Conf DR Antillón

Biología Molecular en la Leucemia
Linfoblástica Aguda pediátrica.
Dr. Federico Antillón K.

7 de Julio, 2006
Cáncer Pediátrico en el mundo
• Incidencia 11/100,000 niños y

adolescentes < 20 años
• 260,000 caso cáncer pediátrico/año
• ~700 incidencia esperada en
Guatemala 2006
• > 70% de curación en países con
recursos
N = 13,298 Children
New Cases per Year per 100,000

Diagnosed with Cancer 25
U.S. SEER, 1973-1992
20
140 15
No. Patients Diagnosed with Cancer
10
120
5
Gurney JG, et al. Cancer 75:2186,1995
0
100 0 5 10 15
80
60
40
20 Data kindly provided by Benjamin F. Hankey, Sc.D.,

courtesy of the Surveillance Program, DCPC, NCI
0 2 4 6 8 10 12 14
Age (Years)
All Cancers
Neuroblastoma
Wilms’ Tumor ALL Sarcomas
Retinoblastoma NHL Osteosarcoma
PNET Glioma Ewing’s Sa
Soft-Tissue Sa
Hodgkin’s disease
Testicular Ca
Ovarian Ca
Melanoma
Birth 5 10 18
Age (Years)
Cáncer Pediátrico en Guatemala el pasado
(Antes de AYUVI y UNOP)
• 1990-95 datos históricos
42% abandono
28% supervivencia a 2 años del diagnóstico
100 casos/año
Luna S, Slowing K, Valverde P, Antillon F, et al. Pediatric Cancer in Guatemala. A

retrospective study. [abstract] Med Pediatr Oncol 1997;229:353.
Pacientes Cáncer en UNOP
Año Total #/mes Sin Total
cáncer Cáncer
2003 231 19.3 69 300
2004 305 25.4 109 414
2005 315 26 107 422
2006 153 25.5 23 167

Junio
Pacientes con Cáncer en UNOP
Abril 2000/ Junio 2006 (NO.= 1745)
CONSOLIDADO DE CASOS CON CANCER (NUEVOS+REFERIDOS)

LEUCEMIAS
ABRIL 2000/JUNIO 2006
No. = (1745) LINFOMAS
RETINOBLASTOMA
2%
SISTEMA NERVIOSO CENTRAL
4%
TUMORES DE HUESO
4%
4% SARCOMAS
43% RIÑON
6%
TUMORES GERMINALES
6% HIGADO
NEUROBLASTOMAS
11% OTROS NEOPLASMAS MALIGNOS NO

ESP.
CARCINOMAS Y OTROS
16%
NEOPLASMAS EPITELIALES
EN ESTUDIO
UNIDAD NACIONAL DE ONCOLOGIA PEDIATRICA
OTROS NEOPLASMAS ESPECIFICOS
GUATEMALA, CENTROAMERICA
Incidencia de Leucemia aguda
• 32 casos por 1,000,000

población <15 años
• Pico incidencia 2-5 años
• ~30% del cáncer pediátrico
• 80% linfoides, 20% mieloides
Presentación Clínica
Contaje Globulos Blancos
< 10.000 53%
10,000-49,000 30%
> 50,000 17%
Clasificación Morfológica,
Citoquímica e Inmunológica
Li nf oide CD3, CD7, CD 10, CD 19, CD 79
Mi eloi de M6/ M7 CD 41a, CD 61, y CD42b
Li nf oi de Vs. M0- M7
2 3 o Inmunofenotipo
4
4
10
10
Leucemias linfoides
3
3
Leucemias mieloides
10
10
CD22 -->
CD45 -->
R1
2
R2
10
10
o Indice DNA
1
1
10
10
10 1 10 2 10 3 10 4
4
10 1 10 2 10 3
5
10 4
Pronóstico LLA y neuroblastoma
RALS --> CD7-->
7 8 12 13
4
4
10
10
o Biología Molecular
3
3
10
10
Tranlocaciones establecidas
CD56 -->
CD33 -->
R7 R12
2
2
10
10
o Citogenética
1
1
10
10
9
10 1 10
CD7-->
2 10 3
10
10 4
14
10 1 10
CD34-->
2 10 3
15
10 4 Cromosomas
Leucemia Aguda Linfoblástica
Inmunofenotipo
pre-B-temprana:
(CD22, CD19) 57%
Pre-B: (cIgm) 25%
B: (sIg) 2%
T: (CD3, CD7) 15%
51-65 46
Whitehead, St.Jude Blood 80:1316:1992

Clasificación de LLA
B-lineage
Hyperdiploidy
>50 chromosomes
Hypodiploidy
25% TEL-AML1
<45 chromosomes
1% t(12;21)
22%
Others
22%
BCR-ABL
t(9;22)
3% E2A-PBX1
t(1;19)
5%
TAL1
MLL rearrangements Ip32
e.g. t(4;11),t(11;19), HOX11L2 HOX11 MLL-ENL
5q35 7%
t(9;11) 10q24 0.3%
2.5% LYL1
8% 0.7%
19p13
1.5%
T-lineage
Pui CH et al, NEJM, 2004
Factores Pronósticos LLA
• Contaje globular al diagnóstico
• Edad al diagnóstico
• Inmunofenotipo
• Características Genéticas
• Compromiso extramedular
Respuesta a la terapia
Quimioterapia en LLA
Drogas Año aprobado en USA
Mercaptopurina 1953
Methotrexate 1953
Prednisona 1955
Dexametasona 1958
Ciclofosfamida 1959
Vincristina 1964
Citarabina 1969
Asparaginasa 1978
Daunorubicina 1979
Etoposido 1983
Teniposido 1990
Resultados de protocolos contemporáneos
Estudio No. Pacientes %5-yr EFS (±SE)

BFM 90 (1990-95) 2178 78±0.9
CCG-1800 (1989-95) 5121 75±1
COALL-92 (1992-97) 538 76.9±1.9
DFCI-91-01 (1991-95) 377 83±2
NOPHO III (1992-98) 1143 77.6±1.4
SJCRH XIIIB (1994-98) 247 81.6±6.3
Supervivencia libre de evento en el BR
Guatemala
U133 A. Perfil de expresión genes en LLA
Genes for class distinction (n=588)
0
10
0
10
20
30
40
60
70
10
0
9
-
20 2391_ at "gb :NM _006 317. 1 /DEF=Ho m .

20 2478_ at "gb :NM _021 643. 1 /DEF=Ho m .
20 2479_ s_at "gb :BC0026 37. 1 / DE F=Hom o .
21 3502_ x_at Conse nsus i ncl ude s g b:A A3.
21 0786_ s_at "gb :M 9 3255 .1 / DEF= Hum an .
21 5117_ at Conse nsus i ncl ude s g b:A W.

47 069_a t Clu ste r In cl . AA53 3284 :nj 66 .
21 3773_ x_at Conse nsus i ncl ude s g b:A W.
20 2421_ at "Co nsens us in clu des gb: AB.
22 6590_ at Conse nsus i ncl ude s g b:A A9.
21 8683_ at "gb :NM _021 190. 1 /DEF=Ho m .
20 1825_ s_at Conse nsus i ncl ude s g b:A L5.
22 9770_ at Conse nsus i ncl ude s g b:A I0 .

20 5173_ x_at "gb :NM _001 779. 1 /DEF=Ho m .
21 1744_ s_at "gb :BC0059 30. 1 / DE F=Hom o .

20 3999_ at Conse nsus i ncl ude s g b:A V7.
21 2827_ at Conse nsus i ncl ude s g b:X 17.
40 148_a t "Cl ust er I nc l. U6232 5:Hum an .
21 2985_ at Conse nsus i ncl ude s g b:B F1.

22 1669_ s_at "gb :BC0019 64. 1 / DE F=Hom o .
22 6233_ at "Co nsens us in clu des gb: BG.
21 8087_ s_at "gb :NM _015 385. 1 /DEF=Ho m .
23 3273_ at "Co nsens us in clu des gb: AU.
20 2181_ at "gb :NM _014 734. 1 /DEF=Ho m .

20 1579_ at "gb :NM _005 245. 1 /DEF=Ho m .
21 8283_ at "gb :NM _016 305. 1 /DEF=Ho m .

20 5769_ at "gb :NM _003 645. 1 /DEF=Ho m .
20 9760_ at gb: AL136 932. 1 /DEF=Hom o .

20 6181_ at "gb :NM _003 037. 1 /DEF=Ho m .
24 3533_ x_at Conse nsus i ncl ude s g b:H09.

21 3005_ s_at "Co nsens us in clu des gb: D7 .
22 1113_ s_at "gb :NM _016 087. 1 /DEF=Ho m .
22 4022_ x_at "gb :AF1699 63. 1 / DE F=Hom o .

21 8640_ s_at "gb :NM _024 613. 1 /DEF=Ho m .
22 2699_ s_at Conse nsus i ncl ude s g b:B F4.
38 340_a t "Cl ust er I nc l. AB014 555: Hom .

20 9558_ s_at "gb :AB0133 84. 1 / DE F=Hom o .
20 6028_ s_at "gb :NM _006 343. 1 /DEF=Ho m .
21 1913_ s_at "gb :L0 8961 .1 / DEF= Hom o sa .

23 4261_ at Conse nsus i ncl ude s g b:A L1.

22 7441_ s_at Conse nsus i ncl ude s g b:A W.
23 1095_ at "Co nsens us in clu des gb: AW .

20 8644_ at "gb :M 3 2721 .1 / DEF= Hum an .
35 974_a t "Cl ust er I nc l. U1048 5:Hum an .
20 4674_ at "gb :NM _006 152. 1 /DEF=Ho m .

20 1695_ s_at "gb :NM _000 270. 1 /DEF=Ho m .
20 2796_ at "gb :NM _007 286. 1 /DEF=Ho m .
20 5253_ at "gb :NM _002 585. 1 /DEF=Ho m .
23 2289_ at "Co nsens us in clu des gb: BF .

22 5483_ at "Co nsens us in clu des gb: AI9.
23 0306_ at "Co nsens us in clu des gb: AA.
22 7949_ at "Co nsens us in clu des gb: AL .


20 2106_ at "gb :NM _005 895. 1 /DEF=Ho m .
22 3693_ s_at gb: AL136 731. 1 /DEF=Hom o .
21 9551_ at "gb :NM _018 456. 1 /DEF=Ho m .

21 9155_ at "gb :NM _012 417. 1 /DEF=Ho m .
20 1889_ at "gb :NM _014 888. 1 /DEF=Ho m .

20 4114_ at "gb :NM _007 361. 1 /DEF=Ho m .
20 4613_ at "gb :NM _002 661. 1 /DEF=Ho m .

20 5504_ at "gb :NM _000 061. 1 /DEF=Ho m .
21 9563_ at "gb :NM _024 633. 1 /DEF=Ho m .

39 318_a t "Cl ust er I nc l. X8224 0:H.sa pi .
20 9995_ s_at "gb :BC0035 74. 1 / DE F=Hom o .
20 3753_ at "gb :NM _003 199. 1 /DEF=Ho m .

21 3891_ s_at "Co nsens us in clu des gb: AI9.

20 8650_ s_at Conse nsus i ncl ude s g b:B G3.

20 9771_ x_at Conse nsus i ncl ude s g b:A A7.
21 6379_ x_at "Co nsens us in clu des gb: AK.
26 6_s_a t "L3 3930 / FEATURE= /DEFINI T.
20 8651_ x_at "gb :M 5 8664 .1 / DEF= Hom o s.
20 5267_ at "gb :NM _006 235. 1 /DEF=Ho m .
22 0068_ at "gb :NM _013 378. 1 /DEF=Ho m .

20 3556_ at "gb :NM _014 943. 1 /DEF=Ho m .
22 3553_ s_at "gb :BC0045 64. 1 / DE F=Hom o .
20 6398_ s_at "gb :NM _001 770. 1 /DEF=Ho m .

22 9487_ at Conse nsus i ncl ude s g b:W 7.
22 7646_ at Conse nsus i ncl ude s g b:B G4.

23 2204_ at "Co nsens us in clu des gb: AF .
20 3143_ s_at Conse nsus i ncl ude s g b:T 79.

21 4924_ s_at "Co nsens us in clu des gb: AK.
20 4774_ at "gb :NM _014 210. 1 /DEF=Ho m .
21 2873_ at Conse nsus i ncl ude s g b:B E3.
20 0811_ at "gb :NM _001 280. 1 /DEF=Ho m .

20 9130_ at "gb :BC0036 86. 1 / DE F=Hom o .
21 1126_ s_at "gb :U4 6006 .1 / DEF= Hom o sa .
22 7432_ s_at Conse nsus i ncl ude s g b:A I2 .
20 3332_ s_at "gb :NM _005 541. 1 /DEF=Ho m .

21 8346_ s_at "gb :NM _014 454. 1 /DEF=Ho m .
21 8348_ s_at "gb :NM _014 153. 1 /DEF=Ho m .
20 2603_ at Conse nsus i ncl ude s g b:N51.

20 2604_ x_at "gb :NM _001 110. 1 /DEF=Ho m .
21 4895_ s_at Conse nsus i ncl ude s g b:A U1.

20 5055_ at "gb :NM _002 208. 3 /DEF=Ho m .
21 2588_ at "Co nsens us in clu des gb: Y0 .
21 1733_ x_at "gb :BC0059 11. 1 / DE F=Hom o .
21 3513_ x_at Conse nsus i ncl ude s g b:B G0.
21 8140_ x_at "gb :NM _021 203. 1 /DEF=Ho m .
20 1563_ at "gb :L2 9008 .1 / DEF= Hum an L -.

21 4214_ s_at "Co nsens us in clu des gb: AU.
22 4516_ s_at "gb :BC0064 28. 1 / DE F=Hom o .
20 3474_ at "gb :NM _006 633. 1 /DEF=Ho m .
22 5841_ at "Co nsens us in clu des gb: BE.
22 0643_ s_at "gb :NM _018 147. 1 /DEF=Ho m .
22 4150_ s_at "gb :AF2894 95. 1 / DE F=Hom o .

21 5925_ s_at Conse nsus i ncl ude s g b:A F2.

52 164_a t "Cl ust er I nc l. AA065 185: zm 5 .
20 1162_ at "gb :NM _001 553. 1 /DEF=Ho m .
20 1163_ s_at "gb :NM _001 553. 1 /DEF=Ho m .
20 5550_ s_at "gb :NM _004 899. 1 /DEF=Ho m .

21 9218_ at "gb :NM _024 696. 1 /DEF=Ho m .
20 1875_ s_at "gb :NM _024 569. 1 /DEF=Ho m .
20 3375_ s_at "gb :NM _003 291. 1 /DEF=Ho m .
21 9988_ s_at "gb :NM _018 150. 1 /DEF=Ho m .
20 6471_ s_at "gb :NM _005 761. 1 /DEF=Ho m .

21 3241_ at Conse nsus i ncl ude s g b:A F0.
20 1078_ at "gb :NM _004 800. 1 /DEF=Ho m .

20 5668_ at "gb :NM _002 349. 1 /DEF=Ho m .
20 2975_ s_at Conse nsus i ncl ude s g b:N21.
22 1676_ s_at "gb :BC0023 42. 1 / DE F=Hom o .

20 1152_ s_at Conse nsus i ncl ude s g b:N31.
20 1153_ s_at "gb :NM _021 038. 1 /DEF=Ho m .
21 4651_ s_at "Co nsens us in clu des gb: U4 .

20 4069_ at "gb :NM _002 398. 1 /DEF=Ho m .

21 9463_ at "gb :NM _012 261. 1 /DEF=Ho m .

21 8217_ at "gb :NM _021 626. 1 /DEF=Ho m .
20 9191_ at "gb :BC0026 54. 1 / DE F=Hom o .

22 6668_ at "Co nsens us in clu des gb: W8 .
20 3836_ s_at "gb :D8 4476 .1 / DEF= Hom o sa .
20 3837_ at "gb :NM _005 923. 2 /DEF=Ho m .
20 1105_ at "gb :NM _002 305. 2 /DEF=Ho m .
21 8847_ at "gb :NM _006 548. 1 /DEF=Ho m .

20 2593_ s_at "gb :NM _016 641. 1 /DEF=Ho m .

20 8071_ s_at "gb :NM _021 708. 1 /DEF=Ho m .

21 8402_ s_at "gb :NM _022 081. 1 /DEF=Ho m .
21 2071_ s_at "Co nsens us in clu des gb: BE.
20 1656_ at "gb :NM _000 210. 1 /DEF=Ho m .

21 9821_ s_at "gb :NM _018 988. 1 /DEF=Ho m .
23 0179_ at "Co nsens us in clu des gb: N5 .
21 6026_ s_at "Co nsens us in clu des gb: AL .
20 5049_ s_at "gb :NM _001 783. 1 /DEF=Ho m .

20 5297_ s_at "gb :NM _000 626. 1 /DEF=Ho m .
20 3932_ at "gb :NM _002 118. 1 /DEF=Ho m .
20 1137_ s_at "gb :NM _002 121. 1 /DEF=Ho m .
20 9619_ at "gb :K0 1144 .1 / DEF= Hum an .
20 8306_ x_at "gb :NM _021 983. 2 /DEF=Ho m .

21 7478_ s_at "Co nsens us in clu des gb: X7 .
20 4670_ x_at "gb :NM _002 125. 1 /DEF=Ho m .
20 9312_ x_at "gb :U6 5585 .1 / DEF= Hom o sa .
21 5193_ x_at "Co nsens us in clu des gb: AJ .

20 8894_ at "gb :M 6 0334 .1 / DEF= Hum an .
21 0982_ s_at "gb :M 6 0333 .1 / DEF= Hum an .
21 1990_ at "Co nsens us in clu des gb: M 2 .
21 1991_ s_at "Co nsens us in clu des gb: M 2 .
20 4446_ s_at "gb :NM _000 698. 1 /DEF=Ho m .
21 4366_ s_at Conse nsus i ncl ude s g b:A A9.

22 1002_ s_at "gb :NM _030 927. 1 /DEF=Ho m .
21 9686_ at "gb :NM _018 401. 1 /DEF=Ho m .

20 0742_ s_at "Co nsens us in clu des gb: BG.
20 8872_ s_at "Co nsens us in clu des gb: AA.
20 2113_ s_at "gb :AF0434 53. 1 / DE F=Hom o .

20 2114_ at "gb :NM _003 100. 1 /DEF=Ho m .
20 7571_ x_at "gb :NM _004 848. 1 /DEF=Ho m .
21 0785_ s_at "gb :AB0354 82. 1 / DE F=Hom o .

20 3372_ s_at "gb :AB0049 03. 1 / DE F=Hom o .
20 3373_ at "gb :NM _003 877. 1 /DEF=Ho m .

21 7983_ s_at "gb :NM _003 730. 2 /DEF=Ho m .
21 9256_ s_at "gb :NM _018 986. 1 /DEF=Ho m .

21 1302_ s_at "gb :L2 0966 .1 / DEF= Hum an p .
20 0989_ at "gb :NM _001 530. 1 /DEF=Ho m .

20 7655_ s_at "gb :NM _013 314. 1 /DEF=Ho m .
21 0487_ at "gb :M 1 1722 .1 / DEF= Hum an t.

20 0953_ s_at "gb :NM _001 759. 1 /DEF=Ho m .
20 4030_ s_at "gb :NM _014 575. 1 /DEF=Ho m .
21 9243_ at "gb :NM _018 326. 1 /DEF=Ho m .

20 6150_ at "gb :NM _001 242. 1 /DEF=Ho m .
22 3449_ at "gb :AF2254 25. 1 / DE F=Hom o .
22 5660_ at "Co nsens us in clu des gb: W9 .

21 8988_ at "gb :NM _018 656. 1 /DEF=Ho m .

20 3435_ s_at "gb :NM _007 287. 1 /DEF=Ho m .

20 6492_ at "gb :NM _002 012. 1 /DEF=Ho m .
21 8966_ at "gb :NM _018 728. 1 /DEF=Ho m .
21 7967_ s_at "gb :AF2883 91. 1 / DE F=Hom o .
22 0024_ s_at "gb :NM _020 956. 1 /DEF=Ho m .

21 6033_ s_at "Co nsens us in clu des gb: S7 .
20 3217_ s_at "gb :NM _003 896. 1 /DEF=Ho m .

20 3508_ at "gb :NM _001 066. 1 /DEF=Ho m .
21 2203_ x_at Conse nsus i ncl ude s g b:B F3.

20 9193_ at "gb :M 2 4779 .1 / DEF= Hom o s.

20 2602_ s_at "gb :NM _014 500. 1 /DEF=Ho m .
20 3744_ at "gb :NM _005 342. 1 /DEF=Ho m .
20 4404_ at "gb :NM _001 046. 1 /DEF=Ho m .
21 0058_ at "gb :BC0004 33. 1 / DE F=Hom o .

20 0709_ at "gb :NM _000 801. 1 /DEF=Ho m .
21 0186_ s_at "gb :BC0051 47. 1 / DE F=Hom o .
21 8152_ at "gb :NM _018 200. 1 /DEF=Ho m .
22 5913_ at "Co nsens us in clu des gb: AK.


20 1334_ s_at "Co nsens us in clu des gb: AB.
22 3468_ s_at gb: AL136 826. 1 /DEF=Hom o .
20 4297_ at "gb :NM _002 647. 1 /DEF=Ho m .

20 3370_ s_at "gb :NM _005 451. 2 /DEF=Ho m .
21 1891_ s_at "gb :AB0421 99. 1 / DE F=Hom o .
21 0650_ s_at "gb :BC0013 04. 1 / DE F=Hom o .

20 9685_ s_at "gb :M 1 3975 .1 / DEF= Hom o s.
20 9735_ at "gb :AF0989 51. 2 / DE F=Hom o .

21 8625_ at "gb :NM _016 588. 1 /DEF=Ho m .
20 5259_ at "gb :NM _000 901. 1 /DEF=Ho m .
20 3611_ at "gb :NM _005 652. 1 /DEF=Ho m .

20 9035_ at "gb :M 6 9148 .1 / DEF= Hum an .
21 8813_ s_at "gb :NM _020 145. 1 /DEF=Ho m .
20 9963_ s_at "gb :M 3 4986 .1 / DEF= Hum an e .
37 986_a t "Cl ust er I nc l. M 6045 9:Hum an .
20 9962_ at "gb :M 3 4986 .1 / DEF= Hum an e .
21 8627_ at "gb :NM _018 370. 1 /DEF=Ho m .

20 2838_ at "gb :NM _000 147. 1 /DEF=Ho m .

20 4615_ x_at "gb :NM _004 508. 1 /DEF=Ho m .
20 8881_ x_at "gb :BC0052 47. 1 / DE F=Hom o .
20 8056_ s_at "gb :NM _005 187. 2 /DEF=Ho m .
23 2227_ at "Co nsens us in clu des gb: AV.

20 6591_ at "gb :NM _000 448. 1 /DEF=Ho m .
20 3038_ at "gb :NM _002 844. 1 /DEF=Ho m .
21 8804_ at "gb :NM _018 043. 1 /DEF=Ho m .

20 3464_ s_at "gb :NM _014 964. 1 /DEF=Ho m .

22 6817_ at Conse nsus i ncl ude s g b:A U1.
20 6033_ s_at "gb :NM _001 941. 2 /DEF=Ho m .
20 4849_ at "gb :NM _006 602. 1 /DEF=Ho m .

20 5794_ s_at "gb :NM _002 515. 1 /DEF=Ho m .



22 0451_ s_at "gb :NM _022 161. 1 /DEF=Ho m .
21 9866_ at "gb :NM _016 929. 1 /DEF=Ho m .
20 5109_ s_at "gb :NM _015 320. 1 /DEF=Ho m .

20 6231_ at "gb :NM _002 248. 2 /DEF=Ho m .
21 1222_ s_at "gb :AF0407 23. 1 / DE F=Hom o .
20 3910_ at "gb :NM _004 815. 1 /DEF=Ho m .
20 3184_ at "gb :NM _001 999. 2 /DEF=Ho m .
20 1266_ at "gb :NM _003 330. 1 /DEF=Ho m .

21 2399_ s_at "Co nsens us in clu des gb: D5 .

21 3301_ x_at Conse nsus i ncl ude s g b:A L5.
24 2881_ x_at Conse nsus i ncl ude s g b:B G2.

20 2382_ s_at "gb :NM _005 471. 1 /DEF=Ho m .
21 5149_ at Conse nsus i ncl ude s g b:A F0.
20 9228_ x_at "gb :U4 2349 .1 / DEF= Hum an N.

21 3423_ x_at Conse nsus i ncl ude s g b:A I8 .
20 0783_ s_at "gb :NM _005 563. 2 /DEF=Ho m .

21 1795_ s_at "gb :AF1980 52. 1 / DE F=Hom o .
20 2794_ at "gb :NM _002 194. 2 /DEF=Ho m .

20 1689_ s_at Conse nsus i ncl ude s g b:B E9.
20 9321_ s_at "gb :AF0338 61. 1 / DE F=Hom o .
20 9229_ s_at "gb :BC0027 99. 1 / DE F=Hom o .
20 3005_ at "gb :NM _002 342. 1 /DEF=Ho m .

20 7196_ s_at "gb :NM _006 058. 1 /DEF=Ho m .
21 8084_ x_at "gb :NM _014 164. 2 /DEF=Ho m .

20 3198_ at "gb :NM _001 261. 1 /DEF=Ho m .
20 2123_ s_at "gb :NM _005 157. 2 /DEF=Ho m .
21 6985_ s_at "Co nsens us in clu des gb: AJ .

20 1445_ at "gb :NM _001 839. 1 /DEF=Ho m .
48 106_a t "Cl ust er I nc l. H1424 1:y m 63e .

20 0864_ s_at "gb :NM _004 663. 1 /DEF=Ho m .
21 9871_ at "gb :NM _024 614. 1 /DEF=Ho m .

64 064_a t "Cl ust er I nc l. AI43 5089 :th95 .
22 9367_ s_at "Co nsens us in clu des gb: AW .
20 5376_ at "gb :NM _003 866. 1 /DEF=Ho m .
21 8013_ x_at "gb :NM _016 221. 1 /DEF=Ho m .



21 4255_ at "Co nsens us in clu des gb: N3 .

20 0665_ s_at "gb :NM _003 118. 1 /DEF=Ho m .
22 3075_ s_at gb: AL136 566. 1 /DEF=Hom o .

20 2369_ s_at "gb :NM _012 288. 1 /DEF=Ho m .
21 9938_ s_at "gb :NM _024 430. 1 /DEF=Ho m .

20 1876_ at "gb :NM _000 305. 1 /DEF=Ho m .

21 0830_ s_at "gb :AF0016 02. 1 / DE F=Hom o .
22 0684_ at "gb :NM _013 351. 1 /DEF=Ho m .
22 2762_ x_at Conse nsus i ncl ude s g b:A U1.

20 9365_ s_at "gb :U6 5932 .1 / DEF= Hum an e .
20 4429_ s_at "Co nsens us in clu des gb: BE.

20 4430_ s_at "gb :NM _003 039. 1 /DEF=Ho m .

20 2947_ s_at "gb :NM _002 101. 2 /DEF=Ho m .
20 1906_ s_at "gb :NM _005 808. 1 /DEF=Ho m .
21 9315_ s_at "gb :NM _024 600. 1 /DEF=Ho m .

20 3694_ s_at "gb :NM _003 587. 2 /DEF=Ho m .
20 5191_ at "gb :NM _006 915. 1 /DEF=Ho m .
20 0799_ at "gb :NM _005 345. 3 /DEF=Ho m .
20 4194_ at "gb :NM _001 186. 1 /DEF=Ho m .
20 6846_ s_at "gb :NM _006 044. 2 /DEF=Ho m .

21 3334_ x_at "Co nsens us in clu des gb: BE.
20 6874_ s_at "Co nsens us in clu des gb: AL .

46 323_a t "Cl ust er I nc l. AL120 741: DKF .
20 3680_ at "gb :NM _002 736. 1 /DEF=Ho m .
20 0655_ s_at "gb :NM _006 888. 1 /DEF=Ho m .
20 4835_ at "gb :NM _016 937. 1 /DEF=Ho m .
21 5773_ x_at Conse nsus i ncl ude s g b:A J2.

21 7954_ s_at "gb :NM _015 153. 1 /DEF=Ho m .
20 9440_ at "gb :BC0016 05. 1 / DE F=Hom o .
20 3102_ s_at "gb :NM _002 408. 2 /DEF=Ho m .
20 1894_ s_at "gb :NM _001 920. 1 /DEF=Ho m .

20 3041_ s_at "gb :J0 4183 .1 / DEF= Hom o sa .

20 8683_ at "gb :M 2 3254 .1 / DEF= Hum an .
20 2829_ s_at "gb :NM _005 638. 1 /DEF=Ho m .
20 3909_ at "gb :NM _006 359. 1 /DEF=Ho m .
20 1312_ s_at "gb :NM _003 022. 1 /DEF=Ho m .

21 1342_ x_at "gb :BC0043 54. 1 / DE F=Hom o .
21 6071_ x_at "Co nsens us in clu des gb: AF .


20 1136_ at "gb :NM _002 668. 1 /DEF=Ho m .
22 3082_ at "gb :AF2309 04. 1 / DE F=Hom o .
20 1100_ s_at "gb :NM _004 652. 2 /DEF=Ho m .
21 8386_ x_at "gb :NM _006 447. 1 /DEF=Ho m .

21 9038_ at "gb :NM _024 657. 1 /DEF=Ho m .
21 8573_ at "gb :NM _014 061. 1 /DEF=Ho m .
20 8073_ x_at "gb :NM _003 316. 1 /DEF=Ho m .
21 0645_ s_at "gb :D8 3077 .1 / DEF= Hom o sa .
21 8495_ at "gb :NM _004 182. 1 /DEF=Ho m .
20 1923_ at "gb :NM _006 406. 1 /DEF=Ho m .

20 4219_ s_at "gb :NM _002 802. 1 /DEF=Ho m .
21 8163_ at "gb :NM _014 060. 1 /DEF=Ho m .

20 0943_ at "gb :NM _004 965. 1 /DEF=Ho m .
20 0944_ s_at "gb :NM _004 965. 1 /DEF=Ho m .
20 1472_ at "gb :NM _003 372. 2 /DEF=Ho m .
20 0642_ at "gb :NM _000 454. 1 /DEF=Ho m .
20 2325_ s_at "gb :NM _001 685. 1 /DEF=Ho m .

20 9565_ at "gb :BC0008 32. 1 / DE F=Hom o .
20 2214_ s_at "gb :NM _003 588. 1 /DEF=Ho m .
21 8757_ s_at "gb :NM _023 010. 1 /DEF=Ho m .
20 1807_ at "gb :NM _004 896. 1 /DEF=Ho m .
21 8694_ at "gb :NM _016 608. 1 /DEF=Ho m .
21 7356_ s_at "Co nsens us in clu des gb: S8 .

20 0737_ at "gb :NM _000 291. 1 /DEF=Ho m .
20 0738_ s_at "gb :NM _000 291. 1 /DEF=Ho m .

20 0600_ at "gb :NM _002 444. 1 /DEF=Ho m .
20 1443_ s_at "gb :AF2489 66. 1 / DE F=Hom o .
20 5324_ s_at "gb :NM _012 280. 1 /DEF=Ho m .
20 8598_ s_at "gb :NM _005 703. 2 /DEF=Ho m .
20 0980_ s_at "gb :NM _000 284. 1 /DEF=Ho m .
20 1899_ s_at "gb :NM _003 336. 1 /DEF=Ho m .

20 1092_ at "gb :NM _002 893. 2 /DEF=Ho m .
20 8861_ s_at "gb :U7 2937 .2 / DEF= Hom o sa .
21 8499_ at "gb :NM _016 542. 1 /DEF=Ho m .
20 1132_ at "gb :NM _019 597. 1 /DEF=Ho m .
20 2371_ at "gb :NM _024 863. 1 /DEF=Ho m .

21 9485_ s_at "gb :NM _002 814. 1 /DEF=Ho m .
20 9056_ s_at "Co nsens us in clu des gb: NM .

20 1722_ s_at Conse nsus i ncl ude s g b:A V6.

20 3126_ at "gb :NM _014 214. 1 /DEF=Ho m .
20 2854_ at "gb :NM _000 194. 1 /DEF=Ho m .

20 2242_ at "gb :NM _004 615. 1 /DEF=Ho m .
20 6233_ at "gb :AF0971 59. 1 / DE F=Hom o .

20 3076_ s_at "gb :U6 5019 .1 / DEF= Hum an .
21 8764_ at "gb :NM _024 064. 1 /DEF=Ho m .
21 2135_ s_at "Co nsens us in clu des gb: AW .


20 2771_ at "gb :NM _014 745. 1 /DEF=Ho m .
20 3089_ s_at "gb :NM _013 247. 1 /DEF=Ho m .

20 5467_ at "gb :NM _001 230. 1 /DEF=Ho m .
20 1028_ s_at "gb :U8 2164 .1 / DEF= Hum an tr.
20 1029_ s_at "gb :NM _002 414. 1 /DEF=Ho m .

20 2717_ s_at "gb :NM _003 903. 1 /DEF=Ho m .
21 2458_ at "Co nsens us in clu des gb: H9 .

21 8491_ s_at "gb :NM _014 174. 1 /DEF=Ho m .
22 3711_ s_at "gb :AF1824 13. 1 / DE F=Hom o .
20 8788_ at gb: AL136 939. 1 /DEF=Hom o .

20 2208_ s_at "gb :BC0010 51. 1 / DE F=Hom o .
20 1310_ s_at "gb :NM _004 772. 1 /DEF=Ho m .

20 2540_ s_at "gb :NM _000 859. 1 /DEF=Ho m .
20 1384_ s_at "gb :NM _005 899. 1 /DEF=Ho m .
21 0116_ at "gb :AF0729 30. 1 / DE F=Hom o .
21 1210_ x_at "gb :AF1005 39. 1 / DE F=Hom o .

21 1211_ x_at "gb :AF1005 42. 1 / DE F=Hom o .
20 5674_ x_at "gb :NM _001 680. 2 /DEF=Ho m .
20 7434_ s_at "gb :NM _021 603. 1 /DEF=Ho m .
20 5518_ s_at "gb :NM _003 570. 1 /DEF=Ho m .

21 1075_ s_at "gb :Z2 5521 .1 / DEF= H.s api en.
21 3857_ s_at "Co nsens us in clu des gb: BG.
20 3965_ at "gb :NM _006 676. 1 /DEF=Ho m .

20 1194_ at "gb :NM _003 009. 1 /DEF=Ho m .
21 9724_ s_at "gb :NM _014 796. 1 /DEF=Ho m .
21 4049_ x_at Conse nsus i ncl ude s g b:A I8 .
21 4551_ s_at "Co nsens us in clu des gb: NM .
21 9191_ s_at "gb :NM _016 293. 1 /DEF=Ho m .

21 6191_ s_at Conse nsus i ncl ude s g b:X 72.
21 7143_ s_at Conse nsus i ncl ude s g b:X 06.
21 1796_ s_at "gb :AF0431 79. 1 / DE F=Hom o .
21 0915_ x_at "gb :M 1 5564 .1 / DEF= Hum an T .

21 3193_ x_at Conse nsus i ncl ude s g b:A L5.

20 3675_ at "gb :NM _005 013. 1 /DEF=Ho m .
20 4777_ s_at "gb :NM _002 371. 2 /DEF=Ho m .

20 9881_ s_at "gb :AF0369 05. 1 / DE F=Hom o .
21 1005_ at "gb :AF0369 06. 1 / DE F=Hom o .
21 9528_ s_at "gb :NM _022 898. 1 /DEF=Ho m .
20 4214_ s_at "gb :NM _006 834. 1 /DEF=Ho m .

22 0418_ at "gb :NM _018 961. 1 /DEF=Ho m .
20 5254_ x_at "Co nsens us in clu des gb: AW .
20 4890_ s_at "gb :U0 7236 .1 / DEF= Hum an .
20 4891_ s_at "gb :NM _005 356. 1 /DEF=Ho m .

20 5255_ x_at "gb :NM _003 202. 1 /DEF=Ho m .
20 5456_ at "gb :NM _000 733. 1 /DEF=Ho m .

21 3539_ at "Co nsens us in clu des gb: NM .

20 3589_ s_at "gb :NM _006 286. 1 /DEF=Ho m .
20 1349_ at "gb :NM _004 252. 1 /DEF=Ho m .
20 4852_ s_at "gb :NM _002 832. 1 /DEF=Ho m .
20 5270_ s_at "gb :NM _005 565. 2 /DEF=Ho m .

HD>50 BCR-ABL TEL-AML1 E2A-PBX1 T-ALL MLL

Ross ME et al, Blood 102:2951-9, 2003
EFS por Genotipo (Estudios XIIIA y B)
1 89% 86%
E2A-PBX1, n=18
0.9
85% Hyperdiploidy >50, n=103
0.8
79% TEL-AML1, n=74
0.7
Others, n=193
0.6
0.5
0.4
31%
0.3
30% MLL-AF4, n=11
0.2
BCR-ABL, n=13
0.1
0
0 2 4 6 8 10 12
Years from Diagnosis
Pui, J Formos Med Assoc, 2004
Uso del Genotipo para individualizar tratamiento
Pacientes con
posibilidad de O en riesgo de
no responder alta toxicidad
Tratar con drogas o dosis alternativas
Pacientes con alta

Posibilidad de respueta
Tratar convencionalmente
Contribución de los Polimorfismos genéticos
en el metabolismo de las drogas
CYP1A1/2
Phase I epoxide
hydrolas
CYP1B1 Phase II NAT2
CYP2A6 NAT1
esterases others CYP2B6
CYP2C8 GST-M
DPD
others GST-T
NQ01 GST-P
GST-A
CYP2C9
ADH
ALDH CYP2C19
STs
UGTs
CYP2D6
HMT
CYP3A4/5/7 CYP2E1 COMT

TPMT
Thiopurine Methyltransferase Polymorphisms
Affect Mercaptopurine Therapy
Relling & Dervieux, Nature Reviews Cancer 2001;1:99-108

Acute lymphoblastic leukemia: response to treatment
“complete remission”
1012
1010
13%
10 8
49%
26%
12%
0 2 6 20
Weeks after diagnosis
remission - induction continuation
Pui & Campana, Leukemia 14:783-5, 2000

EFS According to Percentage of Lymphoblasts
in Bone Marrow on Day 15 Induction
(Studies XI and XII)
1
0.9
0.8 0% blasts, n=340

0.7
0.6
0.5 1–4% blasts, n=34

0.4
0.3
0.2 ≥5% blasts, n=23
0.1
0
0 2 4 6 8 10 12 14
Years from Diagnosis
Sandlund et al, Blood 100:43-7, 2002
Cumulative Incidence of Relapse According to
Levels of Residual Disease at Day 19
1
Cumulative Incidence of Relapse
RD ≥ 1% (n = 26)
0.8 P = 0.0021 RD 0.1%-<1% (n = 14)
RD 0.01%-<0.1% (n = 19)
RD <0.01% (n = 51)
0.6
40.8 ± 10.6
0.4
33.2 ± 11.7
0.2 14.3 ± 9.7

6.0 ± 3.4
0
0 1 2 3 4 5 6 7
Years
Total XV: Risk Classification Schema
B-lineage T-lineage
t(9;22)/BCR-ABL WBC <50 X 109/L WBC ≥50 X 109/L,

& age 1 to 9.9 years, Age ≥10 years,
DNA index ≥1.16, or CNS leukemia,
TEL-AML1 Testicular leukemia,
MLL rearrangement,
t(1;19)/E2A-PBX1
<45 chromosomes
Minimal residual Minimal residual

leukemia detection leukemia detection
at remission date at remission date
≥1% <0.01% 0.01% to 1% ≥1% 0.01% to <1%
High-risk Low-risk Standard-risk

~5% ~45% ~50%
Pui et al Lancet Oncology 2:597-607, 2001

Nuevos agentes en investigación
Agente Subtipo LLA

Imatinib mesylate (Gleevec) BCR-ABL
Anti-CD20 (Rituximab) CD20+
Arabinosylguanine (GW506U78) T-cell
FLT3 inhibitor (PKC412) Rearranged
MLL
NEJM 2004;350:15
Carrera Arco Iris
¿Cúal es le Futuro? Individualizar terapia,
drogas adecuadas, dosis correctas,
para cada niño

Conf DR Antillón

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Biología Molecular en la Leucemia

Linfoblástica Aguda pediátrica.

Dr. Federico Antillón K.

• Incidencia 11/100,000 niños y

New Cases per Year per 100,000

20 Data kindly provided by Benjamin F. Hankey, Sc.D.,

Luna S, Slowing K, Valverde P, Antillon F, et al. Pediatric Cancer in Guatemala. A

2004 305 25.4 109 414

2005 315 26 107 422

2006 153 25.5 23 167

CONSOLIDADO DE CASOS CON CANCER (NUEVOS+REFERIDOS)

11% OTROS NEOPLASMAS MALIGNOS NO

• 32 casos por 1,000,000

Li nf oide CD3, CD7, CD 10, CD 19, CD 79

Mi eloi de M6/ M7 CD 41a, CD 61, y CD42b

Whitehead, St.Jude Blood 80:1316:1992

Estudio No. Pacientes %5-yr EFS (±SE)

20 2391_ at "gb :NM _006 317. 1 /DEF=Ho m .

21 5117_ at Conse nsus i ncl ude s g b:A W.

22 9770_ at Conse nsus i ncl ude s g b:A I0 .

23 1040_ at Conse nsus i ncl ude s g b:A W.

21 1744_ s_at "gb :BC0059 30. 1 / DE F=Hom o .

21 2985_ at Conse nsus i ncl ude s g b:B F1.

24 4565_ at Conse nsus i ncl ude s g b:A I6 .

21 8283_ at "gb :NM _016 305. 1 /DEF=Ho m .

20 9760_ at gb: AL136 932. 1 /DEF=Hom o .

24 3533_ x_at Conse nsus i ncl ude s g b:H09.

22 4022_ x_at "gb :AF1699 63. 1 / DE F=Hom o .

38 340_a t "Cl ust er I nc l. AB014 555: Hom .

21 1913_ s_at "gb :L0 8961 .1 / DEF= Hom o sa .

22 7440_ at Conse nsus i ncl ude s g b:A W.

23 1095_ at "Co nsens us in clu des gb: AW .

21 2371_ at Conse nsus i ncl ude s g b:A L0.

23 2289_ at "Co nsens us in clu des gb: BF .

21 2148_ at "Co nsens us in clu des gb: AL .

23 5099_ at "Co nsens us in clu des gb: AW .

21 9551_ at "gb :NM _018 456. 1 /DEF=Ho m .

20 1889_ at "gb :NM _014 888. 1 /DEF=Ho m .

20 4613_ at "gb :NM _002 661. 1 /DEF=Ho m .

21 9563_ at "gb :NM _024 633. 1 /DEF=Ho m .

21 2386_ at "Co nsens us in clu des gb: BF .

21 2382_ at "Co nsens us in clu des gb: BF .

20 8650_ s_at Conse nsus i ncl ude s g b:B G3.

22 0068_ at "gb :NM _013 378. 1 /DEF=Ho m .

20 6398_ s_at "gb :NM _001 770. 1 /DEF=Ho m .

22 7646_ at Conse nsus i ncl ude s g b:B G4.

20 3143_ s_at Conse nsus i ncl ude s g b:T 79.

20 0811_ at "gb :NM _001 280. 1 /DEF=Ho m .

20 3332_ s_at "gb :NM _005 541. 1 /DEF=Ho m .

20 2603_ at Conse nsus i ncl ude s g b:N51.

21 4895_ s_at Conse nsus i ncl ude s g b:A U1.

20 1563_ at "gb :L2 9008 .1 / DEF= Hum an L -.

22 8580_ at "Co nsens us in clu des gb: AI8.

22 5019_ at "Co nsens us in clu des gb: BF .

20 5550_ s_at "gb :NM _004 899. 1 /DEF=Ho m .

20 6471_ s_at "gb :NM _005 761. 1 /DEF=Ho m .

20 1078_ at "gb :NM _004 800. 1 /DEF=Ho m .

22 1676_ s_at "gb :BC0023 42. 1 / DE F=Hom o .

21 4651_ s_at "Co nsens us in clu des gb: U4 .

24 2172_ at Conse nsus i ncl ude s g b:N50.

22 6415_ at Conse nsus i ncl ude s g b:A A1.

20 9191_ at "gb :BC0026 54. 1 / DE F=Hom o .

21 8847_ at "gb :NM _006 548. 1 /DEF=Ho m .