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...

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