Síndrome Mielodisplásico en Pediatría: Particularidades en el diagnóstico y tratamento
“Mario Torero – Artist, Painter, Visionary, Cosmic Art Teacher >Peru”
Luiz Fernando Lopes lf.lopes@yahoo.com
A Classificação FAB French American British Cooperative Group Bennett et al. Br J Haematol 1982; 51: 189-99 SP
MO • LMA blastos >30% ---------------------- -------• AREB-t blastos >5% ou blastos >20% • LMMC monocitos >1x109 blastos <20% • AREB blastos >1% ou blastos >5% • AR blastos <1% e blastos <5% • ARSA sideroblastos em anel>15%
Síndrome Mielodisplásica
RA RAEB RAEB-t cmmL MDS2d
1 8 1 3 1 Lopes, LF . Ped Hematol / Oncol, 1999; 16:347
Síndrome Mielodisplásica Hospital do Câncer 1984 - 1995 + ++ +++
Atipia em Medula Óssea
S. eritrocítica S. granulocítica S. megacariocítica
sem atipia leve moderado severa
+7, ++6, +++1 +5, ++9 +2, ++3, -4, ausente 5
Lopes, LF . Ped Hematol / Oncol, 1999; 16:347
Childhood MDS in Brazil HOSPITAL DO CÂNCER São Paulo
14 pa&ents C.I. BOLDRINI Campinas
13 pa&ents ESPHI – Moscow, Russia, Sept., 1994
-7 Syndrome
!
?
? RA
RAEB-T !
?
AML ?
! JCML ? RAEB ? ? ? ! ? ! JCML CMML !
?
?
Unclassified ?
?
Cytopenia
?
? ? CMML ! ?
Pediatric MDS Classifications Hann 1992
Gardner & Haas 1992
Schwartz & Cohen 1993
Altman 1993
Juvenile CML RA Infan&le monosomy RARS RA RA RAEB RARS RAEB RAEB-t CMML Down Synd Monosomy 7 syndrome RAEB Leukemoid reac&on Juvenile CML RAEB-t Myelodysplasia with JCML in traforma&on Juvenile CML Eosinophilia Atypical CML Ph-nega&ve CML Familial CML Familial CML CMML Essen&al thrombicythemia Chronic monocy&c leukemia Polycythemia rubra vera Secondary myelodysplasia
1997
Antonio Machado y Ruiz (1875-1939) “Caminante, son tus huellas el camino, y nada más; caminante, no hay camino, se hace camino al andar...”
1997 – São Paulo
European Working Group of MDS in Childhood EWOG-MDS - 1997
Number of referred cases per year
20 # of patients
no MDS MDS
15 10 5 0 1983
1988 1991 1993 1995 1997 1999 2001 1987 1989 1992 1994 1996 1998 2000 2002
Cases with MDS/JMML retrospectively and prospectively referred and confirmed (n=96)
no. of patients
60 50 40 30 20 10 0
RA
RAEB
RAEB-t
JMML
others
1998-2003 1983-1997
% of blasts (BM) Cum Survival (%)
1,0 ,8
<5%
,6 ,4
11-20% 5-10%
,2 0,0 0
>20% 12
24
months
36
48
60
p=0.0169
GCB-SMD-PED
GRUPO COOPERATIVO BRASILEIRO SÍNDROME MIELODISPLÁSICA EM PEDIATRIA
Survival curves according to dysplasia lineage in pa&ents with MDS mod/severe
1,0
Cum Survival (%)
3 lineages ,8
2 lineages
,6
1 lineage
,4 ,2 0,0 0
12
24
36
months
48
60
Classifications of 96 pediatric MDS RA
FAB
8
WHO
2
PEDIATRIC Hasle
FRENCH
7
RCMD
RARS
RAEB
RAEB-t
CMML
46
6
14
7
22/24
9
41
5
14
40
5
13
Down S
CON. ABN.
SEC. MDS
Non class.
Total
74
14
4 8 10
73
5
82
5
80
Mario Jose Aguiar de Paula - Tese-2004-FAP
GCB-SMD-PED
GRUPO COOPERATIVO BRASILEIRO SÍNDROME MIELODISPLÁSICA EM PEDIATRIA
Low-dose chemotherapy Survival Functions 1,1 1,0 ,9 ,8 ,7
LD chemo
Cum Survival
,6
yes ,5
n=80
,4
no
n=16
,3 -10
censored
0
10
20
30
40
50
60
-censored 70
Months
P=0.7593
GCB-SMD-PED
GRUPO COOPERATIVO BRASILEIRO SÍNDROME MIELODISPLÁSICA EM PEDIATRIA
Stem-cell transplantation 1,0
,8
Cum Survival (%)
,6
,4
n=85
BMT yes
n=11 ,2
no 0,0 0
12
24
36
48
60
months
p=0.9699
Two Important Questions for Therapy of Advanced MDS
1. Can chemotherapy alone cure the patient ? 2. Is cytoreduction prior to HSCT necessary ?
EWOG-MDS 98 EFS in Advanced MDS (> 5% blasts) According to Therapy 1.0
.8 None or low-dose therapy, p=0.55, SE=0.08 N=58, 22 events
.6
P AML-like chemotherapy, p=0.49, SE=0.10 N=41, 18 events
.4
.2
0.0 0
Niemeyer C SĂŁo Paulo, 2003
Log Rank: p=n.s. 2
4
6
8
10
years
Survival in Advanced MDS without SCT or HSCT after > 6 Months of Intensive Therapy 1.0
.8
.6
P .4
p=0.31, SE=0.07 N=65, 35 events
.2
0.0
0
2
4
6
8
10
years12
EWOG-MDS unpublished
EWOG-MDS 98 Survival according to diagnosis 1.0
Prim. MDS, p=0.67, SE=0.07 N=173, 32 events
.8
.6
P .4
JMML, p=0.52, SE=0.08 N=85, 27 events
.2
Sec. MDS, p=0.33, SE=0.09 N=58, 24 events
Log Rank: p<0.01 1
Niemeyer C SĂŁo Paulo, 2003
2
3
Years from Diagnosis
4
5 01.04.03
New Pediatric Classifica&on Hasle H et.al., Leukemia 2002, 17: 277-282 •
•
•
2003
I. Mielodisplasia / Doença Mieloprolifera&va • Leucemia mielomonoci,ca Juvenil (LMMJ) • Leucemia mielomonoci,ca Crônica (LMMoC) • Leucemia mieloide crônica BCR-ABL nega,ve (LMC Ph-) II. Síndrome Down (SD) • Mielopoiése anormal transitória (TAM) • Leucemia Mielóide em SD III. Síndrome Mielodisplasica (SMD) • Citopenia refratária (CR) • (Sp blastos <2% e MO blastos <5%) • Anemia refratária com excesso de blastos (AREB) • (SP blastos 2-19% ou MO blastos 5-19%) • AREB em transformação (RAEB-t) • (SP ou MO blastos 20-29%)
Brazilian Cooperative Group on Pediatric Myelodysplastic Syndrome 4th Biennial Hannover Symposium on Childhood Leukemia May 3-5, 2004
Leuk Res 2007; 31:175
Results
nd – not determined
Genes
Frequency (n)
CALCA CDH1 GSTP1 MGMT RARβ CDKN2A HIC1 p14ARF p73 DAPK APC TIMP-3 CDH13 CDKN2B CDKN1A
85.7% 73.3% 72.7% 20% 14.3% 0% 0% 0% 0% 0% 0% 0% nd nd nd
Niemeyer- BLOOD, 19 MARCH 2009 VOLUME 113, NUMBER 12
To the editor: Intriguing response to azacitidine in a patient with juvenile myelomonocytic leukemia and monosomy 7
MDS vs JMML (308 patients) SMD (n=142)
LMMJ (n=166)
8,1
2,1
N (%)
N (%)
78(55)
115 (69)
• Normal
67(47)
108(65)
• -7
36(25)
40(24)
• 8+
9(6)
1(1)
• Other
13(9)
7(4)
Mean age (years)
Sex • male Cytogenetics
Hasle, Leukemia 2004;18: 2008-14
MDS vs JMML MDS (n=142)%
JMML (n=166)%
SMD Adults (n=759)%
IPSS Low
7
15
31
Int-1
47
48
39
Int-2
25
26
23
Alto
21
11
8
Treatment AML Protocol
49(36)
55(33)
Transplant
99(70)
100(60)
Obito without transplantation
13(9)
57(33)
308 patients Hasle ,Leukemia 2004;18: 2008-14
MDS vs JMML Annual incidence per million - children &ll 14 years1,8 SMD – 1,2 JMML – 0,9 LMA S. Down Media Age (years) - 6,8 MDS – 1.8 JMML Sex Distribu&on – equal MDS – > boys JMML
Acquired or Congenital Abnormalities Constitutional? Associated with MDS or LMMJ
Aggressive transformation of juvenile myelomonocytic leukemia associated with duplication of oncogenic KRAS due to acquired uniparental disomy. Kato M, Yasui N, Seki M, Kishimoto H, Sato-Otsubo A, Hasegawa D, Kiyokawa N, Hanada R, Ogawa S, Manabe A, Takita J, Koh K. J Pediatr. 2013 Jun;162(6):1285-8, 1288.e1. doi: 10.1016/j.jpeds.2013.01.003. Epub 2013 Feb 10.
Ligand-stimulated Ras activation, the Ras/MAPK pathway, and the gene mutations.
Loh L. Mignon and Mullighan G. Charles
Current diagnostic criteria for juvenile myelomonocytic leukemia
juvenile myelomonocytic leukemia
Alert
EBV Herrod HG et al., 1983 • • • • • •
21 months - male - lymphonodomegaly, hepatosplenomegaly. Hb 9.9 g/dl, platelet 90 x 10³/μL, WBC 61 x 10³/µL (24% PMNL, 16% monocytes) BM smears hypercellular M:E ra&o of 7: 1 normal karotype. Fetal hemoglobin was 3.2%, with 23% F cells LMMJ ? EBV
• • •
Studies
Recent acquired infec&on (↑VCA-IgG, an&body EA and absent EBNA an&bodies). Subsequently, an&bodies to EBNA + ↑VCA-IgG, EA - remained elevated for over 3 years. Persistent Epstein-Barr Virus Infec&on
Concomitant active viral infection and JMML • Kirby M et al., 1990: JMML differen&a&on from infan&le cytomegalovirus infec&on
• Toyoda H et al., 2004 – JMML with concomitant cytomegalovirus infec&on • Vallero S et al., 2009 - JMML and ac&ve Parvovirus B19 infec&on at diagnosis • Prabhu SB et al., 2010 - JMML Presen&ng With Coexistent Cytomegalovirus Infec&on
Silvia Luporini SJCampos 2011
The possibility that viruses contribute to MDS pathogenesis by stimulating pre-exiting malignant clones Van den Berg, H et al., 1999 - MDS (Refractory anemia) and HIV/AIDS Manabe A et al., 2004 - monoclonal integra&on of the EBV genome in LMMJ Kishore J, Mukhopadhyay C , 2004 - case of pure red cell aplasia in a 45-year- old female for last 7 years due to chronic persistent parvovirus B19 infec&on to myelodysplasia arer 4 years
Silvia Luporini SJCampos 2011
Cytomegalovirus infection mimicking juvenile myelomonocytic leukemia showing hypersensitivity to granulocyte-macrophage colony stimulating factor. Moritake H, Ikeda T, Manabe A, Kamimura S, Nunoi H. Pediatr Blood Cancer. 2009 Dec 15;53(7):1324-6. doi: 10.1002/pbc. 22253.
BARRETOS- Children´s Cancer Hospital NAP
Research Support
Contacts: lf.lopes@yahoo.com Glaucia.nap@hcbinfantil.com.br Phone:17-33215400
CPOM
Molecular Oncology Research Center
2013
CHILDRE’S HOSPITAL Ø Clinic Ø BMT
Brazil
São Paulo
Childrenâ&#x20AC;&#x2122;s Cancer Hospital Barretos
RECEPTION INFORMATION
MAIN RECEPTION
CAFETERIA
GARDEN
OUTPATIENT PLAYROOM
GAMES ROOM
FAMILY SPACE
EMERGENCY CENTER
CENTER OUTPATIENT CHEMOTHERAPY
WARD
PLAYROOM WARD
PALLIATIVE CARE UNIT
INTENSIVE CARE UNIT
Morfologia Citometria de Fluxo
Epidemiologia
Anita Frisanco Oliveira- Barretos
Luiz Fernando Lopes- Barretos
Eduardo Caetano- Barretos
Glaucia Regina C. Murra- Barretos Beatriz Pereira Martins- Barretos
2016
Elizabeth Xisto Souto-H.Brigadeiro- SP Irene Lorand-Metze- UNICAMP Lígia Niéro-Melo- UNESP Maria Claudia Zerbini-USP- SP
Terapêutica
Nydia Bacal- H.A.Einstein- SP
Mieloproliferativas
Rafael Dezen Gaiolla-UNESP
Maria Lucia de Martino Lee- UNIFESP
Adriana Seber-H.S.Camilo-SP Neysimelia Villela- Barretos Roseane Gouveia-H.S.Camilo- SP
Falencias Medulares Celia Martins Campanaro –F.M.Jundiaí
Genética
Marlene Garanito –USP- SP Silvia Luporini-Sta Casa- SP
Genética Molecular
Citogenética
Genética clínica
Daniel O.Vidal- Barretos
Elvira D.R. P. Velloso-USP- SP
Henrique Galvão- Barretos
Maria de Lourdes Chauffaille-
Simone Jacovaci Colleta-
UNIFESP
Barretos
Serviços de Referencia Benigna – Belo Horizonte
NAP-Barretos
Isis Magalhaes- Brasília
Diego Alves- Barretos
Viviany Viana - Fortaleza
Gabriela Bernal Salvador
2016- 6 commi:ees -28 members Coordinator – Dr Luiz Fernando Lopes
Anita Frisanco Morphology
Glaucia Murra Nurse Coordinator MDS
Henrique GalvĂŁo Oncogene&cs
Neysimelia Villela BMT
Aline Tansini Flow cytometry
Eduardo Caetano Phatology
Daniel Vidal Molecular Biology
Simone Jacovaci Colleta Cytogene&cs
# centers
total
2000
21
114
64
2002
41
176
96
2004
55
233
120
2016
149
572
227
(September)
MDS
Total of cases registred / period 250
213- 37,2 200
139 - 24,3%
150
99- 17,3%
95 - 16,6%
100
50
26 - 4,5%
0
1985-1996
1997-2001
2002-2006
2007-2011
2012-2016
Total = 572
Case Distribution MDS x Non MDS GCB-SMD-PED Case Distrinu&on MDS x Non MDS GCB-SMD-PED 22 - 3,7% 58 - 10,1% 265 - 46,3%
Not MDS MDS
227 - 39,7% On Going Inconclusive
Total = 572
Conclusive Diagnosis (1985-2016 -September)
600
492
500
400 MDS Not 300
265 227
200
150
132 96
100
0
26 19 7 1985-1996
49 47 1997-2001
66 66 2002-2006
88 57
86 64
31 2007-2011
2012-2016 (September)
MDS Total
Pediatric Classification ClassiďŹ ca&on HASLE 2002 98 - 43,2% 100 90 80 70 60 50 40
48- 21,1% 31 - 15,4%
30
18 - 7,9%
14 - 6,2%
20
14- 6,2%
10 0 RC
RAEB
RAEB-t
JMML
MDS / AML
Not appropriate
Total= 227
50
RC
45
44
40
RAEB/RAEB-t JMML
35
Others
30 25
25
20
21 20
15 10 5
14
14 7
6
11
9
6
9
9
6
5
2
0 1997-2001 (N= 47)
2002-2006 (N= 66)
2007-2011 (N= 31)
2012-2016 (N= 64)
1997-2001 %
2002-2006 %
2007-2011 %
2012-2016 %
RC
14,8
9,0
19,3
21,8
RAEB/ RAEB-t
53,1
66,6
45,1
32,8
JMML
12,7
16,6
29,0
31,25
Others (Cons&tu&onal/
19,1
7,5
6,4
14,0
2nd MDS)
Non MDS cases § AML – 52 § Hypo – 36 Ø Ø Ø Ø Ø Ø Ø Ø Ø Ø Ø Ø Ø
Agranulocitose Amegacariocitose Congênita Anemia Carencial Anemia Diseritropoé,ca/ Congênita Anemia Megaloblás,ca Anemia Sideroblás,ca Anemia Hemolí,ca Hemopa,a Primária Hipoplasia de Mo Mielofibrose Leucopenia/ Neutropenia Idiopá,ca Trombocitemia Púrpura Trombocitopênica Idiopá,ca (PTI)
§ BM reac&on – 36
§ Hereditary – 18
Ø Ø Ø Ø Ø Ø Ø Ø
Fanconi Síndrome Wisko_ Aldrich Síndrome Pearson Doença de Gaucher Blackfan Diamond Neutropenia Familial Talassemia Síndrome Kostmann
§ Aplas&c anemia – 20 § ALL – 09 § Hyper – 11
§ Infec&on – 7 Ø Ø Ø Ø Ø Ø
Leishmania Pavovirus Vírus EB Hepa,te HIV Toxocariase
§
CML– 5
§
Others – 71
The only current curative therapy for MDS and JMML is allogeneic hematopoietic stem cell transplantation (HSCT).
Locatelli et al., Blood 2005
100 pa,ents
Strahm et al., Leukemia 2011
97 pa,ents
Use of hypomethylating agents Hypomethylating agents have been successfully used in adults with MDS. Field et al., BMT 2010
Hypermethylation occurs in children as well as in adults with MDS. Vidal et al., Leuk Res 2007 Furlan et al., Blood 2009
There are few reports about the use of azacitidine for children with JMML and MDS. Furlan et al., Blood 2009 Cseh et al., Blood 2015 Cseh et al., Bri,sh Journal of Haematology 2016
Brazilian Pediatric Myelodysplastic Syndrome Study Group: Off-label use of Azacitidine for children with advanced MDS (RAEB/ RAEB-t) and JMML:
- Pre transplant for children with no related match donor, while waiting the search for an unrelated match donor. - As salvage treatment for patients who relapse after transplantation, usually as a bridge to a second transplant. - Post-transplant (prophylactic) trying to reduce the relapse rate.
JMML
•
5 (33,5%) presented PTPN11 missense mutations
•
3 (20%) in KRAS
•
2 (13,5%) in NRAS
•
2 (13,5%) in NF1
•
1 (6,5%) in CBL
•
1 (6,5%) in PTPN11 and NRAS
•
1 (6,5%) no mutations
JMML
JMML-PTPN11
JMML-PTPN11
JMML-NRAS
Conclusions
•
Frequency of gene mutations is similar to literature;
•
PTPN11 is associated with adverse prognostic factors;
•
PTPN11 seems to have a persistent clinical/molecular disease;
Challenges: itinerant courses
BrasĂlia November 2002
Challenges: itinerant courses
Manaus â&#x20AC;&#x201C; June 2008
Challenges: itinerant courses
Salvador â&#x20AC;&#x201C; October 2014
MDS- Barretos Morphology Meetings April – November 2015 • 4 invited hematologists • Morphologists – GCB-SMD-PED:
• Barretos team:
Ø Maria Lucia Lee
Ø Aline Tansini - flow cytometry;
Ø Claudia Zerbini
Ø Daniel Vidal - Molec Biol; Ø Simone Jacovaci Colleta – Cytogenetics;
Ø Ligia Niero Ø Rafael Gaiolla
Ø Eduardo Caetano – Phatology; Ø Henrique Galvão – Genetic;
Ø Elizabeth Xisto
Ø Anita Frisanco - Morphology;
Ø Irene Lorand-Metze
Ø Neisymelia Vilella- BMT
www.cure4kids.org Last Friday of the month – 13:00 (&me Memphis) Room Brazil
MDS - Barretos Morphology Meetings Belo Horizonte - MG • Mi&ko Murao • Frederico de Melo Fortaleza - CE • Viviany Viana • Carlos Gustavo Hirth Porto Alegre - RS • Elissandra Machado • Adriana San&ni Rio de Janeiro - RJ • Anna Beatriz Willeme • Ana Paula Bueno São Paulo - SP • Claudia Oliveira • Rafael Baceiro • Lilian Cristofani • José Eduardo Bernardes Salvador - BA • Isa Lyra • Marcia Lima
Muchas Gracias!!!