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

Abstract

This guideline was compiled according to the British Society of Haematology (BSH) process at b-s-h.org.uk. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org A literature search was conducted on 15 June 2016. Databases searched include MEDLINE (OVID) and Embase (OVID) from 1995 to July, week 1, 2016. Key words were: Hydroxycarbamide; Hydroxyurea, Sickle cell disease; Sickle cell anaemia; Mode of Action: HbF; Pain; Chest crisis; stroke; silent infarct; cerebral flow velocities; primary prevention of stroke; secondary prevention of stroke; end organ damage; renal function; nephropathy; avascular necrosis; pulmonary hypertension; reduced morbidity; reduced 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 and single case reports, no abstracts or irrelevant to guideline. Review of the manuscript was performed by the BSH Guidelines Committee General Haematology Task Force, the BSH Guidelines Committee and the General Haematology sounding board of BSH. It was also placed on the members section of the BSH website for comment. The manuscript was also reviewed by the Sickle Cell Society; this organisation does not necessarily approve or endorse the contents. Sickle cell disease (SCD) is a generic term for an inherited group of disorders that includes homozygous sickle cell anaemia (SS), sickle cell/haemoglobin C (SC) sickle cell/βthalassemia (S/β thal) and other compound heterozygous conditions. SCD is characterised by the presence of the mutated β-globin gene, HBBs (also termed βs-globin). On de-oxygenation, this forms a polymeric structure resulting in deformed, rigid red blood cells, and is associated with a chronic haemolytic anaemia due to shortened red cell life span and vaso-occlusion causing frequent episodes of severe bony pain (vaso-occlusive crises) and other acute and chronic complications. These include an increased risk of stroke, pulmonary hypertension, acute and chronic lung damage, chronic renal failure and leg ulcers. Fetal haemoglobin (haemoglobin F, HbF, α2ϒ2) is protective against these complications and infants are relatively protected in the first few months of life before HbF in infancy is replaced by HbS (α2βS2) rather than adult haemoglobin (HbA, α2β2). Co-inheritance of raised HbF levels is also associated with a milder phenotype (Perrine et al, 1978; Platt et al, 1994). Hydroxycarbamide (also known as hydroxyurea) is currently the only medication licensed in the UK for the prevention of recurrent painful crisis in patients with SCD. The randomized controlled Multicenter Study of Hydroxyurea (MSH) study showed definitively that treatment with hydroxycarbamide could decrease episodes of pain and acute chest syndrome (ACS) and reduce the need for transfusion (Charache et al, 1995). Since then, multiple trials have confirmed its efficacy in disease modification in children and in the prevention of additional disease complications, and have shown an improved survival in patients taking hydroxycarbamide (Steinberg et al, 2010; Voskaridou et al, 2010; Lobo et al, 2013). Despite the clear benefits of hydroxycarbamide, it remains under-utilized due to reluctance in both clinicians and patients to use it and there is marked variability in its use across the UK (http://www.wmqrs.nhs.uk/review-programmes/view/haemoglobin-disorders-2014-16-reviews-adults-and-children). This is partly due to concerns about its side effects, which include myelosuppression, with a need for regular blood monitoring, and uncertainties about its effect on spermatogenesis and misconceptions about possible teratogenicity. This guideline aims to outline the current evidence for specific indications and to provide clinician aids for consultation and monitoring of hydroxycarbamide. This will enable joint decision-making between clinicians and patients and will improve equity of access to hydroxycarbamide. As with any medical intervention, specific recommendations are to be utilised within the context of informed consent, verbal or written, and shared decision-making process and on-going discussion between the provider and patient. The majority of available evidence has been obtained only for patients with genotypes SS and Sβ0thalassaemia (S β0) and its role in other sickle genotypes (e.g. SC, Sβ+thalassaemia) is discussed separately. Hydroxycarbamide is an inhibitor of ribonucleotide reductase and has been used as an oral anti-proliferative drug for several decades. Its mode of action in SCD is based on both its ability to increase HbF levels, which was first shown in the 1980s (Platt et al, 1984; Veith et al, 1985), and its ability to reduce intercellular adhesion and hence improve blood flow. The effect on HbF levels is thought to be partly due to the induction of mild intermittent bone marrow suppression, which results in a state of stressed erythropoiesis, where production of HbF is increased relative to steady state. This is not an immediate effect and it may take several months of dose escalation to achieve an optimal rise in HbF levels. The effect of hydroxycarbamide on HbF levels is variable and this is partly due to genetic variants which cause variation in baseline HbF levels, including polymorphisms in the XmnI site, BCL11A and SALL2 (Green & Barral, 2014; Sheehan et al, 2014) and further studies to understand HbF-inducing genes are ongoing. Hydroxycarbamide has also been shown to have beneficial effects in SCD outside its modification of HbF and acts via multiple mechanisms to improve blood flow and reduce vaso-occlusion (Green & Barral, 2014). In part, this is due to decreased expression of integrins and other adhesion molecules on red cells, white blood cells (WBCs) and vascular endothelium. The interactions between these cells are involved in neutrophil migration and red blood cell flow and reduction of adhesion leads to decreased vaso-occlusion. Nitric oxide (NO) levels are decreased in patients with SCD and stimulation of NO production by hydroxycarbamide may result in local vasodilation, which will improve blood flow and reduce vaso-occlusion. In addition to the increase in HbF%, the laboratory effects of hydroxycarbamide also include raised haemoglobin concentration (Hb) levels and mean cell volume (MCV) and a reduction in absolute reticulocyte count (ARC) and WBC count; these effects have been shown to be consistent and sustained across all ages (Charache et al, 1992; et al, et al, et al, Voskaridou et al, The benefits of hydroxycarbamide have been with a rise in HbF and et al, et al, et al, 2010; et al, et al, The reduction in in both and children on hydroxycarbamide treatment is a for hydroxycarbamide has that increased survival is associated with hydroxycarbamide This may be to the reduction in acute pain chest and in patients on hydroxycarbamide or may be due to effects of hydroxycarbamide in or end organ the controlled study a of use of hydroxycarbamide was associated with a reduction in (Steinberg et al, a the of in according to hydroxycarbamide in the showed that reduced by patients taking hydroxycarbamide (Steinberg et al, of due to pulmonary complications and of these in patients hydroxycarbamide or it for In an study of and children et al, the patients with hydroxycarbamide a survival than not with the drug with In a study from in with SCD and with hydroxycarbamide with in The of survival was for on hydroxycarbamide, with for not on hydroxycarbamide the group severe HbF levels a of survival et al, The hydroxycarbamide from the first of the the of children of on hydroxycarbamide treatment et al, 2013). was in the group with hydroxycarbamide with due to from and In a of an including patients a of hydroxycarbamide use was associated with reduced et al, Hydroxycarbamide has efficacy in the reduction of painful episodes and chest This was first shown in the Multicenter Study of Hydroxyurea (MSH) (Charache et al, 1995). In this with SS hydroxycarbamide with In the group hydroxycarbamide the of painful the was from to reduction to crisis was increased from to months and to crisis was increased from to months In addition the of was reduced a and transfusion need was reduced patients in patients on hydroxycarbamide. A of children and with SS et al, hydroxycarbamide or in with a showed an of pain in patients the hydroxycarbamide treatment with only the treatment It also showed a reduction in mean in the with of hydroxycarbamide, increased to A further study in at children with SS with hydroxycarbamide and et al, and showed a decrease in pain blood and in the The benefits of hydroxycarbamide have also been shown in of benefits was a secondary in the study et al, a of children months with SS and for and with a dose of children in the hydroxycarbamide group with children in the group and showed reduction in pain in patients in of in patients in and a reduction in Hydroxycarbamide use was associated with reduced transfusion and HbF and reduced WBC count and it was with only reduction in absolute neutrophil count this to further months et al, and all and laboratory benefits sustained with the Despite mild myelosuppression, there was no increase in or These and efficacy for hydroxycarbamide in children with SS and In in of an hydroxycarbamide, there episodes of and HbF%, and WBC count and with and in with baseline hydroxycarbamide reduced pain episodes risk et al, This confirmed that hydroxycarbamide has in children and 2014) have from hydroxycarbamide to with severe to where hydroxycarbamide is to all with the of this has shown no in children due to hydroxycarbamide the on-going of the study will be in the effects of hydroxycarbamide in a of children studies have shown a reduction in for pain et al, et al, and reduced for pain and chest et al, studies have shown patients on hydroxycarbamide have both a reduction in to the et al, and a reduction in et al, 2013). This reduction in has been benefits of taking hydroxycarbamide et al, 2013). in the patients not to can a of life and is to on the patients from the study et al, and it was found that hydroxycarbamide not only shortened of and of also decreased the of used at et and use in the sickle cell pain which was on hydroxycarbamide as was use of The reduction in pain was to HbF treatment for acute in include cerebral silent cerebral and these risk hydroxycarbamide may have a role to in the risk of In the risk are and the role of hydroxycarbamide in primary and secondary prevention has not been in the cerebral and cerebral a risk of acute A of studies have a reduction in with use of hydroxycarbamide et al, et al, et al, In the in to the and children on the hydroxycarbamide by the end of the This was not of these children at and in these children this not include or The increase in the the study was in the hydroxycarbamide group & 2013). reduction in in the hydroxycarbamide group was hydroxycarbamide could be for primary to et al, was a to study the efficacy of hydroxycarbamide in from to this was due to and only in in the group with hydroxycarbamide, children to and a reduction was in mean a mean of months of treatment in children on hydroxycarbamide. This not in the Hydroxycarbamide has not been as first for children with risk in can as as months treatment et al, have an role in the primary prevention of acute et al, The role of hydroxycarbamide as an to was in the to et al, This was a in which children at of regular for primary prevention to regular with or hydroxycarbamide and with severe and the mean at was and from the of and the mean at was the first was with no in the was It was that hydroxycarbamide is an to transfusion in primary children to cerebral flow to dose of hydroxycarbamide et al, and in the not hydroxycarbamide was silent cerebral hydroxycarbamide may against as silent or vascular et al, children regular have been shown to have a in of stroke, not silent cerebral et al, 2014). Hydroxycarbamide may also against of including and cerebral by risk in et al, studies are to the of hydroxycarbamide on cerebral the benefits may be in children and may be secondary transfusion remains the of from the only controlled with to Hydroxyurea use of hydroxycarbamide in secondary prevention a of patients to hydroxycarbamide and to and & This was not to transfusion with hydroxycarbamide rather as a was for an increased of recurrent the of hydroxycarbamide with in was In this in to with in on The within the patients severe and of the the Hydroxycarbamide been shown to reduce and be where are or et al, et al, et al, et al, 2013). to in has been study a from hydroxycarbamide in et al, 2013). studies hydroxycarbamide may have a role in of this has not been in a controlled is evidence that hydroxycarbamide may chronic organ in children with SS and may organ in adults. This may be optimal hydroxycarbamide is in that achieve levels of Hydroxycarbamide use has not been associated with of organ et al, and hydroxycarbamide be before organ The evidence for efficacy on organ is of in SS has been as as months of and by of of children with SS are studies that hydroxycarbamide may in children et al, et al, 2014). children in the Hydroxycarbamide Study of baseline of and and showed or improved of treatment et al, baseline HbF and to drug associated with This is further in a study by et where before and and months of hydroxycarbamide improved in patients in was also in the of the Hydroxycarbamide and et al, infants on treatment at for with escalation to in the at and study in to the of children with SS based on The which infants with with of hydroxycarbamide or for not a in on between the et al, are to the effect of hydroxycarbamide on in SCD are and are associated with and In the controlled study of infants with with hydroxycarbamide showed ability and renal than on there was no in et al, The study showed a reduction in in children been with hydroxycarbamide for et al, 2013). studies in children have also a reduction in with hydroxycarbamide et children with and showed that and was frequent in with hydroxycarbamide as was intermittent on that treatment with hydroxycarbamide may improve renal of on hydroxycarbamide has shown a of than in a group et al, 2014). The mode of action for this renal may be via of levels of are in children on hydroxycarbamide et al, A of HbF to be a risk for the of an study of children with showed that children with HbF have a of or not hydroxycarbamide was In children with hydroxycarbamide, HbF levels with not have induction of HbF levels with hydroxycarbamide may have a protective effect on the in children et al, 2013). in of adult patients with and is associated with an increase in et al, is no evidence to the use of hydroxycarbamide in pulmonary in children or adults. can increase episodes of and chest failure et al, The group of patients are at an increased risk of both and The benefits of hydroxycarbamide may be to decrease the of crisis and hence of failure and In hydroxycarbamide has been associated with in pulmonary increase in and et al, improved and & These benefits may be due to the associated increase in of hydroxycarbamide to recurrent & et al, its of NO there is no evidence to its role in acute episodes et al, A study in with with hydroxycarbamide and not and improved in the patients on hydroxycarbamide with a HbF rise in the group & Hydroxycarbamide has been in SCD other than there are no trials of hydroxycarbamide use in patients with sickle (SC) studies a beneficial role in pain and in children and et al, et al, with an increase in HbF and with in and have been an increase in was not The efficacy of hydroxycarbamide in SCD other than SS and further A single study of hydroxycarbamide in children with is Hydroxycarbamide is with few side patients may mild et al, or of the and of which is not et al, patients have been not to be any frequent than in not on hydroxycarbamide (Charache et al, 1995). suppression, which is and is the This side effect also to the benefits section on and is evidence that hydroxycarbamide, used in the treatment of patients with no increased risk of & 2014; et al, 2014). In a of patients in the et al, and (Steinberg et al, studies there no of syndrome or In from a from 15 of treatment from there was no evidence of syndrome et al, is to in children with hydroxycarbamide no increased of genetic et al, from the a study in children and effects of hydroxycarbamide with to mean has shown no in with in patients et al, does not to be increased in cells from children on hydroxycarbamide and there was no evidence of increased in from the study & et al, These provide of hydroxycarbamide for children with and no in or The on as infants months to with 15 to hydroxycarbamide that on the for both and and was also et al, 2014). The results of the of the study will be in the efficacy and of hydroxycarbamide in a of children in is no available evidence in or that hydroxycarbamide In a study by et that patients of at In the effect of hydroxycarbamide on spermatogenesis remains studies are case with few of risk of or in with sickle cell et a study and the and of patients and the of hydroxycarbamide. was found to be in of patients This is or not or has been Hydroxycarbamide is an and studies have shown that to of hydroxycarbamide in cell and spermatogenesis et al, et al, In the study by et all to be than months treatment with hydroxycarbamide, a there was no in in patients before hydroxycarbamide treatment and in patients of of patients severe reduction in of hydroxycarbamide may be to A of children & studies have to the effect of hydroxycarbamide on et included and performed before hydroxycarbamide and months its SCD patients hydroxycarbamide and patients with hydroxycarbamide, and was a reduction in and to of hydroxycarbamide for months in of 15 and of this study was that of patients not with hydroxycarbamide not there was no A study from et al, the effect of months of hydroxycarbamide treatment on count with SS hydroxycarbamide treatment of patients and months of treatment with hydroxycarbamide there was a decrease in and as patients an patients and This study not these are and not the on These studies are and it is not possible to the to which hydroxycarbamide spermatogenesis and the of its effects, the in in with sickle cell disease to be increased by hydroxycarbamide The of and is not clear as with and can be et al, and the effect of hydroxycarbamide on have not been The effect of hydroxycarbamide on spermatogenesis and the drug is in children are et that the of of the a with at These in This that have hydroxycarbamide have In of these uncertainties it has been that it is to patients and to treatment with hydroxycarbamide et al, are of and this to be to and included within for It is not clear hydroxycarbamide be to in patients not this or at A study to evaluate the effect of hydroxycarbamide on spermatogenesis is a are on in with on hydroxycarbamide or the effects of hydroxycarbamide on spermatogenesis and also is this is and long hydroxycarbamide have to be to any It is also to reduction in with Hydroxycarbamide at is in to in the and in is on in including or from the in the about with hydroxycarbamide and possible effects to the further are the use of is for both and patients taking hydroxycarbamide. Despite this have or on hydroxycarbamide. in the study by et there to hydroxycarbamide and there and study known hydroxycarbamide at the of the in and no and have a discussion with about the and benefits of hydroxycarbamide to or in and as are to sickle cell complications. taking hydroxycarbamide, the drug be in the first and a be performed at in and have a severe disease phenotype are to the of hydroxycarbamide and for may any possible of teratogenicity. These be discussed with the patients to enable to an informed The of is to causing bone marrow In a study of with to be and was with hydroxycarbamide dose et al, This was not in patients with HbF levels. of hydroxycarbamide have been used in studies and from et al, et al, et al, to all 2010; et al, A of hydroxycarbamide, was shown by et to a HbF at 15 for to the (Charache et al, and for children et al, as the dose the has chronic disease and hydroxycarbamide be The dose can be by for a neutrophil count of and or there is other This is the patients will HbF induction with hydroxycarbamide there is variability of the of HbF may be due to possible genetic of HbF induction have been and than children and the to a HbF of HbF not the to hydroxycarbamide 2014). is variation in the neutrophil count and used to the need for dose modification in patients with hydroxycarbamide. and are an of the process of organ in sickle cell to and not be an rather a from in in children and with acute that treatment is not or the neutrophil count is as an risk at this is is not with a count than of the for neutrophil used to treatment are from trials in which are studies and is The a of in children and in 2014). The study a neutrophil count of before hydroxycarbamide & that clinicians treatment the neutrophil count is The majority of trials have used a of in and with monitoring this could be is also variation the for for hydroxycarbamide. The et al, used an of than with or from baseline or a decrease in baseline for than In of the risk of marrow suppression, a blood count and reticulocyte count be and dose and at for the of an for and and HbF levels be for evidence of consistent laboratory optimal and laboratory to treatment with hydroxycarbamide may take a on the dose is to due to treatment due to of or failure to to and have the of before effect as not to the has a hydroxycarbamide is A failure to to hydroxycarbamide can be as failure to improve and of painful episodes or of be based on criteria rather than laboratory as can be at a 2014). A of failure to to hydroxycarbamide is due to or failure to to the be to patients and as to the benefits of hydroxycarbamide, to assess and for including and may be to improve be that the of hydroxycarbamide on to be not to a dose is Hydroxycarbamide be or due to or with include use with and and with and benefits be Review treatment be informed to to with and and to a in case of in can be found in Hydroxycarbamide has been shown to increase survival in SCD is evidence that it is in of pain and chest crisis and cerebral flow in which has also been in the et al, It also in It is and has no The of the study and further in children will provide on the use of hydroxycarbamide in This and further trials are also to use of hydroxycarbamide can reduce organ damage, including the risk of pulmonary and chronic renal studies are also to of life of patients on hydroxycarbamide. is the effect of hydroxycarbamide on The of is the of on and any effect is to be be for all The effect on cells is also The of in children to be the ability to this in the remains to be The of be as it has been in patients hydroxycarbamide is the only available to patients with SCD. Its which are and side effects be discussed with all patients and of children with SCD. The of patients on hydroxycarbamide in be included in as it both the and of life of a with SCD. for patients is to which is the its benefits are not the and in this is to be and at the of to the the the any for the of this guideline. The to BSH for in the literature The BSH members at the of this guideline and The to the BSH sounding board and the BSH Guidelines Committee for in this guideline. The BSH the the of this have a of to the BSH and Task which may be on The members of the group have no of to is on for of the group will the group any evidence available that the strength of the recommendations in this or it The will be and from the BSH current website it recommendations are an will be on the BSH website Hydroxycarbamide (also known as hydroxyurea) is a drug which has been used in of patients with sickle cell disease and has been shown to reduce the of pain at or resulting in and complications crisis and It can improve the of a life by for It may also have a role in long term lung and and It by haemoglobin red cells that are in and this against the by sickle It also the blood by the white cell It can reduce the white count to levels and this may increase risk of and as a result the blood count to be on a the dose is This reduction in white count is It may cause of the and and These side effects are It may reduce production evidence for this is and no studies have been to that hydroxycarbamide that production can be in with sickle cell and may be taking hydroxycarbamide. is no evidence that sickle cell disease or hydroxycarbamide and to taking hydroxycarbamide. Hydroxycarbamide the there is no clear evidence of and hydroxycarbamide a consultation with The of hydroxycarbamide need to be with to the are taking hydroxycarbamide and are with and an to the and for an blood count in case white cell count has Despite hydroxycarbamide clear benefits in sickle cell the available literature that only a of sickle cell patients to take hydroxycarbamide & patients to take this drug is not or it with that patients will not to take it & and patients can also have about hydroxycarbamide or The consultation provide clear about hydroxycarbamide, of consultation include the which can both be used to the on hydroxycarbamide also in