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PParoxysmalaroxysmalNNocturnalocturnalHHemoglobinuriaemoglobinuria
New ideas about an old New ideas about an old diseasedisease
Ahmad Shihada Silmi Msc, FIBMS
Staff Specialist in Hematology
Medical Technology Department
Islamic University of Gaza
ObjectivesObjectives
Try to answer some of the frequently Try to answer some of the frequently asked questions about:asked questions about:
The cause of the PNHThe cause of the PNH The clinical presentation of PNHThe clinical presentation of PNH Diagnosing PNHDiagnosing PNH The complications of PNHThe complications of PNH New treatments for PNHNew treatments for PNH
What is PNH?What is PNH?
A disorder of blood affecting all the cells which A disorder of blood affecting all the cells which
come the bone marrow. come the bone marrow. Prevalence 1-4 per million The disease is quite rare, only 10, 000 patients The disease is quite rare, only 10, 000 patients
in the US and Europe.in the US and Europe. There is no ethnic preference for the disorder.There is no ethnic preference for the disorder. It may present early or late in life.It may present early or late in life. The manifestations may be “classic” or The manifestations may be “classic” or
obscure. obscure.
PNH Prognosis
Significant morbidity and mortality Patients have lived for extended periods of time and
have seen spontaneous recovery Report of 80 patients showed that 60% of deaths due
to venous thrombosis or bleeding Retrospective study of 220 patients
Kaplan-Meier survival 78, 65, and 48% at 5, 10, and 15 years 8 year rates of major complications of PNH (pancytopenia,
thrombosis, MDS) 15, 28, and 5% Up to 5% of patients can develop acute leukemia; onset about
5 years after Dx of PNH Likely incident of leukemia lower than 5%
What is PNH Mutation? What is PNH Mutation?
PNH is due to a mutation in a gene in a blood PNH is due to a mutation in a gene in a blood stem cell.stem cell.
The gene is called the The gene is called the PIG-APIG-A gene gene (phosphatidylinositol glycan complementation group A) and is located on the X chromosome. and is located on the X chromosome. >100 mutations in PIG - A gene known in PNH The mutations (mostly deletions or
insertions) generally result in stop codons - yielding truncated proteins which may be non or partially functional - explains heterogeneity seen in PNH
What is PNH?What is PNH?
In most cases of PNH, the change in In most cases of PNH, the change in the gene (mutation) is acquired, the gene (mutation) is acquired, not not something you are born with. When something you are born with. When and why is unknown.and why is unknown.
The gene contains the genetic The gene contains the genetic information for the information for the GPI anchorsGPI anchors which link proteins to the cell which link proteins to the cell membranemembrane
What is PNH?What is PNH?
A mutation is a “mistake” or a “change” A mutation is a “mistake” or a “change” in the gene that arises during copying in the gene that arises during copying and is not correctedand is not corrected
When the cell divides, the mutation is When the cell divides, the mutation is transmitted to daughter cellstransmitted to daughter cells
The effect of a mutation:The effect of a mutation: NoneNone An altered protein (sickle hemoglobin)An altered protein (sickle hemoglobin) No protein is produced as in PNH, hemophilia No protein is produced as in PNH, hemophilia
etcetc
Stem CellsStem Cells
Embryonic Stem Cell
Somatic Stem Cells
Blood
Muscle Nerve
Etc.Egg or Sperm
Egg
Egg Sperm
The Cells of Each Specific Organ
Stem CellsStem Cells
Embryonic Stem Cell
Somatic Stem Cells
Blood
Muscle Nerve
Etc.Egg or Sperm
Egg
Egg Sperm
The Cells of Each Specific Organ
Stem CellsStem Cells
Embryonic Stem Cell
Somatic Stem Cells
Blood
Muscle Nerve
Etc.Egg or Sperm
Egg
Egg Sperm
The Cells of Each Specific Organ
Stem CellsStem Cells
STEM CELL
T LYMPHOCYTES
B LYMPHOCYTES
ERYTHROCYTES
GRANULOCYTES
MONOCYTES
PLATELETS
Stem CellsStem Cells
STEM CELL
T LYMPHOCYTES
B LYMPHOCYTES
ERYTHROCYTES
GRANULOCYTES
MONOCYTES
PLATELETSALTERED GENE
Stem CellsStem Cells
ABNORMAL CLONE
NORMAL CLONES
GPI-AP Biosynthesis:GPI-AP Biosynthesis:Involves 10 Steps and >20 Involves 10 Steps and >20
GenesGenes
N NN
PIG-A
Endoplasmic Reticulum
Plasma Membrane
Raft
GlcNAc-PI
PI
The Beginning of PNHThe Beginning of PNH
The change that occurs in PNH stops The change that occurs in PNH stops the production of an anchor that ties the production of an anchor that ties protein molecules to the cellprotein molecules to the cell Sometimes the stop is only partial and Sometimes the stop is only partial and
PNH II cells occurPNH II cells occur
The GPI Anchor Defect in The GPI Anchor Defect in PNHPNH
2 2CH CH CH
C=O
O
O
O-P-O
O
O
(18:0,1)
(22:4,5)
C=O
Asp
C=O2 2
O
O=P=O
O
O
CH CH CH
C=O
O
CH2
CH2
NH
CH2CH2
NH
O2
O
O-P=O
O-P-O
O
O
(18:0,1)
(22:4,5)
(16:0)
N
( 1-2)
( 1-6)
( 1-4)
PROTEIN
NORMAL PNH
PIG - A gene codes for 60 kDa protein glycosyltransferase which effects the first step in the synthesis of the glycolipid GPI anchor (glycosylphosphatidylinositol). Results in clones lacking GPI anchor - in turn, attached proteins
Pathogenesis - The Defect
GPI GPI AnchorAnchor
PIG - APIG - A protein protein
What is PNH?What is PNH?
As a result of the PIG-A mutation, As a result of the PIG-A mutation, there is little of no GPI anchor there is little of no GPI anchor produced.produced. PNH II cells- mild reductionPNH II cells- mild reduction PNH III cells- severely reduced.PNH III cells- severely reduced. When the anchor is reduced, certain When the anchor is reduced, certain
proteins can’t attach to the cells. proteins can’t attach to the cells. The most important proteins for The most important proteins for
PNH are CD 59, CD55PNH are CD 59, CD55..
Proteins anchored by GPI Anchorand
Surface Proteins Missing on PNH Blood CellsSurface Proteins Missing on PNH Blood Cells
Antigen Expression PatternAntigen Expression Pattern
EnzymesEnzymesAcetylcholinesterase (AchE) Acetylcholinesterase (AchE) Red blood cellsRed blood cellsEcto-5'-nucleotidase (CD73) Ecto-5'-nucleotidase (CD73) Some B- and T-Some B- and T-lymphocyteslymphocytesNeutrophil alkaline phosphatase(NAP) Neutrophil alkaline phosphatase(NAP) NeutrophilsNeutrophilsADP-rybosyl transferase ADP-rybosyl transferase Some T-lymphs, Some T-lymphs, NeutrophilsNeutrophils
Adhesion moleculesAdhesion moleculesBlast-I/CD48 Blast-I/CD48 LymphocytesLymphocytesLymphocyte function- Lymphocyte function- associated antigen-3(LFA-3 or CD58) associated antigen-3(LFA-3 or CD58) All blood cellsAll blood cellsCD66bCD66b NeutrophilsNeutrophils
Complement regulating surface proteinsComplement regulating surface proteinsDecay accelerating factor (DAF or CD55) Decay accelerating factor (DAF or CD55) All blood cellsAll blood cellsHomologous restriction factor,Homologous restriction factor,Membrance inhibitor of reactive lysis Membrance inhibitor of reactive lysis All blood cellsAll blood cells(MIRL or CD59)(MIRL or CD59)
Surface Proteins Missing on PNH Blood CellsSurface Proteins Missing on PNH Blood Cells
Antigen Expression PatternAntigen Expression Pattern
ReceptorsReceptorsFc-Fc- receptor III (Fc receptor III (Fc Rlll or CD16) Rlll or CD16) Neutrophils, NK-cells, Neutrophils, NK-cells, macrophages,macrophages,
some T-lymphocytessome T-lymphocytesMonocyte differentiation antigen Monocyte differentiation antigen Monocytes, macrophagesMonocytes, macrophages(CD14)(CD14)Urokinase-type Plasminogen Urokinase-type Plasminogen Monocytes, granulocytesMonocytes, granulocytesActivator Receptor (u-PAR, CD87)Activator Receptor (u-PAR, CD87)
Blood group antigensBlood group antigensComer antigens (DAF) Comer antigens (DAF) Red blood cellsRed blood cellsYt antigens (AchE) Yt antigens (AchE) Red blood cellsRed blood cellsHolley Gregory antigen Holley Gregory antigen Red blood cellsRed blood cellsJohn Milton Hagen antigen (JMH) John Milton Hagen antigen (JMH) Red blood cells, lymphocytesRed blood cells, lymphocytesDombrock reside Dombrock reside Red blood cellsRed blood cells
Neutrophil antigensNeutrophil antigensNB1/NB2 NB1/NB2 NeutrophilsNeutrophils
Surface Proteins Missing on PNH Blood CellsSurface Proteins Missing on PNH Blood Cells
Antigen Expression PatternAntigen Expression Pattern
Other surface proteins Other surface proteins of unknown functionsof unknown functionsCAMPATH-1 antigen (CDw52) CAMPATH-1 antigen (CDw52) Lymphocytes, Lymphocytes, monocytesmonocytesCD24 CD24 B-lymphocytes, B-lymphocytes, Neutrophils, Neutrophils,
eosinophilseosinophilsp5O-80p5O-80 NeutrophilsNeutrophilsGP500 GP500 PlateletsPlateletsGPI75 GPI75 PlateletsPlatelets
PathogenesisCD 55
Also known as decay accelerating factor Accelerates decay of enzyme that
destroys red cell membranes CD55 inhibits the formation or destabilizes
complement C3 convertase (C4bC2a) When GPI anchor absent, CD55 not
available and RBC membranes hemolyze
PathogenesisCD59
Also known as membrane inhibitor of reactive lysis, protectin, homologous restriction factor, and membrane attack complex inhibitory factor
CD59 Protects the membrane from attack by the C5-C9 complex
Absence or reduction of CD59 leads to increased hemolysis and perhaps thrombosis
Pathogenesis of CD55 & CD59
Inherited absences of both proteins in humans have been described
Most inherited deficiencies of CD55 - no distinct clinical hemolytic syndrome
Inherited absence of CD59 - produces a clinical disease similar to PNH with hemolysis and recurrent thrombotic events
Pathogenesis
Many normal people have very small numbers Many normal people have very small numbers (perhaps 6 per 1,000,000 bone marrow cells)(perhaps 6 per 1,000,000 bone marrow cells)
In PNH, the abnormal cells have an advantage In PNH, the abnormal cells have an advantage and become a major population in the marrow and become a major population in the marrow and blood (anywhere from 1% to over 90%)and blood (anywhere from 1% to over 90%) This may be a result of change in the immune This may be a result of change in the immune
system –inability to recognize something system –inability to recognize something foreign. foreign.
Or it may be related to aplastic anemia, a Or it may be related to aplastic anemia, a disease of poor production of blood from the disease of poor production of blood from the marrow-WHY?marrow-WHY?
Pathogenesis - Clonal evolution and cellular selection
Expansion of abnormal hematopoietic stem cell required for PNH disease expression Theories for expansion
Blood cells lacking GPI-linked proteins have intrinsic ability to grow abnormally fast
In vitro growth studies demonstrate that there are no differences in growth between normal progenitors and PNH phenotype progenitors
In vivo - mice deficient for PIG -A gene also demonstrates no growth advantage to repopulation of BM.
Additional environmental factors exert selective pressure in favor of expansion of GPI anchor deficient blood cells
Close association with AA - PNH hematopoitic cells cells may be more resistant to the Immune System than normal hematopoitic cells.
Evidence in AA is that the decrease in hematopoitic cells is due to increased apoptosis via cytotoxic T cells by direct cell contact or cytokines (escape via deficiency in GPI linked protein???)
PNH Clinical FeaturesPNH Clinical Features Aplastic Anemia Aplastic Anemia
Some PNH patients have aplastic anemia or Some PNH patients have aplastic anemia or a history of aplastic anemiaa history of aplastic anemia
Many PNH patients have evidence of a bone Many PNH patients have evidence of a bone marrow that doesn’t work well or well marrow that doesn’t work well or well enough to maintain normal blood countsenough to maintain normal blood counts
Therefore, whatever causes aplastic anemia Therefore, whatever causes aplastic anemia (immune suppression or dysregulation or (immune suppression or dysregulation or damage to the stem cells) may allow PNH to damage to the stem cells) may allow PNH to developdevelop
What is PNH?What is PNH? ComplementComplement
Complement is a group of blood Complement is a group of blood proteins that act together to help the proteins that act together to help the body get rid of microbiological invadersbody get rid of microbiological invaders One of the ways it does this is by One of the ways it does this is by
penetrating the membrane (outside penetrating the membrane (outside surface) of the invading bacteria or surface) of the invading bacteria or viruses.viruses.
When this happens to PNH blood When this happens to PNH blood cells, the cells are destroyed.cells, the cells are destroyed.
What is PNH?What is PNH?
Complement circulates in an inactive Complement circulates in an inactive formform
It is activated spontaneously and by a It is activated spontaneously and by a variety of eventsvariety of events It is normally activated more at nightIt is normally activated more at night It is more active with infections, It is more active with infections,
trauma, vaccinations, surgery, trauma, vaccinations, surgery, immune complexes, autoimmune immune complexes, autoimmune diseasesdiseases
What is PNH?What is PNH?ComplementComplement
Complement activity is regulated by proteins Complement activity is regulated by proteins in the blood and on the membranes of the cell.in the blood and on the membranes of the cell.
Proteins on the cell surface interfere Proteins on the cell surface interfere with complement to prevent breakdown with complement to prevent breakdown (lysis) of the cell membrane(lysis) of the cell membrane The most important of these is The most important of these is CD59CD59, which , which
is missing on the abnormal cells of PNHis missing on the abnormal cells of PNH For this reason, PNH red cells are extremely For this reason, PNH red cells are extremely
sensitive to very small amounts of activated sensitive to very small amounts of activated complementcomplement
C5b
C5
C5a
Adapted from Cellular and Molecular Immunology AK Abbas, AH Litchman and JS Pober, 3rd Edition. 1991 WB Saunders; Philadelphia.
C7C8
C5b
C7
C6
C7
C6
C5b,6,7
C8
C5bC6
C5b-8
C9
C7
C8
C5bC6
C9
C7
C8
C5bC6
C9 x 12 - 15
C5b-9
CD59 CD59
X X
C5
co
nvert
ase
C5
co
nvert
ase
Absence of CD59 Allows Absence of CD59 Allows Terminal Complement Complex Terminal Complement Complex
FormationFormation
C3b
Bb+
C3
What is PNH?What is PNH?
Complement successfully attacks the red Complement successfully attacks the red cells and they break up (hemolysis)cells and they break up (hemolysis) This releases hemoglobin (the red pigment in This releases hemoglobin (the red pigment in
red cells) into the plasmared cells) into the plasma Causes anemia Causes anemia Pieces of the membrane come off.Pieces of the membrane come off.
The white cells release granule contents The white cells release granule contents and change to express other proteins.and change to express other proteins.
The platelets form vesicles (membrane The platelets form vesicles (membrane blisters) and activate.blisters) and activate.
What is PNH?What is PNH?
Normal red blood Normal red blood cells are cells are protected from protected from complement complement attack by a shield attack by a shield of terminal of terminal complement complement inhibitorsinhibitors
Complement activation
PP
Without this Without this protective protective complement complement inhibitor shield, inhibitor shield, PNH red blood PNH red blood cells are cells are destroyeddestroyed
What is PNH?What is PNH?Clinical FeaturesClinical Features
Some of the hemoglobin passes through Some of the hemoglobin passes through the kidneys and into the urine, causing the kidneys and into the urine, causing red to dark brown urine (hemoglobinuria)red to dark brown urine (hemoglobinuria) This causes a loss of iron from the This causes a loss of iron from the
bodybody In the long run, this may damage the In the long run, this may damage the
kidneykidney Free hemoglobin binds nitric oxide Free hemoglobin binds nitric oxide
causing vascular and smooth muscle causing vascular and smooth muscle spasmspasm
Causes inflammationCauses inflammation
Action of Nitric Oxide Action of Nitric Oxide (NO)(NO)
Smooth MuscleContraction
Smooth MuscleRelaxation
NONO
Free Hemoglobin Binds Free Hemoglobin Binds NONO
Smooth MuscleContraction
Smooth MuscleRelaxation
NONO
NOFree Hemoglobin
What Are The Effects of What Are The Effects of Nitric Oxide Trapping by Nitric Oxide Trapping by
HemoglobinHemoglobin Spasm of the esophagusSpasm of the esophagus Abdominal painAbdominal pain Erectile dysfunctionErectile dysfunction Other symptoms such as “fatigue”Other symptoms such as “fatigue”
What is PNHWhat is PNHClinical aspectsClinical aspects
Vascular (arterial constriction, HBP)Vascular (arterial constriction, HBP) Pulmonary artery pressure increase Pulmonary artery pressure increase
(PHTN)(PHTN) Spasm of the esophagusSpasm of the esophagus Abdominal painAbdominal pain Erectile dysfunctionErectile dysfunction Other symptoms such as “fatigue”Other symptoms such as “fatigue” Platelets are more “reactive”Platelets are more “reactive”
What is PNH?What is PNH?Clinical FeaturesClinical Features
WBC: WBC: GranulocytesGranulocytes - release content stimulating - release content stimulating
inflammationinflammation MonocytesMonocytes - activate expressing TF which leads - activate expressing TF which leads
to blood clots. TF-Microvesiclesto blood clots. TF-Microvesicles
Platelets Platelets become “activated”become “activated” They stick together and form clumpsThey stick together and form clumps The membrane changes, allowing them to The membrane changes, allowing them to
bind to monocytesbind to monocytes Pieces of the membrane come off Pieces of the membrane come off
(microvesicles) (microvesicles)
What is PNH?What is PNH?Clinical FeaturesClinical Features
Hemolytic anemia due to Hemolytic anemia due to complement activationcomplement activation Hemoglobinuria and, eventually, kidney Hemoglobinuria and, eventually, kidney
damagedamage Anemia to a variable degreeAnemia to a variable degree Effects of NO depletion- HBP, smooth Effects of NO depletion- HBP, smooth
muscle dystonia, reduced blood flow to muscle dystonia, reduced blood flow to the kidney and lungsthe kidney and lungs
Impaired bone marrow functionImpaired bone marrow function
What is PNH?What is PNH?Clinical FeaturesClinical Features
Thrombosis (Blood clots)Thrombosis (Blood clots) Often in unusual places (liver veins, Often in unusual places (liver veins,
abdominal veins, cerebral veins, abdominal veins, cerebral veins, dermal veins)dermal veins)
Fatigue – overwhelming, poor Fatigue – overwhelming, poor correlation to level of hemoglobincorrelation to level of hemoglobin
inflammation inflammation anemiaanemia Portal hypertensionPortal hypertension (PHTN).PHTN).
MONOCYTES
PLATELET
Endothelial cells
C5b-9
HEMOLYSIS
COMPLEMENT INJURY
TF
THROMBINGENERATIONCOMPLEMEN
T
Thrombosis in PNH Thrombosis in PNH PathophysiologyPathophysiology
TF = Tissue factor.
NOPS
CYTOKINES IL-6INFLAMMATION
C5a
Laboratory Evaluation of PNH
Acidified Serum Test (Ham Test 1939) Acidified serum activates alternative
complement pathway resulting in lysis of patient’s rbcs
May be positive in congenitial dyserythropoietic anemia
Still in use today Sucrose Hemolysis Test (1970)
10% sucrose provides low ionic strength which promotes complement binding resulting in lysis of patient’s rbcs
May be positive in megaloblastic anemia, autoimmune hemolytic anemia, others
Less specific than Ham test
PNH Diagnosis by Flow Cytometry (1986) Considered method of choice for
diagnosis of PNH (1996) Detects actual PNH clones lacking GPI
anchored proteins More sensitive and specific than Ham
and sucrose hemolysis test
Laboratory Evaluation of PNH
PNH Diagnosis by Flow Cytometry
AntigenAntigen Cell LineageCell Lineage FunctionFunction
CD14CD14 monocytesmonocytes LPS receptor, MDFLPS receptor, MDF
CD16CD16 neutrophilsneutrophils FcFcIII receptorIII receptor
CD24CD24 neutrophilsneutrophils B-cell differentiation B-cell differentiation markermarker
CD55CD55 all lineagesall lineages DAFDAF
CD58CD58 all lineagesall lineages possible adhesionpossible adhesion
CD59CD59 all lineagesall lineages MIRL, HRF, protectinMIRL, HRF, protectin
CD66bCD66b neutrophilsneutrophils CEA-related CEA-related glycoproteinglycoprotein
Of the long list of GPI anchored protein, monoclonal Of the long list of GPI anchored protein, monoclonal antibodies to the following antigens have been used in antibodies to the following antigens have been used in the diagnosis of PNHthe diagnosis of PNH
The most useful Abs are to CD14, 16, 55, 59, and 66. The most useful Abs are to CD14, 16, 55, 59, and 66. Are all required? Probably not - more studies needed Are all required? Probably not - more studies needed
Antigen expression is generally categorized into three antigen density groups type I Normal Ag expression
type II Intermediate Ag expression
type III No Ag expression
Patient samples that demonstrate cell populations with diminished or absent GPI-linked proteins (Type II or III cells) with multiple antibodies are considered to be consistent with PNH.
Should examine multiple lineages (ie granulocytes & monocytes)
PNH Diagnosis by Flow Cytometry
PNH Diagnosis by Flow CytometryExamples of variable GPI linked CD59 expression on Examples of variable GPI linked CD59 expression on granulocytes on four PNH patientsgranulocytes on four PNH patients
PNH Diagnosis by Flow Cytometry
Example of variable Example of variable expression of expression of several GPI linked several GPI linked Ags on several Ags on several lineageslineages
From Purdue Cytometry CD-ROM vol3 97
Flow Cytometry is method of choice but only supportive for/against diagnosis
More studies are needed to better define whether the type (I, II, or III), cell lineage, and size of thecirculating clone can provide additional prognosticinformation.
Theoretically - should be very valuable
PNH Diagnosis by Flow Cytometry
Historical Management Historical Management Options for PNH Options for PNH
TransfusionsTransfusions AnticoagulantsAnticoagulants SupplementsSupplements
Folic acidFolic acid IronIron Erythropoiesis stimulating agentsErythropoiesis stimulating agents
Steroids/androgen hormonesSteroids/androgen hormones Allogeneic bone marrow transplantAllogeneic bone marrow transplant
(limited eligibility(limited eligibility))
Generally conservative, supportive, and dependent on symptom severity1,2
What is SolirisWhat is Soliris®®??
Monoclonal antibody (protein) that Monoclonal antibody (protein) that blocks complement at C5 preventing blocks complement at C5 preventing the formation of the terminal the formation of the terminal complement complexcomplement complex
Quickly and markedly reduces Quickly and markedly reduces hemolysishemolysis Stops hemoglobinuriaStops hemoglobinuria Increases hemoglobin levelIncreases hemoglobin level
Reduces transfusionsReduces transfusions Hematocrit may not be quite normalHematocrit may not be quite normal
SOLIRIS Blocks Terminal SOLIRIS Blocks Terminal ComplementComplement
Lectin Classical Alternative
C3 C3a
C3b
C5
Pro
xim
al
Term
inal
MicroorganismsAntigen-Antibody Complexes
Constitutive/Microorganisms
Figueroa, et al. Clin Microbiol Rev. 1991;4:359-395.Walport. N Engl J Med. 2001;344:1058.SOLIRIS™ (eculizumab) [package insert]. Alexion Pharmaceuticals; 2007.
C5b-9Cause of Hemolysis in PNH
C5a
C5b
SOLIRISSOLIRIS
• Proximal functions of complement remain intact•Weak anaphylatoxin
•Immune complex and apoptotic body clearance
•Microbial opsonization
• Terminal complement activity is blocked
• SOLIRIS binds with high affinity to C5
Reduction in LDH During SolirisReduction in LDH During Soliris®® Treatment in TRIUMPH and SHEPHERDTreatment in TRIUMPH and SHEPHERD
Time, WeeksTime, Weeks
Lac
tate
Deh
ydro
gen
ase
(U/L
)L
acta
te D
ehyd
rog
enas
e (U
/L)
TRIUMPH placebo patients switched to SOLIRIS after week 26. All TRIUMPH patients entered the long term extension study.
00
500500
10001000
15001500
20002000
25002500
30003000
00 1010 2020 3030 4040 5050
TRIUMPH – Placebo/extensionTRIUMPH – Placebo/extension
TRIUMPH – SOLIRIS/extensionTRIUMPH – SOLIRIS/extension
SHEPHERD – SOLIRISSHEPHERD – SOLIRIS
PI: All patients sustained a reduction in intravascular hemolysis over a total SOLIRIS exposure time ranging from 10 to 54 months.
4 4 7 7 5 5 8 8 5 8 4 1 1 8 1 1 1 1 1 1 1 1 1 1 1 1 1
Pre-eculizumab Post-eculizumab
Urine score 2 weeks before & after Eculizumab
1
Effect of SolirisEffect of Soliris® ® on Ability on Ability to Maintain a Good to Maintain a Good
HemoglobinHemoglobin
PP<0.000000001<0.000000001
SOLIRISSOLIRISPlaceboPlacebo
Hem
og
lob
in S
tab
iliz
atio
n (
%)
Hem
og
lob
in S
tab
iliz
atio
n (
%)
0
10
20
30
40
50
Effect of SolirisEffect of Soliris®® on on Transfusion in PNHTransfusion in PNH
PP<0.0000001<0.0000001
Tra
nsf
use
dT
ran
sfu
sed
Un
its/
Pat
ien
tU
nit
s/P
atie
nt (
med
ian
) (
med
ian
)
SolirisSoliris®®PlaceboPlacebo
0
2
4
6
8
10
What is the effect of What is the effect of SolirisSoliris®® in PNH in PNH
Stops the symptoms associated with Stops the symptoms associated with hemolysishemolysis ““Fatigue”Fatigue” Esophageal and abdominal spasmEsophageal and abdominal spasm Erectile dysfunctionErectile dysfunction Improves sense of well beingImproves sense of well being Reduced the need for transfusionReduced the need for transfusion
Appears to reduce thrombosis (blood Appears to reduce thrombosis (blood clots)clots)
Effect of Eculizumab on the Effect of Eculizumab on the blood clots in PNH blood clots in PNH
Equalized Patient Years (195)Equalized Patient Years (195) Patients on Antithrombotics n=103Patients on Antithrombotics n=103 ((P P < 0.000000001< 0.000000001
39
3
05
1015202530354045
Pre-Soliris Treatment Soliris Treatment
Thro
mbo
tic E
vent
s (#
)
P=0.0001
10.61
0.62
0.00
2.00
4.00
6.00
8.00
10.00
12.00
Pre-Soliris Treatment Soliris Treatment
Th
rom
bo
sis
Ev
en
t R
ate
(TE
pe
r 1
00
Pt-
Ye
ars
)
91% reduction in TE event rate with Eculizumab
92% reduction in TE events with Eculizumab
Pre-EculizumabPost-Eculizumab
Pre-Eculizumab Post-Eculizumab
What is the Effect of What is the Effect of SolirisSoliris®®??
Improves kidney functionImproves kidney function reduced hemoglobinuria and iron reduced hemoglobinuria and iron
depositiondeposition Reduced thrombosisReduced thrombosis
Improves hypertensionImproves hypertensionMay in part be due to availability of nitric May in part be due to availability of nitric
oxideoxide
Side Effects of SolirisSide Effects of Soliris®® TreatmentTreatment
Susceptibility to sepsis by meningococcal Susceptibility to sepsis by meningococcal organismorganism All patients must be vaccinated at least 2 weeks All patients must be vaccinated at least 2 weeks
before starting Solirisbefore starting Soliris All patients must know to seek medical help All patients must know to seek medical help at onceat once
when fever happenswhen fever happens All patients must carry cards describing this All patients must carry cards describing this
complicationcomplication Headache – first week or 2Headache – first week or 2 CostCost InconvenienceInconvenience
Must be given every 12-14 days by veinMust be given every 12-14 days by vein
What SolirisWhat Soliris®® Cannot Do Cannot Do
Does not appear to improve impaired Does not appear to improve impaired bone marrow functionbone marrow function Low white count or low platelet count Low white count or low platelet count
may persist in some patients, especially may persist in some patients, especially if it is due to aplastic anemiaif it is due to aplastic anemia
Other treatments may be indicatedOther treatments may be indicated Bone marrow transplantationBone marrow transplantation immunosuppressivesimmunosuppressives
When is Soliris When is Soliris Ineffective or Less Ineffective or Less
Effective Effective Patient has been incorrectly Patient has been incorrectly
diagnosed with PNH.diagnosed with PNH. Patient has a very small PNH clone Patient has a very small PNH clone
(less than 10%)(less than 10%)
bone marrow failure- AAbone marrow failure- AA Breakthrough – infections, increased Breakthrough – infections, increased
clearance, delayed dosingclearance, delayed dosing Extravascular hemolysis Extravascular hemolysis
Which PNH Patients are Which PNH Patients are Candidates for Soliris?Candidates for Soliris?
Patients with hemolysis (LDH )Patients with hemolysis (LDH ) Patients with large CD 59 deficient clones- Patients with large CD 59 deficient clones-
RBC , WBCRBC , WBC Patients with hemolysis with evidence of renal Patients with hemolysis with evidence of renal
impairement GRF<90, proteinuria etcimpairement GRF<90, proteinuria etc Patients with history of thrombosisPatients with history of thrombosis Patients with hemolysis and elevated DdimersPatients with hemolysis and elevated Ddimers Patients with hemolysis with fatigue Patients with hemolysis with fatigue Patients with hemolysis and transfusion Patients with hemolysis and transfusion
dependencedependence Patients prior to ?BMT, surgery, ???pregnancy Patients prior to ?BMT, surgery, ???pregnancy
Who Should Get SolirisWho Should Get Soliris®®??
In all cases, the decision should be made bya physician that understand PNH, its complications and its treatment in conjunction with the patient, whose life is affected by the disorder.