l’anemia falciforme: nuovi approcci terapeutici · l’anemia falciforme: nuovi approcci...
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L’ANEMIA FALCIFORME: NUOVI APPROCCI TERAPEUTICI
LuciaDeFranceschi
Dept.diMedicina,AOUIVeronaeUniversita’diVerona-Verona
Treviso17Novembre2017
Hemoglobinopathies are Emerging Problem of Public Health based on YLD and DALYs (1999-2010; 2010-2055)
YLDs: years lived with disability for hemoglobinopathies (β-thal and SCD): 10.197 vs 21.342 cardiovascular disorders DALYs: disability adjusted life years for hemoglobinopathies (β-thal and SCD): 15.640 vs 75.000 diabetes
MurrayCJetalLancet380:2197,2012;KassebaumNJBlood123:615,2014
SCD is a Monogenic Disorder but a MulCorgan Disease
Cerebrovascular disease Retinopathy
ACS, PH
Spleen sequestration, Spleen infarts Hepatomegaly
(Cholelithiasis, jaudice)
Microvascular Occlusions (e.g. mesenteric)
Renal Pathology (e.g. hematuria, enuresis, papillar necrosis)
Priapism Bone disease
Endothelial cells
Exposed Extracellular Matrix
Laminin TSP
BCAM/LU Sulfated Glycolipids
PS
Vesicles PS
PS Erythrophagocytosis
Procoagulant
activity
Endothelial cells
PS
CD36
CD36 TSP
VCAM-1
α4β1 integrin ICAM-4
Abnormal RBC
or Reticulocyte
αVβ3 integrin vWF
MPs
!NO bioavailability
Free Heme
Free Hb
"ROS
Endothelial cells
Endothelial cells
Mac 1
ESL-1
E-Selectin
TF TF
TF TF-MPs
Neutrophils
PS
PS
PLTs
MPs
Activation
coagulation system Cytokine storm:
ET-1
P-Selectin
iNKT iNKT
The high Biocomplexity of SCD Substains MulC-Organ Damage
Modified from De Franceschi L et al. Seminars in Thrombosis, 37: 266; 2011
Hassel K et al. 38: 5512, 2010
Available Treatments for SCD
HU(Hydroxyurea) Tranfusion
HSCT
SCD
FreeHemeFreeHb
RBCdehydraQon
Genetherapy
Endothelial cells
Free Heme Free Hb
éROS
Neutrophils
P-Selectin E-Selectin
Imbalance in vascular tone
ê NO
HbS/HbF
Abnormal Endothelial Activation
Reduction of
Inflammation
Reduction of
Chronic
Hemolysis
HU is a MulCmodal Therapy
Platt OS NEJM 358: 1362, 2008; Saleh AW et al. 102: 31, 1999; Charache S et al. 34: 15, 1997; Yarbro JW et al. 19: 1-10, 1992 ; Maier ER et al Pediatric Res doi 10/1038, 2016;
HU
InSCD,HUamelioratesmortalityandmorbidityandreduces:
• FrequencyofVOCandrateofhospitalizaQon• ACS• Transfusionrequirements• SeveredacQliQsinSCDpediatricpopulaQon
SCDChildren
SCDAdults
HU
WongTEetalBloodEpubOct2014;CrosbyLEetal.PedriatrBloodCancerEpub2014;VoskaridouEetal.Blood115:2354,2010;WangWCetal.TheLancet377:1663,2011;YawnBPetalJAMA312:1033,2014.
HU as Acceptable AlternaCve to Chronic Transfusion in SCD Children with History of TCD AbnormaliCes
• InSCDchildrenunderchronictransfusionregime,acareful transiQontoHUmight be consideredwith normal TCD,mantaining every 3monthsTCDfollow-up;
• IdenQfiedpredicQvefactorsforreversiontoabnormalTCDvelocites:• BeforeHU:HighreQccount(>400x109cells/uL)• AgerHU:WBC.
BernaudinFetalBlood127:1814,2016;HeltonKJetalBlood124:891;2014;WareREBlood119:3925;2012;WareREetalLancet387:661-70,2016
Adherence to HU is a Challenge in SCD
• 35-50%SCDpaQentsachievehighadherencetoHUtherapy;
• MulQplefactors:• ChronicmedicaCon• Socio-economicreasons• AdhesionbarriersrelatedtoadolescenceandtransiConfrompediatriccaretoadultcare
• OngoingstudiesonadherencetoHUtherapy:• ImplementaQonofpharmacyservice• Glowcapdevice• HABITstudy:homevisitsbyCHNandtextmessagingseemtobeeffecQve
InoueSetal.IntJHematol104:2000,2016;HanJetalPharmacotherapydoi10.1002/phar.1834,2016;CerarySetal.JMIRResProtoc5:e193,2016;GreenSetalPediatr.BloodCancer63:2146,2146;2016;GreenNSetalASHposter#1310,2016
Q: WHY DO WE NEED NEW TREATMENTS FOR SCD?
A: Lack Of Therapeutic Options For Acute Events And Prevention of SCD Related Vasculopathy
Novel Therapeutic
Targets in SCD
Sickle Red Cells
Membrane ion transports
Anti-sickling agents
HbF inducers
Vasculopathy and adherence events
Molecules targeting heme connection
Agents modulating vascular tone
Agents interfering with RBCs-vascular adhesion
events
Reversal of adhesion mediated vaso-occlusive events
Blockade of adhesive mechanisms
Molecules modulating INFLAMMATORY pathways involved in adhesion events
Anti-PLTs- anti-coagulant therapies
Oxidative stress
HbS PolymerizaCon and Sickling: TherapeuCc Strategies
• Block intermolecular contacts topreventHbSfibergeneraQon(GBT440)
• DecreaseHbSconcentraQon:o RBCvolumeincreased(CLT,Senicapoc)o HbFinducQon(HU)
• IncreaseHboxygenaffinity
• Weaken fiber contacts (intracellular pHor2-3DPG)LiQetalPNAS11:e689,2017;
DeFranceschiLetalHaematologica89:348,2004
GBT440 (Originally named GTx011) and SCD
• GBT440 is an oral available potent and direct anC-sicklingagent
• GBT440 binds to HbS and promotes a leK shiK inp50 of HbS, delaying HbS polymerizaQon andsickling
• GBT440 ameliorates in vitro red cell deformabilityand viscosity and improves sickle mouse red cellsurvivalwithreducQoninreQculocytecount
DufuKetal..Blood.2014;124:217;OderEetal.BJH175:24,2016;OksenbergDetalBJH175:141,2016;LiQetalPNAS11:e689,2017;
GBT440andClinicalImpactinSCD
• InPhaseI/IIstudydoubleblindplacebocontrolledtrialinhealthyvolunteersandSCDpaQents(SS-Sβ°pts),GBT440showed:o Tobewelltoleratedwithoutmajoradverseeventso Tomodify10-30HbSo ToreduceRBCshemolysiso TodecreasereCculocytecountso TodecreaseEPOlevels
• PhaseIIopenlabelstudyinSCDadolescent:GBT440pharmacokineQcsimilartoadultSCDpaQentsOderEetalBJH175:24,2016;OksenbergDetalBJH175:141,2016;Lehrer-GraiwerJetalBlood126:542,2015;WashingtonCetal.EHAabstract#P620,2017
Novel Therapeutic
Targets in SCD
Sickle Red Cells
Membrane ion transports
Anti-sickling agents
HbF inducers
Vasculopathy and adherence events
Molecules targeting heme connection
Agents modulating vascular tone
Agents interfering with RBCs-vascular adhesion
events
Reversal of adhesion mediated vaso-occlusive events
Blockade of adhesive mechanisms
Molecules modulating INFLAMMATORY pathways involved in adhesion events
Anti-PLTs- anti-coagulant therapies
Oxidative stress
Molecules Interfering with
Sickle-RBCs-Endothelial Adhesive Mechanisms:
Selectin and SCD
• Endothelial cell P-selectins are cell adhesion molecules • P-selectins play a key role in leukocyte recruitment and sickle red cell
adhesion to endothelium • P-selectin values are increased in plasma of SCD patients
PanJJBC273:10058,1998;MatsuiNMBlood98:1955,2001;TurhanAPNAS99:3047,2002;KatoGJBrJHaematol130:943,2005;BlannADJThrombThrombolysis25:185,2008.
TherapeuCc Strategies to Block SelecCn-mediated processes in SCD
• ToblockallselecQns:• Pan-SelecCnantagonist(GMI-1070,Rivipansel)(ChangJetal.Blood116:1779-86,2010;Telen
MJetal.Blood125:2656-64,2015;WuTetal.PlosOne2014:9:e101301,2014)
• TotargetonlyP-selecQn:• HumanizedanC-P-SelecCnanCbody(SelG1)(MandarinoDetalBlood122:abstract#970,2013;
AtagaKIetalabstract#1,2016ASH)
• Sevuparin(TelenMJBJHdoi10.111/BJH14303,2016)
• P-selecCnaptamer(GustaevaDRetal.Blood117:727-35,2011)
Pan-Selectin Antagonist (Rivipansel)
• GMI-1070-RivipanselisaglycomimeQcpan-selecQnantagonist• Inphase1/2,GMI-1070showed:
– asafeprofileandtolerability– reducedE-SelecQnlevelsduringacuteVOCs– StudylimitaQon:failureofprimaryendpoint,enrolmentofSCpaQents
• OngoingphaseIII(NCT02187003)foracuteVOCs.ChangJetal.Blood116:1779-86,2010;TelenMJetal.Blood125:2656-64,2015;WuTetal.PlosOne2014:9:e101301,2014
Humanized Monoclonal Ab against P-selecCn (Crinalizumab) and Acute events in SCD
Inadoubleblindplacebo-controlledmuQnaQonaltrial:• wassafeandwelltollerated• Induceda1monthP-selecQnblock• Reducedpaincrisis• IncreasedtheQmebetweenpaincrisis
Mandarino D et al Blood 122: abstract 970, 2013; TelenMJ Blood 127: 810-19,2016;AtagaKIetalBlood-ASH1,2016;KutlarAetalHaematologicaS454,2017
• SUSTAIN:doubleblindplacebocontrolledphaseIIstudy(NCT0185361)withP-selecQninhibitor-Crizanlizumab
• Genopyte:SS,SC,S/β0,S/β+
• 66ptson2.5mg/Kgevery4weeksand67ptson5mg/Kgevery4weeks
• Crizanlizumab(5mg/Kgevery4):• increasesthelikelihoodofSCDadultpaQentsbeingsicklecellpaincrisisfree• iseffecQvealsoinpaQentsunderHU
KutlarAetalHaematologicaS454,2017
Sevuparin: blocking mulCple adhesion targets in SCD
• SevuparinisaderivaQveoflow-molecularweightheparin,lackinganQcoagulantacQvity
• Sevuparinblocks:
• PandL-selecQns• Thrombospondin-FibronecQn-VonWillebrandfactor
• OngoingphaseIImulQcenterinternaQonaltrialonsevuparininacuteVOCs
TelenMJBlood127:810-19,2016;TelenMJBJHdoi10.111/BJH14303,2016
RBCdehydraQon
Vasculopathy
InflammaQon
PLTsandcoagulaQon
FreeHbFreeheme
ROS
SCDRequiresMulQtargetTreatment
PerspecCves: CombinaCon Therapies for SCD
• HUincombinaQonwith:-ChronicP-selecQnblockade(AtagaKIetal.abstract#1,2016;TelenMJetaldoi10.111/BJH14303,2016)
-NutriQonal/dietarysupplementaQon(i.e.:ω-3faryacid,Mg2+supplementaQon)(KalisBetalHaematologica100:870-80,2015;DaakAAetal.AJCN97:37,2013;HankinsJSetal.BJH140:80,2008)-AnQ-inflammatoryagents(Regadenoson)(FieldJJBlood121:3329,2013;FieldJJBlood122abstract#977,2013)
• CombinaQontreatmentwithoutHU:
• AnQ-sicklingagent(s)combinedwithP-selecQnblockade(SwigRetalabstract#121,2016;LehrerJetal.abstract#2488,2016;AtagaKIetal.abstract#1,2016;TelenMJetaldoi10.111/BJH14303,2016)
• AnQ-sicklingagent(s)andanQ-inflammatoryagentssuchasRegadenoson(SwigRetalabstract#121,2016;LehrerJetal.abstract#2488,FieldJJBlood121:3329,2013;FieldJJBlood122abstract#977,2013)
CONCLUSIONS
• New therapeuQc strategies for SCD involve pathophysiology-basedtargets;
• Noveltreatmentsaredirectedtomodifynaturalhistoryofthe
disease such as acute VOC and related chronic organcomplicaQonsinSCD
• A new field of combinatorial therapy for SCD will require aholisQcapproach,consideringtheimprovementofpaQentQoLasanimportantoutcomeindesigningnewclinicalstudies.
Studio SITE per la Mappatura dei Pazienti con SCD e in Trattamento Medico Intensivo con
HU
Rigano P et al. Blood Mol and Disease Epub 2017
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