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
HEREDITARY BONE MARROW FAILUREHEREDITARY BONE MARROW FAILURE
E.Gluckman,2004
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HEREDITARY BONE MARROW FAILUREHEREDITARY BONE MARROW FAILURE
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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HEREDITARY BONE MARROW FAILUREHEREDITARY BONE MARROW FAILURE
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
EBMT Handbook, revised 2004
~ 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 -
EBMT Handbook, revised 2004
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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 :
EBMT Handbook, revised 2004
+/-
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GvHD PREVENTION
CSA + short MTX
G-CSF
D+5engraftment
MONITORING for CHIMERISM
Cytogenetics / FISH (X/Y chromosome)
LPRF
EBMT Handbook, revised 2004
- 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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