Living with PNHParker CJ, Williams Hematology, 8th Edition, 2010, pg. 526 Thrombosis Is the Leading...
Transcript of Living with PNHParker CJ, Williams Hematology, 8th Edition, 2010, pg. 526 Thrombosis Is the Leading...
7/3/2013
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Living with PNH
Laurence A. Boxer, MD
University of Michigan
Case Study15 year old awakened in the morning with chest pain and a sore throat. She experienced chest pain all day accompanied with coughing up blood. CXR was negative in the ER but her CBC revealed a WBC of 3.2, HCT 32%, platelets 20,000, D-Dimers were elevated. PHX of abdominal pain for past 5 years, urinalysis was positive in the past for blood or hemoglobin.
Lab Tests: Hemoglobinuria, PNH screen was positive on red cells ˜39%, flaer test on neutrophils and monocytes was 39%. Bone marrow biopsy revealed normal number of precursors. The diagnosis was PNH presenting with pancytopenia.
Therapy: Solaris
Paroxysmal Nocturnal Hemoglobinuria
(PNH):
A Chronic, Systemic, and Life-
Threatening Disease
What is PNH? PNH: What it’s Not
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The Defect in PNH
The Role of Complement
The Complement System: Always on,
Strongly Amplified, Dependent on
Natural Regulators
Factors That Accelerate Complement
Activation
Testing for PNH in RBCsPatient 1:
Normal RBCs with normal
CD59 expression
(Type I cells)
Patient 3:
PNH clone with complete
CD59 deficiency
(Type III cells) and
partial CD59 deficiency
(Type II cells)
Patient 2:
PNH clone with complete
CD59 deficiency
(Type III cells)
Gating on GPA+ Gating on GPA+ RBCsRBCs
GPA = glycophorin A.
Data Source: Dahl-Chase Diagnostic Services..
Why Look Beyond RBCs for PNH?
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ICCS Recommendations for Follow-Up
Testing of Patients With an Identified
PNH Clone
PNH Clone Expanded in <1 YearPNH Clone Expanded in <1 Year
3 Months 6 Months
May May 20092009
Gran clone: 23.3%Gran clone: 23.3%
RBC clone: 2.4%RBC clone: 2.4%
CD
24
-Gra
nu
locy
tes
FLAER-GPI Anchor Marker
CD59 –GPI Anchor Protein
March 2009March 2009
Gran clone: 14.2%Gran clone: 14.2%
RBC clone: 1.8%RBC clone: 1.8%
CD
24
-Gra
nu
locy
tes
FLAER-GPI Anchor Marker
CD59 –GPI Anchor Protein
CD
14
-Gra
nu
loc
yte
s
December 2008December 2008
Gran clone: 7.6%Gran clone: 7.6%
RBC clone: 1.6%RBC clone: 1.6%
FLAER-GPI Anchor Marker
CD59 –GPI Anchor Protein
CD
24
-Gra
nu
locy
tes
Gran clone: 3.8%Gran clone: 3.8%
RBC clone: 0.8%RBC clone: 0.8%
September 2008September 2008
CD
24
-Gra
nu
locy
tes
FLAER-GPI Anchor Marker
CD59 –GPI Anchor Protein
9 Months
Importance of Monitoring Granulocytes and RBCs Over Time
Data Source: Dahl-Chase Diagnostic Services.
Chronic Uncontrolled Complement
Activation
Leads to Devastating Consequences
LDH = lactate dehydrogenase.
1. International PNH Interest Group. Blood 2005;106:3699–3709; 2. Brodsky R. Paroxysmal nocturnal hemoglobinuria. In: R Hoffman et al, eds. Hematology - Basic
Principles and Practices. 4th ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2005;419–427; 3. Rother RP et al. JAMA. 2005;293:1653–1662; 4. Socie G et al. Lancet
1996;348:573–577; 5. Hill A et al. Br J Haematol 2007;137:181–192; 6. Lee JW et al. Hematologica 2010;95(s2): Abstracts 505 and 506; 7. Hill A et al. Br J Haematol
2010;149:414–425; 8. Hillmen P et al. Am J Hematol 2010;85:553–559.
Thrombosis
FatigueFatigue
Renal Failure
Abdominal Pain
Dyspnea
DysphagiaDysphagia
HemoglobinuriaHemoglobinuria
Erectile DysfunctionErectile Dysfunction
Significant Impact on
Survival
Significant Impact on
Morbidity
Pulmonary Hypertension
Chest Pain
ComplementComplement
ActivationActivation
Free HemoglobinFree Hemoglobin
Decreased NODecreased NO
Elevated LDHElevated LDH
Incidence of PNH Clones in High-Risk
Patient Populations
Standard Diagnostic Test for PNH Basic Evaluation for PNH
• Flow cytometric evidence of partial or complete
absence of multiple glycosyl phosphatidylinositol -
anchored proteins on red cells and granulocytes.
• CBC retic count, LDH, bilirubin, haptoglobin, iron
stores, D-Dimers
• Marrow aspirate and biopsy, cytogenetics
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Classification of PNH*Category Rate of intravascular Hemolysis Marrow Flow Cytometry Benefit from Eculizumab
Classic Florid (macroscopic hemoglobin- Cellular marrow with erythroid Large population (>50%) of Yes
uria is frequent or persistent) hyperplasia and normal or near- GPI-AP deficient PMNs**
normal morphology
PNH in the setting of Mild to moderate (macroscopic Evidence of a concomitant Although variable, the Dependent on the size
another marrow hemoglobinuria is intermittent marrow failure syndrome^ percentage of GPI-AP of the PNH clone
failure syndrome^ or absent) deficient PMNs is usually
relatively small (<30%)
Subclinical No clinical or biochemical Evidence of a concomitant Small (<1%) population of No
evidence of intravascular hemolysis marrow failure syndrome GPI-AP deficient PMNs
detected by high resolution
flow cytometry
*Based on recommendations of the International PNH Interest Group (Blood 106:3699, 2005)
Parker CJ, Williams Hematology, 8th Edition, 2010, pg. 526
Thrombosis Is the Leading Cause of
Death in PNH1
Multifactorial Pathogenesis of
Thrombosis in PNH
Chronic Uncontrolled Complement
Activation Leads to Vasoconstriction and Thrombosis
Thrombosis Occurs in
Both Typical and Atypical Sites* Hematopoietic Stem Cell Transplantation for PNH
Indications for transplantation
• Marrow failure- approach to management depends
primarily on the underlying marrow abnormality (e.g.,
aplastic anemia) but the treatment regimen must be
sufficient to eradicate the PNH clone
• Major complications of PNH
• Refractory, transfusion-dependent hemolytic anemia
• Recurrent, life-threatening thromboembolic complications
Outcomes
• There are no PNH-specific adverse events. Severe, acute
graft-versus host disease occurs in approximately 33% of
patients and the incidence of chronic graft-versus host
disease is roughly 35%
• Overall survival for unselected PNH patients who undergo
transplantation using an HLA-matched sibling donor is in
the range of 50-60%
Parker, CJ, Williams Hematology, 8th Edition, 2010, pg. 529
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Soliris: Humanized, First-in-Class, Anti-
C5 Antibody
Please see full prescribing information for Please see full prescribing information for SolirisSoliris®® ((eculizumabeculizumab).).
RotherRother R R et al. Nat et al. Nat BiotechBiotech 2007;25:1256.2007;25:1256.
Human IgGHuman IgG44 Heavy ChainHeavy Chain
Constant Regions 2 and 3Constant Regions 2 and 3
(eliminates (eliminates complement activation)complement activation)
Complementarity Determining RegionsComplementarity Determining Regions
(murine origin)(murine origin)
Human Framework RegionsHuman Framework Regions
�� No mutationsNo mutations
�� GermlineGermline
Hinge Hinge
CH
3C
H2
Human IgGHuman IgG22 Heavy ChainHeavy Chain
Constant Region 1 and HingeConstant Region 1 and Hinge
(eliminates (eliminates Fc receptor binding)Fc receptor binding)
Soliris Blocks Terminal Complement1,2
C5C5
Pro
xim
al
Term
inal
Please see full prescribing information for Please see full prescribing information for SolirisSoliris®® ((eculizumabeculizumab).).
1. SolirisSoliris®® ((eculizumabeculizumab) [package insert]. ) [package insert]. AlexionAlexion Pharmaceuticals; Revised 03/2012Pharmaceuticals; Revised 03/2012. . 2. Rother RP et al. Nature Biotech. 2007;25(11):1256-1264.
3. Walport MJ. N Engl J Med. 2001;344(14):1058-1066. 4. Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4(3):359-395.
C5aC5a
Soliris Soliris
� Proximal functions of
complement remain intact1,2
• Weak anaphylatoxin2,4
• Immune complex clearance2
• Microbial opsonization2
� Terminal complement - C5a
and C5b-9 formation blocked1,2
� Soliris binds with high affinity
to C51,2
Complement CascadeComplement Cascade2,32,3
C5bC5b--99C5bC5b
C3C3 C3aC3a
C3bC3b
86% Reduction in LDH Sustained Over
Entire
Course of 36 Month Treatment Period
Summary of Clinical Efficacy
Immunosuppressive Therapy (IST) Has
Increased Efficacy in AA Patients With
PNH Cells
Key labs and tests involved in management
Flow cytometry
Annual bone marrow
CBC, retic count
LDH, D-Dimers
Bilirubin, creatinine
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Self Management
• Folic acid and oral iron for ongoing
hemolysis
• Carry identity card
• Vaccinate against meningococcus
Patient Safety Information Card