The transfusion management of beta thalassemia in the United States

Abstract

The β thalassemia syndromes constitute the most frequent inherited anemia managed with chronic red cell transfusions around the world.1, 2 The prevalence of thalassemia in the United States was underestimated in past surveys that were limited only to the major specialty centers.3 Recent data show that the aggregate number of patients followed at smaller centers and community practices surpasses those at the major centers.4 A precise estimate of the total number of individuals with thalassemia in the U.S. is unavailable due to the lack of either a state or national database. Surveys have shown that 10 large thalassemia centers in the country collectively follow about 1100 patients, while additional 1500 patients are estimated to receive care at other hospitals.4, 5 The Thalassemia Western Consortium (TWC) study showed that of the 717 patients, 44% of patients had β thalassemia syndromes (including 15% with HbE β thalassemia) and 55% had various α thalassemia disorders. Transfusion-dependent patients comprised 35% of the population, 9% had received 1 or more life-time transfusions, and 56% had never been transfused. Thus, characterization of the patients reveals a diverse population consisting of multiple ethnic groups due to trends in immigration that have a wide mix of pathogenic mutations and heterogeneity of disease expression.4, 6-8 This introduces a unique challenge to developing a standardized approach to transfusion therapy for thalassemia in the U.S. The TWC is an alliance of 10 academic hematology centers in the Western region (located in California, Washington, Oregon, Nevada, and Arizona) that is supported with federal project funds to study the transfusion practices and complications in thalassemia.4 Previous data from TWC showed that important differences exist in the approach to transfusions for various types of thalassemia, targets for pre-transfusion hemoglobin level, processing of red cell units, degree of phenotypic matching, and the management of red cell alloimmunization.4, 9 The Consortium recognized the need for evidence-based recommendations for transfusions in thalassemia. However, there is a lack of clinical trials that consider the advances in supportive care in the past two decades, such as the introduction of oral iron chelators and the decline of splenectomy. In the absence of directly relevant research, the existing transfusion guidelines for thalassemia were developed by expert panels.10, 11 We convened a multi-disciplinary committee consisting of pediatric and adult hematologists and transfusion medicine specialists to develop recommendations for the transfusion management of β thalassemia (Appendix S1). The α thalassemia disorders, which include deletional and non-deletional forms of hemoglobin H disease and α thalassemia major (Hb Bart hydrops fetalis), have several unique genetic and clinical aspects7, 8, 12 that should be addressed by a separate set of recommendations for management. Here, we discuss the rationale for transfusion therapy in β thalassemia, the challenges in developing transfusion recommendations, and the sources and limitations of existing guidelines for the U.S. patient population. The transfusion recommendations are the unified opinion of the Consortium based on the multidisciplinary principles of optimizing patient outcome and satisfaction, reducing transfusion complications, and facilitating blood inventory management. These are the first recommendations directed toward hematologists and transfusion medicine specialists that are designed to specifically address concerns that are pertinent to the thalassemia population in the U.S. Beta thalassemia is caused by β-globin gene (HBB) mutations that reduce synthesis of normal adult hemoglobin molecule (HbA).13 The severity of the resulting anemia and the need for transfusion support are influenced by the nature of the β-globin mutations, compensation by fetal hemoglobin, and the imbalance between α- and non-α-globin chains.13, 14 The primary management of severe anemia in β thalassemia is the provision of adequate red cell transfusions.15-17 Chronic anemia has serious consequences for individuals with thalassemia. In children, low hemoglobin levels are associated with reduced physical activity, impaired growth, enlargement of liver and spleen, osteopenia, delayed puberty, and cognitive impairment.17-20 In adults, chronic fatigue, reduced work capacity, cognitive impairment, osteopenia and fractures, hypersplenism, and reduced quality of life are observed.21-25 Ineffective erythropoiesis is a distinctive and principal characteristic of β thalassemia, leading to anemia and massive bone marrow hyperplasia.13, 20, 26, 27 As α-globin chains aggregate in developing red blood cells due to β-globin deficiency, 60%–80% of progenitors die at the polychromatophilic stage.28-31 The erythropoietin-driven expansion of erythroid precursors and shortened red cell survival causes hepatosplenomegaly, elevated basal metabolism, extra-medullary hematopoietic masses, skeletal deformities of face and skull, and fragile bones.20, 32-35 Concurrently, the suppressed production of hepcidin increases dietary iron absorption and releases iron from body stores.36, 37 The hemoglobin threshold to suppress ineffective erythropoiesis may be higher than the level needed to alleviate symptoms of anemia.37, 38 Mutations affecting the β-globin gene which lead to either an absence of β-globin chain production (β0 thalassemia) or a variable reduction in their output (β+ thalassemia) eventually result in anemia as well as abnormal hemoglobin composition.39 HbA is reduced or absent in β thalassemia, accompanied by a variable increase in the absolute amount and proportion of HbF.40 The predominance of HbF with high oxygen affinity in the red cells makes oxygen delivery less efficient.13, 23, 41 Compared with the other transfusion-dependent anemias, individuals with thalassemia can become symptomatic with fatigue at a higher hemoglobin level and display an increase in bone marrow activity. Individual differences in adaptation to anemia are due to variability in hemoglobin composition and other unknown factors.41-43 This is particularly noted in HbE β thalassemia where HbE has normal oxygen affinity similar to HbA and contributes toward an improved tolerance to anemia.41, 44 The focus of contemporary management of thalassemia is health-related quality of life throughout the lifespan. Where studies on transfusion therapy in children have addressed key clinical endpoints (growth delay, skeletal changes, and splenomegaly), the adult studies have examined pathophysiological markers (reductions in blood volume, erythroid mass, and plasma iron turnover). Transfusion practices during childhood may impact the prevalence of bone disease and chronic pain in the aging adult patients.45 It is also likely that extending chronic transfusions to many patients with thalassemia intermedia will lead to better long-term quality of life.22, 23 However, it is not be feasible to address these critical questions through short-term clinical trials. Apart from these considerations, creating transfusion guidelines for thalassemia is impeded by other challenges. Many factors, some poorly understood, influence individual response to anemia apart from the hemoglobin level.46, 47 This introduces complexity in developing standard or uniform transfusion guidelines for all thalassemia syndromes. The 2016 AABB Red Blood Cell Guidelines48 recommending a hemoglobin threshold of 7–8 g/dl specifically do not apply to chronic transfusion-dependent anemias such as thalassemia. Red cell transfusions can sustain normal physical appearance, growth, and activity in children with thalassemia through the reversal of anemia and marrow hyperplasia.49 Likewise, adults can achieve normal functioning in the professional and personal spheres.50, 51 These are the benchmarks to judge the success of transfusion therapy in thalassemia today. However, even among the contemporary cohort of individuals with thalassemia, many are unable to receive transfusions that enable this goal. Improper targets for hemoglobin in thalassemia can lead to persistence of symptomatic anemia and bone marrow hyperplasia.38, 52 Over-transfusion is also a risk, but this appears to be much less common based upon clinical experience.4 Thalassemia is a rare disease in the U.S., and there is a possibility that treatment standards developed for other conditions (aplastic anemia, sickle cell disease, chemotherapy-induced myelosuppression) could be applied erroneously to patients with thalassemia. Although the management of thalassemia has evolved, low provider expectations for physical and professional achievement may persist due to outdated information. Furthermore, physicians often identify concern over iron loading instead of anemia as the most important management issue in thalassemia.4 Concern over donor exposure can also lead to using less than the recommended volume of blood. Transfusion guidelines for thalassemia should identity these barriers and provide solutions that can be used to educate providers and patients. In the past decade, the classification of patients into transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT) was widely adopted.10 This nomenclature has proved useful in planning the management of iron overload or making decisions about stem cell transplantation. However, these terms can potentially hide the tremendous heterogeneity of TDT and NTDT. Beta thalassemia major caused by two severe β globin mutations is the largest subgroup within TDT.53 These children usually become symptomatic during the first year of life and regular transfusions are instituted before 2 years of age.15, 42 The disease course for β thalassemia major is the best studied among TDT, and transfusion guidelines developed by various organizations are similar.5, 10 There are other forms of TDT where the application of standards developed for β thalassemia major may not be appropriate. Conceptually, these entities can be thought of as severe β thalassemia intermedia. While these patients may require intermittent transfusions during infancy, such as during an illness, the institution of regular transfusions is often delayed until 3 years or later.42 In a subgroup of thalassemia intermedia, transfusions are started in adult life in response to deteriorating quality of life or development of a complication from severe anemia.22, 23 Two main subtypes of thalassemia in this category are β thalassemia intermedia and HbE β thalassemia, which differ from β thalassemia major in the capacity for hemoglobin synthesis and adaptation to anemia (see Section 2.3).41 Guidelines for management have been published by the Thalassemia International Federation and other professional organizations.5, 10, 54-58 However, since β thalassemia major has been the principal focus of these guidelines, there are limitations in their application to the U.S. thalassemia population with its prominent genotypic diversity. In contrast with many other countries, thalassemia in the United States is observed disproportionately among the immigrant communities.6 Historically, the broad categories of ethnicities were Mediterranean and Asian (Southeast Asia and China), but to these should also be added South Asian and the Middle Eastern populations.6 There are significant proportions of patients with HbE β thalassemia and α thalassemia, where the approach to chronic transfusions is distinct from β thalassemia major.59-61 The red cell antigen disparity between donors and recipients is considerably greater due to differences in ethnicity, which amplifies the risk of alloimmunization.9, 62, 63 On the other hand, the assured availability and safety of blood supply in the U.S. has led to an earlier adoption of chronic transfusions in more patients with β thalassemia intermedia and HbE β thalassemia compared with other countries. The gradual decline of splenectomy in thalassemia major has had a significant impact on transfusion management. An association between higher pre-transfusion hemoglobin levels and decrease in the rate of splenectomy has been documented.52, 64-66 This supports the clinical observation that development of splenomegaly in thalassemia is the consequence of maintaining low hemoglobin levels. Aiming for lower pre-transfusion hemoglobin can be counterproductive as it promotes splenic enlargement with a secondary rise in transfusion needs.19, 52 Caution is needed when referring to older transfusion guidelines developed in an era when most adults with thalassemia were splenectomized. Transfusional iron overload is the most important complication of red cell transfusions in thalassemia, and the iron loading rate affects the efficacy of chelation therapy.15, 16, 67, 68 Until the availability of oral agents, the only available iron chelator was deferoxamine, which was difficult to use and had significant toxicity in young children.69-71 These concerns about iron overload influenced the development of guidelines for transfusion therapy.49, 72 The management of iron overload has been transformed with the availability of oral chelators deferasirox and deferiprone, and the development of novel chelation regimens.40, 73 In current practice, transfusion volume and frequency should be selected based on the need to correct anemia and suppress marrow hyperplasia. A suitable chelation regimen can then be devised to maintain iron overload in the safe range. Ever since it was recognized that regular blood transfusions prolong the survival of children with β thalassemia major,17 there were efforts to identify patients who should be placed on transfusions. Additional concerns included delineating optimum hemoglobin target and specification of RBC units and creating safe transfusion practices in individuals projected to have a normal life expectancy. Table 1 summarizes the pathophysiological and clinical features of β thalassemia that underlie these recommendations. The decision to initiate transfusions attempts to balance consequences from anemia and ineffective erythropoiesis against complications of chronic transfusion therapy.19, 49, 74-79 The paradigm of an infant with severe, symptomatic anemia who requires transfusions for survival served as the historical foundation of transfusion guidelines for β thalassemia major.17, 74, 79 These high-risk infants have a combination of β0 and/or severe β+-globin gene mutations and should be identified through newborn screening. Early access to specialty care is essential so that the decision to commence transfusions can be made at the appropriate time to support normal growth and development (Table 1).66, 80, 81 Nearly 50% of such infants receive their first transfusion by 6 months and 80% by 12 months of age.42 When patients identified through newborn screening have care established before the development of severe symptoms, the time to initiation of transfusions is expected to be shorter. Conversely, when affected individuals preserve significant endogenous hemoglobin synthesis, the decision for starting transfusions can become complex.22, 23, 61, 82 Such patients have thalassemia intermedia and can survive without being transfused at regular intervals. In the past, despite the compromised growth and quality of life,83 it was felt that the consequences of a lifetime of regular transfusions were more serious.22, 23 Since many complications are delayed until adult life (chronic pain, fractures, thrombosis, and pulmonary hypertension),22, 23, 25, 84, 85 physicians making the initial decision to withhold transfusions from patients with thalassemia intermedia are disconnected from those who manage them as adults. The use of splenectomy in children to avoid transfusions has been a particular predicament as the risk of several serious complications becomes manifest only later in adult life.21, 24, 62, 65, 86-91 Over the past 3 decades, the long-term consequences of withholding transfusions from patients with severe thalassemia intermedia have become apparent, and this experience is being used to guide the development of the current standards of care.22, 23, 84, 92 These patients should be seen at 3–4 month intervals to determine whether it is appropriate to continue follow up without transfusions (Table 2). The intensity of transfusion therapy for thalassemia is evaluated using the pre-transfusion hemoglobin level. There has been an evolution of the target hemoglobin over the years to balance improvement in anemia and ineffective erythropoiesis with transfusional iron overload 5, 10, 49, 72, 93 An adequate pre-transfusion hemoglobin level was initially estimated by improvement in growth and activity in young children,17, 18, 79 which led to regimens that maintained hemoglobin above 9 or 9.5 g/dl.19, 49 More intensive regimens that kept the pre-transfusion hemoglobin in the normal range (>12 g/dl) were developed,93, 94 but concern for greater iron overload from increased blood use prompted moderation of the hemoglobin target.19, 49, 72 Prevention of splenomegaly should be the goal of an effective transfusion regimen, thereby mitigating the adverse effects of potential splenectomy. Another approach to determine the adequacy of transfusions is the suppression of marrow activity, which is achieved by maintaining pre-transfusion hemoglobin between 9 and 10 g/dl.37, 38, 95 Reticulocyte count does not have a consistent relationship with pre-transfusion hemoglobin, though circulating nucleated red blood cells are suppressed at higher hemoglobin levels.38 In general, children respond well with mean pre-transfusion hemoglobin 10 g/dl and a range of 9.5–10.5 g/dl, which prevents splenic enlargement and skeletal changes while promoting normal growth.49, 65, 96, 97 Certain patients who experience significant fatigue or skeletal pain toward the end of the transfusion cycle may benefit from a higher hemoglobin target. Individuals with severe β thalassemia intermedia and HbE β thalassemia may initially require only intermittent transfusions, often during an illness causing acute worsening of the baseline level of anemia.22 The institution of regular transfusions for these groups may be delayed until children are older than 3 years, or even later until adulthood as a response to deteriorating quality of life or complications listed in Table 2.22 Many such patients may tolerate a less intensive regimen using a lower pre-transfusion hemoglobin range of 9–10 g/dl. The volume of blood transfused is influenced by the interval between transfusions, with those on a 4-week schedule receiving a larger volume compared with those on a 3-week schedule to attain a similar pre-transfusion hemoglobin target.49 Transfusion volume also depends upon the type of storage solution, since red cell units stored in additive solution have lower hematocrit.98 The effect of the pre-transfusion hemoglobin target on the transfusion volume is not clear in the current era where splenectomy is no longer a frequent procedure.93 Maintaining a higher hemoglobin can reduce the intravascular volume to allow a greater post-transfusion hemoglobin increment from a unit of RBC.52, 99, 100 On the other hand, low pre-transfusion hemoglobin levels can cause a poorer post-transfusion increment through enlargement of the spleen and expanded peripheral and bone marrow intravascular space. In current practice, when most patients retain their spleen, the pre-transfusion hemoglobin level to achieve the optimal balance between post-transfusion increment and iron loading is not well defined. The interval between transfusions will determine the amplitude of change in hemoglobin from the peak post-transfusion value to the level before the next transfusion. A study in adults receiving chronic transfusions for myelodysplastic syndrome linked lower hemoglobin amplitude to better quality of life,101 but more frequent transfusions create inconvenience for patients and also burden the health system. The rate of blood administration is of great relevance to outpatient RBC transfusion programs, as patients and providers share an interest in the shortest duration of transfusion that is safe. A rate of 5 ml/kg/h has been traditionally used in patients without cardiovascular compromise, which allows transfusions to be completed in a half day. In adults, a rate of administration up to 1 unit per hour can be tolerated. Volume of transfusion at a single visit is usually limited to a maximum of 20 ml/kg, though higher volumes have been used.79 These recommendations are summarized in Table 3. Regular RBC transfusions present substantial risks to individuals with thalassemia that are additive due to the repeated lifelong exposure.4, 9, 76, 102 Transfusion reactions, ranging from mild to fatal, can compromise the management of thalassemia. Several donor parameters impact the efficacy of transfusion (hemoglobin increment), such as donor age, sex, and hemoglobin concentration.103 Leukoreduction is essential to prevent febrile non-hemolytic transfusions and should be done by filtration in the pre-storage period.104 When citrate phosphate dextrose-adenine is used as the anticoagulant-preservative the of the unit is and the volume More units are stored with additive solutions which longer life but have lower of and higher volume of units are not recommended for transfusions in adults due to smaller hemoglobin who should be units using a that of of or to transfusion is a less to for patients on chronic The of the unit at transfusion is an important due to the impact of the storage on red cell In this chronic transfusion regimens differ from acute transfusions where hemoglobin increment at is the primary and by the of It is not RBC is in thalassemia with increased of RBC in the spleen, or the increase in iron is duration has a impact on hemoglobin to next which potentially increases transfusion need and iron Although transfusion of RBC unit may be it be with the need for inventory management and of rare blood Where RBC units for transfusion in thalassemia should be use and should not have to to There is a concern over the impact of storage and on RBC of the to RBC in the transfusion is as is the potential for increased splenic of red cells with and low of RBC units for thalassemia is and but more common with the adoption of of blood by The of is for quality of transfusions in thalassemia where most donor and are Prevention of red cell is an important goal of transfusion management in However, blood availability can the is to provide blood to all patients. Since and are the most common observed in 9, 62, 63 the of can be by provision of there is a lack of about for the of alloimmunization.9, who develop are at high risk for developing and/or an 9, These patients should receive RBC units with phenotypic and is essential for all patients, since an can become with time in the absence of with a of continue to receive blood to prevent acute and delayed transfusion RBC should be as of the initial of a patient who may require transfusions. RBC is feasible for transfused patients and has the of It is also a useful when the development of an to a rare or common antigen or in the of an such as an or The development of consisting of donors with RBC will access to red cell units for patients with multiple (Table Thalassemia is a rare disease in the U.S. where the for management is in specialty centers in a large It is recommended that transfusion therapy should be directly by a with in thalassemia. Where this is not due to the from a specialty the transfusion should be devised and by a with in thalassemia. for stem cell should be the is and disease should be where appropriate. It is to develop for patients receiving regular RBC transfusions to optimal long-term In the absence of a national blood health several for and quality in transfusion The for use of RBC units should be identified as thalassemia for between and blood An of transfusion volume at visit be which can be then used to transfusion and iron loading of iron overload should be evaluated with the first 6 months of transfusions. When patients are transfused at multiple be from other and in The lack of a recipients of chronic transfusions is a serious as patients may receive transfusions at multiple for to changes in of care to adult to a for transfusions, and for or receiving regular or intermittent transfusions should be into a or which can then be to develop a national database. Such an should be by federal health as a for transfusion management of thalassemia, sickle cell disease, and other transfusion-dependent The of for critical and on the The to for support to the Thalassemia Western Consortium and with the of This project is supported by the for and Prevention of the U.S. of and as of a with with The are those of the and do not the an by or the U.S. This project is supported by the and of the U.S. of and as of an with with The are those of the and do not the an by or the U.S. more visit The have no of The is not for the or of by the than should be directed to the for the

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