Optimizing chronic transfusion therapy for survivors of hemoglobin Barts hydrops fetalis

To the editor:

Hemoglobin Barts hydrops fetalis (homozygous α⁰-thalassemia) results from deletion of all 4 α-globin genes.¹  It was previously considered a universally fatal condition; however, with recent advances in prenatal care and the availability of intrauterine blood transfusions, an increasing number of patients are now surviving into adulthood.²  Similar to patients with transfusion-dependent thalassemia due to β-thalassemia (TDT-β), these patients require lifelong and regular transfusions, as the option of curative stem cell transplant may not be available for the majority of these patients. Although the Thalassemia International Federation guidelines recommend a transfusion strategy similar to TDT-β for these patients,³  no report exists on the optimal transfusion management of patients with homozygous α⁰-thalassemia, which could be referred to as transfusion-dependent thalassemia due to α-thalassemia (TDT-α). In TDT-β, initiation of transfusions results in improvement of anemia and suppression of ineffective erythropoiesis, the main underlying pathophysiologic processes.

In early 2014, we critically reviewed the treatment strategy for four patients with homozygous α⁰-thalassemia at our institution who were previously on regular blood transfusions to keep their hemoglobin levels >100 g/L. Research was approved by the institutional review board, and patients gave consent in accordance with the Declaration of Helsinki. All patients had significant splenomegaly, progressive peripheral blood reticulocytosis, and biochemical markers of hemolysis (high lactate dehydrogenase [LDH], aspartate aminotransferase, indirect bilirubin), erythropoiesis (elevated soluble transferrin receptor [STR]), and tissue hypoxia (high serum erythropoietin). In addition, 3 of the 4 showed brain magnetic resonance imaging changes in keeping with “silent” ischemic infarcts (Table 1; Figure 1).

On further investigation, hemoglobin analysis (by high-performance liquid chromatography and capillary zone electrophoresis) showed hemoglobin H (Hb H) percentage ranging from 24% to 64% in our patients, with older patients having higher Hb H. Hb H, a tetramer of 4 β-globin chains, has extremely high oxygen affinity and poor tissue oxygen delivery, making it essentially nonfunctional.^4-6  With the high Hb H levels observed in our chronically transfused patients with homozygous α⁰-thalassemia, we estimated the patients’ “functional” hemoglobin as total hemoglobin × (1 – Hb H%/100), which ranged from 42.7 to 79.0 g/L.

To improve tissue oxygenation and suppress hemolysis, we elected to modify our transfusion strategy by aggressively suppressing endogenous erythropoiesis with a goal to reduce Hb H percentage to <15% and to keep the functional hemoglobin >100 g/L in our patients. These targets were chosen to correspond to the average Hb H levels observed in patients with Hb H disease and the recommended pretransfusion hemoglobin level in TDT-β patients. To achieve these targets, 3 patients with Hb H levels of >25% also required 1 to 4 exchange transfusions (one received 1 exchange, another received 3, and the third patient received 4 exchange transfusions). One year following the implementation of the new transfusion regimen, we observed a significant and persistent improvement in all hematologic and biochemical markers of hemolysis and decreased spleen size in all patients (Table 1; Figure 1). Over the course of 1 year, the new transfusion strategy required a higher total volume of transfusion compared with the standard approach (286 [SD: 21] vs 208 mL/kg per year [SD: 14]). However, over the latest 4 months of the year-long intensive transfusion approach, the volume of transfusion decreased to 258 mL/kg per year (SD: 22) when the new steady-state targets for the total pretransfusion functional hemoglobin (>100 g/L) and Hb H level (<15%) had been achieved.

A fifth patient, male and homozygous for common Southeast Asian deletion (--^SEA/--^SEA), was born after the implementation of the new transfusion strategy and has been transfused accordingly since birth. Fourteen months into this new regular transfusion regimen, this patient has normal serum LDH, aspartate aminotransferase, unconjugated bilirubin, and STR levels but continues to have peripheral blood reticulocytosis. The patient has normal growth parameters (age- and sex-adjusted height: 58 percentile, z-score = 0.20), achieved normal developmental milestones, and, at the last follow-up, had no splenomegaly. Total volume of transfused packed red blood cell in this patient has been 251 mL/kg per year.

Despite adequate transfusion intensity based on the TDT-β approach, the homozygous α⁰-thalassemia patients showed high Hb H levels in peripheral blood and profound reticulocytosis, suggesting that these patients maintained relatively more effective erythropoiesis (in contrast to ineffective erythropoiesis in their TDT-β counterparts) that was not adequately suppressed by transfusions. This suggests that homozygous α⁰-thalassemia is a predominantly hemolytic disease with a robust erythropoietic response. This is likely due to the fact that Hb H aggregates preferentially in older red blood cells in the peripheral blood, whereas in TDT-β, unpaired α-globin chains form molecular aggregates that lead to apoptosis of erythroblasts early in the process of erythropoiesis in the bone marrow.⁷  Our patients with homozygous α⁰-thalassemia who were transfused using the TDT-β regimen had preserved erythropoiesis, leading, over time, to increased Hb H levels associated with increased peripheral hemolysis. With the high Hb H percentage, the proportion of functional hemoglobin decreased, and tissue hypoxia worsened (despite stable total hemoglobin), further inducing erythropoiesis.

Suboptimal transfusions (with associated anemia and hypoxia) and severe hemolysis have been shown to be associated with a variety of significant clinical sequelae in β-thalassemia patients and in other disorders.^8-10  Here we demonstrate that in patients with homozygous α⁰-thalassemia (TDT-α), a transfusion strategy similar to those of TDT-β patients does not adequately ameliorate the underlying hemolytic process and the poor tissue oxygen delivery over time, making this approach suboptimal for the management of these patients. Although we are yet to demonstrate any long-term clinical benefits to these patients (which would require a longer duration of regular transfusions), a more intensive transfusion regimen targeted at reducing Hb H levels resulting in an increased functional hemoglobin, reduced tissue hypoxia, and hemolysis seems more appropriate for patients with homozygous α⁰-thalassemia. Splenectomy has been associated with reduced transfusion requirements in TDT-β and improvement in hemoglobin level in Hb H disease patients with significant splenomegaly.¹¹  However, in patients with homozygous α⁰-thalassemia, splenectomy, although prolonging survival of transfused Hb A-containing erythrocytes, would likely also prolong the lifespan of endogenous erythrocytes that almost exclusively carry nonfunctional Hb H. We considered these pathophysiologic differences, in addition to the known long-term complications of splenectomy, to inform our decision not to splenectomize our patients. Recently, an international registry of surviving patients with homozygous α⁰-thalassemia has been established (Douglas R. Higgs, Oxford University, personal communication, January 10, 2014). Clinical data gathered from this registry will be invaluable in shedding light on the long-term clinical benefit of our proposed transfusion strategy compared with standard TDT-β strategy, helping to define optimal care for patients with homozygous α⁰-thalassemia.

The intensive transfusion strategy comes with a price: increased transfusional iron burden that requires escalation of iron chelation therapy, posing significant challenges with treatment costs and patient adherence. Whether these drawbacks can be offset by better longer-term clinical outcomes of patients with homozygous α⁰-thalassemia remains to be proven.