7/3/2013

1

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