Guideline for the management of conception and pregnancy in thalassaemia syndromes: A British Society for Haematology Guideline.

This comprehensive guideline, developed by a representative group of UK-based medical experts specialising in haemoglobinopathies, addresses the management of conception and pregnancy in patients with thalassaemia. A systematic search of PubMed and EMBASE using specific keywords, formed the basis of the literature review. Key terms included "thalassaemia," "pregnancy," "Cooley's anaemia," "Mediterranean anaemia," and others, covering aspects such as fertility, iron burden and ultrasonography. The guideline underwent rigorous review by prominent organisations, including the Endocrine Society, the Royal College of Obstetricians and Gynaecologists (RCOG), the United Kingdom Thalassaemia Society and the British Society of Haematology (BSH) guideline writing group. Additional feedback was solicited from a sounding board of UK haematologists, ensuring a thorough and collaborative approach. The objective of the guideline is to equip healthcare professionals with precise recommendations for managing conception and pregnancy in patients with thalassaemia.

Health-Related Quality-of-Life Impacts Associated with Transfusion-Dependent ß-Thalassemia in the USA and UK: A Qualitative Assessment.

BACKGROUND: Individuals living with transfusion-dependent ß-thalassemia (TDT) experience reduced health-related quality of life due to fatigue and chronic pain, which cause disruptions to daily life. Currently, limited qualitative data exist that describe these impacts. OBJECTIVE: This study aimed to examine the ways in which symptoms and current treatments of TDT impact health-related quality of life, to holistically describe the humanistic burden of TDT, and to identify the unmet needs of individuals living with TDT. METHODS: Adults (aged ≥ 18 years) with TDT and caregivers of adolescents (aged 12‒17 years) with TDT participated in semi-structured one-on-one virtual interviews and focus group discussions. Interviews were conducted in the USA and UK and lasted approximately 60 minutes. After transcription, the interviews were analyzed thematically using a framework approach. RESULTS: A total of ten interviews/focus group discussions (six interviews and four focus group discussions) were conducted with 14 adults with TDT and two caregivers of adolescents with TDT. A framework analysis revealed five themes describing health-related quality of life (negative impacts on daily activities, social life, family life, work and education, and psychological well-being) and three themes describing the lived experience of TDT (impact of red blood cell transfusions and iron chelation therapy, treatment, and stigma). Physical, psychological, and treatment-related factors contributed to negative impacts on daily activities, social and family life, and work and education. Concerns about reduced lifespan, relationships and family planning, and financial independence were detrimental to participants' mental well-being. Participants reported having high resilience to the many physical and psychological challenges of living with TDT. A lack of TDT-specific knowledge among healthcare professionals, particularly regarding chronic pain associated with the disease, left some participants feeling ignored or undermined. Additionally, many participants experienced stigma and were reluctant to disclose their disease to others. CONCLUSIONS: Individuals living with TDT experience substantial negative impacts on health-related quality of life that disrupt their daily lives, disruptions that are intensified by inadequate healthcare interactions, demanding treatment schedules, and stigma. Our study highlights the unmet needs of individuals living with TDT, especially for alternative treatments that reduce or eliminate the need for red blood cell transfusions and iron chelation therapy.

Comparative study between chronic automated red blood cell exchange and manual exchange transfusion in patients with sickle cell disease: A single center experience from Saudi Arabia.

BACKGROUND: Red cell transfusion remains the gold standard in managing sickle cell disease (SCD) with severe complications. Offering red blood cell exchange (RBCX) either manual exchange transfusion (MET) or automated RBCX (aRBCX) can reduce the complications of chronic transfusion and maintain target Hb thresholds. This study audits the hospital experience of overseeing adult SCD patients treated with RBCX, both automated and manual, and compares the safety and efficacy. MATERIALS AND METHODS: This retrospective observational study was conducted as an audit for chronic RBCX for adult patients with SCD in 2015-2019 at King Saud University Medical City, Riyadh, Saudi Arabia. RESULTS: A total of 344 RBCX for 20 adult SCD patients who were enrolled in regular RBCX, (11/20) patients had regular aRBCX with a total of (157) sessions, and (9/20) patients had MET with a total of (187) sessions. The median level of HbS% post-aRBCX was significantly lower than MET (24.5.9% vs. 47.3%, P < 0.010). Patients on aRBCX had fewer sessions (5 vs. 7.5, P < 0.067) with better disease control. Although the median yearly pRBC units per patient for aRBCX was more than the double needed for MET (28.64 vs. 13.39, P < 0.010), the median ferritin level was 42 µg/L in aRBCX versus 983.7 µg/L in MET, P < 0.012. CONCLUSION: Compared to MET, aRBCX was more effective in reducing HbS, with fewer hospital visits and better disease control. Although more pRBCs were transfused, the ferritin level was better controlled in the aRBCX group without increasing alloimmunization risk.

Health-related quality of life in patients with ß-thalassemia: Data from the phase 3 BELIEVE trial of luspatercept.

BACKGROUND: Patients with transfusion-dependent (TD) ß-thalassemia require long-term red blood cell transfusions (RBCTs) that lead to iron overload, impacting health-related quality of life (HRQoL). METHODS: The impact of luspatercept, a first-in-class erythroid maturation agent, versus placebo on HRQoL of patients with TD ß-thalassemia was evaluated in the phase 3 BELIEVE trial. HRQoL was assessed at baseline and every 12 weeks using the 36-item Short Form Health Survey (SF-36) and Transfusion-dependent Quality of Life questionnaire (TranQol). Mean change in HRQoL was evaluated from baseline to week 48 for patients receiving luspatercept + best supportive care (BSC) and placebo + BSC and between luspatercept responders and non-responders. RESULTS: Through week 48, for both groups, mean scores on SF-36 and TranQol domains were stable over time and did not have a clinically meaningful change. At week 48, more patients who achieved clinical response (≥50% reduction in RBCT burden over 24 weeks) in the luspatercept + BSC group had improvement in SF-36 Physical Function compared with placebo + BSC (27.1% vs. 11.5%; p = .019). CONCLUSIONS: Luspatercept + BSC reduced transfusion burden while maintaining patients' HRQoL. HRQoL domain improvements from baseline through 48 weeks were also enhanced for luspatercept responders.

Erythropoiesis in lower-risk myelodysplastic syndromes and beta-thalassemia.

The hematologic disorders myelodysplastic syndromes and beta-thalassemia are characterized by ineffective erythropoiesis and anemia, often managed with regular blood transfusions. Erythropoiesis, the process by which sufficient numbers of functional erythrocytes are produced from hematopoietic stem cells, is highly regulated, and defects can negatively affect the proliferation, differentiation, and survival of erythroid precursors. Treatments that directly target the underlying mechanisms of ineffective erythropoiesis are limited, and management of anemia with regular blood transfusions imposes a significant burden on patients, caregivers, and health care systems. There is therefore a strong unmet need for treatments that can restore effective erythropoiesis. Novel therapies are beginning to address this need by targeting a variety of mechanisms underlying erythropoiesis. Herein, we provide an overview of the role of ineffective erythropoiesis in myelodysplastic syndromes and beta-thalassemia, discuss unmet needs in targeting ineffective erythropoiesis, and describe current management strategies and emerging treatments for these disorders.

Health state utilities for beta-thalassemia: a time trade-off study.

BACKGROUND: Beta-thalassemia (BT) is an inherited blood disorder characterized by reduced levels of functional hemoglobin resulting in phenotypes ranging from clinically asymptomatic to severely anemic. Patients with BT may require lifelong regular blood transfusions supported by appropriate iron chelation therapy (ICT). This study aimed to determine how the UK general population values BT health states associated with differing transfusion burden and ICT. METHODS: Composite time trade-off (cTTO) methodology was employed to elicit health state utilities in BT. Relevant BT literature related to symptom and quality-of-life impact, including physical, functional, and emotional well-being, and safety profiles of BT treatments were considered when drafting health state descriptions. Eleven health state descriptions were developed and validated by hematologists and patient advocates for clinical accuracy and completeness. 200 individuals from the UK general population participated in the cTTO interviews. RESULTS: The mean age of participants was 41.50 years (SD 16.01, range 18-81); 88 (46.8%) were female. Utility values ranged from 0.78 (SD 0.34) for non-transfusion dependent BT with oral ICT to 0.37 (SD 0.50) for high transfusion burden with subcutaneous ICT in transfusion-dependent BT. CONCLUSIONS: This study provides health utilities for a range of BT health states from the UK general population perspective. Importantly, lower transfusion burden and lower burden of anemia were associated with higher utilities. To a lesser extent, differential modes of ICT were found to impact utility valuations in patients with BT. The utilities obtained in this study can be employed as inputs in cost-effectiveness analyses of BT therapies.

Relationship between Serum Ferritin and Outcomes in ß-Thalassemia: A Systematic Literature Review.

Among the difficulties of living with ß-thalassemia, patients frequently require blood transfusions and experience iron overload. As serum ferritin (SF) provides an indication of potential iron overload, we conducted a systematic literature review (SLR) to assess whether SF levels are associated with clinical and economic burden and patient-reported outcomes (PROs). The SLR was conducted on 23 April 2020 and followed by analysis of the literature. Dual-screening was performed at the title, abstract, and full-text levels using predefined inclusion and exclusion criteria. Ten studies identified by the SLR were eligible for inclusion in the analysis. Seven studies were conducted in Europe, and most were prospective or retrospective in design. The patient populations had a median age of 20.7-42.6 years, with a percentage of men of 38-80%. Sparse data were found on the correlation between SF levels and mortality, and hepatic, skeletal, and cardiac complications; however, in general, higher SF levels were associated with worsened outcomes. The bulk of the evidence reported on the significant association between higher SF levels and endocrine dysfunction in its many presentations, including a 14-fold increase in the risk of diabetes for patients with persistently elevated SF levels. No studies reporting data on PROs or economic burden were identified by the SLR. SF levels provide another option for prognostic assessment to predict a range of clinical outcomes in patients with ß-thalassemia.

Promoting Adherence to Iron Chelation Treatment in Beta-Thalassemia Patients.

Thalassaemia is one of the commonest inherited genetic disorders world-wide with around 25,000 births of the most severely affected transfusion dependent children annually. Patients with transfusion dependent thalassaemia require regular blood transfusions to maintain life but because of this will develop iron overload. To remove the excess iron, patients are required to take iron chelation therapy (ICT). ICT requires lifelong adherence to treatment to prevent end organ damage from developing. Many of these preventable complications make adherence to therapy more complex for patients. In this review, we focus on two commonly encountered patient scenarios and discuss how different psychological models and a relational theory can be used to understand and support adherence to treatment.

A Systematic Literature Review of the Relationship between Serum Ferritin and Outcomes in Myelodysplastic Syndromes.

Anemia is the most common form of cytopenia in patients with myelodysplastic syndromes (MDS), who require chronic red blood cell transfusions and may present high serum ferritin (SF) levels as a result of iron overload. To better understand the potential effects of high SF levels, we conducted a systematic literature review (SLR) to identify evidence on the relationship between SF levels and clinical, economic, or humanistic outcomes in adult patients with MDS. Of 267 references identified, 21 were included. No studies assessing SF levels and their relationship with humanistic or economic outcomes were identified. Increased SF levels were an indicator of worse overall survival and other worsened outcomes; however, the association was not consistently significant. SF levels were a significant prognostic factor for relapse incidence of MDS and showed a significant positive correlation with number of blood units transfused but were not associated with progression to acute myeloid leukemia or the time to transformation. Higher SF levels were also an indicator of a lower likelihood of leukemia-free survival, relapse-free survival, and event-free survival. The SLR suggests that SF levels are associated with clinical outcomes in MDS, with higher levels correlated with number of blood units transfused, frequently indicating worse outcomes.

Routine management, healthcare resource use and patient and carer-reported outcomes of patients with transfusion-dependent ß-thalassaemia in the United Kingdom: A mixed methods observational study.

Objectives: We evaluated routine healthcare management, clinical status and patient- and carer-reported outcomes in UK paediatric and adult patients with transfusion-dependent ß-thalassaemia (TDT). Methods: A multi-centre, observational mixed-methodology study evaluated 165 patients (50% male; median age 24.1 [interquartile range (IQR)] 11.8-37.2] years) from nine UK centres. Results: Patients had a mean of 13.7 (standard deviation [SD] ±3.2) transfusion episodes/year (mean retrospective observation period 4.7 [±0.7] years). The median (IQR) for iron overload parameters at the last assessment during the observation period were: serum ferritin (n = 165) 1961.0 (1090.0-3003.0) µg/L (38% > 2500 µg/L); R2 liver iron (n = 119) 5.4 (2.9-11.6) mg/g (16% ≥15 mg/g); T2* cardiac iron (n = 132) 30.3 (22.0-37.1) ms (10% < 10 ms). All patients received ≥1 iron chelator during the observation period; 21% received combination therapy. Patients had a mean of 7.8 (±8.1) non-transfusion-related hospital attendances or admissions/year. Adult patients' mean EQ-5D utility score was 0.69 (±0.33; n = 94 [≥16 years]) and mean Transfusion-dependent quality of life score was 58.6 (±18.4; n = 94 [≥18 years]). For Work Productivity and Activity impairment, mean activity impairment for patients ≥18 years (n = 88) was 48% (±32%) and for carers (n = 29) was 28% (±23%). Conclusions: TDT presents significant burden on patients, carers and healthcare resources.

Protecting vulnerable patients with inherited anaemias from unnecessary death during the COVID-19 pandemic.

With the developing COVID-19 pandemic, patients with inherited anaemias require specific advice regarding isolation and changes to usual treatment schedules. The National Haemoglobinopathy Panel (NHP) has issued guidance on the care of patients with sickle cell disease, thalassaemia, Diamond Blackfan anaemia (DBA), congenital dyserythropoietic anaemia (CDA), sideroblastic anaemia, pyruvate kinase deficiency and other red cell enzyme and membrane disorders. Cascading of accurate information for clinicians and patients is paramount to preventing adverse outcomes, such as patients who are at increased risk of fulminant bacterial infection due to their condition or its treatment erroneously self-isolating if their fever is mistakenly attributed to a viral cause, delaying potentially life-saving antibiotic therapy. Outpatient visits should be minimised for most patients, however some, such as first transcranial dopplers for children with sickle cell anaemia should not be delayed as known risk of stroke will outweigh the unknown risk from COVID-19 infection. Blood transfusion programmes should be continued, but specific changes to usual clinical pathways can be instituted to reduce risk of patient exposure to COVID-19, as well as contingency planning for possible reductions in blood available for transfusions. Bone marrow transplants for these disorders should be postponed until further notice. With the current lack of evidence on the risk and complications of COVID-19 infection in these patients, national data collection is ongoing to record outcomes and eventually to identify predictors of disease severity, particularly important if further waves of infection travel through the population.

A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent ß-Thalassemia.

BACKGROUND: Patients with transfusion-dependent ß-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor ß superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS: In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent ß-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS: A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 µg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS: The percentage of patients with transfusion-dependent ß-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.).

National comparative audit of blood transfusion: 2014 audit of transfusion services and practice in children and adults with sickle cell disease.

OBJECTIVES: To determine the organisational resources in place; what blood was being transfused, why, how, where, when and by whom; whether laboratory support and policies met standards for patients with sickle cell disease (SCD). BACKGROUND: SCD affects 14 000 people in the United Kingdom (UK). Standards and guidelines do not cover all aspects of transfusion in SCD and there are no data on their use; people may become very sick without warning presenting to non-specialist hospitals; blood services are increasingly supplying units for transfusion in SCD with little data on their use. METHODS: A retrospective audit of transfusion services/practice for people with SCD who had received a transfusion in January-July 2014 in participating hospitals in the UK and Republic of Ireland (ROI). RESULTS: Eighty-four hospitals submitted 1290 cases, 75% of cases came from 18 hospitals submitting 25 or more cases. Transfusions (91.2% [1164/1276]) were administered to patients with HbSS, 60% (732/1227) of patients needed Rh CE negative blood. Transfusion episodes (4528) were recorded, of which 84% were elective. Stroke prevention accounted for 42% of all transfusions; adults received 56% of transfusions of which 50% were automated red cell exchange (RCE), children received 44% of transfusions of which 87% were simple transfusions. CONCLUSIONS: There was a paucity of appropriate clinical management protocols, adequately trained staff and network arrangements. The high numbers of children being transfused, disparity in transfusion modality between children and adults and the high frequency of the CE negative Rh phenotype were noted.

Challenges of blood transfusions in ß-thalassemia.

Patients with ß-thalassemia major (BTM) require regular blood transfusions, supported by appropriate iron chelation therapy (ICT), throughout their life. ß-thalassemia is a global disease that is most highly prevalent in Southeast Asia, Africa, and Mediterranean countries. However, the global distribution of patients with ß-thalassemia is changing due to population migration, and Northern European countries now have significant thalassemia populations. Globally, many patients with BTM have limited access to regular and safe blood transfusions. A lack of voluntary nonremunerated blood donors, poor awareness of thalassemia, a lack of national blood policies, and fragmented blood services contribute to a significant gap between the timely supply of, and demand for, safe blood. In many centers, there is inadequate provision of antigen testing, even for common red cell antigens such as CcEe and Kell. Policies to raise awareness and increase the use of red blood cell antigen testing and requesting of compatible blood in transfusion centers are needed to reduce alloimmunization (the development of antibodies to red blood cell antigens), which limits the effectiveness of transfusions and the potential availability of blood. Patients with BTM are also at risk of transfusion-transmitted infections unless appropriate blood screening and safety practices are in place. Hence, many patients are not transfused or are undertransfused, resulting in decreased health and quality-of-life outcomes. Hemovigilance, leukoreduction, and the ability to thoroughly investigate transfusion reactions are often lacking, especially in resource-poor countries. ICT is essential to prevent cardiac failure and other complications due to iron accumulation. Despite the availability of potentially inexpensive oral ICT, a high proportion of patients suffer complications of iron overload and die each year due to a lack of, or inadequate, ICT. Increased awareness, training, and resources are required to improve and standardize adequate blood transfusion services and ICT among the worldwide population of patients with BTM. ICT needs to be available, affordable, and correctly prescribed. Effective, safe, and affordable new treatments that reduce the blood transfusion burden in patients with ß-thalassemia remain an unmet need.

Urdu translation and validation of PHQ-9, a reliable identification, severity and treatment outcome tool for depression.

OBJECTIVE: To translate and validate the self-report brief version of Patient Health Questtionaire-9 in Urdu. METHODS: The descriptive study was carried out at the Combined Military Hospitals in Gilgit and Lahore, and Pakistan Naval Ship Shifa Hospital in Karachi, from February to May 2016, and comprised of patients recruited from primary healthcare centres of the three cities Standardised procedures including forward-translation, back-translation, expert panel discussion, face validation, pilot testing, and target population validation were done. SPSS 21 was used for statistical analysis. RESULTS: Of the 293 patients, 164(56%) were males and 129(44%) were females. Exploratory factor analysis revealed a single factor solution with minimum factor loading being 0.63. Cronbach's alpha for the scale was 0.91 and split-half reliability was 0.77. Females were more likely to have depressive symptoms compared to male participants (p<0.01). Participants' area of dwelling also influenced their reported symptoms (p<0.01). CONCLUSIONS: Patient Health Questtionaire-9 Urdu scale was found to be a valid and reliable tool to screen, rate and monitor outcomes of depressive illness in primary healthcare settings in Pakistan.