Treatment Options
Overview
Corticosteroid therapy involves taking a prescription steroid medication, such as prednisone or prednisolone, that may cause the patient’s bone marrow to create red blood cells. To date, the mechanism of how or why steroids cause the bone marrow to make red blood cells in some patients with DBA syndrome is not understood. The goal of steroid therapy is to ensure the patient maintains a hemoglobin level of 9 g/dL or higher with minimal side effects.
Steroid Trial, Tapering, and Maintenance Dose
The recommendation for corticosteroid therapy is to start after the patient’s first birthday and at least 3 weeks after the administration of live vaccinations (e.g., chicken pox and measles, mumps and rubella). Steroids may be started the day after a transfusion or may be delayed to start about 10-14 days after transfusion. The beginning dose is 2 milligrams (mg) of prednisone or prednisolone per kilogram (kg) of patient weight per day (2 mg/kg/day). Initially, the dose is typically divided, given half in the morning and half in the evening. For example, if a patient weighs 10 kg (approximately 20 pounds), the patient will start with an initial dose of 20 mg of steroid medication per day and would take 10 mg in the morning and 10 mg in the evening. For an adult patient starting a steroid trial, the maximum starting recommended dose is 80 mg per day.
Patients continue on the high dose of steroids for a maximum of 4 weeks, but extending the initial dose beyond 4 weeks is not generally recommended. If the patient is going to be a steroid-responder, the usual response to steroids is an increase in the hemoglobin and reticulocyte count within 2-4 weeks. Typically, labs (CBC and reticulocyte count) will be drawn 10-14 days after starting steroids. Once a response is noted, the patient should begin a steroid taper. Various doctors may approach the weaning process differently, but many recommend decreasing the dose by 0.5 mg/kg once every 2 weeks until 0.5 mg/kg/day is achieved. Tapering should then very slowly decrease to the recommended maximum maintenance dose of 0.3 mg/kg/day (or 0.6 mg/kg every other day). If the response is lost during tapering, the dose should be increased to the dose at which the hemoglobin was at least 9 g/dL. It is important for patients and families to remember that the weaning process should be conducted very slowly and methodically. This can be frustrating, but it is necessary to avoid losing the steroid response by weaning too rapidly. If the hemoglobin cannot be maintained at 9 g/dL or greater on 0.3 mg/kg/day of steroids or less, then the steroid trial is considered a failure and steroids should be discontinued. A second steroid trial may be considered 1-2 years later.
Generally, a sustainable, long-term dose of steroids should not exceed 0.3 mg/kg/day or 0.6 mg/kg every other day. Some doctors may choose to wean the patient to 0.2 mg/kg/day. Ideally, the lowest dose possible is best for the patient’s growth if the patient is a child. The maximal adult dose is 10-15 mg/day. Of course, these are only general guidelines. It is important to remember that each patient must be assessed individually, with the steroid therapy goal being to allow the DBA syndrome patient to make his/her own red blood cells while having as “normal” of a life as possible without side effects.
Statistics about Steroids
According to the Diamond Blackfan Anemia Registry (DBAR), 82% of patients initially responded to steroids; 16% of patients were steroid non-responsive and continued transfusions; and 2% of patients never required treatment with steroids. Currently, about 45% of patients in the DBAR are on steroids. Although patients may initially respond, some patients will stop taking steroids for a variety of reasons, including too high of a dose required, to address growth issues, or because of other side effects. Of those DBA syndrome patients who completed steroid trials, 30% are currently receiving chronic blood transfusions; 32% were never steroid responsive; 17% became steroid refractory (lost response); and 49% could not be weaned to an acceptable dose of steroids.
Side Effects
Parents and patients are often concerned about the side effects of steroids. Patients may react differently and may have many, few, or none of the following short-term side effects:
- Upset stomach (always take with food or milk)
- Increased hunger
- Behavioral changes, such as fussiness, irritability, and inability to sleep
- Increased risk of infections, including pneumonia, thrush (ie., a white coating in the mouth), and other yeast infections
- Delayed or poor wound healing
- Weight gain
- Salt and water retention
- High blood pressure
- Cushingoid features (i.e., increased fat on face leading to a rounded or “moon facies”, upper back, and belly) in 40% of patients
- Stretch marks on the skin
- Acne
- Increased and unusual hair growth
- Increased blood sugar in the body
- Pathologic fractures in 12% of patients
- Cataracts in 7% of patients
Possible long-term side effects (i.e., taking steroids for more than three months even in low doses), may include all of the short-term side effects listed above, as well as the following:
- Poor growth in children (may be severe)
- Osteopenia and osteoporosis (ie., brittle bones) or problems with joints
- Adrenal insufficiency
- Muscle weakness
- Diabetes
- Problems with eyes, including cataracts and glaucoma
Patients on long-term steroid therapy should be routinely followed by an endocrinologist who will monitor for adequate adrenal insufficiency, growth in children, bone density, diabetes, and more.
Complimentary Medications
When patients are on steroids, specific additional medications should be taken to avoid or treat certain side effects:
- Antibiotics: On high doses of steroids, it is recommended to take a prophylactic (preventative), combination antibiotic called sulfamethoxazole and trimethoprim (also known as Bactrim or Septra). This will help prevent a certain type of pneumonia called pneumocystis pneumonia, caused by Pneumocystis jirovecii (PJP).
- Anti-fungals: Anti-fungal medication, such as nystatin, is used to treat yeast-based diaper rash or thrush and is usually taken as needed.
- Acid reflux medication: It is recommended that patients take an acid reflux medication to prevent stomach problems while on steroids. Some common brand names include Pepcid (famotidine), Prevacid (lansoprazole), and Prilosec (omeprazole).
- Vaccines: Patients taking high doses of steroids should NOT get live vaccines, such as chicken pox (varicella) and measles, mumps and rubella (MMR). If given vaccines while on high-dose steroids, the patients may not build an adequate immune response and vaccines may need to be repeated in the future. Ideally, patients should receive live vaccines at least 3 weeks prior to starting a steroid trial.
- Bone health medications: All patients on steroids should consider taking vitamin D daily to assist with good bone health. Often, calcium supplementation may be needed as well.
Complimentary Medical Care
The overall health of a DBA syndrome patient on long-term steroids should be carefully monitored. Recommended medical monitoring includes:
- Annual vision exams to check for cataracts.
- Dental visits twice yearly. Some DBA syndrome patients report high levels of tooth decay and tooth loss.
- Baseline dexascan, which is a special x-ray used to determine the strength of the bones, to monitor future bone loss. This can usually be done after age 5 years, or when the child can remain still for the x-ray without anesthesia.
- An endocrinologist is a doctor who specializes in the endocrine system and hormones of the body. This specialist should monitor patients on steroids, beginning during the steroid taper to watch for adrenal insufficiency. Routine endocrinology evaluation should continue every 1-3 years depending on growth. An endocrinologist should monitor for any issues with growth and development while taking steroids, as well as watch for bone loss or diabetes. An endocrinologist can also help if steroids have been taken for long periods and the patient wants or needs to stop taking them.
- Receive a flu shot every fall. Everyone in the patient’s home is recommended to also receive a flu vaccine.
- Avoid people with viral infections, such as measles or chicken pox.
Effects on Puberty
Puberty is a time of considerable chemical and physical body changes. These changes may affect the patient’s responsiveness or unresponsiveness to steroids. This is a time when DBA syndrome patients should be carefully monitored not only for their blood counts, but for adequate growth. Some patients may need to take a “steroid holiday” (i.e., a break from steroids) during adolescence to reach their growth potential. Girls must be careful during puberty as estrogen may decrease the steroid response. For that reason, girls and women requiring oral birth control pills for regulation of their periods or for contraception should only use non-estrogen-containing medications. Progesterone only medications do not usually affect the hemoglobin levels.
Effects on Pregnancy
Women taking steroids who become pregnant should be carefully monitored. Steroid-responsive pregnant women may require an increase in steroid dose, or even transfusion therapy during pregnancy. The potential for steroid toxicity on the mother and the unborn child should be carefully monitored and patients may be advised to stop steroids and switch to transfusions during pregnancy. Often transfusion therapy is required to maintain a hemoglobin level of 10 gm/dL during pregnancy.
Blood Transfusion Recommendations and Overview
Blood transfusions are a common treatment for patients with DBA syndrome and may be recommended either on an as-needed basis when the hemoglobin is lower than normal, or as part of a chronic blood transfusion program. Chronic blood transfusions typically consist of scheduled transfusions every 3-6 weeks to maintain the hemoglobin level in a safe range. The current recommendation is for hemoglobin to be maintained at a level of at least 9-10 g/dL at all ages for sufficient growth, development, and quality of life. This is typically achieved with 10-15 mL/kg of red blood cells in children or 2-3 units of blood in adults. Some patients may require a higher level of hemoglobin for quality of life and this should be determined on an individual basis with a doctor experienced in DBA syndrome. Most DBA syndrome patients make their own white blood cells and platelets, and therefore, usually only require transfusions of red blood cells.
Blood transfusions are typically given in a hospital setting. Before a transfusion, a small amount of blood will be drawn from the patient for “type and screen” testing. Typing refers to the type of blood the patient has (A, B, AB, or O) and screening refers to identifying the presence of certain antibodies. Generally, people must receive blood of their same type to avoid severe transfusion reactions; however, all blood types may also receive type O blood. These tests are followed by the compatibility testing ("cross-match"). This test ensures that no antibodies are detected in the recipient’s serum that will react with the donor’s red blood cells.
Safety of Donated Blood
Generally, when patients receive a blood transfusion, they receive blood that has been donated from the general population. In the United States, the blood supply is considered safe. The Food and Drug Administration (FDA) is responsible for ensuring the safety of the blood donation industry.
The FDA has established five levels of overlapping safeguards for the industry:
- Donor screening: Potential blood donors must answer questions about their health history and lifestyle. Donors whose blood may pose a health hazard are encouraged to exclude themselves. If a donor’s history suggests that he/she might pose a risk to the blood supply, blood donation will be denied for that individual. Furthermore, a potential donor can be temporarily deferred for a number of reasons, including having a fever, cold, cough, sore throat, taking certain medications, or traveling outside the United States. Additionally, potential donors can be permanently excluded from donating blood if there is evidence or history of HIV infection, intravenous drug abuse, or viral hepatitis among other reasons.
- Donor deferral lists: Blood donation establishments must keep a current list of deferred donors and cross check donor names against the list, not accepting blood from anyone on that list. In addition, each donor goes through the same rigorous process each time they donate. If his/her history or health conditions change, each blood bank has policies for tracking these donations.
- Blood testing: After donation, the blood is tested for bloodborne agents, including HIV, Hepatitis B, Hepatitis C, syphilis, Human T-cell lymphotropic virus, West Nile virus, and Chagas disease. Blood that tests positive for any of these illnesses, or is suspicious for any reason, will be destroyed.
- Quarantine of untested blood: Blood products are not available for general use until the products have been thoroughly tested and proven to be free of infectious diseases.
- Problems and deficiencies: Blood establishments must investigate any breaches of safeguards and correct deficiencies. Any manufacturing problems, errors, or accidents that may affect the safety, purity, or potency of blood products must be reported to the FDA. Furthermore, establishments are required to maintain accurate records for the FDA to review during an annual inspection.
For more information on the blood donation process and safeguards, read the following: FDA Safeguards.
Directed Donors
Some patients and their families elect to use “directed donors.” Directed donors are typically family members and friends with the same blood type as the patient who donate their blood specifically for use by the patient. Some patients and their families feel better about receiving blood from a smaller, known group of individuals, rather than from the general population.
Although directed donation programs are available in most areas, there are some disadvantages to using directed donor blood. Most importantly, blood donated by a very close family member may result in immunologic complications for the recipient, such as transfusion-associated graft-versus-host disease or transfusion-related acute lung injury. Additionally, in the event of a stem cell transplant, complications caused by the development of antibodies against the family member’s blood could prevent that family member from acting as a stem cell donor. Because of these possible complications, immediate family members should never donate blood to the patient.
Directed donor units of blood must go through the same screening processes that volunteer donations do. Therefore, medical research has shown that blood from directed donors is not any safer than blood from volunteer blood donors. Since donors may only donate one unit of blood about every 2- 3 months, multiple directed donors would likely be needed to provide blood for one patient. There may be additional medical charges for this service, which are often not covered by insurance, so the patient may incur these extra charges. Anyone interested in directed donors should discuss this option with their hematologist and/or local blood bank.
IV Access Problems and Solutions
It can be very difficult to start an IV in an infant or a patient who receives chronic transfusions. Some potential solutions include the following:
- IV access team: Many hospitals have a team of nurses who are especially skilled at starting challenging IVs. These teams can often use ultrasound imaging to see the veins and guide the needle placement. In some hospitals, this team is referred to as the vascular access team or “VAT”. In other hospitals, a neonatal nurse may be used. It may be helpful to ask the hematologist whether the hospital has any such skilled nurses. Sometimes there is a long wait for these nurses, but it is worth the wait to avoid multiple failed needle sticks. Do not be afraid to ask for this service if it will benefit your child.
- Intravenous access devices: Some patients who receive chronic transfusions may opt for a device to make the transfusion process easier. Intravenous access devices can be entirely placed beneath the skin (i.e., port) or part of the line may remain externally. While these devices can be beneficial, complications may occur, including infection, thrombosis (i.e., blood clot in the catheter), failure of the device, and infiltration.
- Port: Ports are small medical devices that are installed completely beneath the skin and have a tube that is connected directly to a large vein. A port has a septum which is accessible through the skin, usually with less pain than a typical needle stick. The septum is used for drawing blood samples, giving blood transfusions, and/or for giving medications. Common brand names of ports include Port-a-Cath, Microport, Bardport, PowerPort, PASport, Infuse-a-Port, and Mediport. Ports are surgically inserted in the patient’s upper arm or chest and typically require general anesthesia to insert. DBA syndrome patients should ask their physicians if they recommend a port made without any metal components. This will enable the patient to have full access to any tests for iron levels in the body, such as T2* MRI.
- Central venous catheters (CVC): Another type of intravenous access device is a central venous catheter (CVC). This is a temporary IV line that is placed either into a vein through the patient’s chest (i.e., central line) or arm (i.e., peripherally inserted central catheter or “PICC line”). Unlike a port, part of the catheter remains outside of the body. Like a port, the catheter is used for drawing blood samples, giving blood transfusions, and/or for giving medications. The catheters must be carefully protected when showering and cannot be submerged in water, such as for baths or swimming. Common brand names of catheters include Broviac and Hickman lines. Catheters are also surgically placed in the patient’s chest and may require general anesthesia for insertion. In older patient’s, a PICC line can be placed in the arm without sedation.
Complications
A major risk of chronic blood transfusion therapy is accumulating too much iron in the body (i.e., iron overload). Every cubic centimeter of blood contains 0.5 milligrams of iron. A person without DBA syndrome can use iron from destroyed red blood cells to create new red blood cells. However, a person with DBA syndrome cannot typically make many of his/her own red blood cells and this extra iron cannot be used. When a patient with DBA syndrome receives transfusions, the iron contained in the donated red blood cells goes into the body where there is no mechanism for removing excess iron. This excess iron gets stored in the organs, and if not removed, it will slowly destroy those tissues. Iron overload and organ damage can begin with as few as 10 – 20 transfusions. Therefore, it is critical for the health of a DBA syndrome patient receiving blood transfusions to monitor iron levels in the body. Medications, known as chelation drugs, are available to help remove the excess iron from the body. You will find more information about these medications in the section titled Chelation Therapy.
Recommended Labs
Iron overload can affect many organs and tissues, including the thyroid, heart, pancreas, gonads, and pituitary gland. Given its effects on the endocrine system, iron overload can also impact growth and cause diabetes. In addition to annual T2* MRI/FerriScan, the following lab tests are recommended in transfusion-dependent patients to help monitor and prevent the devastating effects of iron overload:
- Total T3
- Total T4
- TSH
- T3 uptake (instead of free T4)
- IGF-1 (monitors acute fluctuations in insulin action and determines inadequate insulin treatment or poor control of dietary intake)
- NT-proBNP (aids in diagnosis of left ventricular dysfunction in heart failure)
- Antithyroid Abs (antithyroglobulin and antithyroperoxidase)
- Fructosamine (useful in situations where the A1C cannot be reliably measured – as with transfused persons)
- Vitamin D
Iron Overload in DBA Syndrome Patients
Chronic blood transfusions are a mainstay treatment for many DBA syndrome patients. The biggest risk with transfusion therapy is accumulating too much iron in the body. One unit of blood contains about 250mg of iron, which would be equivalent to eating 86 lean 3oz steaks. In a person without DBA syndrome, iron is necessary to make hemoglobin, an essential part of the red blood cell that carries oxygen. However, in an individual with DBA syndrome, the body does not produce its own red blood cells and thus, is unable to naturally get rid of excess iron. Iron contained in blood transfusions goes straight into the body’s circulation. About 70% of the iron transported is incorporated into the hemoglobin inside red blood cells. The remainder is stored in the tissues as mainly ferritin or hemosiderin, with small amounts used to produce myoglobin and enzymes. In a person with DBA syndrome, the iron continues to build up (i.e., iron overload) with chronic transfusions, eventually accumulating to toxic levels, depositing into organs, and causing organ damage. The most commonly affected organs include the liver, heart, and pancreas. Some specific complications include:
- cirrhosis or fibrosis of the liver
- cardiac arrythmias, which can be fatal
- diabetes
- reproductive organ failure
- growth stunting
- endocrine failure affecting the thyroid
Iron overload remains the leading cause of death in patients with DBA syndrome who do not undergo stem cell transplantation. Fortunately, iron overload and organ damage can be prevented with chelation therapy. Food restrictions of iron are unnecessary in preventing iron overload; however, supplemental vitamins should be avoided.
Tests to Monitor Iron Overload
Accurate estimates of iron overload are crucial for guiding chelation therapy. There are various tests used to monitor iron levels, including:
- T2* and FerriScan (R2-MRI): These tests are special types of MRIs that reliably measure iron content in the heart and liver (LIC). These tests are considered very accurate and non-invasive, but young children may require anesthesia in order to remain still for the 30-minute test. The target LIC for transfusion-dependent patients with DBA syndrome should be as close to normal as possible (1 mg Fe/g) and should not exceed 3 mg Fe/g. Likewise, the target cardiac T2* should be as close to normal as possible, with a range of 20 – 35 msec being acceptable. These tests are not available at every medical center. To find locations which offer the FerriScan MRI, see: Resonance Health and FerriScan or ask your doctor about hospitals offering T2* scans.
- Serum ferritin: Ferritin is an iron-containing protein and the primary form of iron stored inside of cells. This test may give a general idea of how much iron is in the body; however, it is not a reliable test to determine iron overload in patients with DBA syndrome. The serum ferritin test may be inaccurate as ferritin is considered an acute phase reactant. This means it can be easily increased with any stress in the body, such as a cold, other illness, or injury. Some physicians may monitor serum ferritin levels over time to watch for trends, but it should not be relied upon without other testing. Acceptable ferritin levels are typically no more than 1000-1500 ng/mL.
- Transferrin: Transferrin is the main protein in the blood that binds to iron and transports it throughout the body. The amount of transferrin that is available to bind to and transport iron is reflected in measurements of the total iron binding capacity (TIBC), unsaturated iron binding capacity (UIBC), or transferrin saturation.
- Total iron-binding capacity (TIBC): This test measures the ability of the blood to attach itself to iron and be transported around the body. If you have too much iron, your iron level will be high, but your TIBC will be low. This test is often used in combination with serum ferritin, and sometimes with transferrin saturation, to monitor for iron overload.
- Transferrin saturation: This value shows how much serum iron is bound in the blood. For example, a transferrin saturation of 25% means that 25% of the iron-binding sites of transferrin are occupied by iron. A high value may indicate iron overload. This test is often ordered in combination with TIBC and serum ferritin.
- SQUID test: SQUID, which stands for super conduction quantum interference device, is a special type of scan that uses magnets to show much iron is in the liver. This test is very accurate and non-invasive. The SQUID test requires the patient to lie still for a 10 – 15-minute procedure. The SQUID test is currently only available in very few locations around the world. For more information on the SQUID test, see: UCSF Oakland SQUID.
- Liver biopsy: A liver biopsy is the most accurate test to measure the amount of iron in the liver, but it is invasive. Patients are typically sedated during the biopsy, which consists of inserting a needle into the liver and removing a small piece of liver tissue. This tissue is then tested to determine the amount of iron present. The tissue can also be analyzed to see if the iron has caused any damage to the liver, such as fibrosis or cirrhosis.
Treatment of Iron Overload
Iron overload can be prevented and treated with chelation therapy. Chelation therapy involves using medication to remove excess metals, such as iron, from the body. Since the body has no natural way of removing excess iron, chelation therapy is the only way to remove the iron. Therefore, chelation therapy is a critical component of the health and well-being of a DBA syndrome patient receiving chronic blood transfusions. The following chelation drugs are available in the United States:
- Exjade/Jadenu (deferasirox): Exjade and Jadenu are the same medication, only different brand names. This medication is an oral chelator that works by binding to iron and removing iron from the body through the stool. The dose of this medication is 20 mg/kg daily. It is important to take this medication every day, as every missed dose is a day that iron is causing damage. Exjade tablets are dissolved in water or juice and taken once per day on an empty stomach, preferably at the same time every day. Jadenu may either be dispensed as tablets to swallow or sprinkle granules to pour over food. This drug may be taken by patients two years of age and older. The most common side effects include gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), temporary skin rash, and elevated kidney (i.e., creatinine) or liver (i.e., ALT, AST) markers. For more information on Exjade, see: Exjade and Jadenu.
- Desferal (deferoxamine/desferrioxamine): Desferal is a chelation medication that works by removing iron from the body through the urine. Patients using desferal will notice their urine is orange or red colored, which means the medication is working. This medicine cannot be taken by mouth and must be given as an infusion. This means that desferal enters the body through a needle that is placed under the skin (i.e., subcutaneously). Desferal is usually given over 8-12 hours, 5-7 nights per week using a battery-operated pump. Many patients do their desferal treatments at night, while they are sleeping. The maximum daily dose is 60 mg/kg. While 50-60 mg/kg/day is typically effective in most patients, a lower dose of less than 30-40 mg/kg/day is recommended in patients younger than 3 years old due to side effects. Some patients may still experience iron overload, especially cardiac iron overload, while using this medication and an additional chelator, such as Exjade or Jadenu, may be added to the chelation course. This medication may also be prescribed for use 24 hours per day in cases with severe iron overload or where the load needs to be lowered quickly (e.g., before stem cell transplant). Deferral does not work when it is not being infused- the longer you can tolerate it, the better it will work (e.g., 12 hours is better than 8 hours). Desferal may cause mild hearing loss or ringing in the ears.
- Ferriprox (deferiprone): This medication is an oral chelator that is very good at removing cardiac iron. However, 10% of patients with DBA syndrome have experienced very low neutrophils when taking this medication. For this reason, Ferriprox is only recommended in patients with severe cardiac iron overload who have failed other chelating options.
READ MORE: CDC Chelation Therapy Fact Sheet
Additional Considerations
- In general, chelation is initiated after about 10-20 transfusions, but this varies and should be based upon evidence of iron overload through monitoring. This tends to correlate with the time of the first failed steroid trial in babies and toddlers.
- Experts recommend starting T2*/FerriScan MRIs as early as possible and repeating once per year in chronically transfused patients to monitor the effectiveness of chelation therapy.
- Before starting chelation, patients should have a complete metabolic panel (CMP) blood test, hearing test, vision exam, echocardiogram, and EKG at baseline and once per year. The CMP may be repeated more frequently on an individual basis.
- If the ferritin level is considered high for an age or number of transfusions, the patient should be tested for the hemochromatosis gene (HFE). Hemochromatosis is another disorder in which the body retains iron and causes the same problems as chronic transfusions.
- A combination of chelators may be required in some patients with DBA syndrome. For instance, Desferal may be used for 5 nights with Exjade taken for the remaining 2 days, or Desferal may be used for 7 nights per weeks with Exjade taken in the morning.
- Iron overload may persist in patients who respond to steroids or undergo stem cell transplant. These patients should continue to be monitored and may require chelation or phlebotomy.
- Most patients who are on chronic blood transfusion therapy and chelate properly will have long, normal lives. Some patients may have unique issues that cause them to accumulate iron. Patients should consult with their individual doctors, have a program for monitoring iron levels, and carefully follow their doctors' orders regarding proper chelation.
- Under-chelation (e.g., missed doses, partial doses, or doses that are not high enough) can cause the medication to pull iron from one area of the body, but not have enough medication in the body to escort it out of the body and thus, it will redeposit elsewhere. In this case, the iron in the liver may lower, but the iron increases in the heart or pancreas.
- Remember that ferritin may not necessarily reflect the amount of iron that needs to be unloaded from transfusions.
- High doses of chelators can cause changes to your hearing and vision and therefore, it is important to have your hearing and vision checked annually.
What is a Stem Cell Transplant (SCT)?
Stem cell transplant (SCT), or formally hematopoietic stem cell transplantation (HSCT), is another treatment option for the bone marrow failure involved with DBA syndrome. SCT may also be called bone marrow transplant (BMT), cord blood transplant, or peripheral blood stem cell transplant, depending on the donor source. SCT involves replacing the unhealthy bone marrow of a DBA syndrome patient with healthy cells from a donor. The stem cells of the donor can be obtained from the bone marrow, peripheral blood, or cord blood. The transplant itself is a simple procedure that involves an infusion of the cells into the patient, performed in a similar fashion to a blood transfusion. The patient with DBA syndrome must undergo an intense chemotherapy regimen prior to transplant and the overall transplant process typically requires several months in the hospital. A successful transplant puts the bone marrow failure of DBA syndrome into remission, meaning the patient will no longer require chronic blood transfusions or steroids for anemia management.
Stem Cell Transplant Outcomes
SCT is the only potentially curative treatment for the bone marrow failure/anemia of DBA syndrome, but it does not come without risks. Historically, SCT has been reserved for transfusion-dependent DBA syndrome patients with HLA-matched sibling donors or those with pre-leukemia (MDS) or leukemia (AML) due to poor survival rates. However, in transplants performed after the year 2000, overall survival rate has improved to 85% for HLA-matched unrelated donors. In more recent studies, overall survival rate has increased to 91-92% in both HLA-matched sibling and unrelated donors. Rates of severe complications, such as graft versus host disease (GVHD), have also improved with 83-89% of post-transplant patients living without chronic GVHD. Given these improved outcomes, SCT may now be considered in more patients, including those without a sibling donor.
Considerations and Complications
While SCT can lead to normal red blood cell production and remission of the bone marrow failure, the genes of the patient will still have DBA syndrome after SCT. Therefore, the patient will remain at high risk of cancers and still have a 50% chance of passing on DBA syndrome to any future children, if fertility is retained after transplant. Also, physical problems associated with DBA syndrome not related to the bone marrow, such as cleft palates or heart defects, will not change.
There are serious risks and risk factors associated with the procedure that should be considered. Iron overload is a major risk factor for complications during transplant and therefore, iron load should be properly managed with chelation prior to transplant. Liver iron concentration (LIC) is a good indication of the body’s iron load and should be as close to 3 mg Fe/g as possible and should not exceed 7 mg.
Possible complications may include:
- Graft versus host disease (GVHD): This is a complication that can occur after transplant and is caused by the donor’s cells seeing the patient’s tissues as foreign and attacking them. While this can occur in any organ, the most commonly affected include the skin, gastrointestinal (GI) system, and lungs. GVHD can be acute, occurring within the first 100 days after transplant, or chronic and can range from mild to life-threatening. During transplant for treatment of some cancers, mild GVHD is desired; however, this is not the case for transplant in DBA syndrome patients.
- Veno-occlusive disease (VOD): VOD, also known as sinusoidal obstruction syndrome (SOS), occurs when the small blood vessels leading to the liver become blocked. When caught early, this complication can often be managed with defibrotide, but it can be life-threatening. Increased LIC can place patients at higher risk for VOD which is why it is important to lower LIC properly prior to transplant.
- Thrombotic microangiopathy (TMA): TMA is a complex complication due to damage of the inside of small blood vessels and formation of subsequent tiny blood clots. This condition commonly presents with destruction of red blood cells (hemolytic anemia), low platelets, and organ damage with kidneys being the most commonly affected. This complication can affect almost any organ and may lead to stroke. Early detection of TMA is essential as this can be life-threatening. Treatment typically consists of eculizumab (Soliris) infusions.
- Infections: Patients are incredibly vulnerable to severe infections throughout the transplant process due to having no or very low immune systems. The chemotherapy used prior to transplant completely destroys the existing bone marrow cells, including all cells of the immune system, and it takes a long time for many of these cells to develop from the new donor cells. Simple viruses, such as the common cold virus, can quickly escalate to severe infections in transplant patients, especially in the acute phase (first 100 days after transplant). Typically, it takes the immune system 1-2 years to return to normal and therefore, transplant patients have to make major lifestyle modifications during this time.
- Graft failure: Sometimes the donor cells fail to engraft (i.e., become incorporated into the bone marrow). This complication may present immediately following transplant such that the patient will continue to require transfusions and white blood cells never recover. Graft failure can also present well after transplant, where the patient recovers normal bone marrow function (i.e., produces blood cells), but eventually needs transfusions again with dropping cell counts. Treatment of this serious complication may involve a second stem cell transplant.
- Infertility: Patients may be infertile after SCT from the chemotherapy. Freezing (i.e., cryopreserving) sperm or eggs prior to transplant is an option for patients who have gone through puberty. For younger patients, freezing of ovarian or testicular tissue is an option, but remains experimental at this time.
- Cancer: DBA syndrome is associated with higher risk of cancers and the chemotherapy from the stem cell transplant increases this risk.
Age Considerations in Stem Cell Transplant
Studies have shown SCT survival rate to be greatest in DBA syndrome patients under the age of 10 years and therefore, this is the age range recommended by DBA syndrome experts. These younger DBA syndrome patients have been on therapies, such as transfusions and chelation, for less time than those in older age groups, and thus, patients under 10 years of age are considered at lower risk for complications related to these therapies during transplant (e.g., iron overload and liver or kidney damage from chelation).
SCT may be recommended for transfusion-dependent patients 10 years and older on an individual basis. For example, a healthy teenager with a short transfusion history and limited iron load may be a candidate for SCT. Transplant is not generally recommended for the anemia in adult DBA syndrome patients or for patients of any age who respond to low dose steroids without serious complications. In these cases, the risks of SCT may outweigh the benefits.
Patients who experience failure of multiple cell lines (red blood cell, neutrophils or other white blood cells, and/or platelets), antibodies to blood transfusions, immune system problems with frequent infections, pre-leukemia (MDS), or leukemia (AML), may require SCT regardless of age.
Donor Matching and Stem Cell Source
Stem cell donors are typically categorized as sibling or unrelated donors and patients are matched to donors based on human leukocyte antigens (HLA). These antigens are proteins/markers on most cells in the body and the immune system uses HLA to determine which cells do and do not belong in the body. There are many HLA markers unique to each person, but matching certain HLA markers is the crucial component to a successful transplant. A “perfect match” or “10/10 match” indicates that these specific HLA markers are an exact match between the donor and the patient. This is desirable as it minimizes the risk of graft versus host disease (GVHD) and maximizes the chance of successful engraftment (i.e., acceptance) of the new bone marrow. HLA markers are inherited and therefore, siblings have a 25% chance of being a perfect HLA match. Sibling donors of DBA syndrome patients must undergo genetic testing to ensure they do not carry the same genetic mutation as the patient. DBA syndrome experts recommend using either 10/10 HLA-matched unrelated or sibling donors for transfusion-dependent patients with DBA syndrome.
Stem cells for transplant can come from the bone marrow, peripheral blood, or umbilical cord. DBA syndrome experts recommend bone marrow as the stem cell source for transplants in DBA syndrome patients. Cord blood is also recommended from matched sibling donors.
What Chemotherapy Is Recommended?
Before the SCT can occur, the defective bone marrow cells in the DBA syndrome patient must be destroyed. This can be accomplished with multiple chemotherapies and radiation therapy. However, long term effects of these agents, such as cancer risk and infertility, must be considered. Therefore, radiation therapy is not typically recommended in patients with DBA syndrome. DBA syndrome experts recommend a myeloablative conditioning, which completely destroys the cells in the bone marrow, with treosulfan or busulfan combined with fludarabine. Some doctors may recommend adding thiotepa. Reduced intensity regimens are not well studied in DBA syndrome patients and should be limited to clinical trials at this time. Other conditioning regimens exist and it is important to discuss a plan with a transplant doctor who is also familiar with DBA syndrome, as there are conditions and complications specific to DBA syndrome that can occur during transplant.
Medical Care After Transplant
After undergoing SCT, patients remain at risk for long term effects from the toxic chemotherapy. To monitor for long term sequalae of transplant, patients can expect to see several specialists in addition to their transplant doctor and will undergo medical tests, such as echocardiographs and pulmonary function tests. Patients who have a SCT prior to puberty will be monitored by an endocrinologist as these patients may require hormonal support at puberty. DBA syndrome patients, who are already at increased risk for cancers, may be at even higher risk after transplant. Therefore, careful attention must be dedicated to cancer surveillance and prevention. For example, it is important for post-transplant patients to minimize sun exposure to decrease risk of skin cancers.
In Vitro Fertilization (IVF) and Preimplantation Genetic Testing (PGT)
For those DBA syndrome patients without unrelated or sibling matches for SCT, in vitro fertilization (IVF) and preimplantation genetic testing (PGT) may be considered by their parents. Discoveries of DBA syndrome genes in approximately 70-80% of patients and advances in PGT technology, improves the likelihood of a pregnancy using IVF resulting in an ideal donor. Through IVF, embryos are created and can be tested for specific mutations, including known DBA syndrome mutations, as well as HLA compatibility through PGT. The healthy matched embryos are then implanted into the mother with the hope of pregnancy and the birth of a child, who would be a perfect sibling match for the patient with DBA syndrome. IVF with PGT is an option for some DBA syndrome families; however, there are many ethical, monetary, and health issues that need to be considered.
Various other treatments have been trialed in DBA syndrome patients, most with little success. With the exception of L-leucine, these therapies are not recommended for the control of anemia in DBA syndrome outside of clinical trials. Some of these treatments have included:
- L-Leucine: Several experts recommend the amino acid L-leucine, which has resulted in a red blood cell response in some patients, such that they required less frequent transfusions. L-leucine has also been shown to increase growth in some patients.
- Cyclosporine A (CSA) and Antithymocyte Globulin (ATG): These agents were combined in an NIH-sponsored study, which closed due to poor responses. These drugs are associated with serious side effects, including compromising the immune system and kidney failure.
- Epogen: Also known as Procrit, EPO, or erythropoietin. Erythropoietin is produced naturally by the kidney to help improve production of red blood cells. It can be supplemented by injection for low levels in the body. Patients with DBA syndrome have no problem with production of erythropoietin and in fact, usually have very high levels. Even giving high doses does not increase RBC production in DBA syndrome and therefore, this treatment has been proven unsuccessful.
- Metoclopramide (Reglan): This medication, often used to treat reflux, induces the release of prolactin from the pituitary gland, thereby increasing prolactin levels. At one time, it was proposed that prolactin may improve erythropoiesis by stimulating cells in the microenvironment of erythroblasts. In one small study many years ago, metoclopramide showed a hematologic response in 33% of the patients, but other studies in the US and Europe did not support these results, showing less than a 10% response rate.
- Eltromopag (Promacta): This medication is in a class of medications called thrombopoietin receptor agonists. It works by causing the cells in the bone marrow to produce more platelets, but can also cause increased red blood cells in some cases. As of 2022, a trial is ongoing to study whether this medication can help the anemia in DBA syndrome patients.
- Sotatercept: This medication has shown some promise in counteracting chemotherapy-induced anemia and is being studied in several other diseases. The clinical trial using this medication in DBA syndrome patients was terminated due to COVID-19 limitations and therefore, no data exists on treatment with this drug in DBA syndrome patients.
- Trifluoperazine: This is an antipsychotic medication that has demonstrated some promise in the DBA syndrome zebrafish model. However, the trial of this medication in DBA syndrome patients was terminated due to COVID-19 limitations and therefore, no data exists on treatment with this drug in individuals with DBA syndrome.
- Rituximab: This is an immune-suppressing medication primarily used to treat certain cancers and autoimmune conditions. A small study was conducted in patients with aplastic anemia, red cell aplasia, or DBA syndrome using this medication; however, the majority of patients had no response to this drug.
Approximately 20% of those affected with DBA syndrome have a chance of going into spontaneous remission. Remission for DBA syndrome is defined as a stable, healthy, and acceptable hemoglobin, maintained for at least six months independent of corticosteroids, transfusions, or other therapy. Remission occurs in some patients who are initially steroid responsive when steroids can be stopped completely with continued maintenance of adequate hemoglobin levels. A small number of steroid non-responders may also enter remission even after prolonged transfusion dependence. The majority (77%) of the remitters in the DBA registry (DBAR) entered remission within the first decade of life. Some patients have a sustained remission, whereas others can go in and out of remission. Hormonal stress in pregnancy appears to be an important factor contributing to relapse; however, this may be transient. It remains unclear what triggers a remission or causes someone to relapse.