Sickle Cell Disease (BSH 2015, bsh 2018, GTG 2011, BSH 2021)

The Haembase notes below are based on the references linked in the title. However, Dr Moosa Qureshi has also kindly provided his summary PDF of the 2018 UK standards of clinic care for sickle cell disease

Intro

~15,00 people with SCD in UK (~9% on LT transfusion programme)

~300 infants born with SCD in UK each year

Caused by inheritance of the sickle mutation on the HBB gene (Glu6Val, bs)

Sickle Cell Trait = HbAS

Sickle Cell Anaemia = HbSS

Sickle Cell Disease = HbSS or sickling compound heterozygotes = HbSC, HbS/b0, HbS/b+, HbSC, HbSOArab

 

In West Africa, SCD responsible for 16% of all deaths in <5 year olds

In Jamaica, 10% of SCD infants die between 6-12 months of age

In the UK, 99% survival to age of 16 years

 

Pathophysiology

In hypoxic states, erythrocytes become rapidly, but reversibly, deformed.

Intracellular polymerization of the abnormal HbS molecule stretches cell into rigid sickle form

Sickled cells cause vaso-occlusion, along with many other cellular and plasma factor interactions

--> Cycle of repeated ischaemia and inflammation

Re-oxygenation restores the normal red cell shape. Cells cycle in and out of this state until forced into intravascular haemolysis or extravascular removal by the reticendothelial system.

 

HbS is a low oxygen affinity haemoglobin --> right shift on the oxygen dissociation curve --> partly explains the chronic anaemia in SCD (which is not all due to haemolysis)

 

Annual Review Clinic

 

Height, weight, BP, O2 Sats

 

No. & severity of crises in the last year

Analgesic use

Cardiovascular symptoms

Iron overload

Other – AVN, ulcers, osteomyelitis, disc protusions

Education, Employment and Training

Family Planning

Medication compliance – folic acid, pencillin, HU, ACEI, chelators

 

Bloods – FBC, U&E, LFT, Ferritin, Hep B Ab titre, Vit D

Red cell Genotyping

Echo

 

Ophthalmology review

Vaccinations – 5 yearly pneumococcus, seasonal ‘flu, Hep B

A&E Management plan

NHR Register

 

Transfusion (see here for more)

 

Extended phenotype at baseline

Rh, Kell, Jk, Fy & Ss

Check U if S-, s-

Offer genotyping

 

Blood Product Requirements

Rh and Kell matched. R0 for R0 where available (rr alternative)

Hb S negative

As of 2023, it is no longer recommended to select ‘fresh blood’ for any patient >1 year old. This change has been circulated by NHSBT. Formal addendums to the BSH guidelines will follow. (This replaces the original recommendation: Red cells should be <10 days old for top-up, <7 days for exchange).

 

TAPS Trial (Transfusion Alternatives Preoperatively in Sickle Cell Disease)

Pre-Op transfusion if Hb <90 reduces risk of acute chest crisis post-op

Trial stopped early due to clear benefit in favour of pre-op transfusion.

 

Top-Up Transfusion

Preferred for treatment of acute severe anaemia

E.g. aplastic crisis, acute splenic or hepatic sequestration, >20g/l drop during a painful crisis

 

Exchange Transfusion

Preferred for immediate or sustained reduction in complications of SCD

Bonus: Achieves neutral or negative iron balance

Manual exchange: Aim to exchange 30% of blood volume – 4 units out, 3 + saline in.

Definite indications

  • Acute Stroke

  • Multi-Organ Failure, Mesenteric-Girdle Syndrome, Sepsis, Cholestasis

  • All SCD for high-risk surgery

 

Hydroxycarbamide (HU)

 

Mechanism of Action

HU is a ribonucleotide reductase inhibitor --> depletes intracellular deoxynucleotide pools required for DNA synthesis and repair --> cytostatic effect.

This alteration to the cell cycle kinetics, along with effects on guanylyl cyclase and SAR1, increases HbF production.

HbF inhibits intracellular HbS polymerization, and higher HbF% associated with reduced morbidity and mortality.

 

Benefits

Reduces mortality

  • 17 years of observational follow-up from the Multicentre Study of Hydroxyurea (MSH) found hydroxycarbamide use was associated with a 40% reduction in adult mortality.

Reduces Acute Pain and Chest Crises

  • MSH 1995 - double-blind, placebo controlled trial of hydroxycarbamide --> 40% reduction in median number of painful crises over two years (4.5 vs 2.5), median time to first crisis doubled and incidence of ACS reduced.

Reduces hospitalisations and pain in the community

  • Shown in repeated observational studies

Prevents first stroke?

  • HU has not been formally assessed as first line therapy for children with raised transcranial Doppler velocities (TCD).

  • A switch to HU after a minimum of one year of initial transfusion has been shown to be non-inferior to ongoing transfusion, provided that there is no MRI evidence of vasculopathy (TWiTCH 2016)

Prevents organ damage

  • Evidence is not entirely clear or in agreement but there may be beneficial effects of HU on preserving splenic function, improving renal dysfunction, improving oxygen saturation, preventing priaprism and improving pain in avascular necrosis.

  • There is no evidence at present to suggest HU is beneficial in preventing pulmonary hypertension.

 

Which HbSS and HbS/BetaO patients should be on HU?

Offer to:

  • Infants aged 9-42 months regardless of clinical severity to reduce sickle complications

  • Children aged >42 months, teenagers and adults to reduce mortality

  • Children on a regular transfusion schedule for primary prevention of stroke, after 1 year of transfusion and provided there is no MRI evidence of vasculopathy

Recommend to adults and children who have:

  • 3+ mod-severe pain crises in a 12 month period

  • Sickle pain that interferes with daily activities

  • A history of severe and/or recurrent ACS

  • Chronic anaemia that interferes with daily activities

  • Chronic hypoxia

Also give consideration to potential benefits listed above regarding prevention of organ damage and discuss these issues with patients.

 

Concerns about HU

Short term Side Effects

  • Transient, reversible myelosuppression

  • Mild GI symptoms

  • Skin and nail hyperpigmentation, hair thinning

  • Skin ulcers are reported but are not any more frequent that in those not on HU

Leukaemogenesis

  • There is no risk of leukaemogenesis when HU is used for the treatment of haemoglobinopathies

Growth and Development

  • There is no evidence to show growth or development is impaired by HU

Fertility

  • There is no evidence that HU affects fertility.

  • However, there is some suggestion of an effect of HU on male spermatogenesis in laboratory studies. It is recommended that post-pubertal male patients who are due to start HU for the first time should be offered sperm cryopreservation.

Teratogenicity

  • There is laboratory evidence of teratogenicity at suprapharmacological doses.

  • Patients on HU should use contraception

  • Women who become pregnant whilst taking HU require careful review of the risks of stopping HU (i.e. increased risk of sickle-related pregnancy complications) as this may outweigh the possible risk of teratogenicity.

 

Dosing

Adults: Start at 15mg/kg/day (rounded up to nearest 500mg)

Children: Start at 20mg/kg/day (rounded up to nearest 500mg)

 

Increase dose by 5mg/kg/day every 8-12 weeks aiming for a neutrophil count of 2-3.

Stop if the neutrophil count falls below 1.

This is the maximum tolerated dose.

 

Aim to deliver the maximum tolerated dose as evidence to suggest best outcomes with this approach.

 

Adjust dose for renal impairment.

 

Continue for minimum of six months before assessing response to therapy.

Failure to respond should be assessed by a lack of clinical response and not by laboratory values.

 

Treatment should be continued during hospital admissions, unless for febrile neutropenia.

 

Newer therapies

 

Casgvey (exagamglogene autotemcel, “exa-cel”) (MHRA UK approved in 2023)

Cellular therapy - Busulfan autograft protocol with gene editing of the apheresed cells prior to re-infusion

Mechanism: CRISPR-Cas9 gene editing of BCL11A in autologous stem cells —> Re-activation of HbF

CLIMB SCD-121 Trial (interim results ASH 2023)

  • Phase 3. 12-35 yo pts with severe SCD (2+ occlusive crises per year)

  • As of Feb 2023, 42 patients treated

  • 95% free of occlusive crisis at 12 months f/up

  • In all patients, HbF >40% at month 6 onwards

Lyfgenia (lovotibeglogene autotemcel, “lovo-cel”) (Not yet UK approved as of 2023)

Cellular therapy - Busulfan autograft protocol with lentiviral-mediated gene addition to the cells prior to re-infusion

Mechanism: Lentiviral vector integrates a modified beta-globin gene —> an anti-sickling Hb (HbA T87Q) which is produced in addition to the original HbS.

Phase 1/2 study, NEJM 2022

Crinzalizumab (negative phase 3 trial. Future of drug uncertain)

Anti-P Selectin Antibody

Administered whilst well in combination with HU

STAND Trial (awaiting publication, 2023) - Did not meet its primary endpoint.

SUSTAIN 2017 – Phase 2. 45% fewer crises vs Control. SAE in 55/151, 5 deaths

Rivipansel (negative phase 3 trial. Future of drug uncertain)

P Selectin inhibitor --> inhibits the adhesion/activation of leukocytes

RESET 2023 - Did not meet its primary or secondary endpoints.

 

Others

Canakinumab, Voxelotor, L-Glutamine, Butyrate, Gardos channel blockers, lenalidomide, azactidine

 

Pregnancy (BSH 2021)

 

Intro

~100-200 pregnancies in women with SCD in UK each year

Significant maternal sickle Hbpathies = SS, SC, SDpunjab, SE, SOarab, SLepore, S-Beta thal

Risk of adverse outcomes greater in HbSS compared to other sickle heterozygozity

Risks to mother, increased rates of:

  • Maternal mortality, acute crises, hypertension, pre-eclampsia, VTE, UTI, transfusion requirements, ITU admission

Risks to fetus/infant, increased rates of:

  • Fetal growth restriction, premature labour, stillbirth

..% of women with SCD experience … in pregnancy:

  • 57% acute pain, 10%, acute chest crisis, 18% severe crisis, 25% post-natal crisis

Pre-Conception

The following should routinely be part of agenda for annual clinic reviews

Discuss risks to mother

Discuss risks to fetus

Screen father for Hbpathy – if HbS, B-thal, O-Arab, HbC, D-Punjab offer prenatal diagnosis

Discuss reproductive options, e.g. prenatal diagnosis, pre-implantation genetic diagnosis

Review systems – Chronic pain, HTN (>130/80), Renal function, Pul HTN, Iron Overload, Retinopathy, Stroke

Optimise meds – Folic Acid 5mg OD, Vit D, Pen V, Vaccinations

Stop hydroxycarbamide three months prior to conception

Stop ACEI before conception (In d/w Renal for potential alternatives)

Stop iron chelators

NSAIDS - caution before 12 weeks, avoid after 31 weeks

 

Antenatal

Consultation

MDT, Fetal Medicine Unit, Offer pre-natal diagnosis

Screen for end organ damage if not done pre-conception

Avoid dehydration, extreme temperatures & overexertion

Review pain management plan, social circumstances

 

Scans

Offer viability scan at 7-9 weeks

Routine 1st trimester scan at 10-14 weeks

Routine anomaly scan at 20 weeks

Additional monthly growth scans from 24 weeks

 

Other

BP &  Urinalysis at every visit

Urine culture monthly

Extended red cell phenotyping (use CMV neg, HbS-neg, extended Rh & Kell matched blood)

 

Treatment

Aspirin from 12 weeks (reduces risk of pre-eclampsia)

Prophylactic LMWH during hospital admissions

?Prophylactic RBC transfusion - no clear evidence, patient-by-patient basis (TAPS-2 trial ongoing)

 

Intrapartum

Offer Induction of labour after 38+0 weeks (any mode of delivery)

Keep warm, adequate hydration

If known red cell antibodies, crossmatch blood for delivery in advance

Intrapartum fetal heart rate monitoring is recommended (increased risk of fetal distress)

 

Postpartum

Prevent dehydration, maintain O2 sats.

LMWH prophylaxis for 6 weeks post delivery

Test neonate for sickle

Offer contraceptive advice

 

Iron Chelation

 

See Iron Overload.

 

Stroke Prevention in Children

 

Before introduction of TCD, 5-15% of children suffered acute stroke

 

STOP 1998 – 1o prevention - TCD >200cm/s --> regular transfusion prevents stroke (92% RR)

STOP2 2005 – 1o prevention - ?Can you stop transfusing --> No, the stop arm had new strokes

SWiTCH – 2o prevention - ?Can you switch from transfusion to HU after 30 months --> No.

TWiTCH 2016 – 1o prevention - ?Transfusion + HU & eventually stop transfusion --> Yes

 

Transplant

 

Only curative procedure

Very difficult to choose right patient at the right time

Best outcomes if proceed prior to organ damage, but want to select only severely affected patients due to the morbidity and mortality associated with HSCT (including infertility).

Most success so far in matched sibling, bone marrow harvest, myeloablative HSCT in children.

Effective in preventing future clinical complications of SCD.

In adults, 87% EFS reported with matching sibling RIC allografts.

Unrelated transplant currently appears unsafe for widespread use. Higher mortality and GVHD.