Roland B. Scott Memorial Symposium
Pharmacologic Treatment of Sickle Cell Disease
Kwaku Ohene-Frempong, MD
Professor of Pediatrics, University of Pennsylvania
Director Emeritus, Sickle Cell Center
The Children’s Hospital of Philadelphia
Disclosure
Nothing to disclose
Kwaku Ohene-Frempong, MD
Professor of Pediatrics, University of Pennsylvania
Director Emeritus, Sickle Cell Center
The Children’s Hospital of Philadelphia
Sickle Cell Disease: Pharmacologic Treatment
Sickle cells - first observation
Walter Noel’s blood smear - Dec 31, 1904
Sickle Cell Disease: Pharmacologic Treatment
Pathophysiology of SCD
In a red blood cell containing mostly Hb S…
When oxygenated…
When deoxygenated
- O2
- O2
+ O2
+ O2
…single Hb S
molecules in free in
solution;
allows red cell to be
soft, round, and
deformable
…Hb S molecules
polymerize into
long fibers;
mishapen,
dehydrated and
adherent sickle
cells.
Sickle Cell Disease: Pharmacologic Treatment
Pathophysiology of SCD
1. Molecular pathology
2. Biochemical pathology
3. Cellular pathology
4. Vascular pathology
5. Clinical pathology
Sickle Cell Disease: Pharmacologic Treatment
Pathophysiology of SCD
Consequences of Hb S polymerization
and RBC sickling
•
•
•
•
•
•
•
•
•
Red cell injury
Hemolysis
RBC dehydration and dense cell formation
Adhesion of RBC to venule endothelium
Formation of heterocellular aggregates (WBC, ISC)
Vasooclusion
Local hypoxia, increased Hb S polymer formation
Propagation of vasooclusion in adjacent vasculature
Dysregulation of vasomotor tone by vasodilator
mediators (NO)
Sickle Cell Disease: Pharmacologic Treatment
Molecular pathology of SCD
It all started in the genes!
Sickle Cell Disease: Pharmacologic Treatment
Molecular pathology of SCD
Regular Hemoglobin Genes and Products
Gower 1: z2 e2
Gower 2: a2 e2
Portland: x2 g2
-----------------F:
a2 g2
< 2%
A2:
a2 d2
< 3%
A:
a2 b2
96%
Hemoglobins by age > 1 yr
Sickle Cell Disease: Pharmacologic Treatment
Molecular pathology of SCD
Hemoglobin Genes and Products in SCD-SS
Gower 1: z2 e2
Gower 2: a2 e2
Portland: x2 g2
-----------------F: a2 g2
2-20%
A2: a2 d2
3%
S: a2 bs2
80-95%
Hemoglobins in SS by age > 1 yr
Sickle Cell Disease: Pharmacologic Treatment
Molecular pathology of SCD
The sickle mutation
The bs Mutation
6th Codon of b-Globin Gene
GAG
Glutamic acid
GTG
Valine
The same mutation found in all
bs genes around the world
Sickle Cell Disease: Pharmacologic Treatment
Molecular pathology of SCD
Normal versus sickle beta globin
Normal
1
2
3
4
5
6
7
8
9
10
bA
146
-------glu
Sickle
val
bS
-------1
2
3
4
5
6
7
8
9
10
146
RBC containing mostly normal Hb
- O2
+ O2
deoxygenated
oxygenated
RBC containing mostly Hb S
- O2
+ O2
+ O2
oxygenated
deoxygenated
Sickle Cell Disease: Pharmacologic Treatment
Clinical Pathology of SCD
1. Anemia
2. Vasoocclusion
3. Chronic organ damage
Sickle Cell Disease: Pharmacologic Treatment
Clinical Pathology of SCD
1. Anemia
 Chronic intravascular hemolytic anemia
 Acute episodes of severe anemia
 Transient red cell aplasia (parvovirus B19)
 Acute splenic sequestration
 Acute hemolysis (“hyperhemolysis”)
Sickle Cell Disease: Pharmacologic Treatment
Clinical Pathology of SCD
2. Vasoocclusive complications
 Microvascular occlusion
 clinically silent
 Macrovascular occlusion
 acute ischemic/infarctive damage






pain episodes
stroke
priapism
acute chest syndrome
renal papillary necrosis
splenic infarction
Sickle Cell Disease: Pharmacologic Treatment
Clinical Pathology of SCD
3. Chronic organ damage
 Splenic dysfunction
 high risk of bacterial infection
 Progressive dysfunction of:
 lungs
-





-
kidneys
gallbladder
eyes
joints
heart
oxyhemoglobin desaturation,
pulmonary hypertension
proteinuria, renal failure
gallstones
proliferative retinopathy
osteonecrosis, arthritis
CHF
Sickle Cell Disease: Pharmacologic Treatment
Pharmacological therapy in SCD
Potential targets
 Intracellular Hb composition
 Intracellular Hb concentration
 RBC Transit time







circulatory factors
local tissue factors
systemic factors
O2 extraction from oxy-Hb S
Vascularity/ vascular pathology
Nitric oxide bioavailability
Multi-genetic and environmental factors
Pharmacotherapy of SCD
Sickle Cell Disease: Pharmacologic Treatment
Pathophysiology of SCD
Vasoocclusion (1)
A. Prolongation of the RBC microvascular transit time
caused by:
 Enhanced red cell adhesion to endothelium and
heterocellular aggregate formation
 Abnormal cation homeostasis with cell dehydration,
dense-cell formation, and
 irreversibly sickled cell formation
 Abnormal vasomotor tone favoring vasoconstriction (via
NO, endothelin-1, and eicosanoid dysregulation)
Sickle Cell Disease: Pharmacologic Treatment
Pathophysiology of SCD
Vasoocclusion (2)
B. Reduction in delay time to HbS polymer formation
caused by:
 Red-cell deoxygenation
 Increase in intracellular HbS concentration
 Low concentrations of protective Hb types (eg, HbF, HbA2)
 Fall in pH
C. Miscellaneous potential modulators
 Free-radical release and reperfusion injury
 Coagulation activation with proadhesive thrombin formation
Sickle Cell Disease: Pharmacologic Treatment
Pharmacotherapy of SCD
Hb F Induction
Agent
Mode of action
Human trials
Hydroxyurea
Stress erythropoiesis;
selection of F-cells
Phase 3, successful
Short chain
fatty acids
Histone deacetylase
Promising in small studies; high
inhibitor; reactivation of doses required; variable
g-gene expression
responses
Decytabine
Cytosine analog; DNA
methyltransferase
inhibitor
Promising in small pilots
Sickle Cell Disease: Pharmacologic Treatment
Pharmacotherapy of SCD
Anti-adhesion agents
Agent
RheothRx
Mode of action
Improve microvascular blood flow
Human trials
Phase 3, reduced duration of pain
episode, analgesic use
Sickle Cell Disease: Pharmacologic Treatment
Pharmacotherapy of SCD
Nitric oxide donors/regulators
Agent
NO
Mode of action
Human trials
Improve microvascular blood flow
Shortens duration of pain
Arginine
NO synthase
substrate
Reduce PA systolic pressure
Sildenafil
Phosphodiesterase-5
inhibitor
May help in pulmonary
hypertension and priapism
Hydroxyurea Therapy
in
Sickle Cell Disease
Kwaku Ohene-Frempong, M.D.
The Children’s Hospital of Philadelphia
Effect of Hb F on Polymerization of Deoxy-Hb S
A. 100% Hb S
- O2
+ O2
Hb S
B. 75% Hb S / 25% Hb F
- O2
+ O2
Hb F
F/S Hybrid
Hydroxyurea Therapy in Sickle Cell Disease
Effect of Hb F on SCD
1.
In vitro gelation studies have shown that Hb F
is effective inhibitor of gelation.
2.
Patients with high Hb F levels (> 20%) documented
to have mild clinical course.
3.
Patients with S-HPFH produce 25-35% Hb F in every
RBC beyond infancy, and are clinically asymptomatic.
Hydroxyurea Therapy in Sickle Cell Disease
Effect of Hb F on SCD
Hydroxyurea Therapy in Sickle Cell Disease
Beneficial RBC Effects of HU Treatment in SCD-SS

Increase in F-cell numbers and Hb F concentration per F cell

Inhibition of cation depletion and dense-cell formation

Reduction in stress reticulocytes and hemolytic rate

Increased deformability with improved rheology

Inhibition of sickle red cell-endothelium adhesion

Inhibition of sickle erythrocyte adhesion to extracellular
matrix components, including fibronectin,thrombospondin,
and laminin
Hydroxyurea Therapy in Sickle Cell Disease
Beneficial non-RBC Effects of HU Treatment in SCD-SS
•
Quantitative reduction in leucocyte count
•
Qualitative changes in leucocytes, including reduction in
leucocyte-free-radical production and activation marker
L-selectin
•
Reduction in soluble VCAM-1 concentrations (indicative of
decreased endothelial activation)
•
In-vivo NO release
Hydroxyurea Therapy in Sickle Cell Disease
Multicenter Study of Hydroxyurea
in Sickle Cell Anemia
(MSH Study)
EFFECT OF HYDROXYUREA
ON THE FREQUENCY OF PAINFUL CRISES
IN SICKLE CELL ANEMIA
Charache, et al.. NEJM, 1995
Multicenter Study of Hydroxyurea in SCA (MSH)
Effect of Hydroxyurea Therapy
on SCD Complications
Pain, episodes/yr.
Placebo
4.5
HU
2.5
p value
< 0.001
Pain hospitalization
2.4
1.0
< 0.001
No. with acute chest
51
25
< 0.001
No. transfused
73
48
0.001
Steinberg, et al: JAMA 2003: 280; 1645
Hydroxyurea Therapy in Sickle Cell Disease
Effect of HU and Hb F on Mortality
Steinberg, et al: JAMA 2003: 280; 1645
Hydroxyurea Therapy in Sickle Cell Disease
Questions
So why is every adult with SCD-SS
NOT on hydroxyurea?
What to do about the children?
Hydroxyurea Therapy in Sickle Cell Disease
Effects of Hydroxyurea on SCD
Hydroxyurea Therapy in Sickle Cell Disease
Effects of Hydroxyurea on SCD
Zimmerman, et al. 2004
Hydroxyurea Therapy in Sickle Cell Disease
Effects of Hydroxyurea on SCD
Zimmerman, et al. 2004
Hydroxyurea Therapy in Sickle Cell Disease
Effects of Hydroxyurea on SCD
Hankins, et al. 2005
Hydroxyurea Therapy in Sickle Cell Disease
Effects of Hydroxyurea on SCD
Hankins, et al. 2005
Hydroxyurea Therapy in Sickle Cell Disease
Effects of Hydroxyurea on SCD
Hankins, et al. 2005
Hydroxyurea Therapy in Sickle Cell Disease
Effects of Hydroxyurea on SCD
Hankins, et al. 2005
Hydroxyurea Therapy in Sickle Cell Disease
What are the treatment goals?
1. Hematologic
•
•
Hb F (> 20%)
Hb concentration (9 - 10 g/dL)
2. Clinical
• pain episodes
•
acute chest episodes
3. Therapeutic dose
• dose adjustments to maintain goals
4. Period of observation
Hydroxyurea Therapy in Sickle Cell Disease
Effects of Hydroxyurea on SCD
Zimmerman, et al. 2004
NIH
Consensus Development Conference
on
Hydroxyurea Treatment
for
Sickle Cell Disease
February 25-27, 2008
Hydroxyurea Therapy in Sickle Cell Disease
Short- and Long-Term Side Effects
Hydroxyurea Therapy in Sickle Cell Disease
Barriers to Treatment
1. Patient Level
•
Fears - cancer, birth defects, infertility, uncertainty of
other potential long-term risks
•
Concern - non-FDA-approved status for children means
HU an experimental drug
•
Lack of knowledge about HU as a therapeutic option
•
Lack of perception that HU is currently the only therapy
that directly modifies disease process
•
Lack of adherence to treatment regimen
•
Need for frequent monitoring of hydroxyurea response
Hydroxyurea Therapy in Sickle Cell Disease
Barriers to Treatment
2. Parent / Family / Caregiver Level
•
Fears - cancer, birth defects, infertility, uncertainty of
other potential long-term risks
•
Concern - non-FDA-approved status for children means
HU an experimental drug
•
Lack of knowledge about HU as a therapeutic option
•
Lack of perception that HU is currently the only therapy
that directly modifies disease process
•
Difficulty in communication between patients and
caregivers regarding the use of HU and other therapeutic
options
Hydroxyurea Therapy in Sickle Cell Disease
Barriers to Treatment
3. Provider Level
•
Lack of knowledge about HU as a therapeutic option
•
Concerns - cancer, birth defects, infertility, uncertainty of other potential
long-term risks
•
Provider bias and negative attitudes toward SCD patients and their
treatment
•
Lack of clarity in HU treatment regimens and undertreatment in adults
•
Limited number of physicians with expertise in use of HU for SCD
•
Failure to engage patients/caregivers in treatment decision making in a
developmentally appropriate manner
•
Lack of perception that hydroxyurea is currently the only therapy that
directly modifies the disease process
Hydroxyurea Therapy in Sickle Cell Disease
Barriers to Treatment
4. Systems Level (a)
•
Financing (lack of insurance, type of insurance, underinsurance,
scope of coverage, copays, reimbursement, payment structures)
•
Geographic isolation
•
Lack of coordination between academic centers and community-based
clinicians
•
Limited access to comprehensive care centers and comprehensive
care models
•
Problems in transitioning from pediatric to adult care
Hydroxyurea Therapy in Sickle Cell Disease
Barriers to Treatment
4. Systems Level (b)
•
Limited access (e.g., geographic distribution, recruitment, and retention
of clinicians competent in provision of comprehensive care to SCD patients)
•
Inadequate Government, industry, and philanthropic support for the
care of patients who have sickle cell disease
•
Development and promotion of hydroxyurea are hindered by lack of
commercial interest in the development and promotion of hydroxyurea
•
Lack of visibility and empowerment of SCD advocacy groups
•
Cultural and language barriers to the provision of appropriate care
•
Inadequate information technology systems to support the long-term
care of patients who have sickle cell disease
Hydroxyurea Therapy in Sickle Cell Disease
Final Question
So why are we not using hydroxyurea for
many more patients with
sickle cell disease?