Hydroxycarbamide Therapy Research Articles

Approaches to the Treatment of Patients with Myelofibrosis and Polycythemia Vera with Constitutional Symptoms in Real-World Clinical Practice in the Russian Federation: Intermediate Results of a Multi-Center Observational Prospective Clinical Study

Aim. To describe the methods of drug therapy implemented for the disease control in patients with polycythemia vera (PV) and myelofibrosis (MF) as well as to analyze manifestations and severity of the disease symptoms in real-world clinical practice.
 Materials & Methods. The analysis focused on the data of 1229 patients. In 629 (51.18 %) patients, PV was diagnosed, MF was identified in 521 (42.39 %) patients. The diagnosis of 79 (6.43 %) patients was not reported. Early stage of primary MF (PMF) was detected in 182 (34.93 %) patients, PMF fibrosis stage was identified in 251 (48.18 %) patients, post-polycythemic MF was registered in 61 (11.71 %) patients, and 13 (2.5 %) patients showed post-thrombocythemic MF. In 14 (2.69 %) patients, MF type was not reported. By the time of diagnosis, the median age of PV patients was 56 years (range 17–86 years), and that of MF patients was 55 years (range 16–83 years) (p = 0.022). The proportion of women among PV patients was 57 %, among MF patients it was 65 % (p = 0.0065).
 Results. The assessment of thrombotic complication risk in PV showed that 51.01 % (n = 302) of patients belong to the low-risk, 39.86 % (n = 236) belong to the intermediate-risk, and only 9.12 % (n = 54) of patients belong to the high-risk groups. Distribution of MF patients between risk groups demonstrates favorable prognosis for most patients. The group of low and intermediate-1 risks includes 56.43 % (n = 294) patients according to the prognostic scoring system IPSS and 68.52 % (n = 357) according to the prognostic scoring system DIPSS. In the vast majority of cases, patients received hydroxycarbamide therapy: 81.81 % (n = 832) in the total cohort, 83.33 % (n = 465) in the PV group, and 79.96 % (n = 367) in the MF group. Interferon-α was administered to 19.71 % (n = 110) of PV patients and 29.85 % (n = 137) of MF patients. Ruxolitinib was assigned to 3.14 % (n = 19) of PV patients and 21.35 % (n = 98) of MF patients.
 Conclusion. Regular monitoring of the PV and MF course and treatment efficacy can provide recommendations for adequate change of therapy in case of the failure of previous treatment. It should be emphasized that the timely switch to the second-line therapy results in reduced disability and mortality among PV and MF patients with myeloproliferative neoplasms.

Systematic, Point-of-Care Newborn Screening and Treatment for Sickle Cell Disease in Rural Mali, West Africa: Results from an Ongoing Implementation Project

Introduction: Sickle cell disease (SCD) is highly prevalent across sub-Saharan Africa and is a significant source of under-5 mortality. Accurate characterization of the disease prevalence is difficult to determine due to the absence of systematic newborn screening in most African countries. Mali is a land-locked West African country with a high burden of sickle cell disease. Despite the critical need for early diagnosis of SCD to improve survival, wide scale diagnostic efforts utilizing IEF or HPLC in sub-Saharan Africa have been limited by a paucity of laboratory equipment and trained personnel, unreliable supply chain for consumables, and overall expense. Point-of-Care (POC) testing for SCD is advancing rapidly and has the potential to reduce these barriers. This analysis will review the results of an ongoing POC newborn screening program for SCD at a single rural hospital in Mali and will evaluate the acceptance rates and basic outcomes of resource-adapted treatment. Methods: Between March 2019 and March 2023, all newborns at Koutiala Women's and Children's Hospital in Koutiala, Mali were offered screening for SCD with the HemoTypeSC ™ POC test kit (Silver Lake Research, California, USA). After verbal consent, heel-stick samples were procured within the first 24 hours of life. The samples were processed according to the package insert. The results were available within 10 minutes and were provided to the caregiver prior to discharge. Newborns who were found to have sickle cell disease were referred to the SCD treatment program where they were offered ongoing access to basic treatment measures such as antibiotic prophylaxis, malaria prevention, and hydroxycarbamide therapy. Parents of infants with HbSS who had not been seen in the clinic for follow-up within at least 6 months were contacted by phone at the time of this analysis to provide an update on their clinical status. Families of infants with HbS trait or HbC trait received appropriate genetic counseling. Statistical analysis was performed using a paired t-test. Results: 11,938 infants were born over the study period and 11,818 (99%) received POC screening. Screening results revealed Hb S trait; n=1,119 (9.47%), Hb C trait; n=1,285 (10.87%), Hemoglobin SS; n=81 (0.69%), Hemoglobin SC; n=100 (0.85%), and homozygous C; n=20 (0.54%). In all, 181 infants (1.54%) were found to have sickle cell disease and were offered follow-up care in the SCD treatment program at Koutiala Hospital. In addition, 2,404 infants (20.34%) were found to be carriers of either HbC trait or HbS trait. The mean age of those children diagnosed with HbSS and HbSC at the time of this analysis was 22.20mo (3-42mo) and 21.46mo (4-37mo), respectively. 89% (n=72) of the infants with HbSS received ongoing disease management. Penicillin prophylaxis was accepted in 82% (n=59) of the children in this cohort. Additionally, 44% (n=32) were started on hydroxycarbamide at a low, fixed dose (20ml/kg/day) based on disease severity parameters. Mean MCV for those children receiving hydroxycarbamide was 89.06fL (+/- 9.5fL) and for the non-hydroxycarbamide group was 79.83fL (+/- 14.3fL) (p= 0.025). While the most common reason for clinical follow-up was routine treatment, patients were also seen for fever, malaria treatment, and bone pain episodes. Based on clinical records and phone follow-up, there were two confirmed deaths (2.5%) in the HbSS cohort. One infant died of non-SCD complications on the first day of life and the other died at 6 months of age without returning to the clinic for follow-up treatment. Conclusions: This program is the first to examine the impact of systematic POC infant screening and treatment for SCD in rural Mali, West Africa. The low cost and rapidity of POC testing resulted in a high rate of newborns screened and positively impacted the success of clinical follow-up. POC testing results were comparable when reviewed alongside historical IEF-based screening at Koutiala Hospital (Table 1). The higher percentage of infants screened by POC when compared to IEF may have been slightly affected by an increase in the general awareness of SCD amongst the regional population. There was a high acceptance rate of ongoing clinical care (89%) and low death rate (2.5%) within the HbSS cohort which may be attributable to early access to diagnosis and treatment. Results from a larger patient size and longer treatment duration will provide more insight into the benefits of POC screening in this setting.

Drug Therapy in Patients with Severe Forms of Sickle Cell Anemia

BACKGROUND AND AIM: Combining Hydroxycarbamide (hydroxyurea) therapy and L-Carnitine (HU+LC) was proved effective and tolerable in patients with thalassemia intermedia; however, its role in sickle cell anemia (SCA) was not investigated. This study aimed to assess various aspects of treatment with HU + LC in adult patients with severe forms of SCA. PATIENTS AND METHODS: Ninety-one adult SCA patients were recruited, then distributed into four treatment groups: Group 1 – 37 patients treated with HU + LC; Group 2 – 16 patients treated with HU; Group 3 – 18 patients treated with LC; and Group 4 – 20 patients received supportive treatment only. Their baseline data were recorded then reassessed 8–12 weeks later. Their compliance was assessed subjectively. RESULTS: Patients were nearly matched as regards gender, age, baseline hematologic, and biochemical data. Compared to baseline, HU + LC treatment significantly increased hemoglobin and reduced reticulocytes, white blood cells, mean corpuscular hemoglobin concentration, and lactate dehydrogenase (LDH). Compared with other lines, HU + LC significantly reduced number of painful episodes, blood transfusions, and in hospital days per year. Adding LC to HU improved patient compliance, with mild side effects. Residence, side effects, baseline hemoglobin (Hb), and Hb F% affected patients' compliance. Both gender and age did not show any influence on response to treatment while side effects, compliance, baseline Hb, and LDH displayed a significant effect. CONCLUSION: Combining LC with HU for the treatment of adult SCA patients showed superior hematologic and clinical effectiveness. The response was more obvious in severe cases. However, health education about the combination is needed to improve patients' compliance and therapeutic responses. Trial registration: Clinical Trials.gov, NCT05081349. https://clinicaltrials.gov/ct2/show/NCT05081349.

P-O13 Spontaneous Splenic Rupture as first presentation of Chronic Myeloid Leukaemia

Abstract Background Although rare, spontaneous splenic rupture (SSR) is a potentially life threatening condition and most commonly associated with infection and malignancy. Haematological malignancies are an important differential diagnosis and among these chronic myeloid leukaemia (CML) has one of the highest associations with SSR. Methods This case report follows a previously fit and healthy thirty-three year old gentleman who presented to accident and emergency with one day history of sudden onset, severe, left upper quadrant pain. CT of the abdomen and pelvis including an arterial phase, confirmed splenic rupture with moderate volume haemo-peritoneum, but no active bleeding. White cell count (WCC) was 225.8 x10^9/l and blood film confirmed suspicion of haematological malignancy. The patient was haemodynamically stable and therefore transferred to the surgical high dependency unit for observation and conservative management. He was commenced on hydroxycarbamide on the advice of haematology. Results Genetic screening detected BCR-ABL1 and Philadelphia chromosome; this along with bone marrow aspirate confirmed diagnosis of CML. His WCC decreased with hydroxycarbamide therapy. He made good clinical progress and was discharged home with haematology follow up. Hydroxycarbamide has since been stopped and he has been initiated on Imatinib therapy. His WCC has returned to normal and he has remained well with no further complications. Conclusions SSR is an extremely rare first presentation of CML. Given its associated morbidity and mortality, it should remain an important differential diagnosis in patients presenting acutely to the General Surgeon with abdominal pain and shock, especially in those with a known underlying haematological malignancy.

Bridging the implementation gap in medication adherence. If you build it, will they come?

Bridging the implementation gap in medication adherence. If you build it, will they come?

Saving lives through early diagnosis: the promise and role of point of care testing for sickle cell disease

Sickle cell disease (SCD) is a devastating and under-recognised global child health issue affecting over 300,000 infants annually, with the highest prevalence in India and sub-Saharan Africa. Most affected infants born in low- and middle-income countries (LMIC) lack access to SCD testing and die from complications in the first years of life without a formal diagnosis. The majority of deaths are preventable with early diagnosis and provision of inexpensive interventions. Despite global recognition of the urgent need, expansion of SCD newborn screening (NBS) programmes beyond the pilot stage has been obstructed by a dependence on an expensive and logistically challenging centralised laboratory testing model. Recently, several point-of-care tests (POCT) for SCD have been developed with promising field validation studies. Here, we summarise the state of POCT for SCD, review barriers and unanswered questions, and discuss optimal strategies for utilising POCT to address the growing global burden of SCD. There is an urgent need to prospectively evaluate the ability of POCT to reduce the morbidity and high early mortality of SCD. To impact a sustainable reduction to this end, it is essential to link a diagnosis with comprehensive SCD care, including wide and affordable access to affordable hydroxycarbamide therapy.

Acoustic Levitation: A Novel Approach to Study the Physical Properties of Blood in Normal Subjects and in Patients with Sickle Cell Disease

Acoustic levitation is a novel technique which we have developed for the purpose of measuring physical properties of blood, plasma and red cells in a non-contact setting, which eliminates issues and concerns related to the interaction of blood with non-physiological surfaces. Figure 1 shows a levitated blood drop between the ultrasound transducer and reflector. By exciting drop shape oscillation, we can study its vibrational behavior and infer its viscoelastic properties.Whole blood samples were collected from volunteers in tubes containing Ethylenediaminetetraacetic acid (EDTA) as anticoagulant. Patients' samples were studied using left-over material after a clinically-ordered CBC had been performed. Samples with different hematocrit (Hct) were obtained in the same subject, by removing or adding autologous plasma after centrifugation.To calibrate the device, we compared the results obtained by our instrument with the blood viscosity determination provided by a cone-plate rotational rheometer (HR-2, Hybrid rheometer - TA Instrument). Figure 2 (Left) shows the results from levitator and rotational rheometer.We also compared normal samples with samples of patients with sickle cell disease (SCD) over a wide range of Hct values, obtained by addition or removal of autologous plasma. As shown in Figure 2 (Right), for any given Hct the viscosity measurements obtained by the levitation device were greater in blood of patients with sickle cell disease compared with normal controls.For each sample of blood from patients with sickle cell disease, we assessed viscosity with the levitation device at different values of Hct (autologous plasma addition or removal) and were able to determine the slope of this regression line. We also compared the viscosity value determined at an arbitrary Hct value of 55% among all the clinical samples collected from patients with SCD. As shown in Figure 3, when these data were analyzed as a function of the fetal Hb content of each blood sample (obtained from the total Hb value of the unmodified clinical sample and the % of Hb F determined by HPLC), a clear negative correlation emerged between total Hb F values (in g/dl) and viscosity, measured as either the slope of the regression line or the value at a fixed Hct of 55%. The clinical samples included several patients treated with hydroxycarbamide, showing an important correlation between higher values of Hb F and lower blood viscosity.These studies demonstrate that acoustic levitation is a non-contact technique which can be successfully used to measure physical properties of human blood. We show that viscosity measurements obtained with this new device compare very favorably with traditional rotational viscometer. Furthermore, this new technology can reproducibly measure viscosity over a wide range of Hct values and for any given Hct, it shows that the viscosity of samples from patients with SCD is greater than normal controls. We also show that our measurement is sensitive enough to detect variation in viscosity associated with different absolute values of fetal Hb in blood, and more specifically showing lower viscosity with higher Hb F values, opening the possibility that this technique could be used to determine changes in viscosity associated with hydroxycarbamide therapy in patients with sickle cell disease. [Display omitted] DisclosuresAnsari Hosseinzadeh:National Science Foundation: Research Funding. Brugnara:National Science Foundation: Research Funding. Holt:National Science Foundation: Research Funding.

Prevalence of High Body Mass Index in Children with Sickle Cell Disease and Its Correlation of Disease Severity

▪BackgroundChildren with sickle cell disease (SCD), particularly those with the homozygous form designated HbSS, have frequently been reported to suffer from impaired growth, delayed onset of puberty and poor nutritional status (1). However, improvement in healthcare of children with SCD in more economically developed countries, along with increased use of SCD-directed therapies such as hydroxyurea and chronic transfusions along with the recent rise in childhood obesity rates may have influenced growth of children with SCD. Two recent reports in the US found that 19-22% of children with SCD were overweight or obese (2, 3) . It is not known whether high body mass index (BMI) in children with SCD results in a worse clinical phenotype. Known association of childhood obesity with obstructive sleep apnoea (OSA) raises the potential of worsening clinical phenotype of SCD by increasing the incidence of nocturnal hypoxaemia which in turn may give rise to increased vaso-occlusive episodes (4). This study aimed to determine the prevalence of high body mass index (BMI) in an urban population of children in the UK with SCD and assess if there is correlation between BMI and disease severity.MethodsA retrospective chart review was performed on all patients aged 2-18 years with SCD who attended an outpatient clinic at Kings College Hospital, London between April 2015 and April 2017. Acute sickle cell-related emergency department (ED) attendances and hospital admissions in this period were recorded. BMI percentile, demographic information and laboratory markers of disease were recorded from the most recent clinic visit. Age and gender specific definitions of BMI percentiles were used, based on the British 1990 growth reference charts. Patients were assigned to 1 of 3 groups based on their BMI percentile: low, normal and high BMI. A high BMI was defined as >85th percentile for age and gender, whilst underweight was defined as <5th percentile.ResultsData was collected on 385 children with SCD in a single tertiary Paediatric Haemoglobinopathy centre in London. 16.6% children with SCD were overweight or obese and 5.2% were underweight. In contrast, government figures indicate that in the South London Borough of Southwark, up to 28% children aged 10-11 years were overweight or obese and 0.9% children were underweight in 2016-2017 (data.london.gov.uk). A high BMI among our SCD patients was associated with HbSC genotype (P= 0.006) and females (P=< 0.001). HbSS patients taking hydroxycarbamide had a significantly higher mean BMI compared to those not taking it (P=0.006). No association was found between BMI group and the number of acute sickle cell-related A&E attendances or hospital admissions for HbSS patients (P=0.450 and 0.780 respectively) or HbSC patients (P=0.838 and P=0.750 respectively). Patients with HbSS SCD in the high BMI group had a significantly higher haemoglobin (Hb) and fetal Hb (HbF) than those in the normal BMI group (P=<0.001 and P=0.010 respectively). HbSS patients in the high BMI group had a significantly lower absolute reticulocyte count (ARC) than those in the normal BMI group (P=0.022), see Table 1. These results suggest that HbSS patients with a high BMI may have a less severe disease than those with a normal BMI. These associations were not demonstrated in patients with HbSC disease.ConclusionsNearly one-sixth of children and adolescents with SCD in this urban population were overweight or obese. The association of hydroxycarbamide therapy and higher BMI in children with HbSS has been demonstrated in this study for the first time. There was no association between BMI group and the number of acute sickle cell-related A&E attendances or hospital admissions. In patients with HbSS disease, laboratory markers of disease severity, including Hb, HbF and ARC, suggest than patients with a high BMI may have a less severe disease than those with a normal BMI. Longitudinal studies monitoring BMI of children over time and markers of severity in SCD would produce greater evidence of the impact of a high BMI on disease severity. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

MPN-214: Chronic Myeloproliferative Neoplasms in Elderlies: Challenging Issues of Diagnosis and Treatment

Context: Chronic myeloproliferative neoplasms (CMN) in elderlies are the frequently registered clonal stem cell malignancies, being characterized in the advanced phases by recurrent evolution and negative socio-economic sequels. OBJECTIVE: To assert the diagnosis and treatment options in elderlies with CMN. DESIGN: This clinico-analytic study included 78 elderly patients with chronic myeloid leukemia (CML), primary myelofibrosis (PMF) and polycythemia vera (PV), treated at the Institute of Oncology from Moldova between 1995–2020. The diagnosis was proved by histopathological, cytological, molecular examinations and FISH. SETTING: The follow-up and study were completed at the comprehensive cancer center. The study is related to the ambulatory and hospitalized care. PATIENTS: Prefibrotic PMF stage was confirmed in 8 (42.1%) cases, fibrotic stage – in 11 (57.9%). CML was proved in chronic phase in 25 (89.3%) patients, in the accelerated phase in 3 (10.7%). PV was diagnosed in stage IIA in 27 (87.1%) patients, in stage IIB in 4 (12.9%). INTERVENTIONS: TKIs were administered in the newly diagnosed CML patients, in cases of resistance to non-TKIs chemotherapy and interferon-α. PV and PMF patients were treated with busulfan, hydroxycarbamide and interferon-α, combined with phlebotomies in PV. RESULTS: There was no difference of the hematological response (HR) and molecular response rates under TKIs therapy between elderlies and CML totality. In patients ≥60 years 5-year overall survival (OS) was 69% after TKIs therapy, being slightly lower than in CML totality (74%). HR was achieved in all PV patients under chemotherapy and phlebotomies. In relapses, interferon-α provided HR for 61 and 79 months. 10-year OS of elderly PV patients constituted 76.4%, being lower than in PV totality (85.9%). There was no difference of the OS in elderlies under chemotherapy with busulfan and hydroxycarbamide. HR rate and OS were lower under busulfan and hydroxycarbamide treatment in PMF patients, than in PV. CONCLUSIONS: No difference of the OS was revealed in PV elderlies under busulfan and hydroxycarbamide therapy, surpassing the OS in PMF patients. TKIs therapy is a curable option for CML patients regardless the age. The OS in elderlies decays due to more frequent vascular-thrombotic events owing to thrombocytosis.

PB2204 SERUM YKL‐40 LEVELS ARE ELEVATED IN PRIMARY AND SECONDARY MYELOFIBROSIS AND MAY BE AFFECTING THEIR SURVIVAL

Background:Primary and secondary myelofibrosis (PMF and SMF) are clonal hematopoietic stem cell disorders characterized by myeloproliferation, bone marrow fibrosis, splenomegaly and a strong inflammatory milieu. Glycoprotein YKL–40 emerged as an important biomarker of inflammation, angiogenesis, tissue remodeling, cell proliferation and differentiation. Serum YKL‐40 levels were shown to be higher in PMF patients when compared to healthy controls. However, the clinical significance of this finding is unknown.Aims:The aim of our study was to investigate serum YKL‐40 levels in PMF and SMF patients and to assess its clinical correlations.Methods:Using commercially available ELISA kit (R&amp;D Systems Europe, Abingdon, UK) we analyzed serum YKL‐40 levels in 30 myelofibrosis patients (13 PMF and 17 SMF) and in 25 sex‐ and age–matched healthy controls. Correlations with clinical parameters were made. Optimal cut ‐ off for survival analyses was determined using the ROC curve analysis. The Kruskal‐Wallis analysis of variance, the Mann‐Whitney U test, the Spearman rank correlation, the log rank test and the Cox regression analysis was used. P values &lt;0.050 were considered statistically significant for all analyses.Results:Serum YKL‐40 levels significantly differed between patients and controls (p = 0.006): both PMF (median 685.3 pg/mL, range 220 – 4000) and SMF (median 1797.8 pg/mL, range 58 – 4000) patients had higher serum YKL‐40 levels in comparison to controls (median 560 pg/mL, range 117 – 1137; p&lt;0.050 for both comparisons), whereas there was no statistically significant difference between PMF and SMF patients. Higher serum YKL‐40 levels were statistically significantly associated with presence of constitutional symptoms (median 465.1 pg/mL vs 3694.5 pg/mL for patients with or without constitutional symptoms; p = 0.001), higher Eastern Cooperative Oncology Group (ECOG) performance status (median 685.3 pg/mL vs 3413.2 pg/mL for patients with 0‐1 and 2‐4 performance status, respectively; p = 0.047), higher platelet count (rho 0.390; p = 0.033), larger spleen (rho 0.750; p&lt;0.001), lower serum lactate dehydrogenase (LDH) (rho ‐0.380; p = 0.039) and less prominent bone marrow fibrosis grade (rho ‐0.480; p = 0.007). Patients receiving ruxolitinib had lower serum YKL‐40 levels (median 552.9 pg/mL) than those on hydroxycarbamide therapy (median 4000 pg/mL; p = 0.005). In univariate survival analysis, patients with higher serum YKL‐40 levels (&gt;2311.15 pg/mL) had inferior overall survival in comparison to patients presenting with lower YKL‐40 levels (≤2311.15 pg/mL) (HR 2.91; p = 0.034). This association remained significant in the multivariate Cox regression model after adjusting for sex, age, DIPSS score and ruxolitinib therapy (HR 5.59; p = 0.029).Summary/Conclusion:This is the first study to report clinical associations and strong prognostic properties of increased serum YKL‐40 levels in patients with parimary and secondary myelofibrosis. Serum YKL‐40 levels might represent a state of pronounced inflammation and increased tumor burden in myelofibrosis, as they are significantly associated with presence of constitutional symptoms, poor performance status and parameters indicative of stronger myeloproliferation. Additional studies are needed to more precisely elucidate the cell(s) of YKL–40 origin and to clarify the role of YKL‐40 in promoting disease progression and bone marrow fibrosis. Prognostic properties of YKL‐40 also need to be confirmed in larger prospective cohorts of uniformly treated myelofibrosis patients. Nevertheless, our results identify YKL‐40 as a potential prognostic biomarker in myelofibrosis.

Elevated fetal haemoglobin levels are associated with decreased incidence of retinopathy in adults with sickle cell disease

Among the many vascular complications of sickle cell disease (SCD), retinopathy is the most prevalent and represents a leading cause of blindness. Hydroxycarbamide therapy ameliorates many symptoms of SCD, and high fetal haemoglobin (HbF) levels have been shown to protect against the development of retinopathy in children with HbSS. Its effect on adults with SCD, who are at a much higher risk of developing retinopathy, has not been studied. We aimed to investigate the effect of hydroxycarbamide use and HbF level on sickle cell retinopathy development in adults. We performed a retrospective cross-sectional study and collected demographics, comorbidities, and ocular and haematological data from 300 adult sickle cell subjects examined at the Henkind Eye Institute at Montefiore Medical Center during a 5-year period, from October 2012 to November 2017. The cohort was comprised mainly of Black and Hispanic subjects with all SCD genotypes, aged 18-71years. Results show that in HbSS patients treated with hydroxycarbamide, those with retinopathy had significantly lower HbF levels compared to patients without retinopathy (P=0·018). Our study identified the optimal HbF cut-off point for retinopathy protection to be 14·87%. Thus, a HbF level of 15% appears to be the threshold above which the odds for developing retinopathy in SS patients are reduced by 50%.

Low-dose hydroxycarbamide therapy may offer similar benefit as maximum tolerated dose for children and young adults with sickle cell disease in low-middle-income settings.

The multiple clinical benefits of hydroxycarbamide in sickle cell disease are supported by a large body of evidence. The maximum tolerated dose (MTD) is the regimen recommended by guidelines from a panel of National Heart, Lung, and Blood Institute (NHLBI) experts, but other dosage regimens have been used in babies (BABY-HUG) 9 to 18 months old (20 mg/kg per day) and developing countries such as India (10 mg/kg per day); however, there has been no direct comparison of the efficacy, effectiveness, or cost-effectiveness of these different regimens. The purpose of this review was to investigate the current situation with various hydroxycarbamide regimens with particular relevance to low-middle-income countries. In regard to methodology, a literature review was undertaken by using multiple databases in PubMed and Google and the search terms included sickle cell disease, hydroxyurea, hydroxycarbamide, sickle cell anaemia, low-middle-income countries, Sub-Saharan Africa, and India. Although MTD regimens have been widely used in research, especially within North America, clinical trials elsewhere tend to use fixed-dose regimens. In a survey of haematologists across Europe and Africa, 60% (75% response rate) did not use the MTD regimen for hydroxycarbamide treatment of sickle cell disease. The recommendations are (1) for practical purposes to commence using fixed-dose hydroxycarbamide in line with BABY-HUG recommendations and then (2) to consider or propose a trial comparing MTD escalation with various fixed doses and to include as end points health-related quality of life, haemoglobin F levels, adherence, and cost-effectiveness.

Cepeginterferon alfa-2b in the treatment of chronic myeloproliferative diseases

A comparative evaluation of the effectiveness of different therapeutic strategies in patients with polycythemia vera (PV) and essential thrombocythemia (ET). Patients with PV or ET, diagnosed according to the criteria WHO 2016 were included in the study. The primary endpoint - 6 months of therapy (clinical-hematological and molecular responses). The secondary endpoint - 12 months of therapy (clinico-hematologic, molecular, histological responses). Sixty three patients were included in the analysis: the first group consisted of 33 patients who received the therapy with ce-pegiterferone alpha-2b (ce-pegalpha-INF-α-2b), 10 of them received previous treatment; the second group - 23 patients btained hydroxycarbamide; the third group - 7 patients were treated with recombinant interferon alpha therapy (rINFα). In comparison groups, differences in age were revealed: patients receiving hydroxycarbamide therapy were older. Phlebotomy occurred in 36% of patients in the first group, 9% in the second group, and 14% in the third group. By the 6th month of therapy, 43% of the patients receiving the ce-pegalpha-INF-α-2b had complete clinical-hematologic response, 36% had partial clinical-hematologic remission and stabilization of the disease was established in 21% cases. No disease progression occured. By the 12th month of therapy, statistically significant differences in terms of efficacy between the different therapeutic groups (p = 0.2462, Fisher's exact test). In all three groups, the allelic load of JAK2V617F decreased: from 50 to 19%, from 22.3 to 15.8%, from 50 to 7.19%, respectively. The lower the allele load positively correlated with better response to therapy, which was observed in all analyzed groups. Hematologic adverse events (AEs) were more frequently observed in patients receiving ce-pegalpha-INF-α-2b therapy. Local reactions developed on 3-7 days of therapy as a hyperemic macula at the injection site. Both these reactions and hair loss did not influence on patient's condition. In the second group (patients with hydroxycarbamide therapy) there were changes in the skin and mucous membranes: dry skin, stomatitis, and in older patients new keratomas appeared. The flu-like syndrome was the most common adverse event associated with the therapy of ce-pegalpha-INF-α-2b, which fully relived during the first month of therapy. There was only one case with the flu-like syndrome we observed at the 11th month of therapy. As a rule, the biochemical blood test changes did not influence on patient's condition, were mostly associated with dietary violations, had a tendency to self-resolution and did not require medical interventions. Serious AEs were reported in one case - pulmonary embolism in a patient treated with rINFα. The reasons for the therapy discontinue in group 1: toxic hepatitis, intolerance, by the request of the patient, inadequate efficacy of therapy; in group 2: skin toxicity, in group 3: thromboses. Treatment of ce-pegalpha-INF-α-2b in patients with PV and ET is highly effective - the most patients pbtained clinical and hematological responses. There were no statistically significant differences in these parameters in comparison with hydroxycarbamide and rINFα. The use of the ce-pegalpha-INF-α-2b had an acceptable safety profile. The estimated therapeutic dose should be calculated according to body weight. To reduce the frequency of hematologic AE, titration of the drug dose is required.

Skeletal and myocardial microvascular blood flow in hydroxycarbamide-treated patients with sickle cell disease.

In sickle cell disease (SCD), abnormal microvascular function combined with chronic anaemia predisposes patients to perfusion-demand mismatch. We hypothesized that skeletal muscle and myocardial perfusion, normalized to the degree of anaemia, is reduced at basal-state compared to controls, and that this defect is ameliorated by hydroxycarbamide (HC; also termed hydroxyurea) therapy. Twenty-one SCD patients, of whom 15 were treated with HC, and 27 controls underwent contrast-enhanced ultrasound (CEU) perfusion imaging of the forearm as well as the myocardium. HC treatment was associated with lower white cell and reticulocyte counts, and higher fetal haemoglobin and total haemoglobin levels. When corrected for the degree of anaemia in SCD patients, skeletal flow in HC-treated patients was significantly higher than in untreated SCD patients (217·7±125·4 vs. 85·9±40·2, P=0·018). Similarly, when normalized for both anaemia and increased myocardial work, resting myocardial perfusion was also significantly higher in HC-treated patients compared with untreated SCD patients (0·53±0·47 vs. 0·13±0·07, P=0·028). Haemoglobin F (HbF) levels correlated with skeletal muscle microvascular flow (r=0·55, P=0·01). In conclusion, patients with SCD not on HC therapy have resting flow deficits in both skeletal muscle and myocardial flow. HC therapy normalizes flow and there is a direct correlation with HbF levels. Clinical trial registration ClinicalTrials.gov Identifier: NCT01602809; https://clinicaltrials.gov/ct2/show/NCT01602809?term=sACHDEV&rank=9.

How I manage sickle cell patients with high transcranial doppler results.

Stroke is one of the most severe complications to affect children with sickle cell anaemia (SCA). Transcranial doppler (TCD) is an accurate and non-invasive method to determine stroke risk. Randomised controlled trials have demonstrated the efficacy of chronic transfusion therapy in stroke prevention based on risk stratification determined by TCD velocities. This has led to the regular use of TCD monitoring for children with SCA in order to determine stroke risk. Significant resource allocation is necessary to facilitate training, quality assurance and failsafe arrangements for non-attenders. In a subgroup of patients, chronic transfusions for primary stroke prevention can be replaced by hydroxycarbamide therapy, provided careful monitoring is undertaken; including repeat TCD studies at frequent intervals. The authors propose an evidence-based algorithm for the management of abnormal TCD velocities and discuss the role of this test in other clinical contexts, such as in Haemoglobin SC disease.

Klf10 Gene, a Secondary Modifier and a Pharmacogenomic Biomarker of Hydroxyurea Treatment Among Patients With Hemoglobinopathies.

The klf10 gene could indirectly modify γ-globin chain production and hence the level of fetal hemoglobin (HbF) ameliorating the phenotype of β-hemoglobinopathies and the response to hydroxycarbamide (hydroxyurea [HU]) therapy. In this study, we aimed to evaluate the frequency of different genotypes for the klf10 gene in β-thalassemia major (B-TM), β-thalassemia intermedia (B-TI), and sickle cell disease (SCD) patients by polymerase chain reaction and to assess its relation to disease phenotypes and HU response. This cross-sectional study included 75 patients: 50 B-TM, 12 SCD, and 13 B-TI patients (on stable HU dose). The relation of the klf10 gene polymorphism (TIEG, TIEG1, EGRα) (rs3191333: c*0.141C>T) to phenotype was studied through baseline mean corpuscular volume, HbF, and transfusion history, whereas evaluation of response to HU therapy was carried out clinically and laboratory. The frequency of the mutant klf10 genotype (TT) and that of the mutant allele (T) was significantly higher among B-TM patients compared with those with B-TI and SCD patients. Only homozygous SCD patients for the wild-type allele within the klf10 gene had a significantly lower transfusion frequency. The percentage of HU responders and nonresponders between different klf10 polymorphic genotypes among B-TI or SCD patients was comparable. Although the klf10 gene does not play a standalone role as an HbF modifier, our data support its importance in ameliorating phenotype among β-hemoglobinopathies.

Ruxolitinib Restores Normal Telomere Length in Patients with Myelofibrosis

Introduction Telomeres are specialized structures of repetitive nucleotide sequences that cap the ends of human chromosomes able to maintain genome stability and protect the cell from progressive DNA shortening. Some recent reports describe reduced telomere length in myelofibrosis (MF) regardless of hydroxycarbamide therapy, suggesting a possible prognostic relevance for this biomarker. As yet, no studies have investigated telomere dynamics following treatment with ruxolitinib. Methods Eight primary MF and 3 post ET MF patients were given 15 mg or 20 mg of oral ruxolitinib twice daily (BID) depending on baseline platelet counts. The drug dose was escalated to 25mg BID in patients with an inadequate response and reduced when platelet counts dropped to <100,000/μL. Treatment was stopped when platelet levels fell below 50.000/μL. Telomere lengths were analyzed by quantitative PCR (q-PCR) as described by Cawthon (2002) and assessed before and after ruxolitinib at a median of 1000 days (range 113-1152). The relative telomere length (RTL) was determined as the telomere (T) to single copy gene (36B4) (S) ratio (T/S) normalized to a reference sample (K-562 DNA). Peripheral blood samples were also collected from 11 age and sex matched healthy controls. Results Median age at diagnosis was 72 years (range 53-83). The JAK2 V617F mutation was detected in 7 patients, while CALR and MPL were found in 2 and 1 patient, respectively. One patient was triple negative. All patients had splenomegaly with a median enlargement of 17 cm below the costal margin. Based on IPSS scores, 6 patients were assigned to the intermediate-2 risk category and 5 to the high risk category. Ruxolitinib was administered for a median of 1000 days (range 113-1152). Overall, patients received a median of 22 grams of ruxolitinib (range 4.6-44.5). Splenomegaly decreased by 60% (range 20-100%). Overall, BM fibrosis was improved in 35% of the cases and remained stable in 65%. Related samples Wilcoxon signed rank test performed before treatment with ruxolitinib, showed that mean RTL was shorter in patients compared to age and sex matched healthy controls (1.08 vs 1.26, respectively; p=0.09). After treatment, median RTL increased significantly (1.30 vs 1.08; p=0.018), showing overlapping values with the healthy controls. Median RTL elongation from baseline was 15% (Figure). Univariate and multivariate analyses included the following parameters: primary MF, presence of the JAK2 V617F mutation, high IPSS score, a decrease in splenomegaly of >50%, >50% bone marrow (BM) cellularity before and after treatment, pre and post treatment WHO scores for BM fibrosis of 3-4, duration of treatment >1000 days, total drug dose of >22 grams. Variables with a p-value lower than 0.2 in univariate analysis were included in multivariate analysis using a multi-step forward binary logistic regression model, where RLT >15% from baseline was considered a dependent variable. Only pre-treatment BM cellularity of >50% significantly correlated with >15% telomere elongation (p=0.004). Conclusion In our small cohort of patients, ruxolitinib proved capable of improving BM fibrosis and restoring telomere lengths to normal values. It is possible that ruxolitinib mediates modulation of the BM microenvironment, thereby stimulating stem cell hematopoiesis. It follows that peripheral blood telomere elongation could be indicative of the stem cellÕs ability to self-renew. This finding, if confirmed, would open a debate about the rationale of treatment with telomerase inhibitors in MF patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized, double-blind, double-dummy, symptom study (RELIEF).

SummaryThe randomized, double‐blind, double‐dummy, phase 3b RELIEF trial evaluated polycythaemia vera (PV)‐related symptoms in patients who were well controlled with a stable dose of hydroxycarbamide (also termed hydroxyurea) but reported PV‐related symptoms. Patients were randomized 1:1 to ruxolitinib 10 mg BID (n = 54) or hydroxycarbamide (prerandomization dose/schedule; n = 56); crossover to ruxolitinib was permitted after Week 16. The primary endpoint, ≥50% improvement from baseline in myeloproliferative neoplasm ‐symptom assessment form total symptom score cytokine symptom cluster (TSS‐C; sum of tiredness, itching, muscle aches, night sweats, and sweats while awake) at Week 16, was achieved by 43·4% vs. 29·6% of ruxolitinib‐ and hydroxycarbamide‐treated patients, respectively (odds ratio, 1·82; 95% confidence interval, 0·82–4·04; P = 0·139). The primary endpoint was achieved by 34% of a subgroup who maintained their hydroxycarbamide dose from baseline to Weeks 13–16. In a post hoc analysis, the primary endpoint was achieved by more patients with stable screening‐to‐baseline TSS‐C scores (ratio ≤ 2) receiving ruxolitinib than hydroxycarbamide (47·4% vs. 25·0%; P = 0·0346). Ruxolitinib treatment after unblinding was associated with continued symptom score improvements. Adverse events were primarily grades 1/2 with no unexpected safety signals. Ruxolitinib was associated with a nonsignificant trend towards improved PV‐related symptoms versus hydroxycarbamide, although an unexpectedly large proportion of patients who maintained their hydroxycarbamide dose reported symptom improvement.

Ruxolitinib therapy and telomere length in myelofibrosis

Telomeres are specialized structures of repetitive nucleotide sequences that cap the ends of human chromosomes. Their main purpose is to maintain genome stability and integrity, and to protect the cell from progressive DNA shortening during repeated division. Human enzyme telomerase complex maintains the length of telomere repeats.1 Despite the high levels of telomerase activity in cancer cells, telomere shortening can still occur. Some recent reports describe reduced telomere length in myelofibrosis (MF) regardless of hydroxycarbamide therapy, suggesting a possible prognostic relevance for this biomarker.2, 3, 4 As yet, no studies have investigated telomere dynamics following treatment with ruxolitinib, a JAK1/2 inhibitor approved for the treatment of intermediate-2 and high risk MF, primary or post-polycythemia vera (PV) and essential thrombocytemia (ET).5

Hydroxycarbamide treatment and brain MRI/MRA findings in children with sickle cell anaemia

Silent cerebral infarction (SCI) is the most common neurological abnormality among children with sickle cell anaemia (SCA). The effect of hydroxycarbamide (also termed hydroxyurea) on the development and progression of SCI is unclear. We evaluated brain magnetic resonance imaging/angiography (MRI/MRA) in children with SCA receiving long-term hydroxycarbamide therapy. Fifty participants (median 9·4years, range 1·1-17·3) enrolled in the Hydroxyurea Study of Long-Term Effects (HUSTLE; NCT00305175) underwent brain MRI/MRA and laboratory evaluations before hydroxycarbamide initiation and after 3 and 6years of treatment to maximum tolerated dose. SCI and vascular stenosis were evaluated. At baseline, 3 and 6years, SCI were present in 19/50 (38%), 20/49 (41%), and 7/17 (41%), respectively. At 3years, one child developed a SCI lesion, and another progressed (single lesion to multiple). Lower haemoglobin (Hb) (80g/l vs. 86g/l, P=0·049), fetal Hb (5·0% vs. 10·4%, P<0·001) and oxygen saturation (97% vs. 98%, P=0·027) before hydroxycarbamide initiation were associated with SCI. No patients had vascular stenosis identified on MRA, transient ischaemic attack or stroke. Our data indicate that children receiving hydroxycarbamide over a 3- to 6-year period have a low rate of new or worsening cerebrovascular disease. Further studies are needed to confirm that hydroxycarbamide can prevent the onset and progression of SCI.