Guidelines for the use of hydroxycarbamide in children and adults with sickle cell disease

• DOI: 10.1111/bjh.15235
• Publication Date: 2018-05-07T06:26:03Z
• Authors: Amrana Qureshi; Banu Kaya; Shivan Pancham; Russell Keenan; Jeremy Anderson; Magbor Akanni; Jo Howard
• Keywords: Hydroxycarbamide; Guideline; Stroke; Hematology

This guideline was compiled according to the British Society of Haematology (BSH) process at b-s-h.org.uk. The Grading Recommendations Assessment, Development and Evaluation (GRADE) nomenclature used evaluate levels evidence assess strength recommendations. GRADE criteria can be found http://www.gradeworkinggroup.org A literature search conducted on 15 June 2016. Databases searched include MEDLINE (OVID) Embase from 1995 July, week 1, Key words were: Hydroxycarbamide; Hydroxyurea, Sickle cell disease; anaemia; Mode Action: HbF; Pain; Chest crisis; stroke; silent infarct; cerebral flow velocities; primary prevention secondary end organ damage; renal function; nephropathy; avascular necrosis; pulmonary hypertension; reduced morbidity; mortality; toxicity; side effects; bone marrow suppression; infertility; spermatogenesis; teratogenicity; cancer; leukaemia, death, dosing, monitoring, long term follow-up; paediatrics; infants; children; adults. Exclusions included non-human single case reports, no abstracts or irrelevant guideline. Review manuscript performed by BSH Guidelines Committee General Task Force, sounding board BSH. It also placed members section website for comment. reviewed Cell Society; this organisation does not necessarily approve endorse contents. disease (SCD) is a generic an inherited group disorders that includes homozygous sickle anaemia (SS), cell/haemoglobin C (SC) cell/βthalassemia (S/β thal) other compound heterozygous conditions. SCD characterised presence mutated β-globin gene, HBBs (also termed βs-globin). On de-oxygenation, forms polymeric structure resulting in deformed, rigid red blood cells, associated with chronic haemolytic due shortened life span vaso-occlusion causing frequent episodes severe bony pain (vaso-occlusive crises) acute complications. These increased risk stroke, hypertension, lung damage, failure leg ulcers. Fetal haemoglobin (haemoglobin F, HbF, α2ϒ2) protective against these complications infants are relatively protected first few months before HbF infancy replaced HbS (α2βS2) rather than adult (HbA, α2β2). Co-inheritance raised milder phenotype (Perrine et al, 1978; Platt 1994). Hydroxycarbamide known as hydroxyurea) currently only medication licensed UK recurrent painful crisis patients SCD. randomized controlled Multicenter Study Hydroxyurea (MSH) study showed definitively treatment hydroxycarbamide could decrease chest syndrome (ACS) reduce need transfusion (Charache 1995). Since then, multiple trials have confirmed its efficacy modification children additional complications, shown improved survival taking (Steinberg 2010; Voskaridou Lobo 2013). Despite clear benefits hydroxycarbamide, it remains under-utilized reluctance both clinicians use there marked variability across (http://www.wmqrs.nhs.uk/review-programmes/view/haemoglobin-disorders-2014-16-reviews-adults-and-children). partly concerns about effects, which myelosuppression, regular uncertainties effect spermatogenesis misconceptions possible teratogenicity. aims outline current specific indications provide clinician aids consultation monitoring hydroxycarbamide. will enable joint decision-making between improve equity access As any medical intervention, recommendations utilised within context informed consent, verbal written, shared on-going discussion provider patient. majority available has been obtained genotypes SS Sβ0thalassaemia (S β0) role (e.g. SC, Sβ+thalassaemia) discussed separately. inhibitor ribonucleotide reductase oral anti-proliferative drug several decades. Its mode action based ability increase levels, 1980s (Platt 1984; Veith 1985), intercellular adhesion hence flow. thought induction mild intermittent suppression, results state stressed erythropoiesis, where production relative steady state. immediate may take dose escalation achieve optimal rise levels. variable genetic variants cause variation baseline including polymorphisms XmnI site, BCL11A SALL2 (Green & Barral, 2014; Sheehan 2014) further studies understand HbF-inducing genes ongoing. beneficial effects outside acts via mechanisms 2014). In part, decreased expression integrins molecules white cells (WBCs) vascular endothelium. interactions involved neutrophil migration reduction leads vaso-occlusion. Nitric oxide (NO) stimulation NO result local vasodilation, addition HbF%, laboratory concentration (Hb) mean volume (MCV) absolute reticulocyte count (ARC) WBC count; consistent sustained all ages 1992; Ferster 1996; Kinney 1999; Zimmerman 2004; 2010). clinical correlated Hb, MCV (Ferster Italia 2009; Singh Mellouli 2013; Quarmyne 2015). mortality adults compelling reason using (Wang, 2016). Observational data suggested use. related episodes, crises hospital admissions reducing preventing damage. Adults entered into randomised MSH were subsequently nonrandomised observational study. At 9 years follow-up 40% (P = 0·04) 2003). After 17·7-year period analysis 3-month intervals usage interval, death rates during when Twenty-four percent deaths 87·1% occurred who never took <5 years. Belgian 469 (Lê 2015), 185 treated had higher 15-year those (99·4% compared 95·4% P 0·04). prospective, non-randomised Greece, outcomes 131 (SS, S β 0thal +thal) 199 untreated patients. probability 10-year 86% 65% 0·001), even though more disease. significant independent predictor (Voskaridou Brazilian paediatric programme retrospectively analysed programme, reviewing 1760 aged 3–18 years, whom 267 selectively (Lobo Survival significantly greater (99·5% vs. 94·5% 0·01) primarily fewer ACS infection. retrospective East Mediterranean cohort 735 (102 children, 633 adults) over median 66 months, 0·009) (Karacaoglu proven crises. double blind trial, 152 received 147 placebo. receiving number 2-year reduced, 4·5 2·5 (44% time 1·5 3 0·01), second 4·6 8 0·0001). incidence (25 51, 0·001) (48 73 patients, cross-over trial young 1996) administered placebo order, washout between, absence events requiring hospitalisation 16/22 (73%) 3/22 (14%) 0·0016). stay group. Participants 20 mg/kg 25 unless cytopenia developed. double-blind India looked 60 5–18 half 10 mg/kg/day (Jain 2012) crises, transfusions hospitalisations very children. Demonstration objective BABY HUG (Wang 2011) double-blinded 9–18 Sβ0thalassaemia. unselected severity standard mg/kg. Ninety-six 97 (177 62 375 75 patients; 2·2-fold lower rate pain, 0·002), dactylitis (24 14 123 42 5·2-fold rate, 0·0001), 0·02 (3·5-fold rate). requirements 0·03) admission 0·05), 0·005) well tolerated, transient (ANC). Of (n 176), 163 (93%) consented 36 (Rogers bacteraemia serious provided important safety information addition, sub-analysis asymptomatic (52 49 placebo) 0·006), ARC (relative 3·05 < 2012). value American guidelines (NHLBI, changed their approach targeted (offering symptoms) non-selective offered writing guideline, initial (i.e., years), adverse exposure. However Baby describing long-term larger since infancy. (de Montalembert 1997; Deshpande 2016) (Koren 1999). Further visits emergency department 0·011) (Raj 2015) 0·001 (Nottage translated public health cost Pain community, do present hospital, seriously affect patient's daily quality much difficult measure. Diaries/hospital 299 (Ballas 2010) duration cumulative days 0·022) but amount opioid home 0·015). Smith al (2011) analgesic among ambulatory Patients rated intensity, 0·0007), analgesics response. Risk factors ischaemic stroke childhood abnormal Transcranial Doppler (TCD) velocities, vasculopathy, infarction, low Hb HbF%. By modifying factors, play limiting stroke. adults, potentially different fully investigated. Abnormal TCD velocities middle anterior arteries confer demonstrated (Gulbis 2005; Kratovil 2006; Lagunju one 98 subjects arm 4 (1 arm) statistically significant. Some entry separately analysed, did neurological change. average velocity however Dwan, Overall seen, suggesting considered prevention. Sparing Conversion Elevation (SCATE) (Hankins phase designed conversion conditional TCD. Although terminated early slow recruitment recruited 38 post hoc converted seen after difference reach statistical significance intention-to-treat analysis. therapy formally tested line high TCDs feasibility suggest reductions occur starting (Galadanci Transfusions established (Adams 1998). alternative investigated TWiTCH (TCD With Changing Hydroxyurea) (Ware non-inferiority 121 least 1 year continuing iron chelation venesections. Children magnetic resonance angiography (MRA)-defined vasculopathy excluded age enrolment similar [9·5 SD 2·6 (standard 9·7 3·2 (alternative)]. eligible 6·5 scheduled interim analysis, new infarctions identified either arm, therefore early. concluded effective reverted whilst escalating maximum tolerated (Bernaudin stopped until established. For infarcts, some protection progression, defined ischaemia stenosis 5–15 impact recurrence overt (DeBaun protect progression imaging abnormalities, leucoencephalopathy altering started (Sommet required establish less older earlier initiation favourable. prevention, care. Data (Stroke changing – SWiTCH) exploring demonstrate likelihood switched venesections continued Helms, compare directly trial. Allowance made combined benefit overload hypothesised. study, 7 strokes 67 hydroxycarbamide/venesection 0 transfusion/chelation. (0·10) remained margin. All 6 venesection phase. has, however, should contraindicated unavailable (Sumoza 2002; Ali 2011; Greenway Interventions prevent studied. One limited SS/Sβ0/+ (Rigano Other neuro-vascular abnormalities There accumulating damage preserve function given doses HbF. improvement (Fitzhugh ideally occurs. separate systems outlined below. Loss splenic 4–6 age, 5 most functionally asplenic. Small show 2008; Nottage Thirty-six (median 8·8 years) enrolled Long-Term Effects (HUSTLE) Tc99 scans liver spleen 36% preserved infiltrative 2014); younger response function. supported Santos (2002) 21 3–22 liver/spleen scintigraphy 12 therapy; (50%). Improvement extension Safety Organ toxicity (HUSOFT study) 2005). Twenty-one (mean 3·4 2 30 Fourteen assessed baseline, 4. Only (43%) asplenic upon completion contrast expected 94% asplenia age-matched red-cell counts 0·001). HUG, SS/Sβ0 thalassaemia (qualitative uptake 99Tc scan) two groups 2011). awaited determine Renal changes common morbidity mortality. thalassaemia, better urine concentrating 0·007) enlargement change estimated glomerular filtration (eGFR) (Alvarez HUSTLE hyperfiltration 23 0·016) (Aygun reported microalbuminuria treatment. Tehseen (2017) 288 >8 persistent albuminuria (21% 24%), (12·5% 25·3%; 0·045). dysfunction. 149 11 prevalence (34·7% 55·4% comparator (Laurin suppression damaging proteins; monocyte chemoattractant protein expressed (dos level seems factor development retinopathy; 15% odds developing retinopathy whether being taken. developed 0·005), (Estepp Pulmonary hypertension occurs around 10% all-cause (Gordeuk direct support artery pressures acutely vaso-occlusive triggering right heart (Machado 2007). latter admission. avoid precipitation death. tests, daytime overnight oxygen saturation (Narang aerobic exercise tolerance physical fitness (Wali Moheeb, cardiovascular haemoglobin. Case reports priapism (Al Jam'a Dabbous, Saad 2004) through mechanism enhancing bioavailability, (Uzoma prospective AVN, 46 18 radiological findings (Jena Swain, 2006). phenotypes genotypes. completed cell/HbC disease, hospitalization, particularly (Lebensburger 2015; Luchtman-Jones Haematological responses total WBC, ANC noted always observed. Sβ0 warrants investigation. centre SC ongoing (NCT02336373). effects. experience gastrointestinal symptoms (Kinney 1999), hyperpigmentation skin darkening nails, dose-dependant (O'Branki 2001). note hair thinning. Skin ulcers seem Marrow reversible, short-term effect. contributes (see Dosing monitoring). now haemoglobinopathies, carries leukaemogenesis (Algiraigri Radwi, Castro 17-year LaSHS cases myelodysplastic leukaemia. extended small teenage HUSOFT (with infancy) medium-term (up 107 showing mutations (Zimmerman 2004). evaluating cellular molecular up exposure, (13·2 ± 4·1