSF,CXCR4

“all”:corticosteroids

“some”:HSCT

abatacept?hydroxychloroquine

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CytopeniasinPID

AI-cytopeniahypogammaglobulinemia

lymphoproliferation | organomegalyenteropathy | IBDsevere infections

parenchymal lung disease | LIP | GLILDarthritis

skin or eye manifestationsendocrinopathy | IDDM

AI-hepatitisnephropathy | tubulopathyneurologic manifestations

failure to thrive

1 2 3 4 5 6 7 8 9 10 11 12before & after SCT: patientA

HSCT cures LRBA deficiency:symptoms before andafter


absent mild-moderate severeandHSCT indication n.a./deceased

Seideletal.-IEWP,revisionssubmitted

#sym

pt pre

#sym

pt post

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2

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6

8

10

# sy

mpt

oms

LRBA-related symptoms

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March2017 18

modifiedfrom:Cutleretal.,Blood2017;129(1):22-29

Cytopenias inPID |CIS2017Seattle|MarkusSeidel

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Graft-versus-HostDisease:anything to transfer to PIDs?

Differentpathomechanisms requiredifferenttreatments

• primaryimmunodeficiencies1. whatcausesthecytopenia?2. whichPID isit?3. whichpathwayisinvolved

(phenotype,functional,&genetics)?4. isatargetedtreatmentavailable?

Ø identifycommoncytopenia-relatedfeatures(“biomarkers”withintheimmunephenotype,e.g.skewedlymphocytesubsets

Ø discoverepigenetictolerance-impedingfactors

• parallelstoGvHD?(amongtheworstimmunecytopenias!)1. whatcanwelearnfromGvHD?2. whatcanweusefromthetreatmentof

multiplemyeloma/CLL?

• “primary”immunecytopenias (85%)1. excludeunderlyingPID or

hematologicaldiseaseASAP2. identifyparallelpatternstoPID

Ø stratify treatmentmodalitytoavoidprolongedphasesoftry-and-errorandtoimprove therapy


backgrou

ndpathom

echanism

stargets&

treatm

ent

perspe

ctives

prospective multicenter study including:– persisting/chronic ITP [from 6months duration]– autoimmunehemolytic anemia [from start]– EvansSyndrome[from start]– isolated Autoimmuneneutropenia

Aims:– discover underlying diseases early– recommend andharmonize diagnostic steps– recommend stratified first &second line therapy– recommend when to refer to which centres– gather data onepidemiology anduse of modern

(incl.off-label)drugs– provide platform atthe interface of hem-immun

• coming soon:www.sic-reg.org (under construction)March2017 CytopeniasinPID|CIS2017Seattle|MarkusSeidel 20

retrospectivesurvey

prospectivestudy:sic-reg

optimizemanagement

identifynovelvariants

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identifymodifiers

Proposal SIC-reg:Registryfor Severe ImmuneCytopenias


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congenitalTP

giantplatelets?MPV,IPF

morphology

familyhistory(kidneys,cataract...)

GPS,BSSFACS

vWS II,HUS,coagulation,

vWF:Ag,vWF:Rco,ADAMTS13

plateletgenepanel

(WES)

anemia morphology,hemolysis

RDW,Retifragmentocytes,ery-enzymes

CoombsbloodgroupPlt/Neutroph-Abs

CADcold/warm

agglutinins,C3d

TMAsC5-9,C3

BMFMDS,RCC,

[SAA],OP,DBAmorph.,FISH

Fanconi A.DEB

DKC,PNH,GATA2

Telomeres,FACS /DCratio

SDSstool/elastaseGaucher’s D.enzyme/gene

hematologygenepanel

(WES)

PIDALPSDNT,

biomarkers

CVIDBmem,IgG,A,Mvaccin.Ab,IgE

CIDnaiveT,gdTproliferation

TEM,TEMRA,senescence?P-STAT3,

CTLA4,LRBA

PIDgenepanel

(WES)

AIDSLE

ANA,dsDNA,ESR,APLA,CH50/AH50

AITD,DMautoantibodies

enteropathyceliac,VitAcalprotectin

IGF,BP3,HGHPTH,VitD3P-STAT5?

otherneurological,joints,skin

infectionCMV

parvo-B19HHV6,...

HCV,HIVEBV,AdV

Helicobacter,Campylobacter

stool:microbiome ©sic-reg.org


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©sic-reg.org

AIHA,ES:goal=remission

firstline:Prednisolone2-5mg/kg/ddays1-3,then1-2mg/kg/day,weanoffafter4wks >8wks…

second line#:Pred +MMF 1200mg/m2/d- if DNT ↑:Pred +sirolimus 1-2.8mg/m2/d[trough level 5ng/mL]

- if signs of CID,consider targeted therapy*,HSCT- wean offpred after4weeks- wean offafter6-12months over 3-6months#

or methyl prednisolone 10-30mg/kg/d>4d(?dexa.)+rituximab 4x375mg/m2or 2x1g/m2q2wks (vaccin.)

third line#:danazol,AZT,VCR,bortezomib,carfilzomib?,eculizumab (CAD,PNH),CY,CSA,[ibrutinib?,daratumumab?],...splenectomy,HSCT

cITP:goal=noriskofhemorrhage,QoL

firstline-iftreatmentisneeded(!?!):IVIG 0.5-0.8g/kg- ifRh+:anti-D (25)50-75µg/kgs.c. ori.v.dexamethasone5-10(20)mg/m2/day>3-5days

second line#:MMF 1200mg/m2/d± prednisolone- if DNT ↑:sirolimus- if signs of CID,consider targeted therapy*,HSCT

TPOR-Agonists:eltrombopag 25-50mg/d(0.8-1.2mg/kg<6yrs);romiplostim (>18yrsor eltr.non-responders)100-250µg/m2/week

- wean offafter6-12months over 3-6months #

third line#:rituximab,danazol,AZT,VCR,Dapson,(Retinoids?)- adults:splenectomy (vaccinate!,OPSI-prophyl.)...

*or targeted therapies if underlying disease is identified (e.g.p110inhib.inAPDS-study,abatacept inLRBA-def.&CTLA4haploins....)#order depending onimmuneor phenotypical abnormality

preliminarytreatmentalgorithms,derivedfrominternationalguidelines/publications

23

Acknowledgements

March2017

Graz– Ped Hem-OncChristianUrbanand team of physicians,nurses,and the laboratoryStyrian Children‘s CancerAid

SLUG,NFIL3Boston– DFCI,Pediatric OncologyTomLookAdolfoFerrando

ImmunogeneticsVienna– CeMMKaan BoztugTatjanaHirschmuglElisabethSalzerLoic DupréLaurènePfaifer

Inherited Platelet DisorderGrazWolfgangMunteanAxelSchlagenhaufChristineBeham-SchmidGreifswald,TübingenAndreasGreinacherTamam BakchoulWürzburgHaraldSchulzeGeorgijManukjanViennaSimonPanzer

LRBA,CD27,ALPS,P-CIDFreiburg-CCIBodoGrimbacherLauraGamez-DiazStephanEhlAnneRensing-EhlCarstenSpeckmannDüsseldorf&KrefeldTimNiehuesArndtBorkhardt

TumorgeneticsVienna– CCRIPeterAmbrosIngeAmbrosFikretRifatbegovicOskarHaasSpecialthanks toprevious mentorsMischaFreissmuthChristinaPetersAndreasHeitgerHelmutGadnerMichaelMicksche&diploma studentsM.GroßekatthöferSabineHeitzenederJohannaSipurzynskiRebeccaVossBettinaWohlmutherVictoriaTeschKatrinBöhmOliverKindler

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Thankyouforyourattention!

autoimmune (and other) cytopeniasin pids · 2017-04-02 · cytopeniasin...

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