Pediatric Blood Disorders: Hemoglobinopathies

Beta-thalassemia and sickle cell disease involve genetic defects that have an impact on the production of hemoglobin, a vital protein that delivers oxygen throughout the body.

There are two types of thalassemia – thalassemia minor and thalassemia major, also known as Cooley’s anemia. An individual with thalassemia minor has only one copy of the beta- thalassemia gene and is said to have the thalassemia trait. People with thalassemia minor may have mild anemia (a slightly low hemoglobin level in the blood) that can closely mirror mild iron-deficiency anemia. No treatment is necessary for thalassemia minor.

A child born with thalassemia major has two genes for beta-thalassemia and no normal beta-chain gene. Thalassemia major is a serious disease. At birth, a baby with thalassemia major appears entirely normal. Anemia begins to develop within the first few months after birth and becomes more severe with the passage of time. Patients rapidly become dependent on blood transfusions.

Management of Beta-Thalassemia

Infants with beta-thalassemia are checked soon after birth (if not in utero) to see if they have a bone marrow matched sibling. Only 25 percent of young patients typically have a matched sibling.

Patients with a Matched Sibling

The standard treatment for patients with a matched sibling involves an allogeneic stem cell transplant from the sibling. This is typically most successful in children under the age of 15 who have received regular blood transfusions and chelation with a drug called deferoxamine to remove excess iron from the blood.

The Lucarelli transplant team in Pesaro, Italy, established the Pesaro Risk Group classification, which characterizes a patient’s chances of success with transplantation. The classification is based on the following factors: whether the child has an enlarged liver, known as hepatomegaly; whether the child has scar tissue in the liver, known as portal fibrosis, as determined by a biopsy; and whether chelation therapy has been successful, as determined by the patient’s iron levels.

Patients with the best results of stem cell transplantation receive this treatment in the early stages of beta-thalassemia, when they have no or minimal scar tissue in the liver and minimal iron levels in the blood.

To date, we have transplanted more than 25 patients with beta-thalassemia major at Memorial Sloan Kettering. This represents one of the largest number of transplants for thalassemia in the US.(1) More than 90 percent of these patients are doing well, and no longer need additional treatment with blood transfusions.

Patients without a Matched Sibling

For patients who do not have a stem cell-matched sibling, the standard care involves treatment with blood transfusions and iron chelation to remove excess iron from the blood.

Transfusion involves giving a patient red blood cells collected from healthy donors. While controlling the anemia, repeated transfusion therapy can cause iron overload, leading to irreversible organ damage that may involve the heart. It is important to combine transfusion with chelation therapy to counterbalance the iron overload.

We have also pioneered the first FDA-approved gene therapy trial for thalassemia in the United States. This is a new clinical trial for patients who do not have a matched sibling. This therapy begins with the extraction of a patient’s blood stem cells from circulating blood, filtering out the stem cells while returning the other blood cells to the patient. Doctors then insert a functional version of the beta-globin gene into the patient’s stem cells using a viral vector – a disabled virus that shuttles its genetic cargo into the stem cells. After receiving a low dose of chemotherapy to suppress the body’s natural production of blood cells, the patient has his or her own genetically engineered stem cells re-infused. This trial opened in 2012 and is enrolling patients from all over the world. Only a handful of diseases are currently treated with this type of gene-transfer therapy. Memorial Sloan Kettering investigators are also preparing a follow-up study to eventually treat patients with sickle cell disease in a similar fashion.

Management of Sickle Cell Disease

Patients with sickle cell disease may have different clinical symptoms during childhood than adulthood. These are primarily due to the “sickle,” or crescent, shape of the hemoglobin in the blood vessels.

Typical problems experienced by patients can include:

  • Pain in the arms, legs, or other body parts
  • Acute chest pain with respiratory complications
  • Central nervous system disease – from minor problems to a stroke
  • Making of antibodies that makes it difficult for some patients to have success with blood transfusions

Patients with a Matched Sibling

The only available cure for sickle cell disease today is with allogeneic stem cell transplantation. At Memorial Sloan Kettering, we have transplanted 15 patients with sickle cell disease. Fourteen of these patients have had long-term survival, without a recurrence of disease.

Patients without a Matched Sibling

For patients who do not have a stem cell matched sibling, this disease is usually managed with supportive care, meaning that the symptoms are either prevented or treated as they arise, without curing the disease. A medication called hydroxyurea can be helpful for some patients by decreasing the percentage of sickle hemoglobin.

For patients who have severe clinical symptoms, blood transfusions can lower the percentage of sickle hemoglobin and iron chelation can help to remove excess iron from the blood.

We are in the process of developing a new gene therapy strategy for patients with severe sickle cell disease who do not have a matched sibling. This therapy begins with the extraction of a patient’s blood stem cells from circulating blood, filtering out the stem cells while returning the other blood cells to the patient. However, the standard medication used to extract blood stem cells from circulating blood, called G-CSF, cannot be used for patients with sickle cell disease because of the severe side effects.

We are first opening a clinical trial to find out whether we can extract blood stem cells from patients with sickle cell disease with a new medication that can mobilize stem cells without causing the same side effects as G-CSF. This medication is called Plerixafor. If this approach is found to be possible, we will be able to open a gene therapy trial for patients with sickle cell disease.

As part of this trial, doctors would insert a functional version of the beta-globin gene into the patient’s collected stem cells using a viral vector – a disabled virus that shuttles its genetic cargo into the stem cells.

After receiving a low dose of chemotherapy to suppress the body’s natural production of blood cells, the patient has his or her own genetically engineered stem cells re-infused.