Managing Sickle Cell Disease: A Comprehensive Guide for Clinicians

Learning Objectives
After participating in this activity, the clinical will be able to:
1. Describe the causes and consequences of increased morbidity and mortality
associated with sickle cell disease (SCD) (knowledge)
2. Integrate key SCD management guideline recommendations into practice
(competence)
3. Compare and contrast standard, new, and emerging therapies for SCD—
including mechanisms of action, dosing, safety and efficacy (knowledge)
4. Employ communication and education strategies to help patients establish goals
to improve their quality of life, prevent disease worsening, and have fewer/less
severe symptoms (competence)

What is sickle cell disease?
• A group of genetic disorders that are progressively disabling
and lead to chronic hemolytic anemia
-Single amino acid substitution at position 6 of ß-globin chain
• RBCs contain Hgb S which causes cells to sickle 
obstruction of blood flow  tissue ischemia/infarction
• Sickle cells can also permanently damage vessels, organs,
and bones  chronic pain

Sickle cell disease ≠ Sickle cell anemia
HbA
(%)
HbS
(%)
HbC
(%)
HbF
(%)
HbA2
(%)
Clinical
Course
Prevalence
(%)
Normal 95-98 0 0 <1 <3.5 – –
Trait conditions
Sickle trait HbAS 55-65 30-40 0 <1 <3.5 Benign 1-8
Hemoglobin C trait 55-65 0 30-40 <1 <3.5 Benign 1-3
-thalassemia trait 90-95 0 0 1-3 >3.5 Benign 1-2
Disease conditions
Sickle cell anemia 0 80-95 0 5-15 <3.5 Severe 50-60
Sickle-C disease 0 50-55 40-45 <3 <3.5 Moderate 25-30
S/0 thalassemia 0 80-90 0 5-15 >3.5 Severe 1-3
S/+ thalassemia 10-25 70-80 0 <3 >3.5 Mild 5-10
S/Other (Hb variant) 0 50-60 0 Variable <3.5 Variable 1-2

Epidemiology
• Sickle cell anemia is the most common inherited disorder in the
United States
• 1400 children are born each year with sickle cell anemia
•  100,000 Americans are affected by SCD
•  1 out of every 365 Black or African-American births are affected by
SCD
•  1 out of every 16,300 Hispanic-American births are affected by SCD
•  1 in 13 Black or African-American babies are born with sickle cell
trait (SCT)
Centers for Disease Control and Prevention. 2017. https://www.cdc.gov/ncbddd/sicklecell/data.html. Accessed
February 3, 2021.
SCD, sickle cell disease

Economic Burden
• Estimated annual healthcare cost ranges from $15,000 to $60,0001,2
• Lifetime cost is unknown1
• Inpatient admissions make up the bulk of healthcare services3
• Vaso-occlusive crisis (VOC) most common admitting diagnosis
• Average LOS 4 to 5 days
• Ages 18-34 comprised 50% of SCD patients admissions
• The 30 day readmission rate for SCD patients is about 3 times higher than that
of non-SCD admissions
1. Salcedo J, et al. Blood. 2019;134(Suppl 1):4671.
2. Shah N, et al. J Health Econ Outcomes Res. 2020;7(1):52-60.
3. Fingar KR, et al. Published 2019. https://pubmed.ncbi.nlm.nih.gov/31622075/ - . Accessed February 10, 2021.

Patient Burden of Disease
• Sickle Cell Anemia: A Patient's Journey – YouTube [01:21-02:02]

For Children, SCD Is No Longer a Life-Threatening Disease,
But a Chronic Disease with Life-Threatening Events
• London cohort with 2158 pt-y of follow up  16-y KM survival rate of
99% for infants1
• Paris cohort with 6776 pt-y of follow up  5-y KM survival rate of
99% for children2
• Strokes are the most common debilitating complication3,4
• 2% to 5% of children have overt strokes
• 39% have silent strokes
• 24-month treatment with hydroxyurea non-inferior to transfusion in
children with abnormal transcranial Doppler velocities but no severe
vasculopathy5
1. Telfer P, et al. Haematologica. 2007;92(7):905-912. 2. Couque N, et al. Br J Haematol. 2016;173(6):927-937.
3. Charache S, et al. N Engl J Med. 1995;332(20):1317-1322. 4. Le PQ, et al. Pediatr Blood Cancer. 2015;62(11):1956-1961.
5. Ware RE, et al. Lancet. 2016;387(10019):661-670.

No Change in Median Survival in Adults with SCD
Over 25 years (1994 vs. 2019)
Contemporary estimates (high-income countries):
38 – 67 years in Hb SS2
1. Platt OS, et al. N Engl J Med. 1994; 330(23):1639-1644.
2. DeBaun MR, et al. Blood. 2019;133(6):615-617.
Cooperative Study of Sickle Cell Disease1
Cumulative
Survival
Hb SS/Sβ0:
48 years
Hb SC/Sβ+:
55 years

Wide Inter-Patient Variation of Progression of Heart, Lung
and Kidney Disease
Disease Modifying
Therapies
• Hydroxyurea
Lifestyle Risk Factors
• Tobacco/Smoking
• Obesity
Genetic Variation
• Hemoglobin F loci
• APOL1 G1/G2

Comprehensive Care of Sickle Cell Disease
Health
Maintenance
-Routine health visits
-Screening
-Education
-Ongoing support
-Lab monitoring
Acute
Complications
Prevention
&
Treatment
Chronic
Complications
Prevention
&
Treatment
Cure
Hematopoietic stem
cell transplantation
Investigational
Options
+ + +

Acute Complications Associated with
Increased Morbidity and Mortality
Acute
Complications
Stroke
Acute Fever
Vaso-
Occlusive
Syndrome
Anemia
Multi-system
Organ Failure
Priapism
Acute Chest
Syndrome
Hepatobiliary

Distribution of Acute Vaso-Occlusive Pain
in Sickle Cell Disease
0
10
20
30
40
50
60
SS SC SB+ SB0
0
0 to <1
1 to <3
3 to <6
≤6
Crisis Rate
Average 0.8 0.4 0.4 1.0
%
Platt OS, et al. N Engl J Med. 1991;325;1:11-16.

PiSCES: The Epidemiology of Acute Vaso-
Occlusive Pain Episodes in Sickle Cell Disease
• Develop and validate a biopsychosocial model of SCD pain, pain
response, and healthcare utilization in a large, multisite adult cohort
• Study involved baseline surveys, six months of daily pain diaries, and
responses to pain
• 232 patients age ≥16 y with SCD
• Pain reported 54.5% of analyzed patient days
• Healthcare utilization occurred in only 3.5% of patient days
• 29.3% reported pain most days of the week
• 14.2% reported pain in ≤5% diary days
Smith WR, et al. Ann Intern Med. 2008;148(2):94-101.

Organ Systems Affected by Chronic
Complications
Chronic
Complications
Pulmonary
Nervous
Musculo-
skeletal
Gastro-
intestinal
Heart Kidney

Heart, Lung, and Kidney Complications Account for
50% of Identifiable Causes of Death
1. Fitzhugh C, et al. Am J Hematol. 2010;85(1):36-40.
Systolic Blood Pressure (BP)1-3
• Systolic BP > 120 mmHg → 16% of children
• Systolic BP > 130 mmHg → 20% of adults
• Associated with
• Silent cerebral infarcts, children only and strokes
• Pulmonary hypertension
• Reduced kidney function
FEV1% Predicted ≤ 70%4-5
• Present in 11% of children and 32% of adults
• Every 1% decline in FEV1 associated with 2% increased risk of
death
Estimated Glomerular Filtration (eGFR)6-8
• Hyperfiltration- measured GFR (>1 SD) observed in 76% of young
children; mean = 154 mL/min/1.73 m2
• eGFR < 90 mL/min/1.73 m2 observed in 19% of adults
• 26% with SCD die within 1 y of starting dialysis
1. Fitzhugh CD, et al. Am J Hematol. 2010;85(1):36-40. 2. Akingbola TS, et al. Hemoglobin. 2014;38(4):236-243. 3. Gordeuk
VR, et al. Am J Hematol. 2008;83(1):15-18. 4. Willen SM, et al. Am J Hematol. 2018;93(3):408-415. 5. Kassim AA, et al.
Blood. 2015;126(13):1544-1550. 6. Aygun B, et al. Pediatr Nephrol. 2011;26(8):1285-1290. 7. Saraf SL, et al. Br J Haematol.
2014;164(5):729-739. 8. McClellan AC, et al. Br J Haematol. 2012;159(3):360-367.

Common Challenges
• Frequent healthcare utilization1,2
• Failed transition from pediatric to adult care3,4
• Providers with limited clinical expertise5
1. Centers for Disease Control and Prevention. Published April 2020.
https://www.cdc.gov/ncbddd/hemoglobinopathies/documents/scdc-data-brief-voe-h.pdf - . Accessed February 10, 2021. 2.
Crego N, et al. J Am Board Fam Med. 2020;33(1):91-105. 3. Dickerson AK, et al. Pediatric Blood Cancer. 2012;58(5):741-745.
4. Quinn CT, et al. Blood. 2010;115(17):3447-3452. 5. Lee L, et al. Public Health Rep. 2019;134(6):599-607.

Barriers to Care
• Poor access to comprehensive
medical care1
• Rural areas
• Medicaid restrictions
• Limited number of providers
versed in treatment guidelines
• Transportation
• Patient mistrust
• Intergenerational
• Stigma2
• The opioid epidemic
• “Drug seeking” mentality
• Unaware of own bias
• Population vulnerability
1. Lee L, et al. Public Health Rep. 2019;134(6):599-607.
2. Bulgin D, et al. Issues Ment Health Nurs. 2018;39(8):675-686.

Mental Health Support
• There is a correlation between pain and depressive/anxiety
symptoms1,2
• Unmanaged/undermanaged mental health disorders result in:
• Poorer quality of life3-5
• Poorer physical health5
• Longer length of stay6
• Increased hospital admissions for VOC management6
• Increased morbidity and mortality7
1. Yang L, et al. BMC Psychiatry. 2014;14:207. 2. Sogutlu A, et al. Psychosomatics. 2011;52(3):272-279. 3. Adam
SS, et al. Blood Adv. 2017;1(23):1983-1992. 4. Sehlo MG, et al. BMC Psychiatry. 2015;15:78. 5. Levenson JL, et
al. Psychosomatic Med. 2008;70(2):192-196. 6. Myrvik MP, et al. Pediatr Blood Cancer. 2012;60(7):1211-1214.
7. Jonassaint CR, et al. Br J Haematol. 2016;174(1):136-147.

Education and Vocational Support
• 504 Plan or Individualized Educational Program
• Ensures that children with disabilities receive appropriate accommodations
(hydration, breakfast breaks, access to nurse)
• Higher education disability services
• ADA occupational accommodations, if needed

Health Maintenance
Age-Appropriate
Preventive Services
Pneumococcal
Infection
-Penicillin prophylaxis age <5 y
Renal Disease
-Screen for proteinuria age ≥10 y
Pulmonary HTN
-Screening echo if symptomatic
or history of abnormal echo
Hypertension
-Screen
-Treat according to guidelines
Retinopathy
-Dilated eye exam age ≥10 y
Stroke
-Annual TCD age 2-16 y for HBSS
& HbSB0
Reproductive
Counseling
-Especially if treated with
hydroxyurea
-Assess for RBC alloantibodies
TCD,
transcranial
Doppler
National Heart Lung and Blood Institute. Published 2014.
https://www.nhlbi.nih.gov/sites/default/files/media/docs/sickle-cell-disease-report%20020816_0.pdf
Accessed February 9, 2021.
Prevention is critical

Non-Medical Therapy Strategies To Decrease
Sickle Cell Disease-Related Complications
• Healthy living
• Exercise in moderation
• Good diet
• Good sleep pattern
• Mental health assessment
• Depression
• Anxiety

Management of Acute Complications
Fever
Vaso-Occlusive
Pain
Acute Anemia
Hepatobiliary
Complications
Acute Chest
Syndrome
Multisystem
Organ Failure
1. Brandow AB, et al. Blood Adv. 2020;4(12):2656-2701. 2. National Heart Lung and Blood Institute. Published
2014. https://www.nhlbi.nih.gov/sites/default/files/media/docs/sickle-cell-disease-report%20020816_0.pdf.
Accessed February 9, 2021. 3. Thompson WE, et al. Pain Med. 2014;15(2):241-246.

Management of Acute Complications (cont)
Fever
-Medical emergency for infants
-Prompt evaluation for older
children and adults with
antibiotic treatment

Vaso-Occlusive Pain
-Non-pharmacologic
management of pain
-Pharmacologic pain plan
-Hydration

Acute Anemia
-CBC, reticulocyte count
-Confirm cause
-Red blood cell transfusion

Hepatobiliary Complications
-Referral to hematologist for
consideration of surgery
-Surgical consult
-Transfusion prior to surgery to
prevent acute chest syndrome

Acute Chest Syndrome
-Antibiotics
-O2 if pO2 <94%
-Incentive spirometry
-Simple transfusion for mild
symptoms, RBC exchange for
severe symptoms

Multisystem Organ Failure
-RBC exchange
-Oxygen treatment
-Nephrology, neurology,
hematology consult
-ICU admission

Management of Chronic Complications
Mental Health Chronic Pain
Overt Strokes and
Silent Strokes
Elevated Tricuspid
Jet Velocity or
NT-BNP
Renal
Asthma or
Recurrent
Wheezing
Brandow AB, et al. Blood Adv. 2020;4(12):2656-2701. Zhao D, et al. J Orthopaedic Transl. 2020;21:100-110.
Accessed February 9, 2021. Liem RI, et al. Blood Adv. 2020;3(23):3867-3897.
Prevention is critical

Management of Chronic Complications (cont)
Mental Health
-Ongoing assessment of depression and
anxiety
-Primary care management
-Referral to mental health therapist

Chronic Pain
-R/O other causes (AVN, other fractures)
-Individualized plan
-Formal evaluation for depression and
anxiety
-Primary care provider referral

Overt Strokes and Silent Strokes
-Standard care
-Blood transfusion therapy
-Iron chelation
-Bone marrow transplant

Elevated Tricuspid Jet Velocity or NT-BNP
-Standard care
-Echocardiogram if symptomatic
-Referral if TRV ≥2.5 m/sec

Renal
-Screen for proteinuria beginning at age 5-6 y
-ACE-I or ARB if albuminuria
ACE-I, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker

Asthma or Recurrent Wheezing
-Standard care for individuals with asthma
-Management with asthma specialist
-Individualized asthma care plan with limited
role of corticosteroids

Treatment Options
SCD
Supportive Care
Medications
Hematopoietic
Stem Cell
Transplantation
Blood
Transfusion

Medication Proposed Mechanism(s) of Action
Hydroxyurea
(Siklos)1
Increases Hgb F levels in RBCs, increases hemoglobin level, decreases
neutrophils, increases water content of RBCs, increases deformability
of RBC, alters adhesion of RBCs to endothelium, increase nitric oxide
L-Glutamine
(Endari)2
Increases availability of reduced glutathione leading to improved
NAD redox potential in sickle RBCs
Voxelotor
(Oxbryta)3
Increases affinity of Hgb for oxygen, inhibits RBC sickling, improves
RBC deformability, reduces whole blood viscosity
Crizanlizumab
(Adakveo)4
Binds to P-selectin and blocks interactions with ligands, as well as
endothelial cells, platelets, RBCs, and leukocytes
1. Siklos [package insert]. Bryn Mawr, PA: Medunik USA; October 2020.
2. Endari [package insert]. Torrance, CA: Emmaus Medical, Inc.; October 2020.
3. Oxbryta [package insert]. South San Francisco, CA: Global Blood Therapeutics, Inc.; July 2020.
4. Adakveo [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; June 2020.
Pharmacotherapy Options for Children and
Adults with SCD

Adults with SCD (cont)
Medication Indication Age
Hydroxyurea
(Siklos)1
Reduce frequency of painful crises and need for blood
transfusions in SCA
≥ 9 months
L-Glutamine
(Endari)2
Reduce pain and acute chest syndrome ≥5 y
Voxelotor
(Oxbryta)3
Improves hemoglobin level for individuals with
symptomatic anemia
≥12 y
Crizanlizumab
(Adakveo)4
Reduce frequency of vaso-occlusive pain episodes ≥16 y
SCA, sickle cell anemia; SCD, sickle cell disease

Medication Route of
Administration
Dosing
Hydroxyurea
(Siklos)1
PO 20 mg/kg once daily; may increase by 5 mg/kg
every 8 wks to maximum of 35 mg/kg/d
[Reduce by 50% if CrCl <60 mL/min]
L-Glutamine
(Endari)2
PO 5 to 15 g twice daily
Voxelotor
(Oxbryta)3
PO 1500 mg once daily
[1000 mg once daily if Child Pugh C]
Crizanlizumab
(Adakveo)4
IV 5 mg/kg on weeks 0 and 2, then every 4 weeks

Medication Advantages Warnings & Precautions1-4
Hydroxyurea
(Siklos)
Improves life expectancy; reduces rate of pain
50%; reduces rate of acute chest syndrome
50%; reduces rate of transfusion 50%; reduces
risk of ischemic stroke
Embryo-fetal toxicity; cutaneous
vasculitic toxicities; drug interaction
with antiretrovirals, live virus vaccine
L-Glutamine
(Endari)
Reduces risk of pain events –
Voxelotor
(Oxbryta)
Increases Hgb level (mean 1.1 g/dL) Hypersensitivity reactions; perform
quantification of Hgb species when not
receiving voxelotor
Crizanlizumab
(Adakveo)
Reduces rate of pain 50% Infusion-related reactions; interference
with automated platelet counts

Hydroxyurea Improves Survival
• Retrospective review of Belgian
SCD Registry
• Data from neonatal screening or
diagnosis until last follow up or
death
• 469 patients with 5110 patient-
years of follow up
• Treatment:
• Hydroxyurea: 185
• No disease-modifying therapy: 170
• Hematopoietic stem cell
transplantation: 90
• Chronic transfusion: 24
Le PQ, et al. Pediatr Blood Cancer. 2015;62(11):1956-1961.
0.14
0.38
0.36
0
0.1
0.2
0.3
0.4
Hydroxyurea No Disease-Modifying
Therapy
Hematopoietic Stem
Cell Transplant
15-Year Mortality Rates per 100 Person-Years
P=0.04
P=0.01

Hydroxyurea Reduces Frequency of
Acute Pain Episodes
• Objective:
• To assess efficacy of hydroxyurea in
reducing frequency of painful crises in
SCA
• Double-blind RCT involving 299
adults with ≥3 crises/y
• Randomized to:
• Hydroxyurea 5 mg/kg initially, then
titrated based on response and blood
counts (max 35 mg/kg)
• Placebo
• Stopped after mean follow up of 21
mos
2.5 1
25
48
4.5
2.4
51
73
0
10
20
30
40
50
60
70
80
Painful Crises Crises Requiring
Hospitalization
Acute Chest
Syndrome
Transfusion
Median Rates per Year
Hydroxyurea Placebo
P<0.001 P<0.001
P<0.001
P=0.001
Charache S, et al. N Engl J Med. 1995;332(20):1317-1322.
The approved dose of hydroxyurea in the United States for sickle cell anemia is 20-35 mg/kg-d

Hydroxyurea: Clinical Role in HbSS and HbS0
• Age ≥ 9 months of age irrespective of disease severity
• Should be offered to infants age ≥9 mos, children, adolescents regardless of
clinical severity to reduce disease-related complications
• Improves cognitive function and decreases risk of stroke by lowering
TCD velocity
• Deceases the frequency of severe acute pain ~ 50%
• Decreases the frequency of acute chest syndrome~ 50%
• Decreased the frequency of blood transfusion requirements ~50%
• Severe symptomatic chronic anemia that impairs ability to perform
ADLs and negatively impacts quality of life
United States Department of Health and Human Services. 2014. Available at:
https://www.nhlbi.nih.gov/sites/default/files/media/docs/Evd-Bsd_SickleCellDis_Rep2014.pdf. Accessed
February 22, 2021.

Safety and Efficacy of L-Glutamine
• Objective
• To confirm earlier findings showing that treatment with l-glutamine resulted
in (non-significantly) lower acute pain crises and hospitalizations than placebo
• Phase 3 placebo-controlled, double-blind RCT
• Patients with SCA or sickle 0-thalassemia and ≥2 pain crises during
past year
• Randomized (2:1) to 48 wks of treatment with:
• L-glutamine 0.3 g/kg BID or
• Placebo
• Continued treatment with hydroxyurea was allowed
Nihara Y, et al. N Engl J Med. 2018;379(3):226-235.
The approved dose of L-glutamine in the United States is 5-15 g twice daily

L-Glutamine Reduces Number and Time to
Acute Pain Episodes
3
2
1
4
3
1
0
1
2
3
4
5
Pain crises Hospitalization ED Visit*
Median Number of Events
L-glutamine Placebo
P=0.005
P=0.005
P=0.09
84
212
54
133
0
50
100
150
200
250
Time to first pain crisis Time to second pain crisis
Number
of
Days
(median)
Median Time to Pain Crises (d)
P=0.02
P=0.03
*Not resulting in hospitalization

Safety and Efficacy of L-Glutamine (cont)
Adverse Event L-Glutamine
(n-151)
Placebo
(n=78)
Constipation 25.2% 24.4%
Nausea 22.5% 16.7%
Headache 21.2% 17.9%
Pain in extremity 15.9% 7.7%
Vomiting 14.6% 12.8%
Chest pain- noncardiac 13.9% 9.0%
Back pain 13.2% 6.4%
Abdominal pain- upper 10.6% 7.7%

Safety and Efficacy of Voxelotor
• Objective
• To compare the efficacy and safety of 2 dose levels of voxelotor with placebo
• Patients with SCD
• Two-thirds had SCA
• Randomized (1:1:1) to once-daily treatment x 24 wks with:
• Voxelotor 900 mg
• Voxelotor 1500 mg
• Placebo
• Median follow up was 42.3 wks
Vichinsky E, et al. N Engl J Med. 2019;381(6):509-519.
The approved dose of voxelotor in the United States is 1500 mg once daily

Voxelotor Raises Hemoglobin Level and
Improves Markers of Hemolysis
38%
59%
9%
0%
10%
20%
30%
40%
50%
60%
70%
Percent of Patients Whose
Hemoglobin Level Increased
>1.0 g/dL from Baseline to
Week 24
0.6
1.1
-0.1
-0.25
0.00
0.25
0.50
0.75
1.00
1.25
Mean Change in
Hemoglobin Level (g/dL)
from Baseline to Week 24
-20.3%
-1.3%
5.1%
1.4%
-29.1%
-19.9%
-8.0%
-4.5%
-3.2%
4.5% 3.1% 3.4%
-50.0%
-25.0%
0.0%
25.0%
Indirect bilirubin % Reticulocytes Reticulocyte Count LDH
Mean Change in Hemolysis Markers from Baseline to Week 24
Voxelotor 900 mg
Voxelotor 1500 mg
Placebo

Voxelotor Results in No Significant
Improvement in Acute Vaso-Occlusive Pain
2.76 2.77
3.19
0
0.5
1
1.5
2
2.5
3
3.5
Voxelotor 900 mg Voxelotor 1500 mg Placebo
Number
of
crises
per
person-years
Annualized Incidence of VOC
0%
10%
20%
30%
40%
50%
60%
70%
Voxelotor 900 mg Voxelotor 1500 mg Placebo
Percent
of
Patients
Percent with ≥1 Vaso-Occlusive Crisis*
Vichinsky E, et al. N Engl J Med. 2019;381(6):509-519. *during 42.3 wks follow up

Safety and Efficacy of Voxelotor (cont)
Voxelotor 900 mg
(n=92)
Voxelotor 1500 mg
(n=88)
Placebo
(n=91)
Headache 15% 26% 22%
Diarrhea 17% 20% 10%
Nausea 16% 17% 10%
Arthralgia 12% 15% 12%
Upper respiratory
tract infection
18% 14% 11%
Abdominal pain 14% 14% 8%
Fatigue 13% 14% 10%
Rash 11% 14% 10%
Pyrexia 11% 12% 7%

Safety and Efficacy of Crizanlizumab
• Objective
• To evaluate the safety and efficacy of crizanlizumab
• Patients with sickle cell disease and 2-10 sickle cell-related pain crises
within previous 12 mos
• Randomized (1:1:1) to 52-wks treatment with
• Crizanlizumab 2.5 mg/kg
• Crizanlizumab 5 mg/kg
• Placebo
Ataga KI, et al. N Engl J Med. 2017;376(5):429-439.
The approved dose of crizanlizumab in the United States is 5 mg/kg

Crizanlizumab Reduces Number of and Time
to Acute Pain Episodes
2.01
1.63
2.98
0
0.5
1
1.5
2
2.5
3
3.5
Median Number of Pain Crises per Year
Crizanlizumab 2.5 Crizanlizumab 5 mg Placebo
6.87
2.20
9.20
4.00 4.07
10.32
6.87
1.38
5.09
0
2
4
6
8
10
12
Hospital days/y Time to first pain crisis
(mo)
Time to second pain
crisis (mo)
Median Events
P=0.02
P=0.001
Ataga KI, et al. N Engl J Med. 2017;376(5):429-439.
P=0.01
The approved dose of crizanlizumab in the United States is 5 mg/kg

Safety and Efficacy of Crizanlizumab (cont)
Adverse Event Crizanlizumab 2.5 mg
(n=64)
Crizanlizumab 5 mg
(n=66)
Placebo
(n=62)
≥1 Serious AE 33% 26% 27%
Headache 22% 17% 16%
Back pain 20% 15% 11%
Nausea 17% 18% 11%
Arthralgia 14% 18% 8%
Pain in extremity 12% 17% 16%
Urinary tract infection 11% 14% 11%
Upper respiratory tract infection 11% 11% 10%
Pyrexia 9% 11% 6%
Diarrhea 8% 11% 3%
Musculoskeletal pain 6% 12% 10%
Ataga KI, et al. N Engl J Med. 2017;376(5):429-439. The approved dose of crizanlizumab
in the United States is 5 mg/kg

Summary
• Hydroxyurea is the mainstay of treatment for individuals with HbSS
and HbS0
• Decreases SCD related morbidity and mortality
• Other FDA approved therapies should be selected on an individual
basis
• L-glutamine
• Repetitive acute vaso-occlusive pain and acute chest syndrome
• Voxelotor
• Symptomatic anemia or selective situations where increase hemoglobin may improve
clinical outcomes
• Crizanlizumab
• Repetitive acute vaso-occlusive pain

Hematopoietic Stem Cell Transplantation
• More than one type of curative therapy
• Should be done in a clinical trial setting
• Matched related donor hematopoietic stem-transplant ~5% of all
potential patients
• Non-myeloablative
• Generally preferred for adults
• Myeloablative
• Mainstay approach for children

Hematopoietic Stem Cell Transplantation (cont)
• Generally reserved for patients with
• Stroke
• Recurrent vaso-occlusive crisis
• Recurrent transfusion
• Renal damage
• Other severe disease complications

Hematopoietic Stem Cell Transplantation (cont)
• Non-myeloablative haploidentical ~99% of all children and ~90% of
adults
• Requires only half of a match
• Transplant complications
• Graft-versus-host disease
• Morbidity/Mortality if transplant mismatch
• Secondary malignancy

Investigational Gene Therapy and Gene Editing
Trials
Product Phase Participants Primary Endpoint(s)
LentiGlobin
(NCT02140554)
1/2* Adolescents/Adults with
severe SCD 2 y post-HSCT
Proportion achieving complete resolution
of severe VOCs
LentiGlobin
(NCT04293185)
3* Children/Adults with SCD in
combination with HSCT
Proportion achieving Globin Response
criteria
BIVV003
(NCT03653247)
1/2 Adults undergoing autologous
HSCT
Percentage alive at post-transplant day
100, week 52, week 104; with successful
engraftment; number with adverse events
*Clinical trial suspended February 2021

Investigational Gene Therapy and Gene Editing
Trials (cont)
Product Description
LentiGlobin Viral vector that delivers a modified but functional copy of the hemoglobin
subunit  gene into hematopoietic stem cells. Once cells differentiate, red blood
cells produce a modified, anti-sickling version of hemoglobin.
BIVV003 Zinc finger nuclease gene editing technology used to modify a short sequence of
the BCL11A gene in red blood precursor cells acquired from a patient’s own
hematopoietic stem cells. When reintroduced into the patient, production of
fetal hemoglobin is raised.

Relationship Between the Health Care System and
the Community – Chronic Care Model
Wagner EH. Eff Clin Pract. 1998;1(1):2-4.

It Takes a Multidisciplinary Team
Patient/
Parent
Hematologist
Primary Care
Clinician
Nurse Case
Manager
Clinical
Psychologist
Mental
Health
Neurologist
Return to
Work
Pi Beta Phi
Rehab

Interventions
• Clinician/Team responsibilities
• Education (family meeting)
• New pain action plan
• Brain MRI (cognitive impairment)
• Psychiatric referral (depression & grief counseling)
• Referral to primary care clinician

Interventions (cont)
• Patient responsibilities (requires adherence)
• Pain action plan [Pain diary]
• Attending appointments
• Includes primary care
• Opioids
• Seen at least every 3 months
• Opioid contract
• Establishes expectations and responsibilities
• May include need for other services, eg, mental health

Care Coordination
• Important to be familiar with resources within the
institution and community
• Between settings: inpatient  outpatient
• Communication between visits
• Involvement of family, especially for children and people
with cognitive deficits
• Advanced care planning
• Primary care clinician, social worker play key roles

The Transition Process
Mind the gap!
Key teaching points
• Advocate for own needs
• Adjust to adult care setting

Case #1
A 4-year-old male with HbSS living in the United States, presents to
your clinic for an annual visit. In discussing plans for his disease
surveillance, you note that the child has recently had two abnormal
TCD measurements (high MCA velocity).
What is the next best step?
A. Repeat test in six months
B. Repeat test in one year
C. Start transfusion/apheresis to reduce sickle hemoglobin level
D. No further action is needed

Case #2
39-yo African-American with hemoglobin SC, recurrent vaso-
occlusive pain events despite treatment with crizanlizumab and L-
glutamine. Tricuspid jet velocity is 3.0 cm/sec and patient has a
declining FEV1% predicted of 75% What therapy options are
available?
A. Hydroxyurea
B. Gene therapy/gene editing
C. Myeloablative matched related donor hematopoietic stem cell
transplant
D. Non-myeloablative haploidentical hematopoietic stem cell
transplant with post transplant cyclophosphamide

Case #3
28-yo African-American male with a history of SCD and AVN to R hip
presents to ED with complaint of VOC pain x 3d
• Pain has been unrelieved by self-management with:
• Duloxetine 30 mg PO QD
• Morphine 15 mg PO q6h prn
• Ibuprofen 800 mg PO q8h
• Epsom salt baths
• Direct heat
• Other medications:
• Hydroxyurea at maximally tolerated dose
• L-glutamine
• Diagnostic testing negative for complicated VOC

Case #3 (cont)
Which would be the most appropriate injectable opioid for
this patient?
A. Hydromorphone 1 mg
B. Hydromorphone 1.5 mg
C. Meperidine 50 mg
D. Morphine sulfate 8 mg

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