How has thalassemia been treated in the past?

Treatment: How are patients with ß-thalassemia treated?

Author: Prof. Dr. med. Holger Cario, created on: February 6th, 2012, editing: Ingrid Grüneberg, approval: PD Dr. med. Gesche Tallen, Prof. Dr. med. Ursula Creutzig, last changed: October 21, 2020

If your child has been diagnosed with ß-thalassemia, it should be registered at a specialized treatment center (Clinic for Pediatric Hematology). There is care by an experienced treatment team consisting of doctors and other employees such as nurses, social workers, physiotherapists and psychologists. The regular presentation of the sick child to such a center is very important so that the course of the disease is carefully monitored. In addition, complications can be detected early and treated immediately by specialists. The specialists can also answer your questions about new treatment methods and research results.

While children and adolescents with thalassemia minor (see “Erkrankungforms“) Rarely require treatment, both thalassemia major and intermedia, if not treated or inadequately treated, can lead to serious, sometimes even fatal, complications. However, there is no established treatment with which the cause of ß-thalassemia, i.e. the defect in the ß-globin chain gene (see “Ursachen“) Can be repaired. Therapy primarily consists of treating the various health problems that may be associated with the disease, so-called symptoms such as anemia and iron overload (see “Signs of illness"). This treatment is therefore also known as symptomatic therapy. A stem cell transplant may be necessary in some patients (curative therapy).

Treatment of anemia and iron overload (symptomatic therapy)

For the safety of the child and to avoid side effects, all therapeutic measures should always be carried out in consultation with the treatment team. They are used to treat health problems that occur in patients with severe and moderate ß-thalassemia (see “Signs of illness") may occur. Some of the measures can be carried out at home by the parents, other measures must be carried out in a specialized center. Patients with life-threatening emergencies must be treated immediately in the emergency room or as part of an inpatient stay in the hospital. The following is an overview of the symptomatic treatment measures that are regularly used for various complications of ß-thalassemia:

Treatment of anemia: transfusion program

Since the 1960s, regular lifelong administration of red blood cells (erythrocyte concentrates) in the form of blood transfusions has been an integral part of the treatment of anemia. Transfusion treatment is usually started in children with ß-thalassemia if the anemia leads to health problems (see “Signs of illness"). This usually occurs when the concentration of the red blood pigment (hemoglobin) is below a certain value (usually below 8 g / dl with individual and sometimes age-dependent fluctuations). However, a regular transfusion program is initiated even if hemoglobin values ​​have been measured regularly that are slightly above this limit, but the child's condition is impaired. During the blood transfusion, the correct amount of red blood cells must be transfused at the necessary speed. These factors are determined individually for each patient and are determined again and again during each transfusion. The doctor takes into account, for example, the age and body weight of the patient, the severity of the anemia and the amount of blood cells contained in the blood reserve.

The main goals of transfusion therapy in children with ß-thalassemia are:

  • Improvement of general well-being
  • the spread of the hyperactive bone marrow and thus skeletal changes (see "Signs of illness“) To be kept as low as possible
  • normal body growth
  • Reduction of the viscosity of the blood and thus a reduction in the risk of blood clots (thrombosis)
  • Normalization of the increased iron absorption in the intestine and thus lower iron deposition (hemosiderosis) in the organs (see "Signs of illness“)

In a blood transfusion, foreign blood is supplied to the patient's body from a donor. These donor cells were extensively tested beforehand to ensure that they were as similar as possible to the patient's blood cells. Yet they are never exactly the same. In this way, they can provoke defense reactions and other complications in the patient. Accordingly, a blood transfusion also harbors risks for the patient. Therefore, their use must be carefully and regularly weighed up anew. Doctors count any adverse event that occurs during or after a transfusion as complications of a transfusion. A distinction is made between the following complications in these so-called transfusion reactions:

Responses of the immune system (immune system) to a blood transfusion

The defense reactions triggered by one's own or, very rarely, also by the donor cells include, for example:

  • fever
  • allergic reactions such as skin wheals (urticaria), disorders of organ functions up to circulatory shock (anaphylaxis)
  • increased breakdown of blood cells (hemolysis)
  • transfusion-related lung disease
  • Donor-versus-host reaction (graft-versus-host reaction, GvH)

Other transfusion reactions

Complications that are not caused by an increased immune system are particularly communicable infectious diseases such as

The frequency of these transmissions varies from country to country. They are extremely rare in Germany. Statistics on transfusion-related infection risks are regularly published by employees of the Paul Ehrlich Institute, the Federal Institute for Vaccines and Biomedical Medicines.

Handling transfusion reactions

Treatment of complications associated with a blood transfusion may include the following, depending on the severity of the reaction:

  • fever-lowering drugs (antipyretics)
  • Measures that weaken the allergic reaction or reduce the immune system for a short time (e.g. administration of antihistamines or corticosteroids)
  • Immediate termination of the transfusion
  • Stabilization of the circulatory functions (shock treatment)
  • Anti-virus drugs

Treatment of iron overload (hemosiderosis): increasing iron excretion with medication

The increased iron intake from food on the one hand and the lifelong transfusion therapy on the other hand lead to increasing iron overload of many organs in children and adolescents with ß-thalassemia. If not properly treated, this iron overload can lead to serious, sometimes fatal complications (see “Signs of illness"). Since the body itself has no effective means of removing excess iron, drugs must be used that bind with iron (so-called iron binders or iron chelators) so that it can be excreted in the urine and stool.

Iron-binding drugs

Depending on the age of the patient, iron binders are regularly used for treatment, which are administered under the skin (subcutaneously) in the hospital (deferoxamine) or which can be swallowed at home (e.g. deferasirox, deferiprone).

Time of treatment with iron binders

When to start the administration of iron binders, the doctors decide on the basis of the following control parameters:

  • Ferritin concentration in the blood too high (in repeated blood tests, each over> 1000 µg / l)
  • Excessive liver iron content (measured using magnetic resonance imaging (MRT), or using SQUID ("superconducting quantum interference device). This is a method that measures magnetic flux.)

Treatment of the overactive spleen (hypersplenia syndrome): removal of the spleen (splenectomy)

The spleen is an organ in the upper left abdomen and part of the body's own defense system (immune system). In it, white blood cells mature into defense cells, the so-called B-lymphocytes and T-lymphocytes. In addition, overaged red blood cells and blood platelets (thrombocytes) in the spleen, as well as pathologically altered red blood cells in ß-thalassemia, are sorted out and increasingly broken down.

Goals of spleen removal

Without regular transfusion therapy started in good time (see above) the spleen in children and adolescents with ß-thalassemia begins to produce blood on its own at some point. The spleen constantly enlarges, becomes overactive and increasingly begins to break down healthy red blood cells (from blood transfusions) and healthy white blood cells. As a result, it can lead to an increased need for transfusions with increasing iron overload, increased susceptibility to infections, pain and mechanical disabilities (see “Signs of illness"). This sometimes results in the need for splenectomy in some patients with the following goals:

  • less need for blood transfusions
  • Reduction of iron overload
  • Reduction of the tendency to infections

Time of spleen removal

For whom a splenectomy (splenectomy) is indicated, as well as details of the surgical procedure, are carefully considered by the treatment team and discussed in detail with the person concerned at the appropriate time. The following factors are taken into account when deciding on a splenectomy:

  • an oversized spleen that can be felt very deep under the patient's left costal arch and causes discomfort
  • if more and more blood transfusions are needed to maintain a certain level of red blood pigment
  • the child should be at least six years old because younger children are more likely to develop certain infections after spleen removal (see below)

Consequences of removal of the spleen

The removal of the spleen can have serious consequences for the organism of children and adolescents. Therefore, the decision to remove the spleen is generally made very cautiously nowadays for all patients. The short- and long-term consequences of removing a spleen include, for example:

  • a lifelong increased risk of serious and sometimes even fatal bacterial infections, especially of the blood (blood poisoning / sepsis) and meningitis ("overwhelming postsplenectomy infection / OPSI" syndrome); this is especially true for children whose spleen was removed between the ages of 1 and 5
  • increased tendency to develop blood clots, especially in the hepatic vein (portal vein thrombosis)
  • increased risk of heart attacks and strokes after the age of 40

Prevention of the consequences of splenectomy

The prevention of health problems in patients after a spleen removal primarily includes the following measures:

  • Penicillin prophylaxis: Penicillin is an antibiotic that children with ß-thalassemia after a splenectomy should take regularly as directed by their doctor. This penicillin intake helps to prevent the severe infections caused by capsule-carrying bacteria (pneumococci, meningococci, haemophilus), to which patients are particularly susceptible after a splenectomy. If there is a penicillin allergy, other substances with a comparable mechanism of action can be used
  • Vaccinations: Patients with ß-thalassemia, like healthy children, should be vaccinated according to the current vaccination calendar. Before and after a spleen is removed, however, they must be particularly protected against bacteria such as pneumococci (pneumonia), meningococci (meningitis), haemophilus (croup, pneumonia, meningitis, joint inflammation). Therefore, certain booster vaccinations are necessary, the times of which you can find out from your child's pediatrician
  • Routine preventive examinations (U-examinations)in the childrdoctor: In the ten U-examinations and later in the J1, the pediatrician checks the age-appropriate physical, mental and also emotional development of the child or adolescent. The vaccinations also take place as part of the preventive medical check-ups. The results of the preventive medical check-ups are entered in the "yellow booklet" that was given to the parents after the birth [see yellow booklet]. In this booklet there is a pocket in which you can keep the vaccination record of the child. The "yellow booklet" with the vaccination certificate should be taken with you to every visit to the doctor
  • Temperature monitoring: Regular measurement of the body temperature helps to detect infections as early as possible and to treat them promptly. If you have a fever of more than 38.5 ° C, a doctor should be contacted immediately, as a dangerous infection could be the cause.
  • Communication with the treatment team: It is important to have the contact details of the clinic and the treatment team available at all times so that they are readily available in an emergency.
  • Infection prevention before traveling abroaden: In addition to the measures recommended by the tropical institutes etc. for the prevention of infections on certain trips abroad, additional precautions must be taken in children and adolescents with ß-thalassemia after removal of the spleen. Therefore, a trip abroad should always be discussed with the treatment team in good time. If possible, a contact address should also be available for any professional medical care required at the holiday destination

Annotation: It is best to ask your child's treatment team for further measures and details of the various precautions.

Treat other complications

Many of the sequelae of patients with ß-thalassemia are direct consequences of iron overload (see “Signs of illness"). You are through a professional treatment with iron binders (see above) as a rule to be kept under control and in some children even declining. Others still have serious complications, such as heart failure and cardiac arrhythmias, which require emergency treatment. Bone pain and increased bone fragility in the so-called osteopenia-osteoporosis syndrome (see “Signs of illness"): These complaints can also occur in thalassemia patients who receive regular transfusion treatment and appropriate therapy for iron overload (see above) receive. The treatment of these complaints is based on four pillars:

  • Avoidance of additional risk factors such as physical inactivity and smoking
  • professional treatment of underlying diseases such as blood formation outside the bone marrow (extramedullary blood formation, see "Signs of illness“) Or iron overload through regular blood transfusions or with iron binders
  • Professional treatment of the diseases that contribute to the ostopenia-osteoporosis syndrome, mostly caused by iron overload, such as diabetes, hypothyroidism and parathyroidism, vitamin D deficiency (see “Signs of illness“)
  • Treatment with so-called bisphosphonates such as aledronate, pamidronate and zoledronate, in combination with calcium and vitamin D supplements. However, this form of treatment is still in the testing phase for children and adolescents with ß-thalassemia

Stem cell transplantation (SCT) (curative therapy)

A patient with ß-thalassemia can be cured with a stem cell transplant (SCT). The typical health problems that occur in addition to anemia in children and adolescents with ß-thalassemia such as iron overload, heart problems or disorders of the hormonal balance (seeSigns of illness“) Can be treated better after an SCT and in some cases even cured. Below is some general information about SCT in children and adolescents:

What is an SCT?

During SCT, the thalassemia patient is given a blood transfusion through a large vein to produce blood stem cells (blood stem cells) that were previously taken from the bone marrow of a healthy donor. Most tissue characteristics (HLA characteristics) of the donor must match those of the patient.Before this SCT, the patient's bone marrow, in which the diseased thalassemia cells are formed, is destroyed by chemotherapy or radiation therapy so that the healthy donor bone marrow can replace it and, after a certain time, produce new, healthy blood cells. The risks and benefits of SCT are carefully weighed against each other for each individual patient before the decision is made for this treatment measure.

In which children and adolescents with ß-thalassemia is SCT indicated?

Patients with β-thalassemia for whom SCT is considered the treatment of choice are primarily children and adolescents with thalassemia major who have an HLA-identical relative donor (sibling). Unrelated donors can also be considered, but must be carefully selected according to strict criteria. The employees of central registers help with this, in which the HLA properties of voluntary donors are collected and cataloged so that a suitable bone marrow can be searched for worldwide. The chance of finding a completely HLA-identical donor in the family depends primarily on the size of the family and is currently around 30%. The difficulty of finding a suitable non-family donor is correspondingly greater. In principle, the following applies: the more HLA characteristics of the donor and recipient match, the lower the risk of rejection reactions and the greater the success of the treatment. SCT is preferably carried out in children and adolescents under the age of 16 because the treatment results in this age group, which is still less iron-laden, are better than in older patients with pronounced iron overload.

Risk factors for developing complications during and after SCT are

  • enlarged liver
  • pre-existing liver damage
  • insufficiently controlled iron exposure

The ideal patient for a successful SCT

  • is younger than 16 years
  • has a maximum of only one risk factor (see above) on
  • has an HLA-identical donor

Lifelong follow-up is necessary after SCT. In addition to monitoring possible complications from SCT such as bleeding, infections or a rejection reaction, it is also important to continue to control the iron overload in the body and to adjust the treatment accordingly. Further information on SCT, in particular on possible complications and their treatment, can be found here.

Gene therapy for ß-thalassemia major

Goal of gene therapy

With gene therapy it is possible for the first time to treat the cause of ß-thalassemia major, i.e. to correct the gene defect for life without the need for a stem cell transplant from a suitable donor. In ß-thalassemia major, a hereditary defect in the ß-globulin gene disrupts the production of hemoglobin (see also "Causes of ß-Thalassemia"). With gene therapy, a correct version of the ß-globulin gene (ßA-T87Q globin gene) is smuggled into the patient's blood stem cells with the help of a lentivirus as a means of transport - the viral vector - and thus the gene defect is repaired.

Gene therapy with ZYNTEGLO® treats severe forms of the hereditary disease ß-thalassemia. If the patient responds fully to this therapy, they can then completely forego blood transfusions.

Previous experience / previous results

A long-term curative (causal) therapy for ß-thalassemia major using gene therapy was reported for the first time in 2010 [CAV2010]. In the meantime, data are available on a larger group (cohort) of patients who were successfully treated with gene therapy using a lentiviral vector (Lentiglobin®) [THO2016]. Long-term freedom from transfusions was achieved in the majority of patients with at least one ß + allele or HbE / ß-thalassemia. In this study, patients with ß0-thalassemia achieved a significant reduction in the need for transfusions, but not a transfusion-free condition. In follow-up studies with a modified protocol, the results of which have so far only been presented at conferences and which have not yet been published, gene therapy seems to be equally successful for these patients.

Which patients are eligible for gene therapy?

So far, only patients who suffer from a blood transfusion-dependent form of ß-thalassemia and who meet the following preconditions are eligible for treatment:

  • they are at least 12 years old
  • they meet the health requirements for performing conditioning therapy
  • no suitable related donor can be found for a hematopoietic allogeneic stem cell transplatation (the presence of a suitable unrelated donor, on the other hand, is not a reason to exclude gene therapy). In that case, the advantages and disadvantages of both therapy options would have to be weighed up and discussed with the person concerned.
  • the disease is not based on the ß0 / ß0 genotype (but on a ß0 / ß + or ß + / ß genotype)

Implementation of gene therapy

Zynteglo® is a gene therapy that changes the genetic material of blood stem cells. The cells come from the patient's body and are called autologous. These blood stem cells are actually located in the bone marrow, where they are responsible for producing the various blood cells. In order to be able to obtain them more easily, they are stimulated to migrate into the bloodstream with the help of a drug, G-CSF. There they are taken from the patient's blood by means of a blood wash (apheresis). A functional gene variant, the ßA-T87Q globin gene, is smuggled into the blood stem cells of the sick person in the laboratory with the help of a virus as a means of transport - the viral vector. The changed blood stem cells are returned to the blood by means of an infusion and then migrate back into the bone marrow. There is only a one-time gift.

These genetically modified blood stem cells now enable the patient to produce sufficient quantities of functional hemoglobin. The patients are treated beforehand with chemotherapy (conditioning), currently with the drug busulfan, in order to reduce the stem cells in the bone marrow and thus facilitate the absorption of the changed blood stem cells in the bone marrow.

This eliminates the genetic defect, and in the case of a complete response, the intervention amounts to a cure.

Side effects of gene therapy

The side effects of gene therapy with Zynteglo® are - given the severity of the disease - within an acceptable range. The only life-threatening reaction in a single patient was persistent thrombocytopenia, a serious blood clotting disorder. Other serious side effects included abdominal and chest pain, pain in the extremities, shortness of breath, and reddening of the skin.

Due to the pretreatment (conditioning) of the patient, currently with busulfan, corresponding side effects can occur:

  • Occlusive hepatic venous disease (venoocclusive disease) come from the liver. The risk can be greatly reduced by giving the drug Defibrotide as a precautionary measure.
  • Since treatment with busulfan greatly reduces or completely destroys the cells in the bone marrow, it usually results in temporary anemia, a temporary shortage of white blood cells and platelets. As a result, there is an increased risk of infection and bleeding.

Against the background of negative experiences in the past, there is concern about the development of malignant blood diseases (leukemia n) with gene therapies. In the meantime, various changes have been made to the vectors in order to minimize this risk. So far, after several years of follow-up of many of the patients treated with Zynteglo®, there is no indication that leukemia is developing. In conclusion, this question can only be answered after a longer observation of a large number of patients.

Current development

The gene therapy was developed by the US company Bluebird Bio. Initially the name was still LentiGlobin, the renaming Zynteglo® took place shortly before the possible approval. The first patient was treated in 2010. In 2016 [NEG2016]. the first clinical study was published, but the effectiveness fluctuated greatly: some patients were better, others not.

Bluebird Bio then changed the manufacturing process of the lentiviral vector and the preparatory treatment of patients. A study from 2018 then showed consistently good results, which formed an essential basis for the application for approval.

In June 2019, gene therapy with the body's own (autologous) CD34 + blood stem cells that encode the βA-T87Q globin gene (Zynteglo®) was approved in the EU. The first patients have been able to be treated since January 2020.

The costs

The cost of Zynteglo® is almost € 1.6 million, to be paid in installments over five years. If the effectiveness of Zynteglo® lasts for less than five years, all outstanding payments will be waived.

Genetic counseling

As with any hereditary disease, with thalassemia there is a risk that the disease or the predisposition to it will be passed on to the offspring. How high this risk is depends on the particular inheritance path. In the case of an autosomal recessive inherited disease such as ß-thalassemia, the risk of passing the disease on to the offspring is 25%. All people in whose families ß-thalassemia has occurred before, as well as carriers of the disease with thalassemia minor and all patients with thalassemia major and intermedia (see “Disease forms“) It is therefore recommended to seek genetic counseling if you want to have children. There the risks that could arise for the child can be determined and discussed. The now sick child is also a hereditary carrier.

The recommendation to seek genetic counseling if you want to have children applies to

  • all people in whose family ß-thalassemia has occurred before
  • the carriers of the disease with thalassemia minor
  • and all patients with thalassemia major and intermedia (see "Types of Disease")

Please ask your child's treatment team about genetic counseling centers in your area.

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