ANEMIA APLÁSTICA- TRANSPLANTE DE MEDULA ÓSSEA

(1)

Ricardo Pasquini

ANEMIA

APLÁSTICA-TRANSPLANTE DE MEDULA ÓSSEA

Ricardo Pasquini

Professor Emérito - UFPR

VI BOARD REVIEW – CURSO DE REVISÃO EM HEMATOLOGIA E HEMOTERAPIA HOSPITAL ISRAELITA ALBERT EINSTEIN

(2)

ANEMIAS APLÁSTICAS

ETIOLOGIA

HEREDITÁRIAS

E

ADQUIRIDAS

(3)

ANEMIAS APLÁSTICAS HEREDITÁRIAS

Anemia de Fanconi

Síndrome de Shwachman-Diamond

Disceratose congenita

Síndrome de Hoyeraal-Hreidarsson

Síndrome de Revesz

Outras

Doenças do Telômero

Outras doenças genéticas:

Síndrome de Down

Síndrome de Dubowitz

Síndrome de Seckel

Disgenesia Reticular

Displasia imuno-óssea de Schimke

(4)

CITOPENIAS UNILINHAGEM

_{Anemia de Diamond-Blackfan}

_{Síndrome de Kostmann}

_{(Neutropenia Congênita)}

_{Trombocitopenia com ausência de rádio}

_{Outras trombocitopenias hereditárias}

_{Síndrome de Bart}

_{Doença de depósito do glicogênio 1b}

_{Anemias diseritropoiéticas congênitas}

(5)

ANEMIAS APLÁSTICAS

ADQUIRIDAS

HC-UFPR

(6)

TRATAMENTO DA ANEMIA APLASTICA

TERAPIA DE SUPORTE

TRANSPLANTE DE CTH

HC-UFPR

TRANSPLANTE DE CTH

(7)

DEFINIÇÃO DA GRAVIDADE DA

ANEMIA APLASTICA

DEFINIÇÃO DA GRAVIDADE DA

ANEMIA APLASTICA

ANEMIA APLÁSTICA SEVERA:

CELULARIDE DA M.O: <25% or 25-50% com <30% e pelo

menos 2/3 dos seguintes; neutrófilos <500/ µL, plaquetas <20000/ µL and reticulócitos <20000/µL

HC-UFPR

MUITO SEVERA:

Como a forma severe, porém com neutrófilos <200 µL NÃO SEVERA:

(8)

(9)

(10)

APLASTIC ANAEMIA TREATED BY MARROW TRANSPLANTATION

E Donnall Thomas , Rainer Storb , Alexander Fefer , SherillJ Slichter , JeanI Bryant , C Dean Buckner , PaulE Neiman , ReginaldA Clift , DonaldD Funk , KennethE Lerner

The Lancet, Volume 299, Issue 7745, Pages 284 - 289, 5 February 1972

• Abstract

• 4 patients with complete marrow failure, 3 due to unknown cause and 1

associated with hepatitis, showed no indication of spontaneous recovery after 7 to 52 weeks of conventional and supportive treatment. They were conditioned for engraftment by the administration of cyclophosphamide, 50 mg. per kg., on each of 4 days, followed in 36 hours by marrow infusion. The marrow donor in each instance was a sibling of opposite sex who matched the recipient with regard to the major human histocompatibility locus (HL-A) as shown by each instance was a sibling of opposite sex who matched the recipient with regard to the major human histocompatibility locus (HL-A) as shown by

cytotoxicity testing of the family and confirmed by non-reactivity in the mixed-leucocyte test. Methotrexate was given for a limited period after grafting as an immunosuppressive agent to modify the graft-versus-host disease. All 4

patients showed prompt engraftment indicated by a return of marrow cellularity and a rise of peripheral blood-counts, confirmed by cytogenetic analysis. 1

patient died of graft-versus-host disease with a cellular marrow 45 days after grafting. Another patient rejected his graft and died 67 days after grafting. 2 patients have excellent-functioning marrow grafts without graft-versus-host disease and are apparently well 138 and 215 days after grafting.

(11)

Bone Marrow Graft in Man after Conditioning

by Antilymphocytic Serum*

G. Mathe, M.D.; J. L. Amiel, M.D.; L. Schwarzenberg, M.D.;

J. Choay, M.D.; P. Trolard, M.D.M. Schneider, M.D.; M. Hayat, M.D.; J. R. Schlumberger, M.D.; Cl. Jasmin, M.D.

British Medical Journal, 1970, 2, 131-136

(12)

Age

PMN

10 yy 20 yy 30 yy 40 yy 50 yy

0 ₂₄

₂₄

₂₀

₁₄

₁₆

_----2222

100 ₁₉

₁₉

₁₄

₈₈₈₈

₁₁₁₁

_----7777

Differences (%) in estimated failure free survival, after

initial treatment, at 5 years FU

Seminars in Hematology 2000; 37: 69

19

14

14 8888

1111

----7777

200 ₁₄

₁₄

₉₉₉₉

₃₃₃₃

_----4444

_----11

₁₁

300 ₁₆

₁₆

₅₅₅₅

_----1111

_----7777

_----14

₁₄

400 ₆₆₆₆

₁₁₁₁

_----4444

_----10

₁₀

_----16

₁₆

500 ₃₃₃₃

_----2222

_----7777

_----12

₁₂

_----17

₁₇

Positive values: BMT has superior (+) survival compared to IS Positive values: BMT has superior (+) survival compared to IS

Negative values: BMT has inferior (

(13)

Algoritmo no Tratamento da Anemia Aplástica Adquirida

(14)

(15)

Probability of Survival after

Probability of Survival after Allogeneic

Allogeneic

Transplants for SAA, Worldwide, 2000

Transplants for SAA, Worldwide, 2000--2009

2009

-- By Donor Type and Age By Donor Type and Age

--60 80 100 70 90 60 80 100 70 90 P ro b a b il it y o f S u rv iv a l, %

HLA-id sibling, ≤ 20y (N=1,191)

HLA-id sibling, > 20y (N=1,256)

Unrelated donor, ≤ 20y (N=574)

Years 0 1 2 3 4 5 6 0 20 40 10 30 50 0 20 40 10 30 50 P ro b a b il it y o f S u rv iv a l, % P < 0.0001 SUM-WW11_31.ppt Slide 31

(16)

COX multivariate analysis

transplantation

P

RR

Age

(<16/=>)

0.0001

1.66 Interval DxTx (< /> 83 dd )

0.0006

1.56

Locasciulli , Haematologica; 2007;92:11.

(17)

Blood 2007; 110:1397

=<20 years(RR 2.4) p=0.02 >20 years(RR 1.2) p=0.1

(18)

(19)

27%

13% 19%

17%

Overall Experience in Allo HSCT

According to the Diagnosis

(1979-June/2011)

13% 14%

10%

Anemia Aplástica Severa (511) A.Fanconi (239)

Leucemia Mielóide Aguda (248) Leucemia Linfóide Aguda (180) Leucemia Mielóide Crônica (345) Outros (308)

TOTAL: 1831 TOTAL: 1831 Unrelated donor 413 Syngeneic 12 SOURCE OF CELLS Bone marrow 1574 Cord blood 180 Peripheral blood 73 bm + (cb or pb) 04

(20)

Aplastic Anemia - Overall Experience

BMT Center UFPR – Curitiba - Brazil

Period: 10/1979 – 31/08/09

_{Patients referred}

₁₂₂₅

Patients treated at our institution

1034

_{Patients treated at our institution}

₁₀₃₄

_{Types of treatment}

- Bone Marrow Transp.

478

(21)

HSCT in SAA

Clinical Characteristics

Period

1979-Junho 2011

Number of patients 511 Age - range (M) 1-49 (19) Gender (M/F) 319/192 Female donor (%) 40 Female donor (%) 40

Previous transf U. - range(M) 0-675 (28)

Disease duration (months) 0.5-232 (4)

Granulocytes/µL 0-3835 (322) Infused Cells

X108_{/Kg (bm)} _{0.69 – 12.9 (3.4)}

Donor type

(22)

0.6 0.7 0.8 0.9 1.0 1.1

S

u

rv

iv

a

l

(%

)

HSCT in SAA - UFPR

Overall survival

0 5 10 15 20 25 0.0 0.1 0.2 0.3 0.4 0.5 0.6

Time (years)

S

u

rv

iv

a

l

(%

)

423 pts

(23)

0.5 0.6 0.7 0.8 0.9 1.0

S

u

rv

iv

a

l

(%

)

P<0.0001

HSCT in SAA - UFPR

Conditioning

0 5 10 15 20 0.0 0.1 0.2 0.3 0.4 0.5 A) Cy200, <16tr (96) C) Cy200, >15tr (74) B) Bu+Cy (153)

Time (

Years

)

S

u

rv

iv

a

l

(%

)

B X C: p=0.006

(24)

0.5 0.6 0.7 0.8 0.9 1.0 _{B) bucy, >50transf(41)} C) cy, >50transf (21) A) bu+flu - todos (23) S u rv iv a l HSCT in SAA > 50 transfusions 0 10 20 30 0.0 0.1 0.2 0.3 0.4 0.5 A X C: p = 0.03

Time post transplant (Y)

S u rv iv a l

(25)

FACTORS AFFECTING THE OUTCOME OF HSCT

FOR SEVERE APLASTIC ANEMIA PATIENTS

multivariate analysis

Odds ratio P value

SURVIVAL

Previous transf. 7.01 <0.001

Disease duration 1.5 0.03

Engraftment 69.0 <0.001

aGVHD 2.98 <0.001

Bussulfan (cond.) 0.52 <0.013

(26)

FACTORS AFFECTING THE OUTCOME OF

HSCT FOR SEVERE APLASTIC ANEMIA

PATIENTS

-

multivariate

analysis-O.R. p value GRAFT FAILURE Age 0.49 0.018 Bussulfan (cond.) 0,17 <0.001 Previous treat. 0.49 0.017 (<16 transf./Pred) Previous treat. 0.49 0.017 (<16 transf./Pred) aGVHD >50 transfusions 0.047 cGVHD Age 2.94 0.001

(27)

Cy

<<<<

16 RBCT

n= 10

Cy

≥≥≥≥

16 RBCT

n= 46

Bu + Cy

≥≥≥≥

16 RBCT

n=23

Graft failure

30%

35%

2%

IPN/ARDS*

0%

13%

11%

Causes of Death

Infection

30%

31%

35%

GVHD

0%

4%

Organ failure

10%

4%

22%

Hemorrhage

20%

4%

13%

Other causes

10%

13%

AAF06_3.ppt

*IPN=Interstitial pneumonia; ARDS=Acute respiratory distress syndrome.

(28)

Anemia Aplástica Severa

Experiência Brasileira em

6 Centros de TCTH

HC-UFPR

6 Centros de TCTH

(930 pacientes)

(29)

Centros de TCTH

_{CEMO – INCA - RJ}

_–

_{Luiz Fernando Bousas}

_{H. Amaral Carvalho – Jaú}

_-

_{Vergilio Culturato}

_{Hospital das Clínicas/USP}

_-

_{Frederico Dulley}

HC-UFPR

_{Hospital de Clínicas}

_–

_UFPR

_{Santa Casa de São Paulo -}

_{José Carlos Barros}

_UNICAMP

_–

_{Afonso Vigoritto}

(30)

Overall survival

All Centers

Overall survival

All Centers 0.6 0.7 0.8 0.9 1.0 S u rv iv a l March/2011 HC-UFPR 0 5 10 15 20 25 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 Time (Years) S u rv iv a l 930 patients

(31)

Overall Survival

Related donor -

All Centers

Overall Survival

Related donor -

All Centers

0.5 0.6 0.7 0.8 0.9 1.0 S u rv iv a l March/2011 HC-UFPR 0 5 10 15 20 25 30 0.0 0.1 0.2 0.3 0.4 0.5 A)1980-1989 (133) B)1990-1999(362) C)2000-2010 (381) Time (Years) S u rv iv a l A X B: p=0.0001 B X C: p=0.0157

(32)

Overall Survival

Related donor -

All Centers Previos transfusion

Overall Survival

Related donor -

All Centers Previos transfusion 0.5 0.6 0.7 0.8 0.9 1.0 S u rv iv a l P<0.0001 March/2011 HC-UFPR 0 5 10 15 20 25 30 0.0 0.1 0.2 0.3 0.4 0.5 <16 (234) >15 (490) Time (Years) S u rv iv a l

(33)

Overall Survival

Related donor -

All Centers Conditioning

Overall Survival

Related donor -

All Centers Conditioning 0.6 0.7 0.8 0.9 1.0

S

u

rv

iv

a

l

P<0.0001 March/2011 HC-UFPR 0 5 10 15 20 25 30 0.0 0.1 0.2 0.3 0.4 0.5 A)BusCy (250) B)Cy200 <16tr (150) C)cy200 >15tr(102)

Time (Years)

S

u

rv

iv

a

l

(34)

Graft failure/Rejection

All Centers (wo CEMO)

Conditioning

Graft failure/Rejection

All Centers (wo CEMO)

Conditioning

0.5 0.6 0.7 0.8 0.9 1.0 A)bucy(36/249) B)cy200<16tr(64/151) C)cy200>15tr(43/102) R e je c ti o n March/2011 HC-UFPR 0 5 10 15 20 25 30 0.0 0.1 0.2 0.3 0.4 0.5 Time (Years) R e je c ti o n AXB, AXC: P<0.0001 BXC: p=0.0442

(35)

Treatment After Rejection

Cy <<<<16 RBCT N=36 Cy ≥≥≥≥16 RBCT N=19 Bu + Cy ≥≥≥≥16 RBCT N=16

Second Transplant

8

6

6 Cyclosporine

21

8

6 Combination

7

5

4

(36)

Survival After Rejection

0.5 0.6 0.7 0.8 0.9 1.0

R

e

je

c

ti

o

n

P=0.0002 0 5 10 15 20 0.0 0.1 0.2 0.3 0.4 0.5 Bucy (20 pts) Cy<16 (42) Cy>15 (24)

Days

R

e

je

c

ti

o

n

(37)

Chimerism after 2 yrs/SCT for SAA

Conditioning CY alone BUS+CY

Transf. <16 >15 politransf. Number of patients 52 14 55

Donor cells %

<50 16 10 01

51-90 10 01 06

>90 26

(50%)

07 (50%)

48 (87%)

(38)

Brazil * 1989-2005 239 20(2-58) 15% 17 20 68% at 7yrs

(39)

Overall Survival

All Centers Donor type

Overall Survival

All Centers Donor type 0.6 0.7 0.8 0.9 1.0 S u rv iv a l p=0.2356 March/2011 HC-UFPR 0 5 10 15 20 25 30 0.0 0.1 0.2 0.3 0.4 0.5 Related (878) Unrelated (51) Time (Years) S u rv iv a l

(40)

TCTH NAP em pacientes com AAS : 34 pts

Período : 1997 a 2012

1997 a 2009 : regime MAC

12.2009 a 05.2012 : regime RIC

Idade: 1 a 36 anos ( M: 14 anos)

Transfusões: 10 a 350 ( M: 51)

Fonte de células:

7 TSCU : Todos morreram

1 PBSC : óbito

(41)

TMO NAP em pts com AAS

1997 a 06.2009 : 10 pts - Mieloablativo

CY(120)+TBI(1440 rads) +/- ATG

12.2009 a 04.2012 : 16pts – Intensidade reduzida

CY1200mg/m2 + FLU +ATG +/- TBI (200) : 9pts

(42)

TMO NAP em pts com AAS

-Mieloablativo: 10 pts

1997 a 06.2009 : 10 pts

CY+TBI +/- ATG

Todos pegaram ( VNTR 100%)

8 vivos – 3 DECH C extenso

Nenhuma perda de enxerto tardia

(43)

TMO NAP – condicionamento RIC

CY1200mg/m2 + FLU+ATG+/- TBI: 9 pts – 6 vivos

Mediana de transfusões ; 101 1 óbito precoce D+ 32 (PI RSV) 3 rejeições – Re TMO – 2 óbitos

Quimerismo misto na maioria.2 pts com pega arrastada;1 pt com AHAI grave

CY60mg/kg +FLU+ATG+TBI 200: 7 pts – 6 vivos

Mediana de transfusões: 101 1 óbito precoce D+39 (FPP ) 6 vivos :

1 rejeição – re TMO Haplo – 100% do doador. Plaq 30000 (1 ano) 5 pts com 100% de quimerismo

(44)

SG após o TMO NAP em pts com AAS

19/25pts vivos com um seguimento 2 anos SG de 76%

(45)

Sobrevida Global de acordo com o tipo de

condicionamento ( MAC x RIC)

10pts – SG de 80% 5 anos

(46)

SG de acordo como os 3 tipos de

condicionamento

MAC 10pts SG: 80%/ 5 anos

RIC CY 60: 6pts SG: 83%/1 ano

(47)

Actuarial survival of 100 patients with acquired SAA undergoing

an alternative donor transplant (WPSAA 2009)

75%

(48)

(49)

Immunossupressive treatment

X BMT in SAA

0.6 0.7 0.8 0.9 1.0

S

u

rv

iv

a

l

Sep/2005 0 1000 2000 3000 4000 5000 6000 0.0 0.1 0.2 0.3 0.4 0.5 0.6 BMT (243 pat) Immuno (198 pat)

Days

S

u

rv

iv

a

l

(50)

Transplante de Medula Óssea HPN

UFPR

• 03/1988-02/2005 • 14 pacientes

• Idade mediana 28 anos • 12 pancitopenia • Condicionamente predominante: bussulfan 12 + ciclofosfamida 120 bussulfan 12 + ciclofosfamida 120 • 12 doadores irmãos • DECHa= 4 pacientes • DECHc= 4 pacientes

• 2 óbitos relacionados TMO (+10,+11) • Sobrevida global 70%

(51)

FANCONI ANEMIA CLINIC

Hospital de Clínicas

Universidade Federal do Paraná

Curitiba - Brazil

(52)

Introdução

Anemia de Fanconi é uma doença rara herdada atravéz de

um gene autossômico recessivo e caracterizada por progreessiva falência da medula óssea, anomalias congênitas e evidente predisposição em desenvolver neoplasias malignas.

A alta sensibilidade aos agentes clastogênico tais como

dietóxibutano( DEB) e mitomicic\na C, é fundamental para o diagnóstico desta entidade.

O transplante de medula óssea é o único tratamento

capaza de curar as complicaões hematológicas relacionadas à doença.

(53)

Fanconi

Fanconi Anemia

Anemia Clinic

Clinic

(1983

(1983--2009)

2009)

Patients evaluated: 411

(71 new patients over the last five years)

Geographic origin: South 121, Southeast

144, Central-west 41, Northeast 84 and

North 13.

Low social economic class: 68%.

Current active patients followed: 183

(54)

Preliminar panel to set up the screening of

common mutations of Brazilian patients

MUTATION LOCALIZATION GENE

987-990del (c.987-990 del ) Exon11 FANCA

2535- 2536del (c.2535-2536del) Exon27 FANCA

IVS29(-19)-1del (c. 2853- 19 del 19) Intron29 FANCA

3788-3790del (c.3788-3790del) Exon38 FANCA

1115-1118 del (c.1115-1118del) Exon13 FANCA

c.1390C>T (c.1393 C>T) Exon13 FANCC

320G>A (c.65G>A) Exon 1 FANCC

IVS4 + 4 A>T (c.711+4 A>T Intron 4 FANCC

322delG (c. 67delG) Exon 1 FANCC

IVS8 -2A>G (c.1077-2A>G) Exon 8 FANCG

(55)

HSCT FOR FANCONI ANEMIA

Brazilian experience – 276 patients

o

Curitiba – PR : HC- Universidade Federal do Paraná – 231pts

o

Rio de Janeiro – RJ : Instituto Nacional do Câncer - 11pts

o

Recife - PE : Hospital Real Português - 8pts

o

Belo Horizonte – MG : HC- Universidade Federal de MG - 7pts

o

São Paulo – SP : Instituto de Oncologia Pediátrico - 6 pts

o

Ribeirão Preto – SP : HC- Universidade de São Paulo - 3pts

o

Hospital Albert Eisntein - SP : 4 pts

o

Jaú – SP : Hospital Amaral Carvalho - 2pts

o

Porto Alegre – RS : HC- Universidade Federal do RS - 2pts

(56)

HLA Matched Related Bone Marrow Transplantation in

85 patients with Fanconi Anemia: The Brazilian

Experience using Cyclophosphamide 60mg/kg

C Bonfim; L Ribeiro; M Bitencourt; J Zanis-Neto,A Seber, R Gouveia, R Florencio, A Souza, L Daudt, A K Vieira, M Ostronoff,

L F Bouzas, R Pasquini

(57)

Patient Selection

o Number : 85pts

o Period: 07/1999- 05/2011

o Graft type: Bone marrow from HLA matched related donors

o Transplanted at 6 Brazilian BMT Centers: o Transplanted at 6 Brazilian BMT Centers:

o Curitiba : Federal University of Parana: 68pts o São Paulo: Pediatric Oncology Institute 6pts o Recife : Hospital Real Português : 4pts

o Rio de Janeiro : National Institute of Cancer: 3pts

o Belo Horizonte :Federal University of Minas Gerais: 2pts o Porto Alegre : Federal University of R G do Sul: 2pts

(58)

Patient Characteristics: 85 pts

o Gender 40F/45M

o Age - years - M (range) 09 (03 - 34) < 10 ys old : 48 pts

> 15 ys old : 07 pts

o Previous transfusions: 0 - 101 Units ( M: 6 U) o Previous transfusions: 0 - 101 Units ( M: 6 U) o Phase of the disease :

o Severe Aplastic Anemia 82pts

o MDS 3pts

o Type of donor:

o Siblings: 74 pts o Other Related HLA identical Donors : 11 pts

(59)

Transplant Characteristics

o

Preparatory Regimen :

o

Cyclophosphamide 60mg/kg (15mg/kg/day x 4)

o

GVHD Immune prophylaxis:

o

Cyclosporine 3mg/kg/d + Methotrexate 15mg/m2 on D+

o

Cyclosporine 3mg/kg/d + Methotrexate 15mg/m2 on D+

1 and 10mg/m2 on D+ 3,+6 and + 11

o

Prophylactic antibiotics :

o

Acyclovir, Bactrim, Fluconazol or Micafungin,

Levofloxacin

(60)

Overall Survival after an HLA Matched

related donor using CY 60mg/kg

72 pts: 84,5% at 5ys 72 pts: 84,5% at 5ys

(61)

Overall Survival according to age

at BMT

48 pts < 10ys: OS - 96% in 5ys

37pts ≥ 10ys: OS - 72% in 5 ys

(62)

ORD 11pts: 91% in 5ys

MSD : 74pts :82,3% in 5 ys

Overall Survival according to type of

donor or BMT center

Curitiba : 68pts – OS 83.7% at 5ys

Other BMT Centers: 17pts OS 86.3% at 5ys

(63)

Unrelated Bone Marrow Transplantation for Children

and Adolescents with Fanconi Anemia using

Cyclophophamide

Cyclophophamide,

, Fludarabine

Fludarabine and ATG: Analysis of

and ATG: Analysis of

C. Bonfim , L. Ribeiro , G. Loth, M. Bitencourt, S.N. Kanaan , A. Koliski , V. Funke , D. Pilonetto , J. Zanis-Neto and R. Pasquini

Bone Marrow Transplantation Unit - Federal University of Parana – Curitiba – Brasil

BMT Tandem Meetings – San Diego - 2012

33 patients transplanted in a single institution.

(64)

Patients Selection and

Inclusion Criteria

o Number of patients: 33

o All patients were transplanted at the Federal University of Parana – Curitiba - Brazil

o Period: 02/2002 to 02/2011 o Period: 02/2002 to 02/2011

o Graft source: Bone Marrow transplants from unrelated donors, typed at least for low resolution in Class I (A,B,C) and High resolution in Class II (DRB1)

o Preparatory regimen : CY+FLU+rATG and GVHD prophylaxis

(65)

Patient Characterisitcs

Gender: 17F/16M.

Age: 5-18ys(M: 10ys).

70%: < 15 previous transfusions

64% : Previous use of Androgens

All patients had Aplastic Anemia and only 4/31 had

cytogenetic abnormalities

(66)

Transplant Characteristics

o Preparatory Regimen :

• Cyclophosphamide 60mg/kg (15mg/kg/day x 4)

• Fludarabine 125mg/m2 ( 25mg/m2 x 5)

• rATG : 4-6mg/kg/ total dose ( 3 days)

o GVHD prophylaxis:

• Cyclosporine 3mg/kg/d + Methotrexate (4 doses)

o Prophylactic antibiotics :

• Acyclovir, Bactrim, Fluconazol or Micafungin, Levofloxacin (2006)

(67)

Donor Characteristics

Compatibility (retrospective analysis):

◦ 29pts: 8/8 compatible (LR class I and HR class II)

◦ 4pts: incompatible

7/8 : 3pts

6/8: 1pt

Immunogenetics Lab: Noemi F. Pereira accredited by ASHI

Unrelated donor search : Luciane Pangracio and Margareth Kleina

9 12

8 4

Before 2008 After 2008 REDOME Other Registries

1995 : HR DRB1 typing 2008: HR class I

(68)

Overall Survival after UBMT in

Fanconi Anemia : CY+FLU+ATG

26/ 33 pts: OS 79% in 3ys

Follow up:

(69)

Overall Survival according to age

<10ys and compatibility

17 pts < 10ys: OS 94%/3ys 16 pts ≥ 10ys: OS 62%/3ys 29pts matched 8/8 : OS 86 % in 3 ys 16 pts ≥ 10ys: OS 62%/3ys p=0,02 4pts mismatched: OS 25% in 3 ys p: < 0,001 OS according to compatibility 1995 : HR DRB1 typing 2008: HR class I Gender/ sex mismatch/previous transfusions,

previous use of androgens and acute or C-GVHD : NS

(70)

Overall Survival according to time of

transplant before or after 2008

UBMT ≥ 2008: 16 pts OS: 100% URD HSCT < 2002: 20 pts OS: 15%

in 10ys

UBMT 2002 - 2008: 17pts OS: 58,8%

(71)

Results of unrelated cord blood transplant in

fanconi anemia patients: risk factor analysis

for engraftment and survival.

Gluckman E, Rocha V, Ionescu I, Bierings M, Harris

RE, Wagner J, Kurtzberg J, Champagne MA, Bonfim

C, Bittencourt M, Darbyshire P, Fernandez MN,

Locatelli F, Pasquini R; Eurocord-Netcord and EBMT.

Biol Blood Marrow Transplant. 2007

(72)

Unrelated Cord Blood Transplantation in patients

with

with Fanconi

Fanconi Anemia

Anemia

100 patients with a minimum 3 months FU:

89

89 children <16y ,11 adults

children <16y ,11 adults

Median age : 8.6 y (1.4

Median age : 8.6 y (1.4 -- 45.4)

45.4)

Median age : 8.6 y (1.4

Median age : 8.6 y (1.4 -- 45.4)

45.4)

Median weight :

26.0 kg (9.0

26.0 kg (9.0 -- 71)

71)

(73)

Significant factors improving survival

Multivariate analysis

HR

p

Number of cord blood cells >4.9

2.44 <0.001

Presence of Fludarabine

2.04

0.012 CMV negative serology

2.78 <0.001

CMV negative serology

2.78 <0.001

(74)

Transplante Haplo-idêntico : 8 pts

Changes for the haplo protocol :

CY pre transplant : 5mg/kg/day/2days :first 3 pts

CY post transplant: 25mg/kg/day/2days

(75)

Protocolo : Haploidêntico do CY

pós transplante

8 pts (3ps no protocolo: PI - HP Kiem e Monica Thakar)

◦ 1 em Seattle e 7 em Curitiba

◦ 6 pts : 1º TMO e 2pts : resgate ( 2º e 3º TMO)

◦ Todos tiveram pega completa do enxerto

◦ 5/8 pts : GVHD-A grau II-IV ( 3pts grau IV)

◦ 3/6*pts : GVHD-C ( extenso e severo)

◦ 2 pts óbito: D+37 ( Toxo + sepsis) e D+681 ( GVHD-C + sepsis)

(76)

(77)

II Encontro Nacional de pacientes e

famílias com Anemia de Fanconi

Curitiba 25 e 26 de novembro 2011

(78)

(79)

(80)

Disceratose congenita

• 9 pacientes

• Período : 04/93 a 11/2011

• Idade: 2 a 24 anos ( M: 16)

• Sexo : 6M/3F

• 7 DC clássica

• 1 doença dos telomeros ( AAS + telomeros curtos)

(81)

Disceratose congenita

• Aparentado compatível (todos medula óssea):

– 5pts

– Todos receberam apenas CY 200

– Nenhum fez GVHD agudo ou crônico

– 3 quimerismo misto, 2 completo

– Apenas 1 paciente viva e bem 9 anos pós TMO

– 3 pts morreram entre 7 e 11 anos pós TMO por progressão da doença pulmonar e hepática

– 1 paciente perdido de seguimento 7 anos pós TMO. Problemas sociais sérios, uso de drogas ilícitas, internamentos em clínicas para

drogados. Na época em que foi perdido o seguimento ele apresentava quimerismo misto, plaquetopenia 34000 e baço palpável

(82)

Disceratose congenita

• Nao aparentado : 4 pts

– TSCU NAP 4/6 : 1pt. Óbito no D+ 70 por VOD, sepsis, recuperação neutrofilica apenas. Condicionada com BU8 + Fludarabina

– TMO NAP 9/10 ou 10/10 : 3 pts

• Todos vivos. Os 3 receberam condicionamento do proposto por Bacigalupo CY+FLU+ATG ( sem TBI)

• 1 pt com 24 anos e doença dos telomeros, sem manifestações clássicas da DC. Pega completa, sem GVHD, excelente 18 meses pós TMO

• 1 pt com 2 anos e síndrome de Revesz. VNTR 100% do doador.

Plaquetopenia persistente. Sangramento GI grave com necessidades múltiplas de cauterizações. O prognóstico da síndrome é muito

reservado (ponto de vista neurológico e GI)

• 1 pt com 10 anos de idade, forma clássica, no D+46 pós TMO com pega completa e provável DECH de intestino.