Treatment Options

Corticosteroid therapy includes taking a prescription steroid medication, Prednisone or Prednisolone, to make the patient’s bone marrow create red blood cells. To date, it is not understood how or why steroids cause the bone marrow to make red blood cells. The goal of steroid therapy is to allow the patient’s bone marrow to make a sufficient amount of red blood cells to ensure the patient maintains a hemoglobin level of 9 gm/dl or higher.

When beginning a steroid trial, patients are typically started on dose of steroids that is the equivalent of approximately 2 milligrams of medication per kilogram of patient weight per day. Initially, the dose is typically split between a morning and evening dose. For example, if a patient weighs 10 kilograms (approximately 20 pounds), the patient would start with an initial dose of 20 milligrams of steroid medication per day and would take 10 milligrams in the morning and 10 milligrams in the evening.
If the patient is going to respond to steroids, there is usually an increase in the hemoglobin or reticulocyte count within two to four weeks.

Patients will typically stay at this high dose for several weeks. This initial dose of steroids is high and therefore patients cannot stay on this high dose for long periods of time. Different doctors may approach the weaning process differently. It is important for patients and families to remember that the weaning process should be conducted slowly and methodically. This can be frustrating, but it is necessary. The DBA Nurse (1-877-DBA-NURSE) can help answer questions related to the weaning process; however you must continue to follow your doctor’s recommendations.

Generally, a sustainable, long term dose of steroids is the equivalent of 0.5 milligrams per kilogram per day or 1.0 milligrams per kilogram every other day, or lower. These are only general guidelines. It is important to remember that each individual patient must be assessed individually, with the steroid therapy goal being to allow the DBA patient to make their own red blood cells while having as “normal” of a life as possible without side effects.

Statistics about steroids

According to the DBAR, 79% of patients initially responded to steroids; 17% of patients were steroid non-responsive; and 4% of patients were never treated with steroids. As of 2008, 38.7% of patients are on steroids. Although 79% of patients initially respond to steroids, some patients will stop taking steroids for a variety of reasons, including too high of a dose, to address growth issues or because of other side effects.

Side effects

Parents and patients are often very concerned about the side effects of steroids. Patients may react differently and may have none, any, or all of the following short-term side effects:

  • Upset stomach (take with food or milk)
  • Increased blood sugar in the body- diabetes
  • Increased hunger
  • Behavior changes, such as fussiness, inability to sleep, irritability
  • Increased risk of infections, including pneumonia, thrush (a white coating in the mouth), and other yeast infections
  • Weight gain, salt and water retention
  • High blood pressure
  • Increased fat on face (rounded or moon face), upper back and belly
  • Stretch marks on the skin, acne, poor wound healing, increased and unusual hair growth

Possible long-term (taking steroids for more than three months) side effects even in low doses,may include all of the short-term side effects listed above, in addition to:

  • Poor growth in children (can be severe)
  • Brittle bones or problems with hip or shoulder joints
  • Muscle weakness
  • Diabetes
  • Problems with eyes

Complimentary Medications

When patients are on steroids, there are certain other medications that may be taken to avoid or treat certain side effects.

  • Antibiotics: When patients are on a high dose of steroids, it is recommended that they take a prophylactic (preventative) dose of antibiotics (Bactrim). This will help ensure the patient does not contract certain types of pneumonia, including pneumocystis pneumonia, also referred to as PCP pneumonia.
  • Anti-fungal: Anti-fungal medications are helpful for treating a yeast-based diaper rash or thrush, only taken as needed- not preventative.
  • Acid reflux medication: It is recommended that patients take an acid reflux medication to prevent stomach problems, while on steroids. Some common brand names of proton pump inhibitors include: Nexium, Prevacid, Prilosec, Pepcid, Zantac.
  • 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 steroids, they may not build an adequate immune response and will need to be repeated in the future.

Complimentary Medical Care

The overall health of a DBA patient on long-term steroids should be carefully monitored. Recommended medical monitoring includes:

  • Annual vision check
  • Twice a year dental visits. Some DBA patients report high levels of tooth decay and tooth loss.
  • Ask about getting a baseline dexascan, which is a special x-ray used to determine the strength of the bones. Monitor future bone loss. This is usually done over the age of 5 years, or when the child can stay still without anesthesia.
  • Ask whether a referral to an endocrinologist is warranted. An endocrinologist is a doctor who specializes in the endocrine system in the body. An endrocrinologist may be particularly helpful if there are issues with growth and development while taking steroids, or if diabetes becomes an issue. An endocrinologist can also help if steroids have been taken for long periods and you would like to stop.
  • Get a flu shot every fall. Do not take the nasal spray flu vaccine, as this contains live viruses. Everyone in the patient’s home should also receive a flu vaccine.
  • Avoid people with viral infections, such as measles or chicken pox.

Effect of 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 patients should be carefully monitored.

Effect of pregnancy

Women taking steroids who become pregnant should be carefully monitored. Steroid responsive pregnant women may require an increased steroid dose or even transfusion therapy during pregnancy. The potential for steroid toxicity on the mother and the unborn child should be carefully monitored.

Recommended reading

For more information on taking corticosteroids, consider reading, “Coping with Prednisone,” by Eugenia Zukerman and Julie R. Ingelfinger. This book published in 2007 and is usually available at your local bookstore.

Link to CDC Corticosteroid Therapy Fact Sheet

One type of treatment that might be recommended for someone with DBA is blood transfusions. Blood transfusions might be recommended just as needed when the hemoglobin is lower than normal, or as a chronic blood transfusion program. Chronic blood transfusions consists of scheduled blood transfusion every 3-6 weeks to maintain the hemoglobin level in a safe range. A DBA patient normally makes his or her own white blood cells and platelets, and therefore would only require transfusion 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 “typing and screening.” Typing refers to the type of blood the patient has (A, B, AB, or O) and screening refers to identifying whether certain antibodies are present. Generally, people must receive blood of their same type to avoid severe transfusion reactions. These tests are followed by the compatibility testing (cross-match). This test insures that no antibodies are detected in the recipient’s serum that will react with the donor’s red blood cells.

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 to be safe. The federal Food and Drug Administration (“FDA”) is responsible for ensuring the safety of the blood industry in the United States.

The FDA has established five levels of overlapping safeguards for the industry:

  1. 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, potential donors can be temporarily deferred for a number of reasons, including having a temperature, cold, cough, or sore throat, or if they are taking certain medications, or if they have traveled outside the United States. Additionally, potential donors can be permanently excluded from donating blood if there is evidence of HIV infection, male homosexual activity since 1977, a history of intravenous drug abuse, or a history of viral hepatitis, as well as for a variety of other reasons. For a complete list of reasons go to http://www.fda.gov/cber/blood.htm.
  2. Blood testing: After donation, the blood is tested for blood-borne agents, including HIV, Hepatitis B, Hepatitis C, Syphilis, and Human T-cell Lymphotropic Virus. Any blood that tests positive for any of the these illness, or is suspicious for any reason will be destroyed and not given to anyone requiring a blood transufusion.
  3. Donor 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 their history or health conditions change, each blood bank has policies for tracking these donations.
  4. Quarantine of untested blood: Blood products are not available for general use until the products have been thoroughly tested.
  5. Investigation of problems: 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.

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 familly 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 all of the screening processes that volunteer donations do. Therefore, medical research has shown that blood from directed donors is not safer than blood from volunteer blood donors. As donors may only donate one unit of blood about every 2- 3 months, multiple directed donors might 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 in a patient who receives chronic transfusions. Some potential solutions include:

IV Transport Team:

Many hospitals have a team of nurses who are especially skilled at starting challenging IVs. In some hospitals this team is referred to as the transport team. 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 the wait is long to get one of these nurses, but the reward of not having to do multiple needle sticks makes it worth it. Do not be afraid to ask for this service if it will benefit your child.

Surgical Intervention:

Some patients who receive chronic transfusions may get a device to make this process easier. Intravenous access devices can be implanted beneath the skin (port) or external.

Intravenous access devices include:

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.

Some common brand names of ports include: Port-a-Cath, Microport, Bardport, PowerPort, Passport, Infuse-a-Port, and Medi-Port. Ports are surgically installed in the patient’s upper arm or chest and typically require general anestheia. DBA patients should ask their physician if they recommend a port made without any metal components. This will allow the patient to be able to have full access to any tests for iron levels in the body.

External Catheter: Another type of intravenous access device is an external catheter. This is a temporary IV line that is placed into a vein through a child’s chest. Unlike a port, part of the catheter remains outside of the child’s body. Like a port, however, the catheter is used for drawing blood samples, giving blood transfusions, and/or for giving medications.

Some common brand names of catheters include: Broviac and Hickman. Catheters are also surgically placed in the patient’s chest and typically require general anesthesia.

Iron Overload

One of the risks of chronic blood transfusion therapy is getting too much iron in the body. Every cubic centimeter of blood contains 1 milligram of iron. A person who does not have DBA uses iron from destroyed red blood cells to create new red blood cells. Since a person with DBA does not make many of his/her own red blood cells, this iron is not needed for the production of red blood cells, and consequently remains in the body unused. When a patient receives transfusions, the iron contained in the donated red blood cells goes into the body. The human body does not have a mechanism for removing any excess iron. This excess iron gets stored in the body’s organs, and if it is not removed, it will slowly destroy those tissues. Iron overload and organ damage can begin with as few as eighteen transfusions. Therefore, it is critical for the health of a DBA 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.

Bloodtransfusiontherapy

Tests to Monitor Iron Overload

There are various tests used to monitor iron levels, including:

  • Ferritin Level: The amount of iron in the body can be checked with a blood test called a serum ferritin. This test will give a general idea of how much iron is in the body. Acceptable ferritin levels are generally less than 1000 – 1500 ng/mL .
  • SQUID Test: SQUID is a special type of x-ray that uses magnets to show much iron is in the body. This test is very accurate and non-invasive. The SQUID test requires the patient to lie still for a ten to fifteen minute procedure. The SQUID test is currently only available in two locations in the United States: Columbia Presbyterian Medical Center in New York City and Children’s Hospital Oakland in Oakland, California.For more information on the SQUID test, see: http://www.childrenshospitaloakland.org/healthcare/depts/Ferritometer.asp
  • T2* MRI and FerriScan MRI: These tests are special types of MRIs. The T2* MRI measures the amount of iron in the heart, while the FerriScan MRI measures the amount of iron in the liver. These tests are considered to be very accurate and are non-invasive. These tests are relatively new and not available at every medical center. To find locations which offer the FerriScan MRI, see: http://www.resonancehealth.com/ and www.ferriscan.com.
  • Liver Biopsy: A liver biopsy is an accurate, though invasive test to measure the amount of iron in the liver. Patients are typically sedated during the biopsy. The biopsy 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 liver tissue can also be analyzed to see if the iron has caused any damage to the liver, such as fibrosis or cirrhosis.

Chelation Therapy

Iron overload can be prevented and treated with chelation therapy. Chelation therapy refers to using medication to remove excess metals, such as iron, from the body. As the body has no natural way of removing excess iron from the body, chelation therapy is the only way to remove the iron. Therefore, chelation therapy is a critical component to the health and well being of a DBA patient receiving chronic blood transfusions.

There are currently two chelation drugs available in the United States: Exjade (Defarasirox) and Desferal (Deferoxamine).

  • Exjade: Exjade is a relatively new chelation drug here in the United States, as it has only been available since 2005. Exjade is an oral medication. Exjade tablets are dissolved in water or juice and taken once a day on an empty stomach, preferably at the same time every day. Exjade works by binding to the iron and removing the iron from the body through the stool. Exjade may be taken by patients age two years and older. For more information on Exjade, see: http://www.us.exjade.com/index.jsp
  • Desferal: Desferal is a chelation drug that has been used in the United States for many years. Desferal cannot be taken by mouth, but must be given as an infusion. This means that desferal enters the body through a needle that is placed under the skin (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. Desferal works by removing the 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.

The vast majority of patients who are on chronic blood transfusion therapy and who 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 doctor’s orders regarding proper chelation.

Link to CDC Chelation Therapy Fact Sheet

What is a Stem Cell Transplant?

Another type of treatment for DBA is to undergo a stem cell transplant. Stem cell transplants (“SCT”) are also known as bone marrow or cord blood or peripheral blood stem cell transplantation (depending on the donor source). A SCT involves replacing a DBA patient’s unhealthy bone marrow with healthy cells from a donor. The donor’s stem cells can be obtained from bone marrow, peripheral blood, or cord blood. This is a complicated medical procedure that requires several months in the hospital and is not without risk. The reward for a successful bone marrow transplant is that the patient’s bone marrow will function normally and the patient will not need chronic blood transfusion therapy or corticosteroid medication.

Stem Cell Transplant Outcomes

Stem cell transplantation (SCT), is a potentially curative, but dangerous procedure. The role of transplantation for patients with DBA remains complex and controversial. In general, patients with DBA, whether steroid-responsive or transfusion-dependent, may be considered for transplant prior to age 10 years, and preferably between the ages of 2 and 5 years, if an HLA-matched related donor is available. As of the last published analysis, most of the sibling transplants used chemotherapy alone as a conditioning regimen, while most of the alternative donor (mismatched family or unrelated donor) transplants used a combination of chemotherapy with radiation therapy for pre-transplant conditioning. Data from the DBAR show overall survival of 77% for allogeneic sibling SCT (94% for allogeneic sibling SCT age 9 years and less) and 36% for alternative donor SCT (86% for alternative SCT done after 2000).

Preimplantation Genetic Diagnosis (PGD) and Invitro Fertilization (IVF)

The ideal donor for a DBA patient choosing to undergo a SCT is a healthy, HLA perfectly matched sibling. Discoveries of “DBA genes” in approximately 50-60% of patients and advances in Preimplantation Genetic Diagnosis (PGD) technology, improves the likelihood of a pregnancy using Invitro Fertilization (IVF) resulting in an ideal donor. This process allows the embryos created through IVF to be analyzed for the known defective gene and/or HLA compatibility. The “healthy matches” are then implanted with the hope of a pregnancy and the birth of a child. IVF with PGD is an option for some DBA families; however, there are many ethical, monetary, and health considerations that need to be considered.

Important Points to Consider

Stem cell transplant can lead to normal red blood cell production, but it is risky. Matching bone marrow donors take time to find, and patients sometimes die of complications of the treatment. A stem cell transplant also can lead to severe chronic illness (such as GVHD) in some patients. Physical problems associated with DBA but not related to the bone marrow, such as a cleft palate or a heart defect, will not change. In addition, the person’s genes will still have DBA, so there is still a 50 percent chance of passing the disorder to any future children, if fertility is retained. Stem cell transplant is not an easy fix. Please educate yourself and explore all your options. If you choose transplantation, speak to SCT doctors that also deal with DBA. There are conditions and complications related to DBA that can occur during a transplant, so it is important your transplant team is DBA educated.

Links:

Blood and Marrow Transplant Information Network
Mayo Clinic
National Bone Marrow Donor Program
To watch a fun animation on what a stem cell is click here
Link to CDC Stem Cell Transplant Fact Sheet

Other treatments, have been used in DBA over the last 30 years. These drugs appear to be largely ineffective and there is currently no evidence that any of these has a major role in the management of DBA. (Vlachos et al, 2008; Geller et al, 1975; Dunbar et al, 1991; Fiorillo et al, 1991; Niemeyer et al, 1991; Gomez-Almaguer & Gonzalez-Llano, 1992; Sumimoto et al, 1992; Bejaoui et al, 1993; Gillio et al, 1993a, 1993b; Bastion et al, 1994; Brown et al, 1994; Olivieri et al, 1994; Ozsoylu, 1994; Ball et al, 1995; Bernini et al, 1995; Buchanan, 2001; Alter, 2003)

Summary of Alternative Therapies from the International Clinical Care Consensus Document:

 

Treatments Number of Patients Response
Androgens >100 20%
High dose corticosteroids 12 7
8 3 complete, 1 partial
9 5 all transient
Erythropoietin 10 1 transient
Interleukin-3 100 10%
Cyclosporine ± prednisone 20 (with steroids) 50% all transient
10 (CSA alone) 2 sustained response
Metoclopromide 9 1 complete
2 partial on steroid taper
1 1 complete
33 2 partial
Valproic acid 1 1 complete
Leucine 1 1 complete
Other (6-MP, cylcophosphamide, Vincristine, stem cell factor, PIXY 321, IVIG) Largely ineffective

In most national registries, approximately 40% of patients with DBA are transfusion-dependent, having failed to respond or having become refractory to steroids, while 40% are steroid-dependent, and 20% are transfusion-independent on no medication (‘‘in remission’’) (Willig et al, 1999a; Lipton et al, 2006). 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 DBAR defines remission as a stable, physiologically acceptable hemoglobin, maintained for at least six months independent of corticosteroids, transfusions or other therapy. Seventy percent of the remitters in the DBAR did so within the first decade of life. Most patients have a sustained remission, but some can go in and out of remission. Hormonal stress in pregnancy appears to be an important factor contributing to ‘‘relapse’’; this may be transient. Remission in DBA patients is not uncommon, but it is still unclear what “triggers” a remission or causes someone to relapse.