terapia alvo na cancerologia pediátrica
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TERAPIA ALVORealidade na pediatria
POR QUE TERAPIA ALVO• Targeted therapies
• Terapia citotóxica convencional
• afeta células em divisão rápida
• efeitos em muitos tecidos normais
• Terapia alvo: via de sinalização específica às células tumorais
• menos efeitos colaterais
• Desenvolvimento racional de drogas com efeito em enzimas ou outras moléculas específicas das células tumorais, baseado em biologia molecular
TERAPIA ALVO• Termo de uso recente, relacionado à indústria farmacêutica
• Tipos de terapia alvo:
• Anticorpos monoclonais
• Drogas de baixo peso molecular
• Vacinas
• Efeitos das terapias alvo:
• Inibição de vias de fatores de crescimento
• Ativação de vias pró-apoptóticas
• Antiangiogênese, imunoterapia
• Kohler & Milstein, 1975 - produção de anticorpos monoclonais por hibridomas
• Koprowski, 1978 - anticorpos contra melanoma
• Busca de uma terapia imunológica
• Ritz, Blood, 1981 - anticorpo anti-CD10 em pacientes com LLA
• Drebin, PNAS, 1986 - oncogene neu, inibido por um anticorpo monoclonal
• Células NIH 3T3 transformadas por neu - crescimento inibido em nude mice
• Células NIH 3T3 transformadas por Ha-ras - crescimento contínuo
ANTICORPOS MONOCLONAIS BIOLOGICALS - MABS
INIBIDORES DE TIROSINA QUINASE - TKI
• Substâncias de baixo PM
• Termo usado para contraste com biologicals
• Yaish, Science, 1988 - desenvolvimento de inibidores da atividade tirosina quinase do receptor do EGF
• Buchdunger, 1995 - inibidor do PDGF - CGP 53716
• 2-fenilamino-pirimidinas
• Buchdunger, 1996 - CGP 57148, depois conhecido como STI 571, depois conhecido como imatinib
ALVOS DAS TERAPIAS ALVO
• Proteínas específicas da superfície das células tumorais - ligante-dirigida (ligand targeted)
• Fatores de crescimento e suas vias de sinalização
• Angiogênese
• Imunoterapia
• Apoptose e outros mecanismos
LIGANTE-DIRIGIDA
• Especificidade por alvos moleculares
• Proteínas de superfície de células imunes ou tumorais
• Marcadores de linhagem celular
• Citotoxicidade celular dependente de anticorpo
• Citotoxicidade mediada por complemento
• Rituximabe (MabThera®): uso adulto (ANVISA e FDA)
• Meinhardt et al, JCO, 2010 - rituximabe pré-QT em crianças com LNH CD20+
• Goldman, Leukemia, 2012 - ensaio fase 1/2 de rituximabe com QT em crianças com LNH CD20+ III/IV
A study of rituximab and ifosfamide, carboplatin, and etoposide chemotherapy in children with recurrent/refractory B‐cell (CD20+) non‐Hodgkin lymphoma and mature B‐cell acute
lymphoblastic leukemia: A report from the Children's Oncology Group
Pediatric Blood & Cancer Volume 52, Issue 2, pages 177-181, 24 SEP 2008 DOI: 10.1002/pbc.21753http://onlinelibrary.wiley.com/doi/10.1002/pbc.21753/full#fig1
B-cell malignancies. Contemporary therapies provide a high
likelihood of survival for most newly diagnosed patients (1–3, 8).
Despite this remarkable success story, the outcome for individuals
who have refractory disease initially or for those who relapse is
dismal. Cairo et al. reported a 12% post-event survival in patients
with BL diagnosed from 1977 to 1997; details of retrieval therapy
were unknown in that cohort [3]. In the Children’s Cancer Group
study 5912, the DECAL regimen was given to 68 patients with
recurrent NHLwith a 50% response rate, which was independent of
histologic subtype. OS was 33% at 2 years but only 2/13 patients
with BL were described as long-term survivors [5]. Kung et al.
reported a 71% CR/PR rate in a Pediatric Oncology Group trial of
21 patients with recurrent NHL using ICE chemotherapy, and Cairo
et al. reported response in 4/6 patients with lymphoma using a
slightly more dose-intensive ICE regimen. Neither of those trials
included a breakdown of the study population by histology,
however, and long-term outcomes were not reported [6,7]. Never-
theless, perhaps in part because of the encouraging results of those
studies ICE has become a commonly employed salvage regimen for
pediatric patients with relapsed NHL.
The small number of patients enrolled in the present study
preclude definitive conclusions regarding the therapeutic efficacy of
the combination of rituximab and ICE chemotherapy. Nonetheless,
the response rate observed (60%) appears to be at least comparable
to previous reports of other salvage regimens, and is especially
impressive in view of the prior, intensive contemporary treatments
received by the patients. Many with OR were able to proceed to
consolidative therapy with SCT, and the proportion of patients still
alive and free of disease at last follow-up is larger than in any
previously published series of such patients. Intriguingly, in the
DLBCL group, two of the survivors did not receive high-dose
consolidation therapy with SCT.
Patients enrolled in this trial had a very short survival if they did
not respond to salvage therapy, while those with chemo-responsive
disease had a chance at successful retrieval. Thus, with what is
perhaps more effective relapse therapy, the correlation between
response to initial retrieval therapy and survival, seen in other
diseases such as Hodgkin lymphoma, may now be evident with
high-grade B-cell malignancies as well.
The commercial availability of rituximab has provided the
opportunity to combine it with chemotherapy combinations, such as
ICE, for use in relapsed or refractory high-grade B-cell lymphoma
outside the setting of a clinical trial. The current study is important
because it provides controlled data regarding tolerability of the
regimen as well as some response data. The combination of
rituximab and ICE chemotherapywas deliveredwithout unexpected
or excessive toxicity. Infusion-related toxicities were encountered
but manageable, and no patient experienced cytokine release
reactions that have been reported in patients with advanced disease
Pediatr Blood Cancer DOI 10.1002/pbc
TABLE III. Reported Toxicities
Targeted toxicities Grade 3 Grade 4
All
grades
Neutrophils 1 3 36
Platelets 1 4 37
Allergy/hypersensitivity 5 0 5
Rash 1 0 1
Other toxicities Grade 3 Grade 4
Vomiting 7 0
Nausea 5 0
Infection 5 1
Febrile neutropenia 4 0
Hypokalemia 2 3
Hemoglobin 0 3
Hemorrhage 2 0
One episode of grade 3 toxicity each reported for elevated SGOT, renal
insufficiency, dehydration, acidosis, seizure, somnolence, syncope,
hematemesis, lymphopenia, and bilirubin.
0.0 0.5 1.0 1.5 2.0 2.5 3.0
0.0
0.2
0.4
0.6
0.8
1.0
Years
Pro
babi
lity
SurvivalTime interval Estimate SE
Numberfailed
NumberCensored
Numberat risk
0-1 year 0.4286 0.1145 11 1 201-2 years 0.3750 0.2096 1 5 82-3 years 0.3750 . 0 2 2
Fig. 1. Overall survival: All eligible patients.
0.0 0.5 1.0 1.5 2.0 2.5 3.0
0.0
0.2
0.4
0.6
0.8
1.0
Years
Pro
babi
lity
P 0.0001
NResp (n=8)Resps (n=12)
Fig. 2. Overall survival: Responders versus non-responders.
180 Griffin et al.
Outline of the treatment strategy for the B-Cell Non-Hodgkin's Lymphoma–Berlin-Frankfurt-Münster Group rituximab window study.
Meinhardt A et al. JCO 2010;28:3115-3121
©2010 by American Society of Clinical Oncology
Rituximab and FAB/LMB 96 chemotherapy in children with Stage III/IV B-cell non-Hodgkin lymphoma: a Children's Oncology Group report. Goldman, S; Smith, L; Anderson, JR; Perkins, S; Harrison, L; Geyer, MB; Gross, TG; Weinstein, H; Bergeron, S; Shiramizu, B; Sanger, W; Barth, M; Zhi, J; Cairo, MS Leukemia. 27(5):1174-1177, May 2013. DOI: 10.1038/leu.2012.255
Figure 2. Probability of EFS and OS of all eligible intermediate-risk patients. (a) Product-limit estimate of probability of EFS in all pilot patients (six doses or rituximab plus chemotherapy) from study entry. EFS at 3 years (CI95% 80-99%). (b) Product-limit estimate of probability of OS in all patients from study entry. OS at 3 years (CI95% 83-99%). (c) Product-limit estimate of probability of EFS in all stage III/IV pilot patients on study compared to all stage III/IV patients treated on FAB/LMB 96 without rituximab.
• Brentuximabe (Adcetris®): uso adulto (FDA)
• LH e LAGC recidivados, ou refratários, CD30+
• Experiência pediátrica limitada
• NCT01492088: estudo fase 1/2 em crianças, nenhum centro brasileiro (fim previsto em 2016)
Pro B et al. JCO 2012;30:2190-2196
©2012 by American Society of Clinical Oncology
Median overall survival (OS) was not reached at the time of the analysis; 18 patients had died.
Meyer-Wentrup, 2013
FATORES DE CRESCIMENTO
• Superexpressão
• Ativação constitutiva anômala
• MABs bloqueiam receptores
• TKIs inibem a via de sinalização
• Trastuzumab - HERCEPTIN® - alvo: Her2/neu ou Erb2
• Aprovado para câncer de mama avançado: prolonga a sobrevida em 20 a 30% pacientes
• Resistência comum
• Ebb, JCO, 2012 - fase II, trastuzumab e QT em osteossarcoma, aparentemente sem vantagem
• Cetuximabe (Erbitux®) - uso adulto (FDA e ANVISA)
• Trippett, JCO, 2009 - estudo fase I de cetuximab e irinotecan
• Melhor resposta em tumores de SNC (gliomas de alto grau e DIPG)
Overall accrual schema (including patients not assessable for toxicity and those withdrawn from the study) and dose-limiting toxicities (DLTs) observed.
Trippett T M et al. JCO 2009;27:5102-5108
©2009 by American Society of Clinical Oncology
• Nimotuzumabe (CIMAHer®) - aprovado pela ANVISA
• Astrocitoma de alto grau expressando EGFR e DIPG
• Bode, JCO, 2008 - DIPG
• Bode, JCO, 2007 - astrocitoma anaplásico e glioblastoma recorrente/progressivo
• Imatinibe (Glivec®) - aprovado pelo FDA, ANVISA uso adulto
• LMC Ph+, LLA Ph+ recidivada/progressiva
• SMD com rearranjos do gene de PDGFR
• Mastocitose sistêmica agressiva (c-Kit D816V negativo)
• Síndrome hipereosinofílica ou leucemia eosinofílica aguda com a fusão FIP1L1-PDGFRalfa
• Dermatofibrossarcoma irressecável
• Tumor estromal gastrointestinal (GIST) Kit+ (CD117)
From: Lancet Oncol. 2012 September; 13(9): 936–945. doi: 10.1016/S1470-2045(12)70377-7
Cumulative incidences of hematologic, cytogenetic, and molecular responses to imatinib.
Millot F et al. JCO 2011;29:2827-2832
©2011 by American Society of Clinical Oncology
Kaplan-Meier analysis of (A) progression-free survival and (B) overall survival for patients in each stratum.
Zwaan C M et al. JCO 2013;31:2460-2468
©2013 by American Society of Clinical Oncology
• Dasatinibe (Sprycel®) - aprovado pelo FDA (ANVISA uso adulto)
FUTURO DO TRATAMENTOLLA Ph +
Baixo risco Alto risco
TMO
QT intensiva Melhor esquema?
TKIImatinibe Dasatinibe Nilotinibe
DRM
ENSAIOS CLÍNICOS
• NCT01077544: A Pharmacokinetic (PK) Study of Nilotinib in Pediatric Patients With Philadelphia Chromosome-positive (Ph+) Chronic Myelogenous Leukemia (CML) or Acute Lymphoblastic Leukemia (ALL) - recrutando até Dez/2013 - 5 instituições brasileiras envolvidas
• NCT00777036: A Phase II Study of Dasatinib in Children and Adolescents With Newly Diagnosed Chronic Phase CML or With Ph+ Leukemias Resistant or Intolerant to Imatinib - 84 centros, 5 do Brasil, 1 instituição recrutando em São Paulo, encerrará coleta de dados em 2016.
PERSPECTIVAS
• Cortes, et al. ASH, dezembro de 2012 - Ponatinib em pacientes com LMC e LLA Ph+ resistentes ou intolerantes ao dasatinib e nilotinib. Único ITK com efeito na BCR-ABL T315I - aprovado pelo FDA para adultos
• Cortes, et al, JCO, 2012. Bosutinib versus imatinib. Opção para pacientes com resistência ou intolerância ao imatinib.
• Vemurafenibe (Zelboraf®) - uso adulto (FDA e ANVISA)
• BRAF V600E
• Melanoma metastático, irressecável, recorrente, refratário
• Astrocitomas (até 30%) e gangliogliomas (>50%)
• Korshunov, 2009 - fusão BRAF-KIAA1549 e IDH1 diferenciam astrocitomas pilocíticos e difusos
• Rush, JCO, 2013 - ganglioglioma de tronco tratado com vemurafenibe
Imagens: Plexxikon
Rush S et al. JCO 2013;31:e159-e160
©2013 by American Society of Clinical Oncology
• Everolimo (Afinitor®) - aprovado pela ANVISA e FDA
• Astrocitoma subependimário de células gigantes (SEGA)
• Franz, Lancet, 2013 - ensaio fase III, duplo-cego, randomizado
• Capellano, 2013 - experiência brasileira
• Tumor neuroendócrino (NET)
Imagens: arquivo pessoal
• Crizotinibe (Xalkori®) - uso adulto (FDA) - inibe ALK e MET
• Mosse, Lancet Oncology, 2013 - ensaio fase 1 do COG
• Resultados mostraram efeito importante em pacientes com linfoma anaplástico de grandes células ALK+
ANTIANGIOGÊNESE
• VEGF - fator de crescimento endotelial vascular
• Bevacizumabe: MAB que liga-se ao VEGF solúvel, impedindo sua ligação ao VEGFR
• Inibidores de tirosina quinase capazes de bloquear a via do VEGF: sunitinibe, sorafenibe
• Bevacizumabe (Avastin®) - uso adulto (ANVISA e FDA)
• Bender, JCO, 2008 - fase I
• Gururangan, JCO, 2010 - sem efeito em glioblastoma e DIPG recorrentes
• Gururangan, NO, 2012 - sem efeito em ependimoma
• Pansy, AD, 2013 - uso limitado em tumores sólidos
Supratentorial glioblastoma multiforme in an 8-year-old girl (rows 1-4) and brainstem glioma in a 4-year-old girl (rows 5 to 8) at three time points: day 0, day 14, and 2 months later.
Gururangan S et al. JCO 2010;28:3069-3075
©2010 by American Society of Clinical Oncology
Kaplan–Meier survival curve showing PFS in 14 eligible patients with recurrent ependymoma.
Gururangan S et al. Neuro Oncol 2012;14:1404-1412
© The Author(s) 2012. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
• Sunitinibe (Sutent®) - uso adulto, FDA e ANVISA
• Dubois, 2011: ensaio fase I. Uso limitado pela toxicidade cardíaca, fase II não planejada.
• Sorafenibe (Nexavar®) - uso adulto, FDA e ANVISA
• Widemann, 2012: ensaio fase I, atividade em LMA com FLT3ITD
IMUNOTERAPIA
• Neoplasias imunogênicas: melanoma, neuroblastoma
• "Treinar" o sistema imune para uma resposta anti-tumoral eficaz
• Bretjens, Science, 2013: células T com receptor quimérico de antígeno, específico para CD19. Indução de remissão com DRM negativa em LLA refratária.
• MAB Ch.14.18 anti-GD2 (disialogangliosídeo): imunoterapia do neuroblastoma alto risco
• Droga órfã no FDA, fornecida pelo NCI
• Yu, NEJM, 2010 - eficácia em pacientes com neuroblastoma avançado
• Investigacional em tumores sólidos
T h e n e w e ngl a nd j o u r na l o f m e dic i n e
n engl j med 363;14 nejm.org september 30, 20101330
ing interleukin-2, with incidences of 26% and 25%, as compared with 5 to 12% during the three cycles involving GM-CSF (P = 0.001). Such reactions may be attributable to symptoms and signs that reflect both toxic effects of interleu-kin-2 and antibody-related hypersensitivity.
Other toxic effects that were common during immunotherapy cycles included fever (in 39% of patients), hypokalemia (35%), hyponatremia (23%), liver dysfunction (abnormal alanine aminotrans-ferase level, 23%), hypotension (18%), diarrhea (13%), urticaria (13%), and hypoxia (13%). Early in the study, two patients were inadvertently given an overdose of the scheduled interleukin-2 (i.e., a dose >20 times the scheduled dose) due to a medication error; one of these patients died
of interleukin-2–related capillary leak and pulmo-nary edema. No other treatment-related deaths were reported. All other toxic effects were self-limited and resolved soon after the cessation of treatment and well before the beginning of the subsequent treatment.
Discussion
This randomized clinical trial tested the use of an immunotherapy regimen administered after autologous stem-cell transplantation, in order to enhance antibody-dependent cell-mediated cyto-toxicity to GD2-positive tumor cells. The results indicate that the inclusion of the immunotherapy resulted in significantly superior event-free and
Even
t-fr
ee S
urvi
val (
%)
100
75
50
25
00 1 2 3 4 5 6
Years since Randomization
A Event-free Survival
P=0.01
No. at RiskImmunotherapyStandard therapy
113113
6959
4732
2920
1510
98
31
Standard therapy
Immunotherapy66±5
46±5
Ove
rall
Surv
ival
(%)
100
75
50
25
00 1 2 3 4 5 6
Years since Randomization
B Overall Survival
P=0.02
No. at RiskImmunotherapyStandard therapy
113113
7779
5951
3726
2012
109
31
Standard therapy
Immunotherapy
86±4
75±5Ev
ent-
free
Sur
viva
l (%
)
100
75
50
25
00 1 2 3 4 5
Years since Randomization
C Event-free Survival for ≥1-Yr-Olds with Stage 4 Disease
P=0.02
No. at RiskImmunotherapyStandard therapy
8990
5646
3726
2219
1110
78
Standard therapy
Immunotherapy
63±6
42±6
Even
t-fr
ee S
urvi
val (
%)
100
75
50
25
00 1 2 3 4 5
Years since Randomization
D Overall Survival for ≥1-Yr-Olds with Stage 4 Disease
P=0.10
No. at RiskImmunotherapyStandard therapy
8990
6465
4945
3025
1612
89
Standard therapy
Immunotherapy
84±4
76±5
Figure 2. Kaplan–Meier Estimates of Survival among the 226 Study Patients Who Had Been Randomly Assigned, According to Treatment Group.
Data are shown for event-free survival (Panel A) and overall survival (Panel B) for all 226 patients and for event-free survival (Panel C) and overall survival (Panel D) for the 179 patients 1 year of age or older at enrollment. The estimated survival (±SE) at 2 years is indicated in each plot.
The New England Journal of Medicine Downloaded from nejm.org on July 18, 2011. For personal use only. No other uses without permission.
Copyright © 2010 Massachusetts Medical Society. All rights reserved.
• Ipilimumabe (Yervoy®): uso adulto pelo FDA e ANVISA
• Imunoterapia antitumoral de espectro potencialmente amplo
• Merchant, ASCO, 2012 - fase I em pacientes pediátricos com melanoma, osteossarcoma e sarcoma de partes moles
• MAB anti-CTLA4, capaz de reverter a tolerância imune tumoral
OUTRAS TERAPIAS-ALVO
• Ácido transretinóico e trióxido de arsênico para LPA
• ATRA (Vesanoid®) - aprovador pela ANVISA e FDA
• Trióxido de arsênico (Trisenox®) - aprovado pelo FDA (ANVISA - uso adulto)
• Cheng, 2013: excelente prognóstico com ATRA e As2O3, mais de 90% de sobrevida prolongada em crianças com LPA
Long‐term prognosis of childhood acute promyelocytic leukaemia with arsenic trioxide administration in induction and consolidation chemotherapy phases: a single‐centre
experience
European Journal of Haematology 17 SEP 2013 DOI: 10.1111/ejh.12194http://onlinelibrary.wiley.com/doi/10.1111/ejh.12194/full#ejh12194-fig-0001
INIBIDORES DE BCL-2
• Indução de apoptose - via mitocondrial intrínseca
• BCL-2: primeiro oncogene anti-apoptótico descoberto
• Amplificação de BCL-2 é comum em leucemias/linfomas
• Proteínas com domínio BH3: inibidores endógenos
• BH3-miméticos: drogas com atividade inibidora da família BCL-2
E MUITO MAIS...
A obra Terapia Alvo - Realidade na Pediatria de Francisco Helder Cavalcante Felix foi licenciada com uma Licença Creative Commons - Atribuição - Uso Não Comercial - Obras Derivadas Proibidas 3.0
Não Adaptada.
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