TIF Guidelines for the Management of Transfusion‐Dependent β‐Thalassemia

The prospect of patients with transfusion-dependent β-thalassemia (TDT), once considered a fatal childhood disorder, has completely transformed over the past 50 years.1 This is primarily attributed to the adoption of hemovigilance in transfusion therapy, the development of effective iron chelators, the validation of non-invasive tools for monitoring organ-specific iron loading, and the introduction of multidisciplinary care. Regrettably, access to these advances and optimal application of best practices remain largely confined to nations with robust economies, where comprehensive health and social care systems provide universal access to treatment.2 Consequently, multimorbidity and shortened survival continue to burden patients in countries with limited resources, where most of TDT patients live.3 In high-income settings, improved survival of TDT did not come without its own “side effect,” where aging allowed several previously unrecognized morbidities to manifest, especially in patients who were exposed to the harmful effects of under- or sub-optimal treatment in the past.4, 5 Thus, the “gold standard” in TDT care is now fundamentally recognized as being a multidisciplinary approach to management, preferably in expert or reference centers, and with active engagement of patients and their families.6 Since its inception in 1986, the Thalassaemia International Federation (TIF) has remained committed to supporting patients/families and patient organizations, healthcare professionals, and policymakers to promote optimal care for patients with thalassemia and other hemoglobinopathies across the world. The preparation, publication, translation, and free distribution of management guidelines is a cornerstone of its educational mission. Widely recognized for their significant impact on the care of patients with TDT, and broadly endorsed by the international medical community, these guidelines serve as a critical resource for healthcare providers and a foundation upon which national policies and practices can be built. The 5th edition of TIF “Guidelines for the Management of Transfusion-Dependent β-Thalassemia (TDT)” has now become available (available for free download at: https://thalassaemia.org.cy/tif-publications/).7 In keeping with the many and multiple unmet needs of patients in different geographies, the guidelines have been carefully crafted to offer evidence-based recommendations (key points and recommendations from select chapters on diagnosis and disease management are provided in Table 1, and a summary of monitoring recommendations is provided in Supporting Information S1: Table S1) while also suggesting solutions and pathways for care in resource-limited settings. Recommendations are provided by a global and diverse group of experts with decades of experience in patient care, through 17 interconnected chapters that echo the need of “true” multidisciplinary care throughout the patient journey from childhood to adulthood. The guidelines also include a chapter dedicated to the value of patient engagement, emphasizing the transformative power of patients as informed and effective advocates for their own needs. Additionally, patients have contributed to the review of various other chapters, ensuring that issues such as lifestyle and mental health are comprehensively addressed from the patients' perspective. A diagnosis of thalassemia should be considered in all those who have hypochromic microcytic anemia (Grade C, Class I). In the diagnostic work-up for hypochromic microcytosis, iron deficiency anemia should always be excluded (Grade C, Class I). Molecular analysis is not required to confirm the diagnosis of a β-thalassemia carrier, but it is necessary to confirm the α-thalassemia carrier status (Grade C, Class I). An α-globin gene triplication or quadruplication should be taken into consideration in heterozygous β-thalassemia subjects with a β-thalassemia intermedia phenotype (Grade C, Class I). Hematological parameters, including red cell indices and morphology, followed by separation and measurement of hemoglobin fractions, are the basis for the identification of β-thalassemia carriers (Grade C, Class I). Since the prevalent pathogenic variants of the β-globin gene are limited in each at-risk population, a PCR method designed to detect the common specific mutation simultaneously should be used initially (Grade C, Class IIa). β-globin gene sequence analysis may be considered first if the affected individual is not of an ancestry at high risk or if targeted analysis reveals only one or no pathogenic variant (Grade C, Class IIa). Methods that may be used to detect rare or unknown deletions include Southern blotting (now fallen into abeyance), quantitative PCR, long-range PCR and, above all, MLPA (Grade C, Class IIa). Considerations of phenotype should not only be based on genotype but should take clinical presentation and disease severity as observed over a duration of time (Grade C, Class IIb). Patients who receive six or more red blood cell units over 6 months with ≤6-week transfusion-free period or receiving frequent transfusions for >1 year can be classified as TDT for purposes of management approach or clinical trial eligibility (Grade C, Class IIb). Confirm the diagnosis of thalassemia, perform appropriate clinical and laboratory assessment, and obtain informed consent before initiation of transfusion (Grade C, Class IIa). The decision to initiate a long-term regular transfusion regimen should not only be driven by patient genotype or hemoglobin level, and should not be driven by a transient drop in hemoglobin due to an intercurrent infection. It should consider the current clinical phenotype of the patient and anticipated short- and longer-term outcomes and should be taken in discussion with the patient or parents (Grade C, Class IIa). Use careful donor selection and screening, favoring voluntary, regular, and non-remunerated blood donors (Grade C, Class IIa). Before the first transfusion, perform extended red cell antigen typing of patients at least for Rh C, c, D, E, e and Kell (K, k), and if available a full red cell pheno/genotype (Grade C, Class IIa). At each transfusion, give ABO, Rh(D) compatible blood. The goal for all blood transfusions to thalassemia patients is units that are also matched for C, c, E, e, and Kell antigens (Grade C, Class IIa). If units are optimally matched, then fresher units can be chosen over older units in less regulated blood banks but in highly regulated blood banks, a first-in first-out principle is reasonable (Grade C, Class IIb). Before each transfusion, perform a screen for new antibodies and an indirect antiglobulin test crossmatch, or in centers that meet regulatory requirements, perform an electronic crossmatch where allowed (Grade C, Class I). Use leukodepleted packed red cells. Pre-storage filtration is strongly recommended, but blood bank pretransfusion filtration is acceptable. Bedside filtration is only acceptable if there is no capacity for pre-storage filtration or blood bank pretransfusion filtration (Grade C, Class I). Use washed red cells for patients who have severe allergic reactions (Grade C, Class IIa). Transfuse every 2–5 weeks, targeting a pretransfusion hemoglobin of 9.5–10.5 g/dL (Grade C, Class I). A higher target pretransfusion hemoglobin level of 10–11 g/dL (or as high as practicable) may be appropriate for patients with heart disease including pulmonary hypertension, clinically significant extramedullary hematopoiesis, or other medical conditions, and for those patients who do not achieve adequate suppression of bone marrow activity at the lower hemoglobin level (Grade C, Class I). Maintaining pretransfusion hemoglobin at 10 g/dL is important in reducing both maternal cardiovascular stress and improving fetal outcomes in pregnant women (Grade C, Class I). Keep the post-transfusion hemoglobin below 13–15 g/dL (Grade C, Class IIa). Hemovigilance and adverse events reporting are key to the safety of blood transfusion. Keep a record of red cell antibodies, transfusion reactions, and annual transfusion requirements for each patient (Grade C, Class IIa). Uncontrolled transfusional iron overload increases the risks of heart failure, endocrine damage, liver cirrhosis and hepatocellular carcinoma in TDT (Grade C). The absolute change in total body iron in response to transfusion and chelation can be calculated from the change in LIC. The direction of change in body iron in response to transfusion and chelation can usually but not always be estimated from the trend in SF. Cardiac storage iron concentration is directly related to the risk of heart failure, which can be reliably estimated by mT2*. Cardiac iron accumulates later than liver iron, and is rare before the age of 8 years or 5 years of transfusion on those beginning regular transfusion later in life, affecting a subset of patients; while chelation of storage iron from the liver tends to be faster than from the myocardium (Grade B, Class I). Serial SF measurement is indicated in all TDT patients, to be conducted regularly at least every 3 months or at shorter/longer frequencies as needed based on iron overload level and iron chelation modification needs (Grade B, Class I). Hepatic and cardiac MRI for the assessment of LIC and mT2* should be performed annually starting at the age of 8–10 years (or earlier if feasible without sedation need). Shorter/longer frequencies can be adopted as needed based on iron overload level and iron chelation modification needs. Reading and interpretation should be done by trained staff or outsourced third-party vendors, using a validated method with appropriate calibration and MRI acquisition techniques (Grade B, Class IIa). LIC determination should be considered in patients whose SF levels are high (>4000 ng/mL) or deviate from expected trends, or when new chelating regimes are being used. LIC assessment cannot predict (or replace) mT2* assessment (Grade C, Class IIb). TDT patients should undergo regular assessment for growth, development, and organ function (including the heart, liver, and endocrine glands) as per recommendations in the respective chapters in these guidelines. Chelation therapy is an effective treatment modality in improving survival, decreasing the risk of heart failure, and decreasing morbidities from transfusion-induced iron overload (Grade C, Class I). Chelation therapy at the correct doses and frequency can balance iron excretion with iron accumulation from transfusions (Grade A, Class I). Prevention of iron accumulation using chelation therapy is preferable to rescue treatment because iron-mediated damage is often irreversible, and removal of storage iron by chelation is slow—particularly after it has escaped the liver (Grade B, Class I). Response to chelation is dependent on the dose applied and the duration of exposure (Grade A, Class I). Response to chelation is affected by the rate of blood transfusion (Grade B, Class I). Chelation therapy removes myocardial storage iron slowly (months or years) (Grade A, Class I). Chelation can reverse iron-mediated cardiac dysfunction rapidly (within weeks) by rapid chelation of labile iron, if 24-hour chelation cover is achieved (Grade B, Class IIa). The optimal chelation regimen and dosing depend on approved local indications and prescribing information of individual chelators, must be tailored for the individual, and will vary based on the current clinical situation and iron overload profile (Grade A, Class I). Overchelation increases side effects from chelation therapy, and doses should therefore be decreased as serum ferritin or liver iron levels fall (demonstrated most clearly with deferoxamine) (Grade B, Class I). Patients receiving iron chelation should be closely monitored for unwanted adverse effects and their management including dose modifications/interruptions according to local prescribing information (Grade A, Class I). Chelation therapy will not be effective if it is not taken regularly—a key aspect of chelation management is to work with patients and their families to optimize adherence (Grade B, Class I). HCT should be offered to TDT patients and their parents at an early age, before complications due to iron overload develop, if an HLA identical donor is available (Grade B, Class I). Either bone marrow or cord blood from an HLA-identical sibling can be used (Grade B, Class I). A matched unrelated donor can be used, provided that high compatibility criteria for both HLA class I and II loci are met (Grade B, Class I). Haploidentical HCT shows promising results but should be considered only in experienced HCT centers in the context of well-designed clinical trials (Grade B, Class IIb). Myeloablative conditioning regimens should always be used for standard transplantation (Grade B, Class I). Special attention is required for adult patients (Grade B, Class I). Post-transplant care should include all transplant and thalassemia-related complications (Grade B, Class I). Only thalassemia-expert transplant centers should perform HCT, always in strict connection with thalassemia reference centers (Grade C, Class I). In TDT patients, HCT is cost-effective when compared to life-long supportive therapy (Grade B, Class I). The outcomes achieved with gene therapy approaches in experimental studies, along with the initial regulatory approval of these treatments, are beginning to reshape the landscape of potentially curative options for TDT, redefining particularly the role of allogeneic transplantation. In this regard, it is critical to emphasize that pediatric patients up to the age of 14 years undergoing allogeneic HCT from HLA-identical sibling donors demonstrate excellent clinical outcomes. Within this framework, allogeneic HCT remains the preferred curative intervention and warrants thorough consideration, particularly in regions outside the USA where no gene therapy is yet commercially accessible for patients below 12 years (Grade B, Class I). Recent registry data further suggest that, in highly specialized transplantation centers, outcomes of allogeneic HCT using fully HLA-matched (10/10) unrelated volunteers are comparable to those achieved with HLA-identical sibling donors. Nonetheless, the decision to pursue HCT from unrelated registry donors in pediatric patients with TDT should be meticulously discussed with the families (Grade B, Class IIa). This discussion should encompass the potentially higher risk of immune-mediated complications associated with unrelated donors, along with the anticipated broader availability of gene addition and gene editing strategies in the near future. For patients aged 14 years and older or for those who do not have an HLA-identical family donor, gene therapy instead constitutes an optimal therapeutic option (Grade C, Class IIa): Findings from the beti-cel exa-cel registrational studies did not reveal any specific clinical characteristics associated with an improved safety and efficacy profile. Results were comparable between adolescent and adult subjects, with no observed differences in outcomes based on iron overload status, genotype, transfusion burden, or other factors. Consequently, there are no absolute indicators, within the studied population, to determine which patients should be prioritized for treatment with either one of the two products. In addition, the unique challenges posed by autologous gene therapy approaches require new frameworks that cannot be directly extrapolated from the experiences and knowledge gained through allogeneic transplantation. Beti-cel is currently available only in the USA, where it is FDA-approved for pediatric and adult subjects with TDT, irrespective of the patient's age and genotype. Exa-cel has been recently approved by regulatory agencies in Europe (EMA), North America (FDA), the UK, Bahrain, and Saudi Arabia for TDT patients aged 12 years and above, without an upper age limit. Despite the absence of age limitations, during the decision-making process, it is advisable to conduct an initial selection based on the primary inclusion/exclusion criteria used in the Northstar and CLIMB THAL-111 studies, which supported the submission for regulatory approvals. At least in the initial phases, it is recommended not to consider the treatment of patients who do not meet the eligibility characteristics defined by the registrational studies (Grade C, Class IIb): With respect to patient's age, the safety and efficacy of beti-cel was studied in clinical trials that enrolled patients between the ages of 4 and 35 years old, while the exa-cel study was conducted on patients aged 12–35 years. Within this age range, the ideal candidate is a patient who exhibits the following characteristics (Grade C, Class IIa): Significant transfusion history (at least 100 mL/kg or at least 10 units/year of packed red blood cells). Adequate control of iron overload (LIC ≤ 7 mg/g dry liver weight and mT2* > 20 ms). Normal ventricular function and respiratory function tests. Absence of significant hepatosplenomegaly. Absence of gallstone disease. Potential for effective fertility preservation. High level of personal This of patient profile is associated with the of and the risk of this of patients is most to from such an intervention due to the following A of transfusion-free years if treatment is to a risk of or of damage related to the disease. High of and of cells the need of the initial risk of and related of the of Patients with at least one of the characteristics below should also be considered for within a provided that the treatment is in centers with in TDT patients using allogeneic HCT or gene therapy approaches (Grade C, Class IIb): between 35 and years. iron overload (LIC > 7 and mg/g dry liver weight and mT2* 20 and ms). or a history of which to in the identification and long-term availability of red blood cell units that transfusion can be during treatment to to allergic reactions or side that in a rapidly of iron is recommended in TDT years) to achieve transfusion burden (Grade B, Class I). The following patient may be prioritized for treatment (Grade C, Class IIb): Patients receiving transfusion regimens packed red blood cell Patients with genotype. Patients to transfusion regimen for target hemoglobin level Patients with iron overload to iron chelation treatment dosing should local prescribing the below should be followed (Grade B, Class dose of every 3 to if patient has no in transfusion burden after at least doses weeks) of In the transfusion burden is if patient has no in transfusion burden after 3 doses weeks) of treatment duration of at least if hemoglobin is g/dL in the absence of can be when hemoglobin is if in hemoglobin is g/dL within 3 and in the absence of transfusions to to to if dose is approved for TDT patients by the the that the dose should be treatment adverse monitoring and management should local prescribing the below should be followed (Grade B, Class adverse events are with For patients who experience adverse may be the adverse may be may be patient assessment and monitoring are should be for 3 or 4 the higher of events observed in patients in the patients should be monitored for and of events and treatment risk assessment and in patients are in patients with β-thalassemia irrespective of patients with an in and blood of 5 from must be only if the blood is should be monitored before each dose may require or may be and patients should be for of were during therapy across β-thalassemia Patients should be monitored at initiation and during treatment with for and of being the most especially in or transfusion-dependent patients who are at higher risk of of transfusion during treatment of the of units the transfusion and any of transfusion response should the (Grade C, Class IIb). Patients receiving should continue to be monitored and for iron with necessary based on in the rate of iron (Grade C, Class IIb). The clinical and of with a based on available in TDT should policies and (Grade C, Class IIb). The of for TDT in the past including curative gene therapy and approaches as as approved for clinical have been met with and for a for patients chapters in the new guidelines of the development, and in therapy for these while also for further to knowledge previously the of patients are to access such This the need to and solutions for particularly those with high disease to policies for and care. strongly healthcare who these guidelines to for their full adoption and within their and their national health their practices are for early diagnosis and effective management, a of all patients, while at the time to the of healthcare which are to and health The to the staff and of the Thalassaemia International Federation and all to the “Guidelines for the Management of Transfusion-Dependent β-Thalassemia (TDT)” for their during the and development of the guidelines. contributed to and or critical from and and from and from and and from and from and and is a for and from and from and and from and are outside the The have no of to is not to this as no new data were or The is not for the or of any supporting information by the than should be to the for the