Dr.

Francisco Gonzlez Otero

Servicio de Dermatologa HUC-UCV
Caracas- Venezuela
NUEVAS ALTERNATVAS
TERAPEUTCAS DE LA
MASTOCTOSS
Mastocitosis Cutneas
Lesiones cutneas carctersticas de : UP, MS, MPCM y MCD
HistoIoga : infiItrado de MC en patrn muItifocaI o difuso
Sin criterios de Mastocitosis Sistmica
WorId HeaIth Organization
Diagnostic criteria for cutaneous and systemic mastocytosis
MASTOCTOMA SOLTARO
Autolimitada con tendencia a resolverse hacia la edad adulta Autolimitada con tendencia a resolverse hacia la edad adulta
MASTOCTOMA SOLTARO MASTOCTOMA SOLTARO
Dr.a Anaixa Gomez
URTCARA PGMENTOSA
%#A%AMIEN%O :
MAS%OCI%OSIS CU%NEA
La Mayora No Requiere Tratamiento
Curso Benigno y Regresin Espontnea
Tratamiento Sintomtico
No Cambia El Curso De La Enfermedad
Evitar Desencadenantes Degranulacin de MC
. Evitar Desencadenantes
DegranuIacin DeI Mastocito
Mastocitosis : %ratamiento
rritacin Mecnica De La Piel (Rascado, Friccin)
Calor, Frio , Cambios De Temperatura
Picaduras De nsectos
Frmacos : Medio Contraste Rx, Cocana,
Anestsicos, Morfina, Aspirina, Meperidina, ANES
nfecciones, Ejercicio Fsico
Alcohol , Alimentos
Estrs Emocional
Desencadenantes
DegranuIacin DeI Mastocito
ANTHSTAMNCOS
H1 H2
Flush
Prurito Urticaria
Hidroxicina
Doxepina
Cimetidina
Ranitidina
Molestias
gastrointestinales
Systemic mastocytosis:current concepts and treatment advances. Tefferi.
Curr Hematol Rep. 2004 May; 3(3): 197-202.
Mastocitosis : %ratamiento
ESTABLZADORES DE LA MEMBRANA DEL MASTOCTO
Bloquean la liberacin de los
mediadores
ncremetan el
AMPc
Bloquean transporte de
Calcio
Cromoglicato disdico
Ketotifeno
Oxatomida
Mastocitosis : %ratamiento
CORTCOESTERODES CRUGA PUVATERAPA ASA / ANES
Mastocitosis cutneas
(ampollosas y difusas)
Mastocitosis sistmicas
Va oral
Tpico oclusivo
ntralesional
Pacientes resistentes
antihistaminicos y
cromoglicato sod.
Disminuye prurito,
ampollas y
pigmentacin.
Mastocitosis del
adulto
Mastocitoma
Mastocitosis : %ratamiento
CIasificacin. Mastocitosis
Orfao A, Garcia-Montero A, Sanchez L, Escribano L. Recent advances in the understanding of mastocytosis: the role of KT
mutations British Journal of Haematology 2007;138:12-30
1 8olssan M leaer l Culllosson !! Arock M c
klL and cklL muLaLlons ln masLocvLosls and
oLher hemaLoloalcal dlseases ! Leukoc 8lol
20006713348
Receptores Tirosina Quinasa (RTKs)
Clase :
Receptore
s de
nsulina
(R)
Clase :
Factor de
Crecimient
o tipo
nsulina-
(GF-R)
CIase III:
Factor de Crecimiento Epidrmico (EGF#
Receptor C-
Kit
Receptor
Factor de
Crecimiento
Derivado de
Plaquetas
(PDGFR)q y
8
Receptor
Factor de
Crecimiento
Vascular
Endotelial 2
(VEGFR2)
Receptor
Factor
Colonia-
Estimulante
de
Macrfagos
(c-FMS)
Andr C., et al. Genomic organization of the human c-Kit gene: evolution of the receptor
tyrosine kinase subclass . Oncogene 1992; 7(4): 68591.
Mastocitosis Sistmicas
Mutaciones Somticas En El Codon 816 Del
Receptor Oncognico De La Tirosina Quinasa (C-
kit), Cuyo Ligando Es Un Factor De Las Clulas
Madres.
Activacin de la quinasa del receptor que este gen
codifica (KT).
Mutaciones en el gen c-KIT
protooncogn que codifica la protena KT
Desregulacin de la activacin del receptor,
Activa de forma independiente a la unin del ligando.
Mastocitosis Sistmicas
Proliferacin Celular
Maduracin y Diferenciacin
Supresin de la Apoptosis
Degranulacin Y Modificaciones en las Propiedades de
Adhesin y Motilidad de las Clulas Activadas
Mastocitosis
ctivacin De La Mutacin C-kit Conduce a La
Transformacin Oncognica y Proliferacin De
Los Mastocitos En La Mastocitosis.
Clasificacin. Mastocitosis
Orfao A, Garcia-Montero A, Sanchez L, Escribano L. Recent advances in the understanding of mastocytosis: the role of KT
mutations British Journal of Haematology 2007;138:12-30
9oLLler 9 9lanchon 8 CrosslCompleLe remlsslon wlLh
|mat|n|b mesvlaLe (Cllvec) of an ldlopaLhlc
hvpereoslnophlllc svndrome assoclaLed wlLh a
cuLaneous mastocytos|s afLer fallure of lnLerferon
alpha8ev Med lnLerne 2003 Aua24(8)3426
Mesylate de matinib
nhibidor de tirosin quinasa
nhibidor del c kit
Leucemia Mieloide Crnica
100 a 400 mgr / d
matinib
Mutaciones ocurren (>90%) en exn 17 del gen c-KT
Otros exones 8, 9, 10 y 11.
93% la mutacin se localiza en el codn 816 (D816V).
Cuando la mutacin cambia en ese lugar el imatinib no se une
Esta sustitucin aporta resistencia frente a imatinib
No pueden beneficiarse con imatinib al ser portadores de
mutacin D816V.
MASTOCTOSS
Mastocitosis
Asp816Val
matinib
SU9529
Asp816Tyr
Asp816Phe
La mutacion KT D816V es
encontrada en la gran
mayoria de los pacientes
con mastocitosis sistemica,
por lo tanto, la terapia con
imatinib no sera apropiada
para ellos
Orfao A, Garcia-Montero A, Sanchez L, Escribano L. Recent advances in the understanding of mastocytosis: the role of KT mutations
British Journal of Haematology 2007;138:12-30
Efectivo MS y Eos. Asociado con FP1L1/PDGFRA+
SM asociada con KT mutaciones de la parte externa del exon 17
MASTOCTOSS
matinib :
Dr.Jesus Cuevas.
Dr.Jesus Cuevas.
Triptasa Dr.Jesus Cuevas.
C Kit +
Dr.Jesus Cuevas.
ctualidad Cientfica.2003; 22(01):138-140.
J Drugs Dermatol. 2006 Mar;5(3):228-31
Bien tolerado.
G: Nuseas o vmitos, diarrea.
Sntomas musculosquelticos (calambres, mialgias)
Edema periorbitario.
Cutneos: exantema pustular generalizado agudo y
despigmentacin de la piel.
matinib . Efectos adversos
Mastocitosis. matinib
Orfao A, Garcia-Montero A, Sanchez L, Escribano L. Recent advances in the understanding of mastocytosis: the role of KT
mutations British Journal of Haematology 2007;138:12-30
1. M. excepcionales con
ASM y MCL que son
negativos para la mutacin
D816V KT
2. Pacientes con mutaciones
yuxtamembrana (K509 y
F522C) asociado a curso
agresivo de la enfermedad
(3) casos con SM-AHNMD
asociado a FP1L1/PDGFRA
URTCARA PGMENTOSA
Novel, activating KT-N822 mutation in familial cutaneous mastocytosis
Experimental Hematology (2011),
Objective:
We report the rare family in which cutaneous mastocytosis was diagnosed in
the father and two children, with urticaria pigmentosa as the only
manifestation of the disease.
Conclusions:
We provided evidence that KIT p.N822I mutation has transforming potential and
can cause a constitutive activation of KT.
n addition, we demonstrated that KT-N822 is resistant to imatinib
and sensitive to dasatinib.
Our findings support the hypothesis that not only KT mutations but other
additional genetic abnormalities are contributing to more advanced forms of the
disease
TRATAMENTO
Dasatinib (BMS 354825) inhibits KTD816V, an
imatinibid-resistant activating mutation that triggers
neoplastic growth in the majority of patients with
systemic mastocytosis.
Shah NP, Lee FY, Luo R, Jiang Y, Domnker M, Akin C.
Blood. 2006 Jan 24.
TRATAMENTO
Dasatinib (BMS 354825) inhibits KTD816V, an
imatinibid-resistant activating mutation that triggers
neoplastic growth in the majority of patients with
systemic mastocytosis.
Shah NP, Lee FY, Luo R, Jiang Y, Domnker M, Akin C.
Blood. 2006 Jan 24.
TRATAMENTO
TERAPA CTOREDUCTORA
nhibidores de la
tirosincinasa
nterfern q Cladribine
matinib
Dasatinib
Nilotinib ?
Mastocytosis: pathology, genetics and current options for therapy. Valent et el. Leuk
Lymphoma 2005 Jan; 46(1): 35-48
TRATAMENTO
Effects of topical treatment with the raft modulator
miltefosine and clobetasol in cutaneous mastocytosis:
a randomized, double-blind, placebo-controlled trial
BJD 2010; 162:185190
Background Mastocytosis is characterized by the accumulation and activation of mast cells in different organs, most commonly the
skin. Miltefosine, a raft modulator, has recently been shown to inhibit the activation of mast cells and to reduce mast cell-driven skin
inflammatory responses.
Objectives To study the safety and efficacy of topical miltefosine treatment of skin lesions in patients with mastocytosis.
Methods Thirty-nine adult patients with mastocytosis with skin involvement were treated in a double-blind, placebo-controlled, parallel
trial with topical miltefosine and clobetasol for 2 weeks. Treatment areas were analysed for changes in skin lesions and symptoms
following mechanical irritation using novel volumetric imaging techniques and quantitative histomorphometry.
Results Miltefosine and clobetasol failed to reduce significantly weals and flare-type skin responses following mechanical
provocation. Miltefosine showed a trend towards reducing the volume of weals. Clobetasol significantly decreased the volume of
weals and the number of mast cells in the upper dermis. Treatment with miltefosine, but not with clobetasol, was often associated
with eczematous skin irritation, which may, at least in part, be related to the formulation of miltefosine containing the potentially
irritating alkanol propanediol as the vehicle.
Conclusions Raft modulators such as miltefosine are promising candidates for novel therapeutic strategies in patients with cutaneous
mastocytosis. Future studies should be performed with improved formulations
CONCLUSOnES
BJD 2010; 162:185190
Mastocitosis Cutnea: Tx Convencional
Mastocitosis Sistmica: nhibidores c-kit
Conocimiento del Receptor
Otros Factores Etiopatognicos
www.dermatologiapediatrica.net