Current trends in the

management of recurrent pain

episodes in sickle cell disease
By
Dr OROLU ALI A.K
CONSULTANT HAEMATOLOGIST
(FMCP, MWACP)
Learning Objectives

• Review of genetics and subtypes of sickle cell disease

• Burden of SCD

• Brief overview of SCD complications

• Current therapies in SCD care

• Emerging therapies in SCD care

• Future Directions/summary
 Introduction
• SCD an inherited genetic disorder resulting from the
presence of a mutated (β⁶) form of hemoglobin (Hb), HbS.

• Peripheral blood film shows anemia with sickle shaped red

cells.

• Hb SS, SC, Sβᵒ- thalassemia, Sβ⁺thalassemia, SD

• SCA is the most common form of SCD (HbSS).

• Individuals with HbSS or sickle β0 thalassemia are most

likely to develop symptomatic disease if untreated.
 Introduction
• Nearly 90 percent of the world's sickle cell disease
population lives in these three countries - Nigeria, DR congo
and India.

• These countries have a carrier prevalence rate (sickle cell

trait) is as high as 10 to 30 percent and a SCD prevalence
rate of up to 2 percent of the population.

• About 150, 000 children are born annually with SCA in

Nigeria. This number is expected to increase by 2050 .

• In 2008 the World Health Organization (WHO) recognized

SCD as a global public health problem. (world SCD day JUNE
14)
 Introduction
• The hallmarks of sickle cell disease (SCD) are
occlusion of blood vessels (vaso-occlusion) and
chronic hemolytic anemia.

• Acute vaso-occlusive events are vaso-occlusive

episodes /VOC), stroke, acute chest syndrome,
priapism and dactylitis.

• The most common vaso-occlusive event is the

acute painful episode (vaso-occlusive
episodes /VOC) , also a frequent reason for ER
visits and hospitalization.
 Introduction
• Evidence based interventions
• ………>>> Recurrent vaso-occlusive episode (VOE)-
should also be part of any
Patient has three or more painful episodes per year
comprehensive discussion of
that requires medical intervention ( parenteral

opoid or NSAID use) or hospital admission care for SCD patients.

• Recurrent VOC = a predicted decreased survival.

• Disease-modifying therapies help prevent /

minimize vaso-occlusive pain episodes as well as

reduce other vaso-occlusive complications.

Increasing life expectancy in US of SCD patients from 1910-2010
Targeting pathobiology of sickle cell
disease
Targeting HbS polymerization by inducing High Hb F (α2γ2)
Traditional polymer based concept –
Rationale for disease modification

•Infants are asymptomatic until after 6months of life.

•HbS phenotypes with high HbF levels (HbF >10%-30%) - referred to as

hereditary persistence of fetal hemoglobin (HPFH) are usually

asymptomatic.

•Inhibits sickling as the mixed hybrid tetramers do not partake in HbS

polymerization(α2γβS) and are more soluble than the homotetramer

(α2βS2).

•Dilutes the intracellular HbS concentration.

 Targeting pathobiology of sickle cell
disease
Multiple pathway model – •Targeting HbS polymerization
Increase Hb F (gene therapy, pharmacotherapy- hydroxyurea)
Increase O₂ affinity (voxelotor/Oxbryta/GBT440)

•Targeting vasoocclusion
Inhibiting rbc adhesion, leucocyte adhesion, rbc-leucocyte-
platelet aggregation, cellular adhesion with endothelium (anti-P-
selection molecule -Crizanlizumab), L-glutamine/Endari.

•Targeting inflammation
Inhibiting neutrophil, platelet coagulation factor and
endothelium activation, thus inhibit the feedback loop
Intravenous immunoglobulin (IVIG), Canakinumab is a
humanized monoclonal antibody that targets interleukin 1-β (IL-
1β),

•Change in the genotype

Prithu Sundd, Mark T. Gladwin and Enrico M. Novelli. Annu Rev Pathol. 2019 ● Allogeneic BMT ●Gene therapy
• A ribonucleotide reductase inhibitor with multiple potential

mechanisms of action Hydroxyurea

(HU)
1) Induces HbF synthesis (decreased sickling, less rbc membrane

damage, improved red cell survival and improved haemoglobin)

2) Induces myelosuppression (less inflammation)

3) Decreased reticulocyte count (less endothelial adhesion)

4) Decreased haemolysis, cellular adhesion and inflammation

5) Increased nitric oxide (NO) bioavailability ( ↓vasoconstriction,

limiting vascular dysfunction.)

6) Decreased endothelial activation and adhesion

7) Decreased thrombosis and microparticle formation

Ware RE, Aygun B, Heamatology 2009

Documented clinical efficacy and safety of
HYDROXYUREA in adults and pediatric age group

Russell E. Ware, M.D., Ph.D. An NIH Consensus Development Conference 2008


Hydroxyurea (HU)
• Approved for use by the FDA in 1998
• Reduced acute painful events (severity and
frequency -4.5 per year to 2.5 per year
Charache et al)
• Extended life span (40% reduction in mortality
Charache et al)
• Decreased clinical severity of SCD (decreased
hospitalizations, transfusions, TCD
measurements and reduced long term
complications – e.g proteinuria )
• Indications for hydroxyurea therapy and the age of HU initiation are not
universally agreed upon, however , they potentially include:
1) Acute vaso-occlusive complications
●Recurrent acute painful events (3 or more severe episodes requiring admission in
the last 12 months ) ●Dactylitis ●Acute chest syndrome (2 or more episodes in a
lifetime)
2) Frequent hospitalizations
3) severe symptomatic anaemia
4) Laboratory markers of severity
● Low hemoglobin ●Low HbF ●Elevated WBC ●Elevated LDH
5) Organ dysfunction
●Neurological disease e.g Elevated TCD velocities Silent MRI or MRA changes
Stroke prophylaxis (primary or secondary stroke) ● Pulmonary disease e.g
Hypoxemia ●Kidney disease e.g Proteinuria ● Recurrent priapism
• Patients and relatives should be educated on benefits and side effects (cytopenias,
teratogenicity) of HU and importance of drug adherence.
Hydroxyurea (HU)
• Baseline investigations before starting HU should include FBC, reticulocyte count, Hb F%,
electrolyte, urea and creatinine , liver function test and LDH levels.
•Hematologic toxicity
• HbF level in excess of 20% significantly ameliorates the disease. criteria Toxicity criteria
• Prescribed/ commenced as 15-20 mg/kg/d given as a single dose and increased by 5 thresholds ANC
Neutrophils requiring
< 1.0 × 10⁹/L
mg/kg after every 8 weeks to a maximum dose of 35 mg/kg or 2.5–5.0 mg/kg below the
dosage where haematologic toxicity is observed (maximum tolerated dose/ MTD).
hydroxyurea
< 7.0 dose
Hemoglobin (Hb) g/dL with low reticulocytes eg
• The maximum daily dose of hydroxyurea should not exceed 35 mg/kg/d or 2000 mg/d absolute reticulocyte count < 100 ×
• If heamatologic toxicity occurs, discontinue HU for 1 week until blood counts recover. modification
10⁹/L .
Decrease by > 20% from previous
• After HU initiation, monitoring of FBC , reticulocyte count, adherence monitoring and
value,with low reticulocytes (as
clinical examination are required every month to assess for cytopenias associated with
previously)
hydroxyurea until MTD is achieved, 2 monthly chemistry profile is also checked.
Reticulocytes < 80 × 10⁹/L unless the Hb
• After the MTD is reached, 8 weeks visits with FBC , reticulocyte count, adherence
concentration is > 8.0 g/dL
monitoring may be appropriate, while blood chemistry and Hb F % will be done every 16
Platelets <80 × 10⁹/L
weeks.
 Hydroxyurea
(HU)

Changes in complete blood cell count parameters and erythrocyte morphology in association
with hydroxyurea therapy, from dose initiation through escalation to maximum tolerated dose (MTD)

Heeney MM, Ware RE.. Hematol Oncol Clin North Am. 2010
 Hydroxyurea (HU)
•Use of HU in Africa is still low due to lack of awareness, lack of specialist care,

fear of toxicity and lack of laboratory testing capabilities.

• Dose escalation with frequent monitoring will not be feasible in Africa due to

high cost of repeated laboratory testing.

•Thus a fixed dose regimen (10-20 mg/kg/day) maybe more feasible than a

dose escalation to MTD in order to achieve similar reduction in clinical severity

of SCA and good drug adherence rates at low costs e.g SPIN Trial and

extended SPIN Trial.

•The extended results of the SPIN trial provide clear evidence that initial

treatment with fixed moderate dose HU (20 mg/kg/day) will prevent strokes

in children with abnormal TCD measurements in a low-resource setting.

•A moderate fixed dose (20mg/kg/day) will improve drug safety (less

cytopaenias) and build the confidence of the clinicians and patients to HU use.
 Limitations with hydroxyurea
• Not all patients respond equally (low baseline HbF levels …. ?? Non responders).

• Most studies are limited to the severe SCD variants Hb SS and Sβᵒ- thalassemia.

• A chemotherapeutic agent requiring dose escalation and frequent laboratory testing.

• Older patients become more sensitive to the dosage and they require frequent blood tests and

readjustment of their dose.

• No clear evidence of the long-term effect of hydroxyurea in preventing end organ damage.

• There is also conflicting evidence of the effects of HU on male fertility.

• Therefore, alternative, non-cytotoxic, durable and more potent methods of inducing HbF are

needed.
 Voxelotor/Oxbryta/GBT440
• Anti sickling agent that binds to the N –terminus of α globin subunit of HbS

to stabilize the oxygenated haemoglobin state by increasing the affinity

between Hb and oxygen. ………..HbS polymerization inhibitor.

• .Phase 3 HOPE clinical trial documented drug efficacy and safety in adults

and adolescents (12-65yrs) with SCD and > 1-10 VOCs in the past 12 months.

• Study results - significant, sustained increase in hemoglobin level ( at least >

1 g/dL at week 24), reduction in heamolysis markers (reticulocyte count,

indirect bilirubin, LDH) ……… extend red-cell half-life and reduced annualized

incidence rate of VOCs.

• Approved by the FDA in November 2019 for SCD patients ≥ 12yrs for SCD

treatment. Once-daily dosing oral medication (1500mg). CAUTION…LIVER DX

voxelotor/Oxbryta/GBT440

A reduction of 73% from baseline in the percentage of irreversibly sickled red cells was demonstrated at 700 mg, compared
with an increase of ∼7% for placebo
Howard et al Blood.2019
 Voxelotor/Oxbryta/GBT440
• HOPE-KIDS 1……. 45 SCD patients (aged 4 to 11

years) clinical trials on safety, efficacy and

pharmacokinetics…COMPLETED (JH Estepp et al

EHA 2021)

• HOPE-KIDS 2… 224 SCD patients (aged ≥ 2 to <

15 years) still undergoing clinical trials on TCD

Measurements. COMPLETION ∼ March 2026……

5 study sites in Nigeria

 L-glutamine (Endari) Pre-treatment Post-treatment
3.5
• L-glutamine is an amino acid and a precursor for
3
nicotinamide adenine dinucleotide (NAD) which is a potent

Endothelial adhesion ratio

antioxidant. 2.5
2
• NAD is depleted in SCD RBC, increasing their susceptibility to
1.5
oxidative damage …..lower redox ratio ([NADH]:[NAD+
+NADH]) than normal red cells. 1
0.5
• L-glutamine (Endari) also decrease endothelial adhesion by
unknown mechanisms (Niihara Y etal 2005) ?? ↓stimulation
0
1 2 3 4 5 6
of inflammation and expression of adhesion molecules. (SS control)

• Oral L- glutamine in its pure form increases the total • In July 2017, Endari (L-glutamine) was approved to

intracellular NAD RBC level, reduces sickled red cell oxidative reduce the frequency of pain crises in sickle cell
stress and haemolysis. patients older than age 5 years who experience two or

more pain crises a year.


L-glutamine (Endari)
• In a multicenter randomized, placebo-controlled,
double-blind, phase 3 study, the efficacy of oral L-
glutamine with or without HU as a therapy for sickle
cell anemia and sickle ß°-thalassemia ( ≥ 5 years old)
was evaluated in 230 participants for 48 weeks.
• The patients in the L-glutamine group had
significantly fewer pain crises than those in the
placebo group (P=0.005), 3.0 Vs 4.0 ……….a 25%
difference.
• The median time to the first pain crisis was 84 days
in the L-glutamine group, as compared with 54 days
in the placebo group (P = 0.02)
•Fewer hospitalizations occurred in the L-glutamine group
than in the placebo group (P=0.005), 2.0 Vs 3.0 …….. a
33% difference
•The median cumulative number of days in the hospital
were 6.5 in the L-glutamine group and 11 in the placebo
group (P = 0.02)
•There were no significant between-group differences in
the change in hemoglobin level, hematocrit level or
reticulocyte count.
•Unpleasant taste and expensive costs, non usage in renal
impairment has limited its use.
•L-glutamine dosing is weight-based and is dosed twice
daily..(< 30kg: 5g, 30-65kg : 10g. ≥ 65kg : 15g)
Crizanlizumab (ADAKVEO)
• A monoclonal antibody to P-selectin (inhibits P-selectin)
• It blocks the adhesion of activated erythrocytes, neutrophils
and platelets to the vascular endothelium.
• In a (SUSTAIN study) phase 2, multicenter, randomized,
placebo controlled double blind study, the Safety and
Efficacy of Crizanlizumab with or without HU Therapy in
Adolescent and Adult Sickle Cell Disease patients were
assessed during 52 weeks of treatment.
• High dose crizanlizumab was effective in reducing the
incidence of pain crises by 45.3% (P = .01) when compared
with placebo, regardless of hydroxyurea use….. 1.63 Vs 2.98.
• The median time to the first crisis was significantly longer
with high-dose crizanlizumab than with placebo (4.07 vs. 1.38
months, P=0.001), as was the median time to the second
crisis (10.32 vs. 5.09 months, P=0.02).
• The annual rate of days hospitalized was 41.8% lower with
high-dose crizanlizumab than with placebo, although the
difference was not significant (P=0.45) … 4.00 per year Vs
6.87 per year.
• No significant differences were observed in markers of
haemolysis between patients receiving crizanlizumab and
those receiving placebo.
 Crizanlizumab •Crizanlizumab is the first parenteral agent approved
(ADAKVEO) for the management of vaso-occlusive crises.

• It is a once-monthly IV infusion and requires no dose

•In November 2019, the US FDA adjustments with use…..MONITOR FOR ALLERGIES.
approved crizanlizumab (ADAKVEO)

to reduce the incidence of vaso- •Other clinical trials investigating crizanlizumab in

occlusive pain crises in sickle cell children (SOLACE Kids) are still ongoing

patients than age 16 years and older •Clinical trials for the pan selectin inhibitor …

(Rivipansel) was stopped. Didn’t meet primary end

who experience frequent pain crises.
point.
In comparison the cost for
hydroxyurea oral capsule
500 mg is around $54 for a
supply of 100 capsules. If
one capsule is taken once
daily an individual’s annual
cost for the drug will be

around $200.
? ?
QUIZ TIME
? ?
 Potential curative therapies/modification
of genotype
• Haemopoietic stem cell transplant (HSCT)
• Allogenic, related matched
• Allogenic unrelated donor
• Haploidentical

• Gene therapy
• Gene addition
• Gene editing
Haemopoietic stem cell transplant (HSCT)

• The first successful HSCT in a patient with SCD was reported

in 1984 in a pediatric patient with coexisting acute myeloid

leukemia (AML).

• Using bone marrow donated from the patient’s brother. The

patient was cured of both AML and SCD.

• Hematopoietic stem cells are found in bone marrow, in the

bloodstream (PBSC) and in umbilical cord blood.

• Recent approaches are exploring the use of stem cells

derived from blood- peripheral blood stem cells (PBSCT)

and umbilical cord- umbilical cord stem cells (UCBT) from a

related newborn baby.

 Haemopoietic stem cell transplant (HSCT)
• Conditioning regimens for SCD HSCT use chemotherapy, radiation

therapy or both are used to destroy leucocytes healthy cells that could

enhance graft rejection………. Myeloablative conditioning (MAC),

reduced-intensity conditioning (RIC) and nonmyeloablative (NMA)

• Myeloablative conditioning (MAC) = busulfan with either

cyclophosphamide or Fludarabine ± total body irradiation ; reduced-

intensity conditioning (RIC = Fludarabine with alemtuzumab, and

melphalan , nonmyeloablative (NMA) = Sirolimus

• RIC HSCT was introduced to mitigate against acute toxicities associated

with MAC, such as hepatic veno-occlusive disease and neurotoxicities

(seizures, stroke, and brain hemorrhage), as well as late effects such as

growth failure in postpubertal recipients, hypogonadism (as high as

70%), sterility and secondary malignancy.

 Haemopoietic stem cell transplant (HSCT)

HSCT donors • With a matched sibling donor, myeloablative

conditioning with busulfan, cyclophosphamide and ATG

• The current standard of care is to use a human leukocyte
achieves the best HSCT outcomes.
antigen–identical sibling/ matched sibling donor (MSD).

• Only 14%–20% of individuals with SCD have unaffected • It is commonly employed in children and young adults.
HSCT offers a cure for SCD
MSDs.
• Improves organ function
• To expand the donor pool, other approaches HSCT include
I. matched unrelated donors (MUDT) • Improves quality of life

II. unrelated cord blood units (UCBT) • Decreases risk of SCD-related complications
III. partially matched human leukocyte antigen
• Improved overall survival and disease-free survival
haploidentical related donors (halo- BMT).

• Unfortunately, graft rejection is a common complication

• GLUCKMAN et al published the results of 1000 of HLA-
matched sibling HSCT for SCD performed world-wide
Haemopoietic stem cell
between 1986 and 2013. transplant (HSCT)
• Most used MAC regimens and bone marrow or umbilical
cord derived stem cells from HLA-identical sibling donors.
•.
• The 5-year overall survival (OS) was 95% and 81% for
patients aged <16 years and those aged ≥16 years,
respectively (p < 0.001), with corresponding event free
survival ( EFS) of 93% and 81%, respectively (p < 0.001).

• The 5-year probability of GVHD-free survival was 86% and

77% for patients aged <16 years and ≥16 years,
respectively (p < 0.001) and graft rejection rate (GR) was
2.3%.

• EFS was higher for transplantations performed after 2006.

• Use of anti-thymocyte globulin ( ATG) to mitigate graft

rejection has improved EFS.
Gluckman et al Blood 2017
 Haemopoietic stem cell
transplant (HSCT)
• Bazuaye et al reported in 2014, the first successful HSCT for SCD
conducted in Nigeria.

• A 7-year-old SCD patient with CVA.

• His 2 siblings had died of SCD complications.

• Reduced Intensity Conditioning with BMSC as donor cells.

• There was no GVHD following HSCT, no history of sickle cell crises and
hemoglobin phenotype has remained AA.

• He is clinically stable with a Chimerism at 2 years post-HSCT of 95% and

responding to physiotherapy.

• Challenges---Ineffective power supply necessitating the use of

generators and inverter batteries, poor supportive care (blood
products) and inadequate diagnostic facilities (fungal and viral studies).
 Current indications for HSCT in patients with severe SCD unresponsive to hydroxyurea
therapy
When MSD is available: When MUD is available: When neither MSD nor MUD is available, related
mismatched marrow/ haploidentical, or unrelated
cord blood donor transplantation could be
considered when:

Stroke or high risk of stroke (elevated Stroke or high risk of stroke (elevated Recurrent stroke in patients on chronic transfusion
transcranial Doppler velocity despite HU). transcranial Doppler velocity despite HU). therapy.

Recurrent acute chest syndrome despite HU. Recurrent acute chest syndrome despite Failure to tolerate the supportive care (e.g.,
HU. chronic transfusion, HU) in severe SCD.

Recurrent severe acute painful crises. Recurrent severe acute painful crises
despite HU despite HU.

Red cell alloimmunization in patients on chronic Red cell alloimmunization in patients on

transfusion protocol. chronic transfusion protocol.

Pulmonary hypertension. Pulmonary hypertension.

Recurrent priapism. Recurrent priapism.

Sickle nephropathy. Sickle nephropathy.

Bone and joint involvement. Bone and joint involvement.

Sickle retinopathy.
• Gene therapy is a relatively new field of medicine that uses genetic
Gene therapy
material (mostly DNA) from the patient to treat his or her own disease.

• An experimental technique…. Many undergoing clinical trials

• In gene therapy, the investigators collect/harvest the patients’

peripheral haemopoietic stem cells, introduce new genetic material via

a virus (vector) into the patient's own blood stem cells and are

reinfused back after conditioning in order to fix or replace the patient's

disease gene, with the goal of curing the disease..

• Has the advantage of eliminating any risk of GVHD, reducing the risk of

graft rejection and less chemotherapy is utilized for the conditioning

portion of the transplant procedure, thus less toxicity.

• Gene therapy can be used even if the patient does not have a matched

donor available.
 Gene therapy

• Gene addition… using lentivirus based

therapy

1) Introduce copies of an engineered

β-globin gene e.g LentiGlobin anti-

sickling T87Q mutation (βA-T87Q)

leaving defective native gene =

Median Total Hb and Hb fractions at various
follow-up time points in HGB-206
sickle cell trait
 Gene therapy
• Gene addition… using lentivirus based therapy

2) Introducing a gene that alters the expression

genes that directly inhibits postnatal production

of fetal haemoglobin-BCL11A/reawaken the fetal

globin gene with gene therapy.

3) Introduction of genes that express fetal

globulin or express fetal like beta globin gene.

 Gene therapy
• Gene editing

1) Reawaken the fetal globin gene using CRISPR

2) Use CRISPR to correct the sickle gene by replacement of sequences

at site of native gene

CRISPR–Cas9 gene-editing technology offer a safer option, because it

enables precisely targeted manipulation of the genome without the

risk of random insertion events.

GENE THERAPY MALIGNANCY FEARS…. Possible risk of malignancy

from HSC damage from chemotherapy or ?? lentivirus-induced

Future Directions/summary
• Intensification of disease modifying therapies

• Hydroxyurea is effective and should be utilized

• Affordability of newer treatments/ Insurance, is it within our reach in Africa?

• How do u combine treatment modalities?

• Risk of infertility and oncogenesis with curative therapies

• Weighing treatment risks and benefits

• Results of gene therapy are exciting

Gabriel S and Swee L Front. Physiol. 2020
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