Department of Pediatrics
Weill Cornell Medicine
New York, New York
Sujit Sheth, MD, has disclosed that he has received clinical trial support from ApoPharma, Celgene, La Jolla, Novartis, and Terumo; consulting fees from Acceleron, Celgene, and bluebird bio; and serves on a clinical trial steering committee for CRISPR Therapeutics/Vertex Pharmaceuticals.
β-thalassemia is a nonmalignant hematologic genetic disorder in the family of blood disorders known as thalassemia syndromes, which are characterized by impaired hemoglobin synthesis. Historically, β-thalassemia has been termed a “benign” hematologic disorder, a label I take exception with, considering that the condition is lifelong, often carries a high treatment burden for patients, and is associated with a significant number of potential morbidities and complications that could shorten lifespan.
Spectrum of β-Thalassemia Severity and the Role of Transfusion
In β‑thalassemia, approximately 250‑350 mutations in the HBB gene encoding β-hemoglobin or its promoter have been described. These mutations cause reduced expression (ie, β+ thalassemia) or a complete absence (ie, β0 thalassemia) of the β-hemoglobin protein, with the genotype a patient carries corresponding to the severity of their disease.
Patients who are homozygous for the β0 allele (β0/β0) typically have more severe anemia and are usually transfusion dependent from an early age, whereas those with the non- β0/β0 genotype or those who are compound heterozygous for both alleles (including β+/β0 or β+/β+ or β0 or +/βE) can manifest anemia symptoms across the continuum from mild to severe depending on the level of β-globin they express. Patients with the more moderate forms of the disease with less anemia have a minimal to no requirement for regular transfusions, but may require sporadic transfusions at times of stress. Finally, carriers of either the β0 or β+ allele along with a normal gene copy are almost always asymptomatic.
The most severe forms of β‑thalassemia, those with β0 genotypes, were previously called “major” β‑thalassemia but are now referred to as “transfusion‑dependent thalassemia.” Patients with transfusion-dependent thalassemia require regular transfusions, often starting in infancy and continuing lifelong in the absence of a curative intervention. The less severe forms of β‑thalassemia, those with β+ genotypes, result in the clinical “intermedia” thalassemia syndrome, which is often not transfusion dependent. These patients may require intermittent transfusions but typically do not require regular transfusions for the rest of their lives. That said, a patient with nontransfusion-dependent β‑thalassemia may develop complications during the course of their disease and then require regular blood transfusions.
Pathophysiology of β-Thalassemia: Syndrome of Ineffective Erythropoiesis
The basic pathophysiology of the β-thalassemia syndromes results from an imbalance in the ratio of α-hemoglobin to β-hemoglobin. In the context of reduced β-hemoglobin production, excess α-hemoglobin can precipitate and form “hemichromes” with iron in the developing red blood cells (RBC), which are toxic to the developing RBC precursor and result in premature apoptosis. As such, thalassemia syndromes are not technically hemoglobinopathies because they do not produce circulating abnormal hemoglobin but instead are considered syndromes of ineffective erythropoiesis.
Depending on the degree of ineffective erythropoiesis, multiple manifestations can occur in patients with β-thalassemia. As mentioned, anemia can result from inadequate red blood cell production with associated symptoms including pale skin, weakness, fatigue, and more serious complications such as high-output heart failure. Expansion of the bone marrow as a result of erythropoietin driven erythroid expansion can cause bone issues such as thinning of the cortex and pathologic fractures and osteopenia. The liver and spleen can become enlarged from extramedullary hematopoietic stem cell expansion in those organs. Nodules of hematopoietic tissue can develop in the spine of patients with β-thalassemia, sometimes as a result of extrusion from the spinal vertebral bodies, and often cause compression on the spinal cord, pain, and radiculopathy (lumbar spinal nerve root disease), which can be quite devastating to the patient.
Iron Overload in β-Thalassemia
Iron overload is a common complication of β‑thalassemia. It typically results from the many blood transfusions patients with transfusion-dependent β‑thalassemia must undergo but can occur even in the absence of transfusion dependency. In both nontransfusion-dependent and transfusion‑dependent patients, ineffective erythropoiesis inherent to β‑thalassemia causes increased absorption of iron from the intestinal track, and without a way for the body to excrete excess amounts of iron, the iron builds up, initially in the liver. In transfusion‑dependent patients, the liver can become so full of iron that it spills out and deposits in other organs, primarily the heart and endocrine organs, resulting in the majority of thalassemia treatment–related complications.
Potential cardiac complications from iron toxicity include electrical abnormalities resulting in arrythmias (irregular heartbeat) as well as contractile dysfunction, which can result in heart failure if not treated appropriately and, even when treated, may never return to completely normal. The most common endocrine complications are related to pituitary deposition, where excess iron can impair growth and development. In the thyroid, iron deposition can result in hypothyroidism. Excess iron in the endocrine pancreas can result in impaired glucose tolerance or diabetes. When deposited in the testes and ovaries, iron can have a range of effects including delayed puberty to primary or secondary amenorrhea, testicular dysfunction, infertility, and a decrease in libido. The endocrinopathies require constant monitoring and can result in complications if untreated. The overall goal of treatment is to prevent all of these complications by maintaining iron balance and minimizing iron overload.
Historically, serum ferritin levels were used to assess iron overload in patients with β-thalassemia, but this since has been shown in multiple studies to not be a reliable indicator of total body iron. In the early 2000s, MRI technology was developed to quantify iron in tissues and has become the standard technique to assess the iron content in the liver and heart of these patients as well as in the pituitary gland and pancreas (latter 2 organs still not standard of care). The advent of MRI technology has greatly improved our ability to tailor therapy to patients, who typically receive an MRI scan annually. Patients can be monitored for iron overload by MRI more frequently if they are significantly iron overloaded and require combination chelation therapy.
Management of Iron Overload in β‑thalassemia: Iron Chelation Therapy
To remove excess iron and decrease the associated complications from its deposition in organs, patients with β‑thalassemia typically receive an iron chelation regimen after approximately 12‑15 transfusions, or in adults, approximately 20 units of blood. Until 2015, the sole chelator available in the United States was deferoxamine, which requires subcutaneous infusion over 8‑12 hours every night. Needless to say, compliance was not very good, and many of the older patients have significant iron-related complications as a result, such as heart failure requiring medication or a pacemaker, or diabetes requiring insulin. In 2005, the chelation agent deferasirox was approved and changed the landscape of thalassemia quite dramatically. This is an oral chelator taken just once daily, which resulted in improved compliance and a dramatic drop in complication rates from iron overload in our younger patients with β‑thalassemia. An additional oral iron chelator, deferiprone, was approved in the United States in 2011, with its first approval in 1994 in Europe. Today, 3 chelators are available and can be used either alone or in combination regimens. Combination therapy is primarily used for patients with severe iron overload who need a rapid decrease in iron levels.
Stem Cell Transplantation: The Sole Curative Therapy for β‑thalassemia
The only curative therapy available that can modify the natural history of β‑thalassemia is hematopoietic stem cell transplantation, with the best results being achieved when the stem cell donor is a matched family member. Matched related donor transplants, overall, have an excellent rate of engraftment and cure, with a freedom from transfusions and a reduction in iron overload and complications. Clinical trials using other types of stem cell donors have shown inferior results and are not recommended by most thalassemia clinicians.
A Shift from Pediatrics to Adult Hematology
Due to their inherited nature, thalassemia syndromes have, typically, been pediatric diseases until the era of better iron chelation and improved survival. Prior to the early 2000s, patients typically died before reaching their 30s and 40s due to heart failure or endocrine complications from iron overload, or HIV infection from transfusions, so at present it is rare to have transfusion-dependent patients with β-thalassemia who are in their 60s. However, this is changing for patients born into the era of optimal iron chelation therapy and improved safety of the blood supply: Those patients born after Year 2000 or 2002 in the United States are doing very well on their regimen of transfusions and oral chelation therapy, and are becoming adults with very few complications related to iron overload, with the expectation of near-normal lifespans as long as they are adherent to their chelation regimen.
Currently, pediatric patients are typically being followed long term by a hematologist dedicated to β‑thalassemia, such as myself, at a major academic center. However, as these patients grow into adults and start to develop the types of comorbidities common in the nonthalassemia population (eg, hypertension and diabetes), it makes sense for them to have adult providers. However, hematologists who treat adults often have little experience treating these patients. To better bridge the transition of this patient population to adult care, pediatric specialists are developing partnerships with adult hematologists in the community to ensure a smooth transition of care for the β‑thalassemia patient population.
Of note, my comments are specific to treating β‑thalassemia in the developed world. In the developing world, patients may not have predictable access to such specialty care, including limited or no access to regular transfusions and chelation therapy.
Continued Burden of Disease and Unmet Needs
Even in this new era of more effective therapy, β‑thalassemia continues to be a chronic disease with very involved treatment and monitoring that significantly affects the quality of life of these patients. Patients who are transfusion dependent have to be transfused at the hospital every 2-4 weeks and must take chelation therapy on a daily basis to maintain their iron balance and prevent complications related to iron overload. Furthermore, patients receive annual MRIs, endocrine monitoring and follow-up, and bone density assessment, often requiring treatment, all of which adds up to a substantial time and financial burden.
As such, there remain unmet needs in the treatment of β-thalassemia. There are still no approved medications that affect the natural course of this disease, whether to increase the hemoglobin levels of patients who are nontransfusion dependent and have moderate to severe anemia or to reduce the transfusion burden in those that are transfusion dependent. There is no curative therapy for patients without a matched related donor.
Emerging Therapies for the Treatment of β-thalassemia
Thankfully, there are treatments for β‑thalassemia in clinical development designed to address these challenges. For example, luspatercept, a first-in-class recombinant erythroid maturation agent, promotes more effective erythropoiesis in these patients leading to improvements in hemoglobin levels. In the phase III BELIEVE trial, this disease‑modifying therapy demonstrated significant reductions in transfusion and iron burden in transfusion-dependent patients with β‑thalassemia. There are also curative therapies on the horizon for patients with β‑thalassemia who do not have matched related donors, namely gene therapy, whether by gene insertion or gene editing approaches. Some of these trials are also in advances stages and results from clinical trials of insertional gene therapy have been excellent so far.
To learn more about β-thalassemia, including how international experts approach patient care and how promising agents may soon change practice, please join us for a live symposium (or live online simulcast) titled, β-Thalassemia: Expert Insights on New Therapies for an Old Disease on Friday, December 6 at ASH 2019. To register, please visit: http://www.clinicaloptions.com/2019OrlandoBetaT
What are your biggest challenges regarding treating your patients with β‑thalassemia? In your current clinical practice, how do you assess iron overload in these patients? Please share your thoughts in the comment box below and answer the polling question to see how others are monitoring for iron overload.
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