Feasibility and benefit of hydroxycarbamide as a long‐term treatment for sickle cell disease patients: Results from the North West London Sickle Cell Disease Registry
Authors: Annette Gilmore, Gavin Cho, Jo Howard, Mark Layton, Michele Afif, Robert George Hughes, Nicola J Philpott, Sameer Patankar, Sally C. Davies
Journal: American Journal of Hematology (2011)

Despite the benefits of hydroxycarbamide (HU) for sickle cell disease (SCD) patients, it is currently underutilized in routine clinical management because of concerns about effectiveness and safety and ambivalence surrounding optimal HU regimes for heterogeneous SCD clinic populations [1-6]. This UK study followed up 62 SCD patients treated with HU for up to 9 years (IQR 1–6 yrs). Patients benefited from sustained significant increases in mean annual hemoglobin (Hb), fetal hemoglobin (HbF%), mean cell volume (MCV) and reduction in absolute neutrophil count (ANC), mean annual inpatient (IP) days, acute chest syndrome (ACS) and transfusion events compared to pretreatment. Mean daily dose and maximum tolerated dose (MTD) achieved were constrained by patients' concordance with treatment and drug tolerance. All serious adverse events were not prevented during therapy. Side effects did not warrant cessation of HU but deteriorating medical condition did. Long-term treatment warrants close monitoring with multiagency involvement in care. Most SCD patients suffer intermittent painful episodes and life-threatening events while life expectancy is reduced [7-9]. HU is the only drug which effectively ameliorates the clinical symptoms of the disease [10, 11] and increases probability of survival with long term use [12, 13]. Findings from small observational studies of children and young adults and from two adult cohorts suggest its effectiveness and safety in the medium to long-term but meagre practical advice and evidence exists to guide clinicians for optimal HU use on an individual patient basis in routine clinical practice [12-17]. The primary objective of this study was to describe the effectiveness and risks of long-term HU treatment in SCD patients cared for in UK National Health Service hospitals. Further we sought to describe which aspects of care and therapy were associated with improved treatment management and outcomes. Sixty two patients, including 51 adults and 11 children (age < 16 yrs) from four hospitals were included in the cohort. There were 38 males; 55 had HbSS, six HbS/β0-thalassaemia, and one HbSD-Punjab. Mean age at start of treatment was 28 (range 16–44) years for the adults and 10 (range 1–14) for the children. The majority of patients were started on HU because of recurrent IP painful episodes or IP painful episodes with ACS (see Supporting Information Table I). Thirteen were switched from transfusion programmes to HU therapy. Follow-up ranged from 1 to 9 years, totalling 249 person-years with a median follow-up of 3 years (IQR 1–6). Tables I and II describe the hematological, biochemical and clinical response to HU treatment. Sustained significant increases in Hb, HbF%, MCV and decrease in ANC were observed from pretreatment levels. Absolute reductions in total bilirubin and mean reticulocyte count were also observed although the reductions were not always significant. There were significant reductions in IP days, ACS events and transfusions administered. The mean annual reduction in painful episodes was not significantly reduced year on year but remained clinically important with a 35% reduction after 1 year, 46% after two, 50% after five and 19% after seven [10, 18]. Clinical event rates were 124.5 per 100 patient-years for IP admissions, 1108 for IP days and 50.6 for transfusion events. The incidence of ACS and IP painful episodes was 9.6 and 98 per 100 patient-years, respectively. The death rate was 0.8 and the stroke rate was 1.2 per 100 person-years. Two patients died, due to sickle cell complications, while on HU; one 39-year-old female, who was on HU for 4 years, and a young man of 20after three and a half years. The female died from a subarachnoid hemorrhage; she had a history of deep venous thrombosis and was on long-term anticoagulation. The male was admitted with an ACS and rapidly deteriorated with multiorgan failure. He did not adhere to his scheduled outpatient department (OPD) appointments or HU regime. Two other patients had infarctive strokes; neither had viscosity symptoms during treatment. No patient developed cancer during the study but there were two occurrences after study closure. One patient, after 11 years of HU with a history of chronic depression, long-term alcohol misuse and severe hepatic iron overload, developed primary hepatocellular carcinoma and subsequently died. The other patient complained of a lump in her thyroid 3 weeks after starting HU which was diagnosed as a "benign colloid module." The lump developed into papillary cell carcinoma after 27 months and was successfully treated with a total thyroidectomy. There were 175 episodes of transient hematological toxicity experienced by 39 patients, yielding a rate of 70 per 100/patient years. There was no change in the incidence of leg ulcers. Four patients had leg ulcers pretreatment and three of these patients suffered leg ulcer events during therapy. Annual surveys, revealed ∼50% of patients experienced mild or moderate melanonychia; two had this before treatment. Skin hyperpigmentation occurred in between 5 and 20% of patients. None stopped HU as a consequence of these side effects. Five pregnancies occurred in four patients while taking HU. In all cases treatment was stopped early in the first trimester. Pregnancy outcomes were two terminations, one miscarriage and two normal live births. One male stopped HU twice and his partner conceived ∼4 months later on both occasions and delivered normal healthy babies. Another female conceived 10 weeks after stopping HU and delivered a healthy baby. The questions "date of last menstrual period" (LMP) and "contraception use" were added to the HU follow-up questionnaire, at one site, to help monitor pregnancy risk in adult patients. The question date of LMP was completed on 19.5% of occasions. The contraception question was completed in 33% of the female proformas and in 8.5% of the male proformas. Thirty six patients achieved MTD, at a median time of 9 months (IQR 5–18 months). Mean MTD was 20 mg/kg/day (SD 4 mg). Reasons for MTD nonattainment were: nonadherence to monitoring/ drug regime (10 patients); insufficient opportunity to achieve MTD as HU was stopped or patients' continued to have frequent IP admissions and blood transfusions (3); dose reduced because Hb increased above 12 g/dl, causing viscosity symptoms (2); patient chose a lower dose (1) and it was not known why MTD was not established in three patients. MTD was not attempted in seven patients for pragmatic reasons: other active diseases which contra indicated high dose HU, difficulties with monitoring (e.g. poor venous access, psychosocial reasons), dose already established by another hospital when care transferred and patient's choice. Thirty patients (83%) were maintained at their MTD. Dose reduction from MTD occurred in six patients because of intolerability over time to original MTD, following an episode of aplastic crisis (parvovirus B19 infection), Hb over 12 g/dl, patients' weight increased but HU dose not increased and to promote healing of leg ulcers. Twenty patients were on HU and being followed up at study close. Another 19 were on HU but follow-up stopped prematurely due to relocation or care transferred to another hospital (5), did not turn up for appointments (6) and funding for data collection ceased in three hospitals (8). Twenty three patients stopped HU: 11 for medical reasons (summarized in Supporting Information Table II), seven refused and it is not known why five stopped. Our study is the first to evaluate the use of HU in a UK SCD cohort and results demonstrate its value as a long-term therapy option. Patients accrued significant long-term clinical and hematological benefits with no major side effects, which concur with existing research [13-16]. It did not prevent all serious adverse events, including two incidences of ischaemic stroke. Exposure to HU was not considered a contributory factor in the development of thyroid cancer and this patient continued with treatment. Our experience identifies some of the difficulties encountered with maintaining optimum long-term HU therapy in routine practice where SCD patients with an array of complex clinical and psychosocial issues are treated. Mean annual dose and mean MTD were lower than expected and less than half of the cohort was treated at MTD in the long-term [9]. MTD may not be achievable or necessary for every patient however continual careful monitoring of dose efficacy is required as there may be a tendency towards declining treatment intensity over time which could lead to HU being less effective [14, 15, 19]. It is possible that reduced treatment intensity in later years contributed to HU being less effective at preventing painful episodes in our cohort. Pregnancy surveillance was not totally effective, which is similar to the experience of others [10, 13, 15, 17, 20, 21]. Patient non adherence with HU and/or the treatment regime was an important contributory factor to MTD non achievement. Attrition rates were substantial; also a finding in other SCD HU studies [14-17, 22, 23]. Patients who refused to continue HU and those lost to follow–up need further investigation to identify barriers to treatment. Tailored electronic patient records (EPR) can be used to monitor and engage SCD patients while on HU. Figure 1, in the Supporting Information, shows an example of the treatment specific EPR used in this study. Patient clinical and hematological information was captured on a single Microsoft Excel (Redmond, WA) graph which was used during clinical consultations to aid doctor-patient communication. It enabled the patient and doctor to review progress with and response to HU and plan treatment accordingly. This management tool has the potential to enable doctors, together with their patients, to systematically monitor treatment response which may help improve the quality of communication between care giver and patient and promote concordance with therapy [24]. Additionally it may be beneficial for doctors to involve other health professionals with management of patients treated with HU to facilitate more holistic and creative approaches to patient education, surveillance and monitoring [19, 25]. Patients and parent/carers build up good long-term supportive relationships with SCD nurses/counsellors [26, 27] and people with chronic illness have better experienced continuity of care where management is shared between their GP and the hospital clinic compared to hospital clinic alone [28]. As with all observational studies, this one has limitations including the risk of introducing a type I error, although the large treatment effects observed were likely to be genuine [29, 30]. Furthermore it was not adequately powered to detect differences for some variables at specific time points, including painful episodes, which should be taken into account when reviewing the results [18]. Data from all patients, with HbSS, HbS/β0-thalassamia and HbSD-Punjab, on HU treatment for at least 1 year, in the four hospitals who participated in the North West London Haemoglobinopathy Registry between 2002 and 2007 were included. The Registry is registered annually with the Information Commissioners Office (Registration no. Z5730583) and has multicentre research ethics approval (No. MREC/99/2/4). Patients give written consent for their information to be used for research. Indications for starting HU and monitoring schedule were decided on an individual patient basis, but all centres used similar eligibility criteria which were a history of more than three IP admissions with painful episodes in the previous year, or more than one IP admission with a painful episode and symptomatic in the community, or a history of two or more life-threatening complications of the disease such as ACS. The aim of treatment was to achieve a MTD or a maximum dose of 30 mg/kg/day unless clinically contraindicated [9]. Effectiveness of HU was evaluated using patients as their own control (before/after design). Retrospective and prospective clinical and laboratory data were collected on all patients from start of treatment. Non adherence with monitoring regime was evaluated by counting the proportion of OPD visits the patient attended compared with the number of scheduled OPD visits. Non adherence with the drug was assessed by nonattendance at OPD visits, comments about adherence in the free text portion of the follow-up proforma and medical notes and from the answers to the question about average number of doses missed per week. During the study patients were prescribed sufficient HU to cover the period between OPD visits therefore if they missed scheduled visits they could not maintain their dosing regime. An EPR was generated to assist with patient monitoring and reviewed for evidence of nonadherence, and the trends in MCV and HbF% were inspected to help verify drug usage. The objective was to compare the changes in variables over time to measure hematological and clinical benefit from treatment. Changes from pretreatment/baseline (year 0), to each of the years 1, 2, 5, and 7 were analysed to identify statistically significant differences associated with HU use. Only eight subjects had 9 years of data which proved too small a sample for robust statistical inferences. Variables were measured on a numerical scale, except for leg ulcers, which was measured on a categorical scale. The statistical package used was Stata (Version 9.0., StataCorp TX). For changes over time, that were normally distributed numerical variables, the paired t-test was used. The mean and standard deviation (SD) was calculated at each time point, together with the mean (95% confidence interval) difference from pretreatment and P-value of the difference. Non normally distributed variables were analysed on the log transformed scale, with the paired t-test for the analysis. The mean ratio of the difference between the years being measured is reported along with the corresponding 95% confidence interval (CI). The results from the analysis of normally distributed variables are reported in Table I and non normally distributed variables in Table II. The Fishers Exact test for small numbers was used for analysis of the categorical variable. Clinical event rates were calculated for patients treated up to 9 years as follows: (number of occurrences / total follow-up time * 100). AG, JH and GC wrote and revised the manuscript. AG, SCD and ML conceived and designed the study. AG and SP were responsible for developing the study protocol, managing the data and statistical analyses. All other authors reviewed the manuscript and were involved in patient follow-up. The authors thank the members of the North West London Sickle Cell Disease registry for their support and enrolment of patients: Shubha Allard, Royal London Hospital; Gail Abrahamson, Colin A Michie, and Cathy Rose, Ealing General Hospital; Inderjeet Dokal, Royal London Hospital; Anne E.M. Davies and Mallika Sekhar, West Middlesex University Hospital. They are very grateful to the late Dr. Mabel Alli, Brent Primary Care Trust (PCT), for her support with administering the registry, Pricilla Plocki, Hammersmith Hospital and Sharon Robinson, University College Hospital for data collection. They also thank Paul Bassett, Statsconsultancy Ltd., for his technical advice and assistance with the statistical analysis. Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Annette Gilmore*, Gavin Cho*, Jo Howard , Mark Layton , Michele Afif*, Robert George Hughes§, Nicola J Philpott¶, Sameer Patankar*, Sally C. Davies* **, * Department of Haematology, Central Middlesex Hospital, London, United Kingdom, Department of Haematology, Guys and St Thomas' Hospital, London, United Kingdom, Department of Haematology, Imperial College, Hammersmith Hospital, London, United Kingdom, § Department of Haematology, West Middlesex University Hospital, Middlesex, United Kingdom, ¶ Department of Haematology, Wexham Park Hospital, Slough, United Kingdom, ** Department of Health, London, United Kingdom.