anemie aplastica semifinal

8/8/2019 Anemie Aplastica Semifinal

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C.Arion, M.D.,PhD; A.Colita,M.D.,PhD;

L.Dumitrache M.D.,PhD; A.Sarsan

M.D.,PhD; A.Glck, M.D

FUNDENI CLINICAL INSTITUTE BUCHAREST

PEDIATRIC CLINIC

PEDIATRIC HEMATOLOGY - ONCOLOGY DEPT

HSCT DEPARTMENT

- OCTOBER 2008 -


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SAA (Young, 2005)

P.B.

Hb


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INCIDENCE: 2(3-6)/1x10 6 population/year

CHARACTERISTICS IN CHILDREN :

Hereditary bone marrow failure

Idiopathic AA : vSAA predominates (>60%)

Lethality from hemorrhage and sepsis (high number

of severe-life-threatening-infections) Unfavourable outcome with supportive therapy

better response with specific therapy (>80% long

term survivors in responding patients)


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PATHOGENY

Clonal anomalies of HSCs Telomere shortening in

progenitor cells

Accelerating apoptose inhematological progenitors

Decreased HSC early progenitor pool

HSC anomaly ?

Immune mediated suppressionof hematopoiesis

Autoimmune disease?

Viral infection (release

of cytokines

suppressing

the hematopoiesis)

MECHANISMS :MECHANISMS :


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BM histology

Absent / reduced number of CD34+ cells

Important reduction of LTC-ICs

Deficient colonies formation in semisolid

media cultures

AA = Anomaly of HSCs

Arguments

AA = Anomaly of HSCs

Arguments


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oligoclonal expansion of CD8+ T cells

evidence of activated T cells

(IFN,TNF)

induction of Fas expression on HSCs

HSCs apoptose

effects of immunosuppressive therapy

AA = Autoimmune diseaseAA = Autoimmune disease


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Acquired AA secondaryAcquired AA secondary

Drug related

Toxine

Radiation/Rx therapy

Infections

Immune

MDS/preleukemia

Others

Dose dependent (i.e. Cytostatics)Idiosyncratic (Chloramphenicol,Fenitoin,Gold salts,NSAI)

Pesticides

Others : benzen,CCl4, toluene

Viral hepatitis (non A, nonB, nonC)

HIV , CMV , Parvovirus B19 , Measles

SLE and other autoimmune diseasesGvHD

PNH

Thymoma

Lanzkowsky , 2004


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Disense

Transmision Gene Chromosome Fenotype

FANC A 16q 2416q 24--33 Hypostature, LBW

FA FANC B 13q 1213q 12--1313 Microcephaly

AR FANC C 9q 229q 22--33 Skin hyperpigmentation, caf au

lait spots

X-linked FANC D1 13q 1213q 12--1313Malformations(skeleton,heart,kidne)

AA

FANC D2 3p 253p 25--33 HbF, FT

FANC E 6p 256p 25--2222 Chromosome breakage/fragility

FANC F 11p 1511p 15 Secondary neoplasia (AML with

FANC G 9p 139p 13clonal anomalies 7- ,5- ,8- chr1,chr11;

Solid tumours)

>12genes

HEREDITARY BONE MARROW FAILUREHEREDITARY BONE MARROW FAILURE

E.Gluckman,2004


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Disense

TransmisionGene Chromosome Fenotype

DKC X-linked

AD

AR

Abnormal skin pigmentation

Leukoplakia

Nail distrophy

Congenital anomalies

AA

Solid tumours/MSD/Leukemia

DKC 1

(X-Linked)

TERC

(AD)

?

(AR)

Xq28


E.Gluckman,2004


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Disense

Transmision

Gene Chromosome Fenotype

DBA

AD

(AR?)

Schwachman

AR

RPS 19

(25%)

SBDS

19q 13

7q 11

Erythroblastopenia

Erythrocytic ADA

Congenital anomalies (30%,

thumbs, upper limbs, cranio facial,

heart, uro-genital)

AA

Exocrine pancreas insufficiency

Seckel

AR

Bird headed nanism Congenital anomalies

AA

SCKL1

SCKL2

SCKL3

3q22.1-24

18q11.31-11.2

14q23E.Gluckman 2004


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Disense

TransmisionGene Chromosome Fenotype

Kostmann

Amegakariocytic

congenital

Thrombocytopenia

ELA 2(Neutrophil

elastase)

MPL

19p13.3

1p 34

Leukopenia / chronic neutropenia

Early onset of severe infection

MSD / AML (10%)

Early onset (neonatal)thrombocytopenia

Amegakariocytic bone marrow

Skeletal anomalies (TAR)

AA

E.Gluckman,2004


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Reduction of blood cell numbers (PB)

Anemia Neutropenia Thrombocytopenia

Palor

Easy fatigue

Dyspnea

Tachycardia

Syncope (orthostaticexertion)

Infections

complications

Skin-mucosal

hemorrhage

Active bleeding

BM decreased production of mature blood cells


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History

Short stature / nanism

Skin hyperpigmentation Rash

Nail dysplasia

Leukoplakia

Exocrine pancreas insufficiency

Skeleton anomalies (radius, thumbs)

Other congenital anomalies


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BM Recovery after HSCT allo MSDBM Recovery after HSCT allo MSDBM Recovery after HSCT allo MSDBM Recovery after HSCT allo MSD

BM Aspect Pre HSCT allo MSD

BM Aspect Post HSCT allo MSD


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time from diagnose to HSCT

number of pre-transplant transfusions (>20)

pre-transplant infections

pre-transplant immunosuppressive therapy

/ androgen therapy

a GvHd II - IV

Unfavourable risk factors for HSCT allo MSD( Young,2005; George,2006; Ades et al.2007 )

Unfavourable risk factors for HSCT allo MSD( Young,2005; George,2006; Ades et al.2007 )


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Heart failure (LVEF 2xN HIV infection Active HBV, HCV infection Karnofsky index (pediatric)


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SUPPORTIVETHERAPY

Bl r t

Hy rati n

Oral n triti n/

TPN

IV IG

Preventi n fba terial,viral,f ngal

infe ti n

I lati nLAF

Sterile envir nment

~ HSCT allo MSD in CHILDREN~

EBMT Handbook, revised 2004


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D -4

D -5

D -3

D -1

D 0

D -2

CTX50mg/kg bw, infusion, 1h with Mesna,pre- and post hydration

CTX 50mg/kg bw, infusion, 1h with Mesna,

pre- and post hydration

CTX 50mg/kg bw, infusion, 1h with Mesna,pre- and post hydration

CTX 50mg/kg bw, infusion, 1h with Mesna,pre- and post hydration

HSCT (BM or PBSC )

CONDITIONING Cy200

~ HSCT allo MSD in CHILDREN~~ HSCT allo MSD in CHILDREN~


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ANC > 500/L for 3 consecutive days

PLT > 10,000/L and transfusional independence

DEFINITION of ENGRAFTMENT

MONITORING for CHIMERISM

Cytogenetics, FISH X,Y chromosomesLength Polymorfism of restriction fragments


~ HSCT allo MSD in CHILDREN~


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Early initiation of immunosuppression (10-14days from diagnose) !

ATG 0.75mL/kgbw , 8-10h infusion X 8 days

PREDNISON 1-2mg/kgbw/day, orally 3rdD28

with progressive reduction

CSA 5mg/kgbw/day, orally (dose adjustment related to serum levels)

After 6 month, progressive reduction of dose in responders

G-CSF 5mg/kgbw/day s.c. (ANC


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MONITORING :: dd2828, d, d4242, d, d112112,, 66mo, then everymo, then every 66 monthmonth DEFINITION OF OUTCOME :

PR

NR

CR

Hb=normal values (regarding to age)

ANC >1,500/LPLT > 100,000/L

~Transfusional independence (erythrocytes)

~Reticulocyte count >30,000/ L

~ANC > 500/ L~PLT > 50,000/ L

-IMMUNOSUPPRESION in vSAA / SAA in CHILDREN--IMMUNOSUPPRESION in vSAA / SAA in CHILDREN-

German / Austrian Aplastic Anemia Group, 1999


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-IMMUNOSUPPRESION in vSAA / SAA in CHILDREN--IMMUNOSUPPRESION in vSAA / SAA in CHILDREN-

CR: 69%5y RFS=80%

vSAA

CR : 44%5y RFS=67%

SAA

Therapeutic Response

8y OS = 84%


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Relapse :: 35% at 5years (including late relapse !)

The best predictor for 5y survival is the

therapeutic response evaluated at 6 month

CR 100% survival

PR 97% survival

NR 67% survival

Many survivors remain transfusion/low dose

CSA dependent

Risk of clonal evolution in children and

adolescents: ??? (in adults: 15-40%)

- IMMUNOSUPPRESION in vSAA / SAA in CHILDREN -- IMMUNOSUPPRESION in vSAA / SAA in CHILDREN -


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Supportive

Therapy

Isolation,Isolation,

LAF,LAF,

sterile environmentsterile environment

Prevention ofPrevention of

bacterial,viral and fungalbacterial,viral and fungal

infectionsinfections

BloodBlood

productsproducts

HydrationHydration

Oral nutritionOral nutrition

TPNTPN

IVIGIVIG

- ALGORITM forIMMUNOSUPPRESSION in vSAA /SAA in CHILDREN -



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D -4

D -5

D -3

D -1

D 0

D -2

FLUDARA 25mg/sqm , 30 minutes infusion

CTX 10mg/kgbw ,1h infusion with Mesna, pre- and posthydration

FLUDARA 25mg/sqm , 30 minutes infusion

CTX 10mg/kgbw ,1h infusion with Mesna, pre- and

posthydration

ATG 1.5mg/kgbw , 8-10 h infusion

ATG 1,5mg/kgbw , 8-10 h infusion

HSCT (BM, PBSC)

BUSULFAN 11..55mg/kgbw/day , p.o.,mg/kgbw/day , p.o., 44 adm Dadm D--99DD--66CONDITIONING :


+/-


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GvHD PREVENTION

CSA + short MTX

G-CSF

D+5engraftment

MONITORING for CHIMERISM

Cytogenetics / FISH (X/Y chromosome)

LPRF


- HSCT allo MUD in vSAA/SAA in CHILDREN -- HSCT allo MUD in vSAA/SAA in CHILDREN -


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Infection

prophylaxy

Substitutionwith

blood

products

Protocol forantibiotic therapy

In febrile

neutropenia

Prevention

Of Oral

Mucositis

Iron Chelation

RestrictivePolicy !

Leucodepleted + Iradiated

Blood products

FQ + AzolesChronic

transfusion

CONSERVATIVE Tx

in vSAA / SAA

in CHILDREN

CONSERVATIVE Tx

in vSAA / SAA

in CHILDREN


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- Tx of HEREDITARY BONE MARROW FAILURES I -- Tx of HEREDITARY BONE MARROW FAILURES I -

ANDROGENS

HSCT allo MSD

HSCT alternative

donors

Oxymetholone

TIMING : Hb


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CRITERIA MSD MUD

Graft rejection30% secondary

rejection

GvHD II - IV 30% 47%

D +100

TRM

27% 57% *

OS 65 85% 5y 10-35% 3y

* Increased rate of mortality due to infections, particularly fungal !

FA OUTCOMES in HSCTFA OUTCOMES in HSCT

- Tx of HEREDITARY BONE MARROW FAILURE II -- Tx of HEREDITARY BONE MARROW FAILURE II -


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Risk factors for unfavorable post-transplant evaluation

long pre-transplant aplasia

extension association of congenital anomalies (3yOS=14% vs 44%) prior androgen therapy (3yOS : 21% vs49% )

CMV + recipient

female donor

leukemia transformation Risk for secondary malignancies

medium period of latency=7-8ys

squamous carcinoma (head and neck), MSD, leukemia

risk factors for secondary malignancies : TBI, cGvHD

- Tx of HEREDITARY BONE MARROW FAILURE III -- Tx of HEREDITARY BONE MARROW FAILURE III -


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- Tx of HEREDITARY BONE MARROW FAILURE IV -- Tx of HEREDITARY BONE MARROW FAILURE IV -

FACTORS INFAVOR OF BETTER

POST-TRANSPLANT OUTOMES :

FACTORS INFAVOR OF BETTER

POST-TRANSPLANT OUTOMES :

Limited associated congenital anomalies

Non utilisation of androgen Tx

Thrombocyte count (pre-transplant)

Normal functional liver tests (post-transplant)

Young age


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SYNDROME UP-FRONT

THERAPY

HSCT AUTHOR

DBA Cortisone Transfusions (Ery)

+

Iron chelation

? (spontaneous remissions ! )

Allo MSD for cortico-resistant

patients

( 5y OS =87.5% )

Allo MUD: unfavourable

outcomes

- Role of HSCT in treatment of hereditary BM failures -- Role of HSCT in treatment of hereditary BM failures -

EBMT 2004, FSH 2007


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- Role of HSCT in treatment of hereditary BM failures -- Role of HSCT in treatment of hereditary BM failures -

SYNDROME UP FRONT

THERAPY

HSCT AUTHOR

Androgens

+

G CSF

+

EPO

CDK

Insufficient experience !

Allo MSD possible

curative

High TRMRisk for AL in state of

mixed chimerism

Allo MUD : unfavourable

outcomes

EBMT 2004 FSH 2007


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