Iron chelation therapy for children with transfusion-dependent ß-thalassemia: How young is too young?

In this review, we provide a summary of evidence on iron overload in young children with transfusion-dependent ß-thalassemia (TDT) and explore the ideal timing for intervention. Key data from clinical trials and observational studies of the three available iron chelators deferoxamine, deferiprone, and deferasirox are also evaluated for inclusion of subsets of young children, especially those less than 6 years of age. Evidence on the efficacy and safety of iron chelation therapy for children ≥2 years of age with transfusional iron overload is widely available. New data exploring the risks and benefits of early-start iron chelation in younger patients with minimal iron overload are also emerging.

Quality of life, mood disorders, and cognitive impairment in adults with ß-thalassemia.

Advances in understanding the disease process in ß-thalassemia supported development of various treatment strategies that resulted in improved survival. Improved survival, however, allowed multiple morbidities to manifest and cemented the need for frequent, lifelong treatment. This has directly impacted patients' health-related quality of life and opened the door for various psychiatric and cognitive disorders to potentially develop. In this review, we summarize available evidence on quality of life, depression and anxiety, suicidality, and cognitive impairment in adult patients with ß-thalassemia while sharing our personal insights from experience in treating patients with both transfusion-dependent and non-transfusion-dependent forms.

A Comparison of Field-in-Field and Intensity Modulated Radiation Therapy in Delivering Hypofractionated Radiation Therapy for Prostate Cancer.

Purpose: This study compares the dosimetric performance of the field-in-field (FIF) technique with intensity modulated radiation therapy (IMRT) for delivering hypofractionated radiation therapy to prostate patients with cancer. The FIF technique uses 6 beams, whereas IMRT uses 9 beams. Methods and Materials: This study was conducted on 15 patients with prostate cancer treated with step-and-shoot IMRT. The prescribed dose was 60 Gy in 20 fractions. The FIF plans contained 6 photon beams, and IMRT plans were designed using a 9-field step-and-shoot technique. Dose-volume histograms and dose distributions were evaluated to compare FIF and IMRT. Results: The results of the planning target volume indices analysis showed a significant difference in the maximum dose, dose to 2% of volume, and homogeneity index in favor of FIF and in the mean dose, dose to 98% of volume, and D95 in favor of IMRT. The results of the organs-at-risk analysis showed significant differences in the volume of the rectum and bladder receiving 60 Gy in favor of FIF and the volume of the rectum and femoral heads receiving 30 Gy, as well as the mean dose to the rectum, in favor of IMRT. IMRT had a higher median number of monitor units (MUs) and segments (886 MU, 64 segments) compared to FIF (434 MUs, 6 segments). Conclusions: The FIF technique and IMRT had comparable results in delivering hypofractionated radiation therapy for prostate cancer. The findings of this study may aid in decision-making for patients undergoing treatment.

von Willebrand factor/factor VIII concentrate (Wilate) prophylaxis in children and adults with von Willebrand disease.

ABSTRACT: Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in patients with von Willebrand disease (VWD) who have a history of severe and frequent bleeds. However, data from prospective studies are scarce. WIL-31, a prospective, noncontrolled, international phase 3 trial, investigated the efficacy and safety of Wilate prophylaxis in severe patients with VWD. Male and female patients 6 years or older with VWD types 1, 2 (except 2N), or 3 who had completed a prospective, 6-month, on-demand, run-in study (WIL-29) were eligible to receive Wilate prophylaxis for 12 months. At baseline, patients (n = 33) had a median age of 18 years. Six (18%) patients had severe type 1, 5 (15%) had type 2, and 22 (67%) had type 3 VWD. The primary end point of a >50% reduction in mean total annualized bleeding rate (TABR) with Wilate prophylaxis vs prior on-demand treatment was met; mean TABR during prophylaxis was 5.2, representing an 84.4% reduction. The bleeding reduction was consistent across age, sex, and VWD types. The mean spontaneous ABR was 3.2, representing an 86.9% reduction vs on-demand treatment. During prophylaxis, 10 (30.3%) patients had 0 bleeding events and 15 (45.5%) patients had 0 spontaneous bleeding events. Of 173 BEs, 84.4% were minor and 69.9% treated. No serious adverse events related to study treatment and no thrombotic events were recorded. Overall, WIL-31 showed that Wilate prophylaxis was efficacious and well-tolerated in pediatric and adult patients with VWD of all types. The WIL-29 and WIL-31 trials were registered at www.ClinicalTrials.gov as #NCT04053699 and #NCT04052698, respectively.

Αlpha-thalassemia: A practical overview.

α-Thalassemia is an inherited blood disorder characterized by decreased synthesis of α-globin chains that results in an imbalance of α and ß globin and thus varying degrees of ineffective erythropoiesis, decreased red blood cell (RBC) survival, chronic hemolytic anemia, and subsequent comorbidities. Clinical presentation varies depending on the genotype, ranging from a silent or mild carrier state to severe, transfusion-dependent or lethal disease. Management of patients with α-thalassemia is primarily supportive, addressing either symptoms (eg, RBC transfusions for anemia), complications of the disease, or its transfusion-dependence (eg, chelation therapy for iron overload). Several novel therapies are also in development, including curative gene manipulation techniques and disease modifying agents that target ineffective erythropoiesis and chronic hemolytic anemia. This review of α-thalassemia and its various manifestations provides practical information for clinicians who practice beyond those regions where it is found with high frequency.

Management of transfusion-dependent ß-thalassemia (TDT): Expert insights and practical overview from the Middle East.

ß-Thalassemia is one of the most common monogenetic diseases worldwide, with a particularly high prevalence in the Middle East region. As such, we have developed long-standing experience with disease management and devising solutions to address challenges attributed to resource limitations. The region has also participated in the majority of clinical trials and development programs of iron chelators and more novel ineffective erythropoiesis-targeted therapy. In this review, we provide a practical overview of management for patients with transfusion-dependent ß-thalassemia, primarily driven by such experiences, with the aim of transferring knowledge to colleagues in other regions facing similar challenges.

Unmet needs in ß-thalassemia and the evolving treatment landscape.

ß-thalassemias are genetic disorders causing an imbalance in hemoglobin production, leading to varying degrees of anemia, with two clinical phenotypes: transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). Red blood cell transfusions and iron chelation therapy are the conventional treatment options for the management of ß-thalassemia. Currently available conventional therapies in thalassemia have many challenges and limitations. Accordingly, multiple novel therapeutic approaches are currently being developed for the treatment of ß-thalassemias. These strategies can be classified into three categories based on their efforts to address different aspects of the underlying pathophysiology of ß-thalassemia: correction of the α/ß globin chain imbalance, addressing ineffective erythropoiesis, and targeting iron dysregulation. Managing ß- thalassemia presents challenges due to the many complications that can manifest, limited access and availability of blood products, and lack of compliance/adherence to treatment. Novel therapies targeting ineffective erythropoiesis and thus improving anemia and reducing the need for chronic blood transfusions seem promising. However, the complex nature of the disease itself requires personalized treatment plans for each patient. Collaborations and partnerships between thalassemia centers can also help share knowledge and resources, particularly in regions with higher prevalence and limited resources. This review will explore the different conventional treatment modalities available today for the management of ß-thalassemia, discuss the unmet needs and challenges associated with them in addition to exploring the role of some novel therapeutic agents in the field.

Cancer Research in Vulnerable Populations: A Call for Collaboration and Sustainability From MENAT Countries.

PURPOSE: Cancer is a major burden across Middle East, North Africa, Türkiye (MENAT). Many MENAT countries experience multiple conflicts that compound vulnerabilities, but little research investigates the linkages between vulnerability and cancer research. This study examines the current level and the potential for cancer research among vulnerable populations in the MENAT region, aiming to provide direction toward developing a research agenda on the region's vulnerable populations. METHODS: Expert-driven meetings were arranged among the 10 authors. After obtaining institutional review board approval, a self-administered online survey questionnaire was circulated to more than 500 cancer practitioners working in 22 MENAT countries. RESULTS: Two hundred sixteen cancer practitioners across the MENAT region responded. Fifty percent of the respondents identified clinical research in vulnerable patients with cancer as a significant issue; 21.8% reported previous research experience that included vulnerable populations, and 60% reported encountering vulnerable populations in their daily clinical practice. The main barriers to conducting research were lack of funding (60%), protected time (42%), and research training (35%). More than half of the respondents believed that wars/conflicts constituted an important source of vulnerability. The most vulnerable cancer populations were the elderly, palliative/terminally ill, those with concomitant mental health-related issues, those with other chronic illnesses, and socioeconomically deprived patients. CONCLUSION: Results support that a major effort is needed to improve cancer research among vulnerable cancer populations in the MENAT region. We call for interdisciplinary research that accounts for the region's unique, compounding, and cumulative forms of vulnerability. This cancer research agenda on different vulnerable populations must balance sociobehavioral studies that explore sociopolitical barriers to quality care and clinical studies that gauge and refine treatment protocols. Building a research agenda through collaboration and solidarity with international partners is prime time.

Eviscerated liver: an extremely rare complication of abdominal wound dehiscense through a midline incision.

Abdominal wound dehiscense, or burst abdomen, is a critical postoperative complication necessitating immediate intervention. We present an extremely rare case of left hepatic lobe evisceration through wound dehiscense in a 65-year-old female receiving palliative care for hypopharyngeal squamous cell carcinoma. The patient's midline incision that was performed for feeding jejunostomy tube displayed liver protrusion on Day 14 postoperatively. Surgical exploration revealed a healthy liver, prompting reduction and secondary sutures to prevent complications. Abdominal wound dehiscense risk factors, including advanced age, poor nutrition, and medical illness, contribute to its occurrence. Although guidelines for liver evisceration management are lacking, our case emphasizes proper technique, wound care, and nutritional support to aid the healing process and to ensure a better outcome for the patients.

Compliance and clinical benefit of deferasirox granule and dispersible tablet formulation in pediatric patients with transfusional iron overload: in a randomized, open-label, multicenter, phase II study.

CALYPSO (NCT02435212), a randomized, open-label, multicenter, phase 2 study evaluated the compliance, clinical benefits, and safety of deferasirox granules and dispersible tablets in pediatric patients with iron overload. Iron chelation therapy-naive and iron chelation therapy-pre-treated patients aged 2 to 0.5 mg/mg; 24.5% and 34.2%), upper respiratory tract infection (28.2% and 29.7%), and pyrexia (26.4% and 23.4%). In iron chelation therapy-naive patients, mean compliance and change from baseline in serum ferritin with both deferasirox formulations were not significantly different. The safety profile was comparable between granule and dispersible tablets formulations, and was consistent with the general safety profile of deferasirox.

Thalassemia and malignancies: Updates from the literature.

Thalassemia management has undergone significant development with the advancement in iron chelation therapy, which has led to a prolonged life expectancy. This has been accompanied by the emergence of several new morbidities and chronic diseases, including cancer. Over the years, multiple cases of solid and hematologic malignancies in thalassemia patients have been reported in the literature, with no clear mechanism for the development of cancer in these patients despite a number of potential mechanisms. However, the results of many studies have been contradictory regarding the risk of development of malignancies in thalassemia. The present review aims to discuss the available data on cancer and thalassemia in the literature, with the latest updates regarding possible malignancy development mechanisms, risks, and the most commonly reported types.

Beta-thalassemia: is cure still a dream?

ß-thalassemia is a monogenic disorder characterized by decreased hemoglobin production, resulting in chronic anemia. There are several factors affecting the clinical presentation of patients with ß-thalassemia, and several complications such as iron overload or ineffective erythropoiesis have been linked to this disease. Until nowadays, several conservative therapies namely blood transfusions, iron chelation, and the FDA-approved drug Luspatercept have been adopted alongside other debatable permanent cures. Other clinical trials are being conducted to develop better and safer management techniques for these patients. This review will discuss the different treatment strategies of ß-thalassemia including novel therapies, besides all possible curative therapies that are being developed for this disease.

Hemorrhagic Vesiculobullous Lesions of Ecthyma Gangrenosum in a Diabetic Patient with Myelofibrosis: A Rare Presentation of Septic Shock without Pseudomonas aeruginosa Bacteremia.

BACKGROUND Ecthyma gangrenosum is a rare skin lesion associated with Pseudomonas aeruginosa, an aerobic gram-negative opportunistic bacterial pathogen. In non-bacteremia patients, sepsis is not a common complication. Immunocompromised patients are more commonly affected. If diagnosis and therapy are delayed, the mortality rate is 18-96%. This report is of a 52-year-old man with diabetes mellitus and myelofibrosis presenting with hemorrhagic vesiculobullous lesions of ecthyma gangrenosum on the upper and lower extremities, oral mucosa, and anogenital area with, interestingly, no associated Pseudomonas aeruginosa bacteremia. CASE REPORT A 52-year-old diabetes patient with myelofibrosis presented with hemorrhagic vesiculobullous and necrotic eschar-covered erosions over the upper and lower extremities, oral mucosa, and anogenital area. Although he appeared septic looking initially, with signs of end-stage organ failure, and he was later determined to have septic shock, the clinical diagnosis was not possible without a positive culture swab of the cutaneous lesions showing growth of Pseudomonas aeruginosa. The diagnosis of cutaneous ecthyma gangrenosum-induced septic shock was confirmed, though bacteremia was not detected. This patient was successfully managed with the early initiation of proper antibiotics. CONCLUSIONS Early detection and vigilance when confronted with the clinical presentation of ecthyma gangrenosum are a vital part of patient management to reduce the high mortality risk of the disease. Although bacteremia is associated with a high risk for fatalities, cutaneous ecthyma gangrenosum can be complicated by septic shock and serious adverse events. The involvement of multidisciplinary teams in patient management is an essential aspect of ecthyma gangrenosum disease management.

How I treat non-transfusion-dependent ß-thalassemia.

The intricate interplay of anemia and iron overload under the pathophysiological umbrella of ineffective erythropoiesis in non-transfusion-dependent ß-thalassemia (NTDT) results in a complex variety of clinical phenotypes that are challenging to diagnose and manage. In this article, we use a clinical framework rooted in pathophysiology to present 4 common scenarios of patients with NTDT. Starting from practical considerations in the diagnosis of NTDT, we delineate our strategy for the longitudinal care of patients who exhibit different constellations of symptoms and complications. We highlight the use of transfusion therapy and novel agents, such as luspatercept, in the patient with anemia-related complications. We also describe our approach to chelation therapy in the patient with iron overload. Although tackling every specific complication of NTDT is beyond the scope of this article, we touch on the management of the various morbidities and multisystem manifestations of the disease.

Epidemiology of clinically significant forms of alpha- and beta-thalassemia: A global map of evidence and gaps.

This systematic literature review assessed the global prevalence and birth prevalence of clinically significant forms of alpha- and beta-thalassemia. Embase, MEDLINE, and the Cochrane Library were searched for observational studies published January 1, 2000, to September 21, 2021. Of 2093 unique records identified, 69 studies reported across 70 publications met eligibility criteria, including 6 records identified from bibliography searches. Thalassemia prevalence estimates varied across countries and even within countries. Across 23 population-based studies reporting clinically significant alpha-thalassemia (e.g., hemoglobin H disease and hemoglobin Bart's hydrops fetalis) and/or beta-thalassemia (beta-thalassemia intermedia, major, and/or hemoglobin E/beta-thalassemia), prevalence estimates per 100 000 people ranged from 0.2 in Spain (over 2014-2017) to 27.2 in Greece (2010-2015) for combined beta- plus alpha-thalassemia; from 0.03 in Spain (2014-2017) to 4.5 in Malaysia (2007-2018) for alpha-thalassemia; and from 0.2 in Spain (2014-2017) to 35.7 to 49.6 in Iraq (2003-2018) for beta-thalassemia. Overall, the estimated prevalence of thalassemia followed the predicted pattern of being higher in the Middle East, Asia, and Mediterranean than in Europe or North America. However, population-based prevalence estimates were not found for many countries, and there was heterogeneity in case definitions, diagnostic methodology, type of thalassemia reported, and details on transfusion requirements. Limited population-based birth prevalence data were found. Twenty-seven studies reported thalassemia prevalence from non-population-based samples. Results from such studies likely do not have countrywide generalizability as they tended to be from highly specific groups. To fully understand the global prevalence of thalassemia, up-to-date, population-based epidemiological data are needed for many countries.

Profile of Luspatercept in the Treatment of Anemia in Adults with Non-Transfusion-Dependent ß-Thalassemia (NTDT): Design, Development and Potential Place in Therapy.

Over the past decade, evidence has been mounting on the detrimental clinical sequelae of untreated anemia in patients with non-transfusion-dependent ß-thalassemia (NTDT). There are no pharmacologic agents that are specifically approved for the management of anemia in NTDT, and available options such as splenectomy, transfusion therapy, and hydroxyurea each come with their own shortcomings, especially for long-term use. Luspatercept is an erythroid maturation agent that has been evaluated in a Phase 2, randomized trial and showed a significant benefit in raising hemoglobin level by at least 1 g/dL in adults with NTDT and a baseline hemoglobin level ≤10 g/dL. These data led to luspatercept's approval by the European Commission for the treatment of anemia in adults with NTDT and presents the first evidence-based approach for a novel agent that is able to ameliorate anemia in this patient population.

Patient preference for deferasirox film-coated versus dispersible tablet formulation: a sequential-design phase 2 study in patients with thalassemia.

Iron chelation therapy (ICT) is the mainstay of treatment in patients with thalassemia requiring blood transfusions. This phase 2 JUPITER study evaluated patient preference between film-coated tablet (FCT) and dispersible tablet (DT) in transfusion-dependent thalassemia (TDT) or non-TDT (NTDT) patients treated with both formulations in a sequential manner. The primary endpoint was patient-reported preference for FCT over DT, while secondary outcomes included patient reported outcomes (PROs) evaluated by overall preference, and by age, thalassemia transfusion status, and previous ICT status. Out of 183 patients screened, 140 and 136 patients completed the treatment periods 1 and 2 of the core study, respectively. At week 48, the majority of patients preferred FCT over DT (90.3 vs. 7.5%; difference of percentage: 0.83 [95% confidence interval (CI), 0.75-0.89; P < 0.0001]). FCT scored better on secondary PROs and showed less severe gastrointestinal symptoms than DT, except in the change of modified Satisfaction with Iron Chelation Therapy (mSICT) preference scores, which were similar for both the formulations. Patients with TDT had stable ferritin levels, while it showed a downward trend up to week 48 in patients with NTDT on deferasirox treatment. Overall, 89.9% of patients reported ≥ 1 adverse event (AE), of which 20.3% experienced ≥ 1 serious AE. The most common treatment-emergent AEs were proteinuria, pyrexia, urine protein/creatinine ratio increase, diarrhea, upper respiratory tract infections, transaminase increase, and pharyngitis. Overall, this study reinforced the observations from the previous study by showing a distinct patient preference for FCT over DT formulation and further supported the potential benefits of life-long compliance with ICT.

The state of cancer research in fragile and conflict-affected settings in the Middle East and North Africa Region: A bibliometric analysis.

Background: Cancer represents a disproportionate burden in LMICs, especially conflict-affected countries in the MENA region. Research output on cancer fails to match the growing burden in the region. This bibliometric study aims to examine the status and trends of cancer research in fragile and conflict-affected settings in the MENA region from 2000 to 2021, while also incorporating economic and demographic indicators as additional factors of analysis. Methods: The Web of Science databases were searched for publications related to cancer research in Iraq, Lebanon, Libya, Palestine, Syria, and Yemen from January 1, 2000, to December 31, 2021. The retrieved publications were screened based on preset eligibility criteria and the final list was analyzed using the Bibliometrix Package in R to generate the annual scientific production and citations, journals, institutions, authors, collaborations, keywords, and title co-occurrence. Each country's annual scientific production was analyzed against its annual GDP per capita. Results: A total of 4,280 documents met the inclusion criteria in this research. The annual number of publications revealed a significant increase over the past 20 years. These publications were mostly published in international journals that had impact factors rated in the 3rd or 4th quartiles. The overall contribution of researchers from Fragile and Conflict-Affected Settings (FCS) to cancer research was 6.5% of the MENA cancer research productivity, despite comprising around 23% of the total MENA region's population. Lebanon had the highest publication productivity at the country level, followed by Iraq and Syria. GDP per capita was not significantly correlated with cancer research across the countries under investigation. At the institutional level, the American University of Beirut was the most prolific institution and had the highest number of collaborations and the widest range of cooperative partners. Most first authors were male researchers. There is an interest in cancer expression, prevalence, diagnosis, and management in terms of commonly researched topics. Conclusion: This study underscores the need for a concerted effort to improve cancer research outcomes in FCS, which can be achieved through targeted research, increased investment in research infrastructure and capacity-building initiatives, and greater regional and global collaboration.