peter vandenberghe hematologie...hematologie doelgerichte therapieën in de hematologie. the...
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Peter VandenbergheHematologie
Doelgerichte therapieën in de hematologie
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The Precision Medicine Initiative
Tonight, I'm launching a new Precision Medicine Initiative to bring us closer to curing diseases like cancer and diabetes — and to give all of us access to the personalized information we need to keep ourselves and our families healthier.”
— President Barack Obama, State of the Union Address, January 20, 2015
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Doelgerichte medicatie
• ~mab (monoclonal antibody)
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Doelgerichte medicatie
• ~mab (monoclonal antibody)– ~ximab (chimeric), ~zumab (humanized),
~mumab (fully human)– ~tu~(tumor target), ~ci~(circulatory
system), ~im~(immune target)
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Ups and downs of therapeuticantibodies
Boston Biotech Watch, May 1998
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Doelgerichte medicatie
• ~mab (monoclonal antibody)– ~ximab (chimeric), ~zumab (humanized),
~mumab (fully human)– ~tu~(tumor target), ~ci~(circulatory
system), ~im~(immune target)
• ~ib (inhibitors)– ~inib (kinase inhibitors)– ~zomib (proteasome inhibitors)
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‘-inibs’ bij hematologische maligniteiten
• Imatinib en 2e/3e generatie-inhibitoren van BCR-ABL1: chronische myeloïde leukemie
• Ruxolitinib, inhibitor van de JAK-familie: chronische BCR-ABL1-negatieve myeloproliferatieveneoplasmen
• Ibrutinib: mature B-lymfoïde lymfoproliferatieveneoplasmen
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CML
BCR-ABL1
ATP
ADP
De Ph-translocatie en het BCR-ABL1 fusiegen: recurrente genetische afwijkingen en doelwit voor
therapie
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BCR-ABL1
STI
CMLX
De Ph-translocatie en het BCR-ABL1 fusiegen: recurrente genetische afwijkingen en doelwit voor
therapie
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Imatinib in CML
14
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2e/3e generatie-inhibitoren in CML
15
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Therapeutische doelstelling in CML?
• Ziekte-eradicatie
• Ziekte-reductie met 3-log voldoende voor lange termijnsoverleving
• Ziekte-reductie met > 4-5 log voldoende voor poging tot stoppen van behandeling
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Timothy P. Hughes, and David M. Ross Blood 2016;128:17-23
©2016 by American Society of Hematology
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t(9;22), BCR-ABL1, TKI in CML
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[Klampfl et al, NEJM 2013]
95%
2%3%
Polycythemia Vera
JAK2 V617FJAK2 exon 12unknown 55%
4%14%
27%
EssentiëleThrombocythemie
JAK2 V617FMPL exon 10unknownCALR
55%11%
4%
30%
Primaire Myelofibrose
JAK2 V617FMPL exon 10unknownCALR
Recurrente mutaties
in Ph(-) myeloproliferatieve ziekten
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Change in SpleenVolume
Change in SymptomScores
Ruxolitinib, JAK2-inhibitor bij PMF
Verstovsek S et al. N Engl J Med 2012;366:799-807. A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis
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Myelopoiesis Lymfoïdsysteem
Hoe werkt JAK2 inhibitie bij PMF?
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Ruxolitinib in PMF/ PV
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‘-inibs bij hematologische maligniteiten
• Imatinib en 2e/3e generatie-inhibitoren van BCR-ABL1: chronische myeloïde leukemie
• Ruxolitinib, inhibitor van de JAK-familie: chronische BCR-ABL1-negatieve myeloproliferatieveneoplasmen
• Ibrutinib: mature B-lymfoïde lymfoproliferatieveneoplasmen
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Bruton tyrosine kinase: doelwit voor ibrutinib in B- lymfoïde aandoeningen
WaldenströmMYD88 L265P
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Ibrutinib, BTK-inhibitor
• B-CLL– Eerste of tweede lijn
• Mantelcellymfoom– Recidief of refractair
• Immunocytoma – m. Waldenström– MYD88 L265P mutatie– 3e lijn
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Dosis sola facit venenum (Paracelsus)
1971 : carpet bombing2001: targeted therapy
2010 : personalised therapy
20?? : precision medicine