Hydroxyurea In Patients Research Articles

CYB5R3 T117S tempers fetal hemoglobin induction by hydroxyurea in patients with sickle cell disease

CYB5R3 T117S tempers fetal hemoglobin induction by hydroxyurea in patients with sickle cell disease

799MO The primary results from a randomized double-blind phase II study of rovadicitinib versus hydroxyurea in patients with myelofibrosis

799MO The primary results from a randomized double-blind phase II study of rovadicitinib versus hydroxyurea in patients with myelofibrosis

Transfusion Requirements in Hospitalized Patients with Sickle Cell Disease Taking Either Voxelotor or Hydroxyurea

Background Sickle Cell Disease is a cause of anemia frequently requiring blood transfusions. Current treatments for Sickle Cell Anemia include Hydroxyurea, or the recently approved medication in 2019, Voxelotor. Although recent research, such as the HOPE study, has shown that Voxelotor increases hemoglobin levels when compared to Hydroxyurea, there is limited data regarding the requirement of blood transfusions in patients with Sickle Cell Disease when comparing the two medications. We conducted a retrospective cohort study to determine the requirement of blood transfusions in hospitalized patients with Sickle Cell Disease who were on either taking Voxelotor or Hydroxyurea. Methods This retrospective cohort study identified 8,815 patients across several facilities diagnosed with Sickle Cell Disease who were taking outpatient Voxelotor or Hydroxyurea. Patients who had CKD Stage 4 or 5, ESRD, pregnancy, major surgery, normal hemoglobin levels, and elevated liver enzymes were excluded with a final sample of 6,240. Patients were stratified into two groups based on the treatment they were on, a group taking Voxelotor (243 patients 3.92%) and a group taking Hydroxyurea (5961 96.08%) outpatient. We assessed patient's characteristics such as age, sex, race, smoking status and events during hospitalization. The primary outcome was the number of blood transfusions required with either treatment. Zero-inflated Poisson regression was used to determine the quantity and prediction of blood transfusions required according to different characteristics. Results Of the 6,240 with Sickle Cell Disease who were either on Voxelotor or Hydroxyurea the mean age was 31.32 years, 58.11% were female and 41.89% were male, 94.63% were African-American and 5.37% were non-African-Americans. The medication group was not significantly associated with the log count of transfusions (ie. increased number of transfusions), when controlling for other variables (χ 2 = 0.81, p = 0.367). The odds ratio is 0.425, indicating that patients on Voxelotor are 0.4247 times as likely to be in the “certain zero” group as those on Hydroxyurea - in other words, patients taking Hydroxyurea are 2.354 (1/0.425) times as likely to be in the “certain zero” group (i.e., patients on Hydroxyurea are 2.354 times as likely to not need a transfusion compared to patients taking Voxelotor). Conclusion Hospitalized patients with Sickle Cell Disease taking Voxelotor or Hydroxyurea outpatient have similar blood transfusions requirements when controlling for other variables. In the case of Voxelotor, it is known to increase hemoglobin levels more than Hydroxyurea in patients with Sickle Cell Disease, but there is limited data regarding the end requirements of blood transfusions when comparing the two medications. Our study is the first to identify that there was no increased requirement in the quantity of blood transfusions (Wald Chi Square 26.36, p<.0001, CI 0.3063~ 0.5890) when comparing each medication group. However, the limitation is having a relatively small sample size, and possible confounders from the patients and the disease itself. Further research is required to investigate this.

Final Analysis of the Daliah Trial: A Randomized Phase III Trial of Interferon-α Versus Hydroxyurea in Patients with MPN

Background: Hydroxyurea (HU) is the most commonly used first-line cytoreductive treatment option for patients with myeloproliferative neoplasms (MPN) worldwide. However, increasing evidence on the efficacy and safety of pegylated interferon-alpha2 (IFNα) is emerging, and optimal first-line treatment is to be established. Aims: To compare the efficacy and safety of HU vs. low-dose IFNα in patients with MPN over five years. Methods: DALIAH (NCT01387763) was a randomized phase III trial of HU vs. IFNα in newly diagnosed or untreated patients with MPN (essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic myelofibrosis (PreMF), and primary myelofibrosis (PMF)). Patients > age 60 were randomized (1:1:1) to HU, IFNα-2a, or IFNα-2b whereas patients ≤ age 60 were randomized to IFNα-2a or IFNα-2b. The primary outcome was the JAK2V617F molecular response (MR) rate at 18, 36, and 60 months per 2009 European LeukemiaNetwork (ELN) (ET, PV, PreMF) or 2005 European Myelofibrosis Network (EUMNET) (PMF) criteria. Secondary outcomes included the complete clinicohematologic response (CHR) rate at 12 months. The JAK2V617F allele burden was measured using quantitative polymerase chain reaction (qPCR) on peripheral blood (assay sensitivity: 0.1%). Primary and secondary outcomes were compared between groups (HU vs. IFNα or HU vs. IFNα > 60 years) using Fisher's exact test (categorical variables) or Wilcoxon rank-sum test (continuous variables). Paired comparisons (within groups) were made using Wilcoxon signed-rank test. Serial JAK2V617F measurements were compared by unadjusted mixed-effects linear regression analysis. Results: We included 203 patients (ET: 73 (36%), PV: 89 (44%), PreMF: 16 (8%), and PMF: 25 (12%)) in the modified intention-to-treat (ITT) population. Baseline characteristics were well balanced except for median age (HU: 68 years vs. IFNα: 59 years, p<0.0001) ( Table 1). The MR rate by ITT analysis was similar between HU and IFNα (18 months: 19% vs. 21%, p=1.00; 36 months: 19% vs. 26%, p=0.64; 60 months: 23% vs. 24%, p=1.00) (Figure 1A). However, the JAK2V617F allele burden was significantly lower in the IFNα group at month 36 and beyond (Figure 1B) and the absolute median (IQR) change in JAK2V617F allele burden (baseline to 60 months) was greater with IFNα (-20% (-9;-49) vs. -7% (3;-15), p=0.0053) (Figure 1C). Two patients (IFNα: n=2) were in complete molecular remission (undetectable JAK2V617F) at 60 months. The CHR rate by ITT analysis was higher with HU at 18 months (58% vs. 38%, p=0.03) but similar at all other time points (12 months: 50% vs. 36%, p=0.21; 60 months: 24% vs. 22%, p=0.83) ( Figure 1D). A post hoc subgroup analysis comparing HU with IFNα > age 60 showed comparable efficacy results. Among patients remaining on treatment (per-protocol analysis), the MR and CHR rates were superior in the IFNα group compared to the HU group at 36 months and beyond. The MR and CHR rates (HU vs. IFNα) by per-protocol analysis were: MR at 36 months: 23% vs. 56%, p=0.01; MR at 48 months: 27% vs. 59%, p=0.02; MR at 60 months: 35% vs. 67%, p=0.03; CHR at 36 months: 33% vs. 67%, p=0.002; CHR at 60 months: 38% vs. 62%, p=0.05. Overall treatment discontinuation at 60 months was 60% (HU: 37% vs. IFNα: 65%, p=0.0019). The most common cause of treatment discontinuation was adverse events (HU: 6/38 (16%); IFNα: 71/165 (43%)). Adverse events ≥ grade 3 occurred in 46% (HU: 58% vs. IFNα: 45%, p=0.15). Nineteen major thrombotic events were reported in 16 patients (HU: 4 events in 4 patients; IFNα>60: 12 events in 10 patients; IFNα≤60: 3 events in 2 patients), corresponding to an incidence rate of 2.6 per 100 person-years for HU and 3.4 per 100 person-years for IFNα (IFNα>60: 6.2; IFNα≤60: 1.2). None of the patients transformed into secondary acute myeloid leukemia. Five patients died during follow-up (HU: 2; IFNα: 3). Bone marrow histologic remission rates at 36 and 60 months will be presented at the meeting. Conclusion: ITT analysis detected no significant difference in the MR or CHR rates between HU and IFNα with long-term treatment (5 years) among patients with MPN, reflecting a higher treatment discontinuation rate in the IFNα group (65%). Thus, using the per-protocol principle, the MR and CHR rates were superior in the IFNα group at 36 months and beyond.

First-in-Class JAK/Rock Inhibitor Rovadicitinib in Myeloproliferative Neoplasms: A Single Arm, Multicenter, Open-Label, Phase I/Ib Study

Introduction: Rovadicitinib (TQ05105) is a first-in-class, oral, small molecule JAK/ROCK inhibitor which inhibits cell proliferation, induces cell apoptosis and decreases inflammatory cytokines by affecting the JAK-STAT signaling pathway in preclinical studies. Here we report the primary results of the phase I/Ib study of rovadicitinib in Myeloproliferative Neoplasms (MPN) patients. Methods: We conducted a single arm, multicenter, open-label, phase I/Ib trial (NCT04339400) at 9 sites in China. The study included dose-escalation cohort (phase I) and dose-expansion cohort (phase Ib). Aged ≥18 with MPN, dynamic international prognostic scoring system (DIPSS) Int-1 or higher risk of MF, naïve or resistant/intolerant to hydroxyurea and/or interferon therapy of PV or ET, were enrolled. Patients with MF must have palpable splenomegaly (≥5 cm below the left costal margin). Eligible patients received escalating doses of oral rovadicitinib 5 mg QD, 5 mg BID,10 mg BID, 15 mg BID, 20 mg BID of each 28-day cycle, and a modified “3 + 3” design was used in phase I. Treatment continued until progressive disease or unacceptable toxicity. The primary outcomes were the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) in phase I, and the proportion of patients whose reduction of at least 35% in spleen volume (SVR35) at week 24 compared with baseline in phase Ib. The main secondary end point was proportion of patients whose Total Symptom Score decreased ≥ 50% (TSS50) at week 24 in phase Ib. Results: Between November 20, 2018, and September 22, 2022, 102 patients were assessed for eligibility across two cohorts, 79 were enrolled and treated with rovadicitinib including, 15 patients in t phase I and 64 in phase Ib. 50 (63%) patients were male. The median age was 59 years (IQR 50-65), and 16 (20%) patients were aged 65 years or older. All patients had a definite diagnosis during the screening period, 64 (81%) patients were MF (55 were PMF, five were post-PV MF, four were post-ET MF), 10 (13%) patients were ET, five (6%) patients were PV. Mutations of JAK2, CALR, and MPL were analyzed, 60 (76%) of 79 patients with JAK2 V617F mutations, 10 (13%) patients with CALR mutations, four (5%) patients with MPL mutations. The median spleen volume was 1907 cm 3 (IQR 964-2994). In phase I, the number of patients enrolled per dose level was one at 5 mg QD, three at 5 mg BID, four at 10 mg BID, three at 15 mg BID, and four at 20 mg BID. The dose-limiting toxicities (DLTs) were experienced by two patients at 20 mg BID (one patient experienced grade 3 platelet count decrease with bleeding, one patient experienced grade 4 platelet count decrease). Given the safety profile and shrinking spleen, 15 mg BID was identified as MTD and RP2D. Rovadicitinib plasma peak concentrations and areas under the concentration versus time curve increased proportionally with dose. Terminal half-life was 1.3 h. No accumulation trend was noted. In phase Ib, 58 patients were included spleen volume set, 56 patients were included TSS set. 63.79% (37/58) patients achieved SVR35 during the study period (Figure 1A). The proportion of patients who had SVR35 was 37.93% (22/58) at week 24 and 39.66% (23/58) at week 48, respectively. The mean duration of splenic response was approximately 16 months. 87.5% (49/56) patients achieved TSS50 during the study period. The proportion of patients who had TSS50 was 71.43% (40/56) at week 24 and 48.21% (27/56) at week 48, respectively. Patients had durable splenic responses and significant symptom responses. The most common treatment-emergent adverse events (TEAEs) were 1~2 grade (Table 1). Grade ≥3 TEAEs were reported in 39 (49%) patients, the most common grade ≥3 hematological TEAE (≥10%) were platelet count decrease (17.72%) and anemia (16.46%). Occurrence of other grade ≥3 non-hematologic TEAEs was very low. There was only one death, due to disease progression and not related to rovadicitinib. TEAEs were generally manageable. Conclusions: Rovadicitinib was generally safe, well-tolerated and showed meaningful clinical activity in patients with MF, especially with palpable splenomegaly. Rovadicitinib may be a new treatment option for myelofibrosis patients. Furthermore, a randomized double-blind phase 2 study is ongoing, aiming to assess the efficacy and safety of rovadicitinib compared to hydroxyurea in patients with intermediate-2 or high-risk myelofibrosis in China (NCT05020652).

Efficacy of Hydroxyurea in Transfusion-Dependent Major β-Thalassemia Patients: A Meta-Analysis.

The present meta-analysis was conducted to determine the efficacy of hydroxyurea in patients with transfusion dependent major β-thalassemia.The present meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines.A systematic search was carried out to evaluate the efficacy of hydroxyurea in patients with transfusion-dependent B-thalassaemia using electronic databases, including MEDLINE, Cochrane Central Register of Controlled Trials, and EMBASE. The keywords used to search for relevant studies included "hydroxyurea", "thalassemia", "transfusion-dependent", and "efficacy".Outcomes assessed in the present meta-analysis included transfusion in one year and intervals between transfusions (in days). Other outcomes assessed in the present meta-analysis were fetal hemoglobin (%), hemoglobin (%), and ferritin levels (ng/dl). Total of five studies were included in the analysis enrolling 294 patients with major B-thalassemia.The pooled analysis reported that the mean interval between transfusions was significantly higher in patients receiving hydroxyurea compared to those not receiving hydroxyurea (mean deviation {MD}: 10.07, 95% CI: 2.16, 17.99).Hemoglobin was significantly higher in patients receiving hydroxyurea compared to its counterparts (MD: 1.71, 95% CI: 0.84, 2.57).Patients receiving hydroxyurea had significantly lower ferritin levels compared to those not receiving hydroxyurea (MD: -299.65, 95% CI: -518.35, -80.96).These findings suggest that hydroxyurea may be a promising and cost-effective alternative to blood transfusions and iron chelation therapies for beta-thalassemia patients. However, the authors noted that further randomized controlled trials are needed to validate these findings and to determine the optimal dosages and treatment regimens for hydroxyurea in this patient population.

Role of Hydroxyurea in Patients of Beta Thalassemia Majo

Objective: To study the role of Hydroxyurea in patients suffering from β-thalassemia major.
 Study Design: Prospective longitudinal study.
 Place and Duration of Study: Department Paediatrics, Combined Military Hospital, Malir Cantt, Karachi Pakistan, from Nov 2019 to Oct 2020.
 Methodology: Data from 73 beta-thalassemia major patients was collected using a structured questionnaire containing inquiries about basic socio-demographic details, disease history, laboratory reports and particulars of former treatment regimens. Hydroxyurea was administered, and its effects were noted among the subjects regarding the frequency of transfusion, haemoglobin levels and severity of clinical symptoms.
 Results: The mean age of study subjects was 9.15±3.99 years, and most study subjects (56.14%) were boys. The preintervention (before administration of Hydroxyurea) levels of Hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular haemoglobin concentration (MCHC), and serum ferritin levels were unremarkable when compared to postintervention levels. However, a significant difference was observed in HbF levels. In addition, an encouraging decrease was reported in the self-rated severity (using VAS) of symptoms such as fatigue (p<0.05), weakness (p>0.05), and shortness of breath (p>0.05). In addition, the transfusion interval was significantly reduced (p<0.05).
 Conclusion: After carefully considering the results, it can be concluded that Hydroxyurea plays a positive role and brings about significant improvement among patients suffering from β-thalassemia major.
 Keywords: Fetal hemoglobin, Genetic disease, Hydroxyurea, Thalassemia major.

Loss of Cyb5R3 Function Silences Fetal Hemoglobin and Hematocrit Responses to Hydroxyurea in Patients with Sickle Cell Anemia

BACKGROUND: Hydroxyurea (HU) is the first FDA-approved and most widely prescribed drug for sickle cell (SS) patients due to its beneficial effects (decreased Hb polymerization, pain crises and hospitalization) and relative safety profile. While the clinical benefits of HU have been found to associate with increased nitric oxide (NO) and fetal hemoglobin (HbF) in most SS patients, there has been considerable interpatient variability in HbF response to the drug. From this standpoint, HU is imperfectly understood mechanistically. Cytochrome b5 reductase 3 (Cyb5R3), also known as methemoglobin reductase, is an enzyme known to modulate redox signaling in erythrocytes and vascular cells by catalyzing one electron transfer reactions using reduced nicotinamide adenine dinucleotide (NADH) as an electron donor. Functionally, membrane-associated CYB5R3 exerts antioxidant properties by modulating heme iron reduction, plasma membrane coenzyme Q reduction, elongation and unsaturation of fatty acids, cholesterol biosynthesis and drug metabolism, while the soluble form of CYB5R3 reduces red blood cell methemoglobin. Unremitting oxidation of the soluble guanylate cyclase (sGC) heme iron in the absence of sufficient Cyb5R3 activity in vascular smooth muscle has been shown to explain some NO resistance that characterizes pulmonary arterial hypertension and other vasculopathy associated with SCD. More than 40 variants of Cyb5R3 have been identified. Of particular interest is a Cyb5R3 variant (T117S) that contains a threonine to serine substitution in the flavoprotein, which lessens the reductase's activity by roughly 50% compared to wild-type. This variant occurs with high frequency (0.23 minor allele) in persons of African ancestry but is rare (<1%) in all other races. Nothing is known about the role of Cyb5R3 in the anemia of sickle cell disease. We hypothesized that Cyb5R3 may act as a modifier of HbF induction by HU in sickle cell anemia. METHODS: Male and female SS patients (n=633, 12-70 years of age) from the Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (walk-PHaSST) trial were recruited for genetic analysis (University of Pittsburgh IRB Protocol Study 19060255). Genotyping of rs1800457 (T117S SNP) was performed using Taqman genotyping assay. One-way ANOVA and Holms Sidak were used for multiple comparisons of HbF levels by Cyb5R3 genotype and HU treatment status. Intrapatient correlation analyses of HbF and hematocrit (HCT) were conducted using Pearsons r. RESULTS: Comparisons of HbF levels by Cyb5R3 genotype (CC, wild-type; CG, heterozygous wild-type and T117S; GG, homozygous T117S) and HU treatment status (treated vs. untreated) at time of study enrollment (baseline) show that HU is a less potent HbF inducer in the GG group (4.32 mean diff, P=0.344) versus the CC and CG patient groups (CC: 6.027 mean diff, P<0.0001 and CG: 6.914 mean diff, P<0.0001). Correlation analyses showed that as HbF levels increased among HU-untreated patients, the trend was for HCT to decrease. This was true for all SS patients, irrespective of Cyb5R3 genotype (CC: r = -0.336, P<0.0001, n=320; CG: r = -0.437 P<0.0001, n=120; GG: r = -0.253, P=0.136, n=36). However, with HU therapy, the inverse relationship between HbF and HCT was less negative in SS patients carrying at least one copy of the wild-type Cyb5R3 gene (CC or CG). In these individuals, increasing levels of HbF (up to 10%) correlated with positive gains in HCT at HbF greater than 5-6% (CC: r = -0.161, P=0.097, n=107) and 6-7% (CG: r = -0.186, P=0.25, n=40). In patients homozygous for T117S, HCT continued trending downward as HbF increased (GG: r = -0.419, P=0.228, n=10). These data indicate that the positive relationship between HbF and HCT is subject to uncoupling by loss of Cyb5R3 function. In vitro studies with human erythroleukemic K562 cells reveal loss of gamma globin induction by HU treatment when wild-type Cyb5R3 is knocked down by siRNA, indicating a requirement for Cyb5R3 in HU-stimulated HbF induction. SUMMARY andCONCLUSION: Loss of Cyb5R3 activity negatively impacts HbF and HCT in HU treated SS patients. We conclude that the T117S variant may be a useful marker for predicting which SS patients will incur beneficial HbF and HCT responses to HU, thereby improving clinical decision-making about best drug choices for preventing HbS polymerization and treating anemia in SS patients.

Impact of the COVID-19 Pandemic on the Implementation of Mobile Health to Improve the Uptake of Hydroxyurea in Patients With Sickle Cell Disease: Mixed Methods Study.

BackgroundHydroxyurea therapy is effective for reducing complications related to sickle cell disease (SCD) and is recommended by National Health Lung and Blood Institute care guidelines. However, hydroxyurea is underutilized, and adherence is suboptimal. We wanted to test a multilevel mobile health (mHealth) intervention to increase hydroxyurea adherence among patients and improve prescribing among providers in a multicenter clinical trial. In the first 2 study sites, participants were exposed to the early phases of the COVID-19 pandemic, which included disruption to their regular SCD care.ObjectiveWe aimed to describe the impact of the COVID-19 pandemic on the implementation of an mHealth behavioral intervention for improving hydroxyurea adherence among patients with SCD.MethodsThe first 2 sites initiated enrollment 3 months prior to the start of the pandemic (November 2019 to March 2020). During implementation, site A clinics shut down for 2 months and site B clinics shut down for 9 months. We used the reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework to evaluate the implementation and effectiveness of the intervention. mHealth implementation was assessed based on patients’ daily app use. Adherence to hydroxyurea was calculated as the proportion of days covered (PDC) from prescription records over the first 12 and 24 weeks after implementation. A linear model examined the relationship between app usage and PDC change, adjusting for baseline PDC, lockdown duration, and site. We conducted semistructured interviews with patients, health care providers, administrators, and research staff to identify factors associated with mHealth implementation and effectiveness. We used a mixed methods approach to investigate the convergence of qualitative and quantitative findings.ResultsThe percentage of patients accessing the app decreased after March 15, 2020 from 86% (n=55) to 70% (n=45). The overall mean PDC increase from baseline to week 12 was 4.5% (P=.32) and to week 24 was 1.5% (P=.70). The mean PDC change was greater at site A (12 weeks: 20.9%; P=.003; 24 weeks: 16.7%; P=.01) than site B (12 weeks: −8.2%; P=.14; 24 weeks: −10.3%; P=.02). After adjustment, PDC change was 13.8% greater in those with increased app use after March 15, 2020. Interview findings indicated that site B’s closure during COVID-19 had a greater impact, but almost all patients reported that the InCharge Health app helped support more consistent medication use.ConclusionsWe found significant impacts of the early clinic lockdowns, which reduced implementation of the mHealth intervention and led to reduced patient adherence to hydroxyurea. However, disruptions were lower among participants who experienced shorter clinic lockdowns and were associated with higher hydroxyurea adherence. Investigation of added strategies to mitigate the effects of care interruptions during major emergencies (eg, patient coaching and health navigation) may “insulate” the implementation of interventions to increase medication adherence.Trial RegistrationClinicalTrials.gov NCT04080167; https://clinicaltrials.gov/ct2/show/NCT04080167International Registered Report Identifier (IRRID)RR2-10.2196/16319

P-007: HYDROXYUREA FOR THE MANAGEMENT OF SICKLE CELL DISEASE IN LOW- AND MIDDLE-INCOME COUNTRIES: A SYSTEMATIC REVIEW (2000–2022)

Purpose: Hydroxyurea (HU) is a disease modifying oral therapy with demonstrated clinical efficacy and safety in patients with sickle cell disease (SCD) for over 30 years. In low- and middle-income countries (LMICs) where the disease burden is high, universal HU treatment is limited. Our aim for this systematic literature review was to summarise the available evidence conducted in low-resource settings on HU efficacy, safety and real-world effectiveness to demonstrate the need for wider access to HU for SCD patients in LMICs. The preliminary observations from clinical studies are presented here. Materials and methods: Articles published in Embase, PubMed, OVID and Web of Science between January 2000–2022 were reviewed; studies assessing the impact of HU in patients with SCD were considered. Results: Out of 3709 screened articles, 124 unique studies were included (Figure) with 20 clinical trials. Majority of the studies are from sub-Saharan Africa (SSA) and Latin America. The initial dose of HU ranged from 10–25 mg/kg/day and the most common initial dose was 15–20 mg/kg/day; the maximum tolerated dose (MTD) was 25–35 mg/kg/day. Across various age groups, as anticipated, a significant increase in haemoglobin, foetal haemoglobin and mean corpuscular volume levels with HU at both fixed (20 mg/kg/day) and escalated dose (≤35 mg/kg/day). HU at doses 15–30 mg/kg/day reduced the need for transfusions during the treatment period. HU treatment initiation reduced VOC-related pain, and reduction was better with escalated (30 mg/kg/day) versus fixed dosing (20–25 mg/kg/day). Similar reductions across various age groups were observed for atherosclerotic events. Initial low-dose HU therapy of 10 mg/kg/day and a 12-month MTD of 24.1±6.0 mg/kg/day reduced the primary stroke risk. Secondary strokes were prevented with HU (3 years; initial dose: 15–20 mg/kg/day; MTD: 30–35 mg/kg/day), and long-term treatment (3.5–9.3 years; 30–40 mg/kg/day) prevented recurrent strokes. HU treatment showed a reduction in the rates of hospitalisation, and this was?50% lower with escalated dose (29.0±3.5 mg/kg/day) when compared to fixed dose (19.3±1.7 mg/kg/day). Treatment with HU was also associated with significant reduction in malaria events and related hospitalisations. Significant reduction in the risk of mortality was observed after treatment with HU, assessed as events per 100 patients/person years, which can be attributed to fewer SCD–related clinical complications, infections, malaria and possibly transfusions. Various dosing of HU was well tolerated in children and adults, and the reported events of myelosuppression were mostly transient. Conclusion: Our preliminary observations suggest that clinical use of HU in low-resource settings is effective in improving haematological outcomes, reducing the risk of VOCs and primary and recurrent strokes, and reduction of malaria-related events. Need for transfusion, rates of hospitalisation and mortality were also reduced with HU treatment. These findings are in line with current consensus guidelines to initiate HU therapy to SCD patients starting as early as 9 months of age. We expect that the complete analysis of this systematic review will enable us to compile sufficient evidence for optimising the use of HU in LMICs.K. MARFO declares a conflict of interest: Stock shareholder: Novartis Other: Employee of Novartis S. KHAN declares a conflict of interest: Other: I am an employee of Novartis

Do Genetic Polymorphisms Affect Fetal Hemoglobin (HbF) Levels in Patients With Sickle Cell Anemia Treated With Hydroxyurea? A Systematic Review and Pathway Analysis.

Hydroxyurea has long been used for the treatment of sickle cell anemia (SCA), and its clinical effectiveness is related to the induction of fetal hemoglobin (HbF), a major modifier of SCA phenotypes. However, there is substantial variability in response to hydroxyurea among patients with SCA. While some patients show an increase in HbF levels and an ameliorated clinical condition under low doses of hydroxyurea, other patients present a poor effect or even develop toxicity. However, the effects of genetic polymorphisms on increasing HbF levels in response to hydroxyurea in patients with SCA (Hb SS) have been less explored. Therefore, we performed a systematic review to assess whether single-nucleotide polymorphisms (SNPs) affect HbF levels in patients with SCA treated with hydroxyurea. Moreover, we performed pathway analysis using the set of genes with SNPs found to be associated with changes in HbF levels in response to hydroxyurea among the included studies. The systematic literature search was conducted on Medline/PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, and Web of Science. Seven cohort studies were included following our inclusion and exclusion criteria. From the 728 genetic polymorphisms examined in the included studies, 50 different SNPs of 17 genes were found to be associated with HbF changes in patients with SCA treated with hydroxyurea, which are known to affect baseline HbF but are not restricted to them. Enrichment analysis of this gene set revealed reactome pathways with the lowest adjusted p-values and highest combined scores related to VEGF ligand–receptor interactions (R-HSA-194313; R-HSA-195399) and the urea cycle (R-HSA-70635). Pharmacogenetic studies of response to hydroxyurea therapy in patients with SCA are still scarce and markedly heterogeneous regarding candidate genes and SNPs examined for association with HbF changes and outcomes, suggesting that further studies are needed. The reviewed findings highlighted that similar to baseline HbF, changes in HbF levels upon hydroxyurea therapy are likely to be regulated by multiple loci. There is evidence that SNPs in intron 2 of BCL11A affect HbF changes in response to hydroxyurea therapy, a potential application that might improve the clinical management of SCA. Systematic Review Registration: (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=208790).

Should be a Third Dose of BNT162b2 mRNA COVID-19-Vaccine Administered in Patients with Myelofibrosis Under Ruxolitinib?

▪Introduction.Patients with Myelofibrosis (MF) are considered fragile and thus eligible in Italy for COVID-19 BNT162b2 mRNA vaccination. According to the International Prognostic Scoring System (IPSS), patients with intermediate and high MF, may receive clinical benefits from ruxolitinib, the first approved JAK1/JAK2 inhibitor. Given the potent anti-inflammatory properties of ruxolitinib against immunocompetent cells, we previously reported a lower but non-statistically absolute IgG anti-Spike humoral response in vaccinated MF patients treated with ruxolitinib. In the present report we extended the cohort of MF patients.Methods. All MF patients received 2 injections of 30 ug per dose of BNT162b2 mRNA COVID-19 vaccine 3 weeks apart, according to the standard protocol. After injection, mild pain at the injection site was frequently reported. No serious adverse events were registered. The serum level of IgG anti-Spike glycoprotein was tested after a median time of 45 days (range 40-60) from the second vaccine dose, using the approved anti-SARS-CoV-2 IgG CLIA (LIAISON® SARS-CoV-2 TrimericS IgG assay, Diasorin, Saluggia, Italy). An Arbitrary Units per milliliter (AU/mL) ratio of <12.0 was considered to be negative, 12.0-15.0 AU/mL to be borderline and >15 AU/mL to be positive. A conversion of AU/mL to binding antibody units (BAU/mL) as recommended by the World Health Organization (WHO) guidelines was achieved considering the following equation: BAU/mL = 2.6*AU/mL.Results. Overall, 30 MF patients (median age 65 years, range 48-83) were vaccinated. A diagnosis of primary MF was reported in 21 cases (70%), post essential thrombocythemia-MF in 6 (20%) patients and post polycythemia vera-MF in 3 (10%) patients; 23 out of 30 patients (76.6%) were positive for the JAK2V617F, 5 (16.6%) for CALR mutation, 1 (3.3%) for MPL mutation and 1 patient (3.3%) resulted triple negative. Splenomegaly was observed in 14 patients (46%) and 19 (63.3%) reported comorbidities. Nineteen patients (63.3%) were classified as DIPSS low or intermediate-1 risk, and 11 (36.6%) as intermediate-2 or high risk. Fifteen patients (50%) were receiving ruxolitinib, at a median total dose of 20 mg/die (range 20-40 mg) and the remaining 15 patients other treatments (8 patients hydroxyurea and 7 only supportive therapy). None of the patients reported COVID-19 infection neither previous nor subsequently to vaccination. Overall, a positive immune response against COVID-19 was observed in 8 out of 15 patients (53.3%) in the ruxolitinib group, in comparison with 13 out 15 patients (86.6%) in the other treatment group (p=0,046). The absolute IgG anti-Spike value was lower in the ruxolitinib group (median 35.2±49.81) in comparison with the other group (median 226.1±163.9; p=<0.001), Figure 1. In univariate analysis, only ruxolitinib treatment was found associated with a lower humoral immune response to the vaccine.Conclusions. MF patients under ruxolitinib achieved a lower humoral immune response in comparison with MF patients who underwent other treatments. No COVID-19 infection was observed in both groups after vaccination, after a median follow up of 3 months since the second dose. Whether patients with a potential insufficient humoral response to vaccine will benefit from a third dose of BNT162b2 mRNA COVID-19 vaccine is a matter of further investigation. Our preliminary data need to be confirmed in larger cohort of MF patients. [Display omitted] DisclosuresMurru: Abbvie: Consultancy, Honoraria, Other: travel and accommodation; Janssen: Consultancy, Honoraria.

Long-term safety and efficacy of hydroxyurea in patients with non-transfusion-dependent β-thalassemia: a comprehensive single-center experience.

Over the past 20years, hydroxyurea (HU) has emerged as an effective therapeutic agent in thalassemic patients to improve anemia and decrease the transfusion dependency. We evaluated long-term safety and clinical response to HU in patients with non-transfusion-dependent β-thalassemia (NTDT). In this retrospective study, medical records of 181 patients with NTDT were evaluated during October to December 2020 in Southern Iran. No requirement to blood transfusion was considered as sustained transfusion independence response. All patients were regularly examined and monitored for the occurrence of any adverse event (AE) of HU. The mean duration of HU consumption ± SD was 18.2 ± 4.0 (8-22) years. Overall, 149 patients (82.3%) had sustained transfusion independence response. β-globin gene mutations and XmnI polymorphisms were not significantly associated with clinical response (P > 0.05). Mild and transient AEs were reported in 60 patients (33%) with no requirement to drug interruption. Hydroxyurea with the dose of 8-15mg/kg can be used as a safe and effective treatment in NTDT patients. It was well tolerated in long term without any serious complication or secondary malignancy. No relationship between XmnI or β-globin gene mutations with HU response was observed in this geographic area of the world.

The relationship between symptom burden and hematologic responses after treatment with interferon/hydroxyurea in patients with polycythemia vera

目的探讨真性红细胞增多症（PV）患者干扰素和（或）羟基脲治疗后症状负荷改善与血液学疗效之间的关系。方法对190例符合WHO（2016）诊断分型标准、接受干扰素和（或）羟基脲连续治疗≥6个月的PV患者，分别应用外周血细胞计数和骨髓增殖性肿瘤总症状评估量表（MPN-10）评价患者血液学疗效和症状负荷。结果全部190例PV患者中，男93例（48.9％），女97例（51.1％）。进行MPN-10评分时，患者中位年龄为60（32～82）岁。全部患者中位MPN-10总分为9（0～67）分，干扰素+羟基脲组（27例）为11（0～67）分，显著高于干扰素组［64例，6（0～56）分，P＝0.019］和羟基脲组［99例，9（0～64）分，P＝0.047］，而干扰素组与羟基脲组差异无统计学意义（P＝0.421）。28.9％（55/190）的患者存在重度症状（单项症状评分≥7分或总分≥44分），干扰素组、羟基脲组、干扰素+羟基脲组重度症状患者占比分别为23.4％、29.3％、40.7％，组间比较差异均无统计学意义（P>0.05）。全部190例患者中，进行MPN-10评分时71例（37.4％）获得完全血液学缓解（CHR），仅55例（28.9％）获得疾病充分控制（获得CHR且无重度症状）。未获得疾病充分控制的患者包括：血细胞增高80例（42.1％），获得CHR但伴重度症状16例（8.4％），血细胞增高且伴重度症状39例（20.5％）。PLT>400×109/L患者中存在重度症状患者比例、MPN-10总分中位数均高于PLT≤400×109/L患者［40.8％（20/49）对24.8％（35/141），P＝0.044；14（0～67）分对7（0～56）分，P＝0.038］。PLT>400×109/L是存在重度症状的危险因素（HR＝2.089，95％CI 1.052～4.147，P＝0.035）。结论经干扰素和（或）羟基脲治疗后，PV患者症状负荷未获满意控制仍较突出，部分患者虽然获得CHR，仍存在重度症状负荷。PLT>400×109/L是干扰素和羟基脲治疗后患者存在重度症状的危险因素。

Reactive Thrombocytosis after Splenectomy in Hereditary Spherocytosis: Case Report and Literature Review.

Reactive thrombocytosis can be a significant complication after splenectomy and can range from mild (500,000-700,000/mm3), to moderate (700,000-900,000/mm3), severe (>900,000/mm3) and very severe thrombocytosis (>1,000,000/mm3).The use of low-dose hydroxyurea in patients with very severe thrombocytosis can reduce the platelet count to safe levels, and thus, the risk of developing thrombosis.

Advances in the Treatment of Polycythemia Vera: Trends in Disease Management.

Treatment modalities for polycythemia vera (PV) have evolved over time. Phlebotomy and low-dose aspirin suffice in low-risk patients, but cytoreductive therapies are indicated in all high-risk patients (age ≥ 65 years or those with a history of PV-related thrombotic event) and may be considered for low-risk patients with progressively increasing splenomegaly, progressively increasing leucocyte and platelet counts, and for those who do not tolerate phlebotomy. Hydroxyurea/hydroxycarbamide or interferons can be used as first-line drugs. Hydroxyurea may not be tolerated by some patients, and it also carries risk of myelosuppression. Interferon alfa is especially useful for PV symptoms, and the newer preparation, ropeginterferon alfa-2b, has lesser incidence of flu-like reactions. Ruxolitinib reduces the JAK2V617F mutation burden and is used as a second-line drug. Anagrelide reduces platelet production and can be used in conjunction with hydroxyurea in patients with excessive thrombocytosis. The alkylating agent, busulfan, can also be used as a last resort in patients with a limited life expectancy. Prospective future treatments include givinostat, a histone deacetylase inhibitor, and idasanutlin, a murine double minute 2 antagonist.

Comparison of efficacy and safety of thalidomide vs hydroxyurea in patients with Hb E-β thalassemia - a pilot study from a tertiary care Centre of India

IntroductionHemoglobin (Hb)-F inducers are known to improve Hb level and transfusion dependence in thalassemia. This pilot study was conducted to assess the efficacy and safety of Hb-F inducer thalidomide compared to hydroxyurea (HU) in Hb E-β thalassemia patients. MethodsThis was a prospective interventional single-centre study with 45 Hb E-beta thalassemia patients equally divided into group-I (thalidomide+folic acid), group-II (HU + folic acid) and group-III (folic acid). Response was assessed at various time intervals with 12-months follow up period. Primary end points were increment in Hb, Hb-F level and improvement in transfusion requirement; secondary end point were tolerability and safety. ResultsThere was 100% responder (R: Hb-increment ≥1 g/dl) in group-I with 66.67% major responder (MaR: Hb-increment ≥2 g/dl), while there were 40% and 0% responder in group-II and III respectively. Hb-increment was significantly (p-value <0.0001) better in thalidomide arm compared to HU. The Hb-increment was attributable to both increase in Hb-F levels and reduction in ineffective erythropoiesis in thalidomide arm. Transfusion reduction was significantly better in group-I compared to group-II (100% vs 34%). No severe adverse effects was reported by patients of any group. ConclusionThalidomide showed a persistent significant Hb-increment and transfusion independence in Hb E-β thalassemia patients compared to HU.

Outcomes of Hydroxyurea Dose Adjustment Via Telehealth

The UAB Pediatric Sickle Cell Clinic cares for patients at both an academic center and satellite clinics. One difference in clinics is that CBC results are not available at the time of patient care during satellite clinics, but are available at the academic center. Therefore, hydroxyurea (HU) dosing adjustments are made within seven days through telehealth; after reviewing faxed CBC results, a sickle cell nurse calls families and educates them on any revised HU dosing plans and reinforces adherence to HU. We hypothesized that this type of telehealth HU dosing adjustments would not impact HU laboratory response. Methods: We performed a one-year retrospective review of 172 HbSS and HbSB0 thalassemia patients prescribed HU during 2019 that were cared for in both the academic center (Birmingham) and satellite clinics (Montgomery, Tuscaloosa, Opelika). We excluded patients on HU and a second sickle cell disease modifying therapy. We abstracted from the EMR: age, sex, clinic location, diagnosis, HU dose (mg/kg), WBC, Hb, MCV, Platelets, Absolute Reticulocyte, HbF, and ANC. We recorded the total number of well-clinic visits and categorized clinic visit/year as ≤ 2or &amp;gt;2; satellite clinic visits are fixed either monthly to every three months which limited our ability to reschedule patients with missed visits. We also recorded the number of ED visits and admissions to the hospital for a) pain and b) all sickle cell complications except for scheduled procedures. We collected acute visit data from the EMR at the academic center for onsite participants and from patient report from satellite participants. We evaluated dosing adjustment as whether dosing was increased for ANC &amp;gt; 4000 per institutional standard of care. We categorized correct dosing adjustments if &amp;gt; 65% of visits had a dose adjustment per institutional protocol; we categorized patients as a deviation from protocol if the physician did not increase the dose based on ANC. We performed descriptive statistics, t-test for continuous variables, chi-square for categorical variables, and regression modeling using JMP Pro 14 (Cary, NC). P-values &amp;lt;0.05 were considered statistically significant. Results: The mean age of the 172 participants was 11±5 years, mean Hb was 8.5±1.1g/dL, mean MCV was 91.3±10.1 fL, mean HbF% was 12.7±6.7, and mean ANC was 4.9±2.3. Fifty two percent of participants were female. We identified 107 participants prescribed HU at the academic center and 65 participants from satellite clinics. We identified no significant differences in HU monitoring laboratory values for Hb (p=0.6), MCV (p=0.7), HbF (p=0.13), ANC (p=0.9) by clinic location. We did not identify a difference in sex of participants by clinic location (p=0.9); also, HbF% (p=0.6) and HU dose (p=0.3) were not associated with sex. We did not identify a difference in all admissions to the hospital (p=0.5) or pain admissions to the hospital (p=0.6) between academic center vs. satellite clinic patients. However, academic center patients did have a higher number of acute pain visits (p=0.03) to either the ED or UAB pediatric pain clinic. As expected, among all participants, non-adherence to HU (HbF &amp;lt;5%) was associated with the highest number of admissions (p=0.02). Among 149 patients with more than one clinic visit, 97 (65%) patients had more than 65% of clinic visits with a correct dose adjustment; we identified no statistical difference in correct dosing adjustment deviations among Birmingham patients (67%) and satellite clinic patients (62%, p=0.5). Patients cared for at the academic center had a statistically higher number of clinic visits (p=0.01) and more patients that attended &amp;gt;2 clinic visits. HbF response was significantly associated with clinic visits (p=0.03). Finally, HbF response was significantly inversely correlated with age (p=0.003). Adjusting for clinic location, number of clinic visits, and age, HbF % was associated with age (p=0.006) and clinic visits (p=0.006), but not associated with clinic location. Conclusion: Our data demonstrate that telehealth for HU dosing provided a similar level of HU response to in-person HU dosing adjustments. This finding importantly suggests that telehealth for monitoring and adjusting HU in patients with poor access to a Pediatric Hematologist or during a pandemic should not impact HU response. Strategies to improve overall adherence need prospective evaluation at our institution, but are not related to telehealth dosing of HU. Disclosures Lebensburger: Novartis: Consultancy.

First Line Treatment with Hydroxyurea in Patients with Policitemia Vera: Evaluation of Efficacy in the Current Clinical Practice Beyond ELN Criteria

First Line Treatment with Hydroxyurea in Patients with Policitemia Vera: Evaluation of Efficacy in the Current Clinical Practice Beyond ELN Criteria

Skin side effects of hydroxyurea in patient with trombocitosis

Skin side effects of hydroxyurea in patient with trombocitosis