High throughput screening aids clinical decision-making in refractory acute myeloid leukaemia.

BACKGROUND: Despite advances in therapeutics for adverse-risk acute myeloid leukaemia (AML), overall survival remains poor, especially in refractory disease. Comprehensive tumour profiling and pre-clinical drug testing can identify effective personalised therapies. CASE: We describe a case of ETV6-MECOM fusion-positive refractory AML, where molecular analysis and in vitro high throughput drug screening identified a tolerable, novel targeted therapy and provided rationale for avoiding what could have been a toxic treatment regimen. Ruxolitinib combined with hydroxyurea led to disease control and enhanced quality-of-life in a patient unsuitable for intensified chemotherapy or allogeneic stem cell transplantation. CONCLUSION: This case report demonstrates the feasibility and role of combination pre-clinical high throughput screening to aid decision making in high-risk leukaemia. It also demonstrates the role a JAK1/2 inhibitor can have in the palliative setting in select patients with AML.

Systemic medications for sickle cell disease and potential applications for sickle cell retinopathy.

PURPOSE OF REVIEW: To review the literature evaluating systemic medications for treatment of sickle cell disease (SCD) and their applications for sickle cell retinopathy. RECENT FINDINGS: Prior studies have demonstrated the efficacy of traditional systemic therapies in reducing the risk of development of sickle cell retinopathy. Since 2017, several new and promising disease-modifying therapies for sickle cell disease have been approved for clinical use, including the first genetic therapies such as exagamglogene autotemcel (exa-cel) and lovotibeglogene autotemcel (lovo-cel). These treatments have shown promising results for systemic management but are not widely utilized due to limited access and high cost. The efficacy of these therapies for the prevention of sickle cell retinopathy remains unknown and opens the door to new avenues for research. Furthermore, the role of systemic therapy for the management of hemoglobin SC (HbSC) disease, which has milder systemic effects but higher likelihood of causing retinopathy, remains poorly understood. SUMMARY: Hydroxyurea has been a mainstay of systemic management of SCD with prior work suggesting its ability to reduce the likelihood of developing retinopathy. There are several new and potentially curative systemic therapies for SCD, though their role in retinopathy prevention and management has not been studied extensively. Future studies are necessary to understand the implications of these emerging therapies for sickle cell retinopathy.

Prevalence of Duffy null and its impact on hydroxyurea in young children with sickle cell disease in the United States.

Consistent with studies showing a high prevalence of the Duffy null phenotype among healthy Black Americans, this retrospective study found that Duffy null was present in >75% of a young and contemporary cohort of children with sickle cell disease (SCD) in the United States. Despite the potential for this phenotype to impact absolute neutrophil counts, hydroxyurea (HU) dosing, and outcomes, it was not associated with being prescribed a lower HU dose or having increased acute SCD visits early in the HU treatment course. Future studies are needed to confirm these findings in older children with SCD.

An update review of new therapies in sickle cell disease: the prospects for drug combinations.

INTRODUCTION: Sickle cell disease (SCD) is an inherited disorder characterised by polymerisation of deoxygenated haemoglobin S and microvascular obstruction. The cardinal feature is generalised pain referred to as vaso-occlusive crises (VOC), multi-organ damage and premature death. SCD is the most prevalent inherited life-threatening disorders in the world and over 85% of world's 400,000 annual births occur low-and-middle-income countries. Hydroxyurea remained the only approved disease modifying therapy (1998) until the FDA approved L-glutamine (2017), Crizanlizumab and Voxelotor (2019) and gene therapies (Exa-cel and Lovo-cel, 2023). AREAS COVERED: Clinical trials performed in the last 10 years (November 2013 - November 2023) were selected for the review. They were divided according to the mechanisms of drug action. The following pubmed central search terms [sickle cell disease] or [sickle cell anaemia] Hydroxycarbamide/ Hydroxyurea, L-Glutamine, Voxelotor, Crizanlizumab, Mitapivat, Etavopivat, gene therapy, haematopoietic stem cell transplantation, and combination therapy. EXPERT OPINION: We recommend future trials of combination therapies for specific complications such as VOCs, chronic pain and renal impairment as well as personalised medicine approach based on phenotype and patient characteristics. Following recent approval of gene therapy for SCD, the challenge is addressing the role of shared decision-making with families, global access and affordability.

Hydroxyurea Adherence for Personal Best in Sickle Cell Treatment (HABIT) efficacy trial: Community health worker support may increase hydroxyurea adherence of youth with sickle cell disease.

Despite disease-modifying effects of hydroxyurea on sickle cell disease (SCD), poor adherence among affected youth commonly impedes treatment impact. Following our prior feasibility trial, the "Hydroxyurea Adherence for Personal Best in Sickle Cell Treatment (HABIT)" multi-site randomized controlled efficacy trial aimed to increase hydroxyurea adherence for youth with SCD ages 10-18 years. Impaired adherence was identified primarily through flagging hydroxyurea-induced fetal hemoglobin (HbF) levels compared to prior highest treatment-related HbF. Eligible youth were enrolled as dyads with their primary caregivers for the 1-year trial. This novel semi-structured supportive, multidimensional dyad intervention led by community health workers (CHW), was augmented by daily tailored text message reminders, compared to standard care during a 6-month intervention phase, followed by a 6-month sustainability phase. Primary outcomes from the intervention phase were improved Month 6 HbF levels compared to enrollment and proportion of days covered (PDC) for hydroxyurea versus pre-trial year. The secondary outcome was sustainability of changes up to Month 12. The 2020-2021 peak coronavirus disease 2019 (COVID-19) pandemic disrupted enrollment and clinic-based procedures; CHW in-person visits shifted to virtual scheduled interactions. We enrolled 50 dyads, missing target enrollment. Compared to enrollment levels, both HbF level and PDC significantly - but not sustainably - improved within the intervention group (p = .03 and .01, respectively) with parallel increased mean corpuscular volume (MCV) (p = .05), but not within controls. No significant between-group differences were found at Months 6 or 12. These findings suggest that our community-based, multimodal support for youth-caregiver dyads had temporarily improved hydroxyurea usage. Durability of impact should be tested in a trial with longer duration of CHW-led and mobile health support.

Reducing transfusion utilization for children with sickle cell anemia in sub-Saharan Africa with hydroxyurea: Analysis from the phase I/II REACH trial.

Children with sickle cell anemia (SCA) in Africa frequently require transfusions for SCA complications. Despite limited blood supplies, strategies to reduce their transfusion needs have not been widely evaluated or implemented. We analyzed transfusion utilization in children with SCA before and during hydroxyurea treatment. REACH (Realizing Effectiveness Across Continents with Hydroxyurea, NCT01966731) is a longitudinal Phase I/II trial of hydroxyurea in children with SCA from Angola, Democratic Republic of Congo, Kenya, and Uganda. After enrollment, children had a two-month pre-treatment screening period followed by 6 months of fixed-dose hydroxyurea (15-20 mg/kg/day), 18 months of dose escalation, and then stable dosing at maximum tolerated dose (MTD). Characteristics associated with transfusions were analyzed with univariate and multivariable models. Transfusion incidence rate ratios (IRR) across treatment periods were calculated. Among 635 enrolled children with 4124 person-years of observation, 258 participants (40.4%) received 545 transfusions. The transfusion rate per 100 person-years was 43.2 before hydroxyurea, 21.7 on fixed-dose, 14.5 during dose escalation, and 10.8 on MTD. During MTD, transfusion incidence was reduced by 75% compared to pre-treatment (IRR 0.25, 95% confidence interval [CI] 0.18-0.35, p < .0001), and by 50% compared to fixed dose (IRR 0.50, 95% CI 0.39-0.63, p < .0001). Hydroxyurea at MTD decreases transfusion utilization in African children with SCA. If widely implemented, universal testing and hydroxyurea treatment at MTD could potentially prevent 21% of all pediatric transfusions administered in sub-Saharan Africa. Increasing hydroxyurea access for SCA should decrease the transfusion burden and increase the overall blood supply.

Role of hydroxyurea therapy in the prevention of organ damage in sickle cell disease: a systematic review and meta-analysis.

BACKGROUND: Hydroxyurea is an affordable drug that reduces vaso-occlusive crises and transfusion requirements in sickle cell disease. However, its effectiveness in preventing chronic organ damage is still unclear. This systematic review and meta-analysis aimed to evaluate the role of hydroxyurea in preventing organ morbidity. METHOD: We included original articles published in English from 1st January 1990 to 31st January 2023, reporting hydroxyurea therapy and organ damage from PubMed, Google Scholar, Scopus, and CrossRef databases. A total of 45 studies with 4681 sickle cell disease patients were evaluated for organ damage. RESULTS: Our analysis showed that hydroxyurea intervention significantly lowered transcranial Doppler and tricuspid regurgitant velocity, with a standardized mean difference of - 1.03 (- 1.49; - 0.58); I 2 = 96% and - 1.37 (CI - 2.31, - 0.42); I 2 = 94%, respectively. Moreover, the pooled estimate for albuminuria showed a beneficial effect post-hydroxyurea therapy by reducing the risk of albuminuria by 58% (risk ratio of 0.42 (0.28; 0.63); I 2 = 28%). CONCLUSION: Our study found that a hydroxyurea dose above 20 mg/kg/day with a mean rise in HbF by 18.46% post-hydroxyurea therapy had a beneficial role in reducing transcranial doppler velocity, tricuspid regurgitant velocity, albuminuria, and splenic abnormality. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023401187.

Disease-Modifying Therapies for Sickle Cell Disease-An Overview.

Sickle cell disease refers to a group of inherited blood disorders in which hemoglobin polymerization leads to hemolysis and vaso-occlusion. This causes a myriad of complications during a patient's life span, ranging from anemia, infections, and acute and chronic pain to stroke and multiorgan dysfunction. Although there have been dramatic improvements in childhood survival thanks to improved supportive care with penicillin prophylaxis, immunizations, and improved transfusion practices, there was a dearth of disease-modifying therapies, with hydroxyurea being the only medication for >20 years. Here, we discuss the newer therapies for sickle cell disease that have emerged in recent years. [Pediatr Ann. 2024;53(2):e52-e55.].

Hidroxiureia para o tratamento de pacientes com doença falciforme (SS, Sbeta0 e SD Punjab), entre 9 e 24 meses de idade, sem sintomas e complicações / Hydroxyureia for the treatment of patients with sickle cell disease (SS, Sbeta0 and SD Punjab), between 9 and 24 months of age, without symptoms and complications

INTRODUÇÃO: As manifestações clínicas da doença falciforme (DF) estão relacionadas à anemia hemolítica e aos efeitos da falcização intravascular repetida, resultando em vasooclusão e lesão isquêmica, além de morbidade e mortalidade consideráveis em idade precoce. Atualmente, a hidroxiureia é o padrão de tratamento para prevenir crises de dor vasoclusivas na DF, sendo recomendada para crianças entre 9 e 24 meses de idade, quando apresentam determinados sintomas ou complicações. Considerando que o uso precoce desta tecnologia (antes de 2 anos de idade) pode evitar o comprometimento a longo prazo relacionados à evolução da DF, o objetivo do presente relatório é analisar as evidências científicas sobre eficácia, efetividade, segurança, bem como evidências econômicas relacionadas ao uso de hidroxiureia para o tratamento de indivíduos com doença falciforme (SS, Sbeta0 e SD Punjab) entre 9 e 24 meses de idade, independentemente de sintomas e complicações. PERGUNTA: O uso de h

Hydroxyurea is associated with later onset of acute splenic sequestration crisis in sickle cell disease: Lessons from the European Sickle Cell Disease Cohort-Hydroxyurea (ESCORT-HU) study.

Acute splenic sequestration crisis (ASSC) is a potentially life-threatening complication of sickle cell disease (SCD), typically occurring in young patients under 5 years of age, with a median age at first episode of less than 2 years. Because a beneficial effect of hydroxyurea (HU) on spleen perfusion and splenic function has been suspected, we hypothesized that HU treatment might be associated with later onset of ASSC in patients with SCD. To investigate this hypothesis, we analyzed data from the ESCORT-HU study on a large cohort of patients with SCD receiving HU, enrolled between January 2009 and June 2017 with a follow-up of 7309 patient-years of observation. The median age at ASSC of the 14 patients who experienced a first episode of ASSC during the study period was 8.0 [IQR: 5.0-24.1] years. The median age at HU initiation was significantly lower in these 14 patients (4.8 [IQR: 3.3-18.7] years) compared to the 1664 patients without ASSC (19.9 [8.8-33.4] years, p = .0008). These findings suggest that ASSC may occur at an unusually late age in patients receiving HU, possibly reflecting longer preservation of spleen perfusion and function secondary to early initiation of HU. Further studies are needed to better characterize the effects of HU on spleen perfusion/function and on the occurrence of ASSC in patients with SCD (ClinicalTrials.gov identifier: NCT02516579; European registry ENCEPP/SDPP/10565).

Hydroxyurea reduces infections in children with sickle cell anemia in Uganda.

ABSTRACT: After starting hydroxyurea treatment, Ugandan children with sickle cell anemia had 60% fewer severe or invasive infections, including malaria, bacteremia, respiratory tract infections, and gastroenteritis, than before starting hydroxyurea treatment (incidence rate ratio, 0.40 [95% confidence interval, 0.29-0.54]; P < .001).

"In-silico Design and Development of Novel Hydroxyurea Lipid Drug Conjugates for Breast Cancer Therapy Targeting PI3K/AKT/mTOR Pathway".

Hydroxyurea (HU) has shown promise in breast cancer treatment, but its hydrophilic nature limits its efficacy. Therefore, conjugating HU with lipids could increase its liphophilicity and improve its cellular uptake, leading to increased efficacy and reduced toxicity. The PI3K/Akt/mTOR pathway is an attractive therapeutic target in cancer not only because it is the second most frequently altered pathway after p53, but also because it serves as a convergence point for many stimuli. The aim of this study is to design and develop novel hydroxyurea lipid drug conjugates for breast cancer therapy targeting the PI3K/Akt/mTOR pathway using in-silico and in-vitro approaches. The conjugates are designed and docked with the proteins selected for each target like PI3K (PDB ID;2JDO), AKT (PDB ID;3APF), mTOR (PDB ID;4JST). The conjugates with higher docking scores are taken for ADME studies and molecular dynamics. Stearic, lauric, palmitic, myristic and linolenic acids have been used for the conjugation. The conjugates are synthesized and characterized. The HLB calculation and partition coefficient are carried out to find the improvement in liphophilicity of the conjugates compared to hydroxyurea. Finally, the in-vitro cytotoxicity studies are performed with MCF -7 cell lines and the compound HU-MA (hydroxyurea with myristic acid) with low IC50 is considered as the compound having good activity with compound code. These conjugates have been shown to have improved drug solubility and better cellular uptake compared to free hydroxyurea, which can increase drug efficacy.

Managing sickle cell disease and related complications in pregnancy: results of an international Delphi panel.

ABSTRACT: Data to guide evidence-based management of pregnant people with sickle cell disease (SCD) are limited. This international Delphi panel aimed to identify consensus among multidisciplinary experts for SCD management during pregnancy. The 2-round Delphi process used questionnaires exploring 7 topics (antenatal care, hydroxyurea use, transfusion, prevention of complications, treatment of complications, delivery and follow-up, and bottlenecks and knowledge gaps) developed by a steering committee. Thirteen panelists (hematologists, physiologists, obstetricians, maternal fetal medicine, and transfusion medicine physicians) from the United States, the United Kingdom, Turkey, and France completed the first survey; 12 panelists completed the second round. Anonymized responses were collected and summarized by a contract research organization (Akkodis Belgium). Consensus and strong consensus were predefined as 75% to 90% (9-10 of 12) and >90% (≥11 of 12) of panelists, respectively, agreeing or disagreeing on a response to a predefined clinical scenario or statement. In several areas of SCD management, consensus was achieved: experts recommended performing at least monthly multidisciplinary antenatal follow-up, administering prophylactic aspirin for preeclampsia prevention between gestational weeks 12 and 36, initiating prophylactic transfusion therapy in certain cases, or choosing automated red blood cell exchange over other transfusion methods for patients with iron overload or severe acute chest syndrome. No consensus was reached on several topics including the prophylactic aspirin dose, indications for starting infection prophylaxis, routine use of prophylactic transfusions, or use of prophylactic transfusions for preventing fetal complications. These recommendations could inform clinical care for patients with SCD who are pregnant in the absence of large clinical trials involving this population; the identified knowledge gaps can orient future research.

Madrid Newborn Sickle Cell Disease Cohort: clinical outcomes, stroke prevention and survival.

In May 2003, Madrid established the universal newborn screening (NBS) for sickle cell disease (SCD). However, there are no studies resembling the evolution of a SCD neonate cohort followed according to national guidelines in Spain. The aim of this study is to describe the morbimortality and the stroke prevention programme in patients diagnosed by SCD NBS in Madrid. This is a multicentre, observational, prospective cohort study between 2003 and 2018; 187 patients diagnosed with SCD were included (151 HbSS, 6 HbSß0, 27 HbSC, 3 HbSß +), and median follow-up was 5.2 years (0.03-14.9). There were 5 deaths: 2 related to SCD in patients with severe genotype (HbSS/HbSß0). Overall survival reached 95% and SCD-related survival 96.8%. The most frequent events were fever without focus, vaso-occlusive crises and acute chest syndromes. Eight strokes occurred in 5 patients which led to a 90.7% stroke-free survival in severe genotype patients (first stroke rate, 0.54 per 100 patient-years). Transcranial Doppler (TCD) was performed in 95% of eligible patients; 75% of children with pathological TCD remained stroke-free. Regarding HbSS/HbSß0 patients, 50.1% received hydroxyurea and 9.5% haematopoietic stem cell transplantation. This study reflects the evolution of Madrid SCD cohort and provides morbimortality data similar to other developed countries.

Checkpoint kinase 1 inhibitor + low-dose hydroxyurea efficiently kills BRAF inhibitor- and immune checkpoint inhibitor-resistant melanomas.

Treatment of melanomas with targeted and immunotherapies has proven effective, but resistance to both treatments is a common outcome leaving a high proportion of patients without effective alternative treatment options. Replication stress is a common feature of melanomas, and this is effectively targeted using a combination of checkpoint kinase 1 (CHK1) inhibitor and low-dose hydroxyurea (LDHU). This combination also promotes inflammatory and anti-tumour immune responses in vivo. Melanoma cell lines resistant to BRAF inhibitor (BRAFi) or immune checkpoint inhibitors (ICI) retain their sensitivity to CHK1i + LDHU, with sensitivity similar to that of parental tumours. In vivo, BRAFi-resistant and BRAFi-sensitive parental tumours produce an identical immune response with treatment.

Impact of community health workers on quality of life in adolescents and young adults with sickle cell disease: The SHIP-HU study.

Health-related quality of life (HRQoL) is an important outcome for patients with sickle cell disease (SCD). It is often poor compared with other chronic medical conditions or measured as a multidomain disease-specific construct. We previously reported outcomes in the Start Healing in Patients with Hydroxyurea (SHIP-HU) randomized controlled trial in adolescents and adults with SCD at six clinical sites. Besides the primary outcomes, we also measured HRQoL as a secondary outcome. Patients in the intervention arm were each assigned community health workers (CHWs) who provided case management services. CHW services were independent of medical management, and medical managers were blinded to the study arm. Patients in the control arm received only standard of care. We hypothesized that having a CHW would improve HRQoL in patients enrolled in SHIP-HU. We did not find significant differences between domains of HRQoL in the two study arms. Possible explanations include selection bias of enrolled versus unenrolled patients, selection bias of sites, medical providers and medical management, enforced blinding, and a lack of cooperation between medical managers and CHWs. The importance of CHWs and HRQoL is nonetheless recognized based on the literature. Future interventions on HRQoL in SCD should consider alternative study designs and multimodal interventions.

High hydroxyurea usage in sickle cell anemia regardless of patient demographics.

Hydroxyurea is highly effective in sickle cell disease, but it is still underutilized. Reports of hydroxyurea utilization largely use Medicaid data, and socioeconomics is often cited as a barrier. To address whether patient demographics influenced the high hydroxyurea usage rate recently reported for the pediatric sickle cell program of Northern Virginia, analysis of data from 2011 to 2021 revealed no statistical difference in hydroxyurea usage rate between Medicaid and non-Medicaid, African American and African, or age less than 13 and age greater than or equal to 13 years cohorts, demonstrating that hydroxyurea can be successfully implemented across demographic groups.

The highs and lows of cyclic thrombocytopenia.

Cyclic thrombocytopenia (CTP) is characterized by periodic platelet oscillation with substantial amplitude. Most CTP cases have a thrombocytopenic background and are often misdiagnosed as immune thrombocytopenia with erratically effective treatment choices. CTP also occurs during hydroxyurea treatment in patients with myeloproliferative diseases. While the aetiology of CTP remains uncertain, here we evaluate historical, theoretical and clinical findings to provide a framework for understanding CTP pathophysiology. CTP retains the intrinsic oscillatory factors defined by the homeostatic regulation of platelet count, presenting as reciprocal platelet/thrombopoietin oscillations and stable oscillation periodicity. Moreover, CTP patients possess pathogenic factors destabilizing the platelet homeostatic system thereby creating opportunities for external perturbations to initiate and sustain the exaggerated platelet oscillations. Beyond humoral and cell-mediated autoimmunity, we propose recently uncovered germline and somatic genetic variants, such as those of MPL, STAT3 or DNMT3A, as pathogenic factors in thrombocytopenia-related CTP. Likewise, the JAK2 V617F or BCR::ABL1 translocation that drives underlying myeloproliferative diseases may also play a pathogenic role in hydroxyurea-induced CTP, where hydroxyurea treatment can serve as both a trigger and a pathogenic factor of platelet oscillation. Elucidating the pathogenic landscape of CTP provides an opportunity for targeted therapeutic approaches in the future.