Myelodysplastic Syndrome in Children

Myelodysplastic syndrome (MDS) is a rare disease of the blood, only occurring in four out of every 1 million children. While it develops in older patients (greater than 60 years old) most of the time, it can occur at any age. MDS develops in the bone marrow, the soft, spongy center of the long bones that produces the three major blood cells:

• White blood cells to fight infection
• Red blood cells that carry oxygen
• Platelets that help blood clot and stop bleeding

MDS occurs when the bone marrow does not properly produce sufficient numbers of healthy red blood cells, white blood cells, and platelets. With this disease, the blood cells lose their ability to mature and function properly.

In normal bone marrow, the growth and development of blood cells are carefully controlled to produce the correct number of each type of blood cell to keep the body healthy.

All blood cells (white blood cells, red blood cells, and platelets) originate in the bone marrow from a single type of cell, called a stem cell. Stem cells make up a very small portion of all the cells in the bone marrow. When more cells are needed, the bone marrow activates stem cells to rapidly produce more blood cells. In MDS, this process by which a stem cells matures into a red or white cell or a platelet is disturbed. Red and white blood cells may mature but not normally or in sufficient numbers. Sometimes, the number of immature blood cells, called blasts, increases, and the number of mature cells goes down. As the disease progresses, these blasts continue to increase and invade the bone marrow, preventing them from working effectively.

MDS used to be called “smoldering leukemia” or “pre-leukemia,” but only about one-third of cases of MDS actually progress to childhood leukemia, a cancer of the blood and bone marrow.

Physicians have identified several subtypes of MDS, based on how blood and marrow cells appear under the microscope. The hallmark of MDS is dysplasia, which describes the abnormal and bizarre-looking cells under the microscope. The cells used to be normal, precursor cells that produce white blood cells, red cells, or platelets. When MDS develops, these cells have an abnormal appearance. Pediatric MDS is largely classified by the fraction of blasts (immature white blood cells) found in the marrow and blood. Importantly, the subtypes that have been identified in children are somewhat different from the ones that physicians are using for adults and older people.

The types of pediatric MDS are:

• Refractory cytopenia of childhood (RCC): Less than 5 percent blasts in bone marrow. However, it can be normal to have a small number of blasts even in healthy bone marrow (up to 5 percent).
• Refractory anemia with excess blasts (RAEB): 5 to 20 percent of blasts in the bone marrow
• RAEB in transformation (RAEB-t): 21 to 30 percent of blasts in the bone marrow

When the amount of blasts in a child’s bone marrow exceeds 30 percent, the condition is considered to be acute myelogenous leukemia (AML), which is a type of leukemia characterized by an increase in a particular type of white blood cell. AML that has developed after MDS is, in general, much harder to cure than de novo AML (regular AML that started anew, without any underlying MDS or other disease).

Because myelodysplastic syndrome is a disease of the bone marrow, initial symptoms are often related to abnormal bone marrow function. The most common presenting symptom is bleeding related to low platelet counts. However, in many children, MDS is discovered accidentally when a child is having a routine blood test for other reasons.

While your child may experience symptoms differently, the most common symptoms of MDS include:

• Anemia: Anemia occurs when red blood cells are not produced properly or are produced in inadequate numbers, and the amount of oxygen-carrying protein hemoglobin is decreased. With anemia, the child may appear tired or pale and may breathe faster to compensate for the decreased ability to deliver oxygen to her body.
• Bleeding: In MDS, platelets, which help stop bleeding, often are reduced. Therefore, patients with MDS may experience bruising or abnormal bleeding (prolonged nose bleeds, bleeding from the gums).
• Infections: In many cases of MDS, the type of white blood cells that fight off bacterial infections (neutrophils) can be very low — a condition called neutropenia. Neutropenia may be the result of a failure of immature precursors in the bone marrow to mature, or an increase in blasts that crowds out normal cells in the bone marrow. In other cases of MDS, the white cell count can be unusually high. In either case, there are not enough normal healthy white blood cells present in the blood to fight infection. The child may have had repetitive infections or even serious infections with high fevers.

The symptoms of MDS may resemble other blood disorders or medical problems, some of which are very common and easy to treat, others of which could be more serious. The symptoms listed above are common presentations of the disease, but do not include all possible symptoms.

There are two different major categories of myelodysplastic syndrome (MDS), divided up by cause:

• Primary MDS: The disease occurs with no known cause in previously healthy children.
• Secondary MDS: The disease is caused by another condition. This group includes MDS resulting from previous chemotherapy or radiation therapy for another cancer. MDS also can be caused by inherited bone marrow failure disorders, such as Fanconi anemia. In rare cases, MDS and leukemia can run in families, called familial MDS. We have recently identified genetic changes that lead to familial MDS.

Some children with MDS have a chromosomal abnormality associated with the disease, most often involving chromosomes 7 and 8. However, these changes are not inherited from a parent. Instead, these abnormalities, which are thought to play a role in the development of MDS, arise on their own only within bone marrow cells and the blood cells they produce.

Sometimes, pediatric MDS can be associated with other rare conditions, such as inherited bone marrow failure disorders and other rare congenital disorders.

In addition to a complete medical history and physical examination, MDS can be accurately diagnosed only by a full evaluation of the blood and bone marrow. Your child’s physician may order some or all of the following tests:

• Complete blood count (CBC): a measurement of size, number, and maturity of different blood cells in blood, which indicates if the bone marrow is working properly. If the results are abnormal, a bone marrow test might be indicated.
• Additional blood tests: may include blood chemistries, evaluation of liver and kidney functions, and genetic studies
• Bone marrow aspiration and biopsy: A bone marrow sample is usually taken from the back of the hipbone by inserting a needle into the hipbone and sucking out some of the liquid part of the marrow with a syringe (a bone marrow aspirate). In addition, a small piece of the spongy bone containing intact marrow may be obtained (a bone marrow biopsy). This procedure is usually done under local anesthesia and some sedation to limit pain or discomfort. The samples will be examined under the microscope by one of our expert pediatric hematopathologists. In most cases, doctors will perform additional special tests on the bone marrow, such as chromosomal analysis.
• Chromosomal analysis (cytogenetic testing): This test evaluates all of our chromosomes, which carry our genetic information, to detect any abnormalities. The test usually takes about one week. Cytogenetic studies often help to confirm the diagnosis of MDS and can help distinguish it from certain forms of leukemia. This is important to help physicians tailor treatment to the specific disease.

MDS is often more difficult to diagnose than other bone marrow disorders and takes an experienced physician and pathologist who is highly skilled to look at bone marrow specimens of children to make the correct diagnosis. This is particularly true for children. Therefore, the diagnostic process may take time. Occasionally, repeated blood and bone marrow tests are needed to make the diagnosis with certainty.

After we complete all necessary tests, our experts meet to review and discuss what they have learned about your child's condition. Then we will meet with you and your family to discuss the results and outline the best treatment options for MDS.

Your child’s physician will determine a specific course of treatment based on several factors, including:

• Your child's age, overall health, and medical history
• The type and severity of MDS
• Your child's tolerance for specific medications, procedures, or therapies
• How your child's doctors expects the disease to progress
• The availability of a suitable stem cell donor

Treatment of MDS usually begins with supportive care, which helps control and treat the consequences of the disease, but does not eradicate it. Children may receive blood transfusions of red cells and platelets to improve symptoms of anemia and to prevent bleeding. Because patients with MDS are at higher risk of developing infections, immediate evaluation by a health care provider for any fevers is critical. Treatment with antibiotics is often necessary and important when a child has a fever.

In almost all instances, MDS in children can be cured only through a bone marrow transplant, also known as a hematopoietic stem cell transplant (HSCT). HSCT uses high doses of chemotherapy or radiation therapy to destroy all the cells in the bone marrow, healthy and diseased ones. Healthy cells from the bone marrow of another person — either a relative (usually a sibling) or an unrelated individual — are given through an infusion to the patient to restore the bone marrow that was previously destroyed by the chemotherapy and/or radiation therapy.

Your child's prognosis greatly depends on:

• The specific diagnostic category of MDS, chromosomal abnormalities, and the number of blasts in the blood and bone marrow
• Whether the MDS is a primary disorder or secondary to another disease
• The availability of a suitable bone marrow transplantation donor

As with any serious medical condition, prognosis and long-term survival can vary greatly from child to child. Prompt medical attention and aggressive therapy are important for the best prognosis.

Continuous follow-up care to determine response to treatment, detect recurrent disease, and manage late effects of treatment is essential for the child diagnosed with MDS. Side effects of chemotherapy, as well as second malignancies, can occur in survivors of MDS. Frequent examinations by a specialist and laboratory tests (including repeat bone marrow examinations) are most important for a successful management of disease.

In about one-third of patients, MDS progresses to acute myelogenous leukemia, usually within months to a few years.

Without a stem cell transplant, the prognosis for MDS is poor. Continuous follow-up care to determine response to treatment, detect recurrent disease, and manage late effects of treatment is essential for children diagnosed with MDS. Side effects of chemotherapy, as well as second malignancies, can occur in MDS survivors.

Children and young adults with MDS are treated at Dana-Farber/Boston Children's Cancer and Blood Disorders Center through our Bone Marrow Failure and Myelodysplastic Syndrome Program, recognized as one of the nation’s best pediatric treatment and research programs for bone marrow failure, MDS, and related conditions.

Your child will have access to advanced diagnostic evaluations and treatments, including individually tailored stem cell transplantation and ongoing clinical trials that are investigating new treatments. Our program also has been designated a “Center of Excellence” from the MDS Foundation — the only large pediatric center in the country awarded this designation.

At the moment, very little is known about the initiating events that lead to MDS; therefore, limited specific therapies exist, and a hematopoietic stem cell transplant is currently the only treatment that can cure the disease.

Dana-Farber/Boston Children's received grant funding from the National Institutes of Health (NIH) to establish the first nationwide pediatric MDS and BMF registry. Over the last three years we have collected information on more than 150 patients with MDS and BMF disorders. This will allow researchers at Dana-Farber/Boston Children's and collaborating institutions for the first time to collect clinical information and tissue samples to help us better understand this condition. Along with other centers, we have recently identified genetic causes for several families with familial MDS. Ultimately, we hope to identify new therapies for this condition, which is currently cured only with a bone marrow transplant.

To learn more about participating in the registry, please call 888-5-pediMDS or email us at mds@childrens.harvard.edu. For more information, visit our website: www.PediMDS.org.

MDS clinical trials

For many children with rare or hard-to-treat conditions, clinical trials provide new options. Search our open clinical trials. For more information on clinical trial availability, email us at clinicaltrials@danafarberbostonchildrens.org. We can help you navigate your options.