When Rebecca was first diagnosed with myelodysplastic syndrome (MDS) in late September, it was a disease we had never heard of. We immediately searched the internet for information, and what we found out was both confusing and terrifying. It is a malignant, potentially fatal blood disease that is related to, and in some ways worse than, leukemia. It is a much rarer disease than leukemia, and it is especially rare in children and young adults: it more commonly occurs in persons over the age of 60, in whom it is difficult to treat. We have since learned a lot more about it, and we now know that in younger persons it can be cured by bone marrow transplantation--especially if the person is lucky enough to have a matched sibling donor and otherwise good health. This is a low-tech description of the disease as we understand it. (For more detailed, technical discussions, see some of the medical links on our web site.)

How bone marrow works: The blood is one of the major organs of the body, and it contains several different types of cells that are needed to stay alive and healthy. These include red cells (which carry oxygen from the lungs to the tissues), white cells (which fight infections), and platelets (which form blood clots). Without enough red cells, you suffer from fatigue, dizziness, and ultimately unconsciousness. Without enough white cells, your body is easily invaded and overwhelmed by bacteria, viruses, and fungi. Without enough platelets, your blood vessels tend to spring leaks that lead to out-of-control bruising, bleeding, and strokes. These various blood cells are all relatively short-lived, so the body needs to continually produce them in large quantities. (Red cells live for about 6 weeks, platelets live for a few days, and some white cells live for only a few hours.) They are all produced in the bone marrow, which grows in the hollow spaces inside the large bones.

The "factory" that produces new blood cells in the bone marrow is powered by very special cells called stem cells. These cells are special because they are undifferentiated: they haven't decided what kind of cells they are going to be when they grow up. As you probably know, all the cells in your body are genetically identical: they have exactly the same DNA. Yet they differ profoundly from one another in appearance and function: some are skin cells, some are bone cells, some are liver or kidney or brain cells, and so on. The process by which cells differentiate to perform specialized functions is somewhat mysterious, but evidently it is governed by the local chemical environment in which the cell develops. In most organs in a mature body, a new cell inherits the same speciality as the "parent" cell from which it splits off. Thus, a new cell that is formed in the liver turns grows up to be a liver cell, one that is formed in the skin grows up to be a skin cell, and so on.

But in the bone marrow, things are different. The bone marrow contains a pool of faceless stem cells that continually reproduce themselves, providing a fresh supply of raw material for making all kinds of cells. The body then sends chemical signals to tell some of the stem cells to "commit" themselves to becoming particular kinds of blood cells, depending on what is needed at the moment. When it responds to such a signal, a stem cell begins to "mature" into either a red cell, a white cell, or a platelet-forming cell. The white cells are further subdivided into those that circulate in the blood (so-called granulocytes and monocytes, which mainly fight bacterial infections) and those that take up residence in the lymph nodes (so-called lymphocytes, which mainly fight viral infections). The first step in the maturation of a stem cell is that it commits to being either a circulating blood cell (a so-called myeloid cell) or else a lymphocyte (a so-called lymphoid cell). A myeloid cell then further commits itself to being either a red cell, a platelet-forming cell, or a granulocyte or monocyte. Stem cells are able to reproduce themselves not only in their undifferentiated stage, but also when they are at different stages of maturation. Thus, a maturing cell may spin off various copies of itself as it goes along, which normally helps to speed up the production of new blood cells when they are needed.

How MDS begins: That is how things are SUPPOSED to work, but sometimes things go wrong. Because the stem cells reproduce rapidly, there is always the possibility that mutations (errors in DNA copying) will occur. Sometimes mutations are caused by exposure to toxic chemicals (e.g., pesticides or industrial solvents--or chemotherapy drugs) or to heavy doses of ionizing radiation. But many mutations are random and unexplained: a molecule just slips out of place as DNA is being unzipped and copied. "Stuff happens." Mutations occur all the time and are usually harmless: the mutant cell is defective and simply dies, or else it is attacked and destroyed by the immune system. But occasionally a mutant cell is able to survive, evade the body's defenses, and reproduce itself. Such a cell is said to be "malignant" or "cancerous," and this is where MDS begins. MDS is caused by a mutation in a stem cell that has already committed itself to becoming a myeloid cell (a circulating blood cell), but hasn't yet decided which type of cell it will mature into.

The particular mutation that is characteristic of MDS has two essential features. First, the mutant stem cell spins off copies of itself at an excessive rate, creating an expanding "clone" of abnormal cells.  (Thus, MDS is said to be a "clonal disorder.") Second, the abnormal myeloid cells do not mature into functioning blood cells. Instead, they develop into cells which have "dysplastic" features such as misshapen or missing nuclei, and which tend to self-destruct prematurely. (Often the dysplastic cells die in the bone marrow, never reaching the bloodstream.) What happens next is that the normal myeloid cells in the bone marrow are either slowly or quickly replaced by the abnormal cells, which are then incapable of producing sufficient quantities of mature blood cells. As a result, the patient begins to suffer from the effects of having not enough red cells (anemia), not enough circulating white cells (neutropenia), and/or not enough platelets (thrombocytopenia). The condition of having a shortage of some kind of blood cells is called cytopenia, and the condition of having a shortage of all types is called pancytopenia.

There are apparently many different places in the chromosomes where mutations can occur that lead to generic symptoms of dysplasia and cytopenia. In some cases, the mutant cells take over quickly, in other cases they take over more slowly. In some cases, only one or two types of blood cells are deficient, in other cases all three are deficient. In some cases, the mutation leads to visible damage to the chromosomes--so-called "cytogenetic abnormalities" such as missing or broken chromosome arms that can be seen under a microscope--while in other cases the mutation is more subtle and hidden inside the chromosome. Where cytogenetic abnormalities are present, the disease can be more precisely classified and a more accurate (and often more depressing) prognosis can be given. In Becca's case, the mutant cells took over relatively quickly and all three cell lines were deficient'but there were no visible cytogenetic abnormalities.

Treatment of MDS: MDS is a potentially deadly disease because it eventually leaves the patient dependent on blood and platelet transfusions (which cannot be tolerated indefinitely) and vulnerable to life-threatening episodes of infection and bleeding. (It is not possible to transfuse circulating white cells, because they are very short-lived, although antibiotics can be used to combat bacterial infections when they arise.) The only curative treatment for MDS is a bone marrow transplant (BMT) or stem cell transplant (SCT), in which high-dosage chemotherapy and/or total body irradiation (TBI) is used to completely eradicate the damaged bone marrow--literally hollowing out the bones--after which healthy stem cells are transfused from a related or unrelated donor.  The dosages are higher than are used for treating most cancers, because when treating cancer, you generally don't want to kill the bone marrow.  Usually either two different chemo drugs are given for several days each, or else one chemo drug plus TBI is used.  (Rebecca received the former treatment, with an experimental combination of the drugs busulfan and melphalan.)

The new stem cells are usually transfused in the form of whole bone marrow from a volunteer donor--ideally a sibling who is a 6/6 or 5/6 HLA match--although they can also be collected from the donor's peripheral blood by pheresis.  (Fortunately Rebecca's sister Amy turned out to be a 5/6 match. In fact, Rebecca and Amy both received the same three-antigen chromosome segment--i.e., the same "haplotype"--from each parent, which normally yields a perfect 6/6 match.  But in Rebecca's case, there was a crossover at one of the locations, so Rebecca has one variant of the "A" antigen that Amy does not have. Our doctors feel that this is not likely to be a problem.)  Stem cells can also be obtained from frozen umbilical cord blood, in which a perfect HLA match is less critical because an infant's stem cells are more "naive."  Cord blood is used in situations where donor cells must be obtained very rapidly and/or a well-matched volunteer donor cannot be found.  (Duke is a world leader in cord blood transplants, pioneered by Dr. Kurtzberg.)

Unfortunately, bone marrow transplantation is a dangerous and grueling procedure:  there are significant immediate mortality risks from the chemotherapy and radiation alone, because of the high dosages involved, and there are longer-term risks of infection and graft-versus-host disease as the body slowly grows a new immune system along with its new blood cells.  Many MDS patients therefore choose to wait-and-watch for some time before going down that road. MDS sometimes worsens only slowly over time, and patients who have less aggressive forms of it may be able to survive for years on transfusions and drugs that help to stimulate cell growth. The latter treatment strategy is normally used in older patients who would not be likely to survive the rigors of a bone marrow transplant. For younger patients who know they are going to need a BMT sooner or later, sooner may be better because the chances of a successful BMT are reduced if the body has been sensitized to foreign blood cells by large numbers of previous transfusions. In Rebecca's case, we waited and watched for the first few months, and started to make plans for a bone marrow transplant in January, with her sister as the donor.

Transformation to AML: Alas, things can--and did--get worse: MDS can transform into leukemia, in which there is a cancerous overproduction of white cells that can be rapidly fatal if not treated. (With MDS alone, there are usually too few white cells rather than too many.) Apparently, once a single malignant mutation has occurred, and once the bone marrow has been entirely repopulated with abnormal cells, it is likely that there will be further mutations leading to further abnormalities in cell production. Leukemia occurs when there is a mutation in a committed white cell (either a lymphoid or myeloid white cell) that leads to out-of-control reproduction of white cells, which damages the body by clogging up organs and taking resources away from normal blood cell production. Since MDS involves the myeloid line of blood cells, a further white-cell mutation in the presence of MDS leads to the type of leukemia known as acute myeloid leukemia, a.k.a. acute myelogenous leukemia, or AML for short.

Acute leukemia is a very deadly disease, and it normally requires fast and aggressive treatment, but it is in some ways more manageable than MDS. Leukemia by itself may be curable by chemotherapy and/or radiation therapy alone if the initial mutation has occurred only in a committed white cell and the bone marrow still contains normal stem cells. (The idea then is to give just enough chemo and/or radiation to kill the cancerous white cells but not to kill all the stem cells.) But leukemia with MDS can be cured only by bone marrow transplantation, because there are no normal stem cells to fall back on. In Rebecca's case, her MDS began to transform to AML in early December. Her weekly blood test on December 7 showed a sharp rise in the percentage of "blasts" (immature white cells) in her circulating blood, and a subsequent bone marrow biopsy showed excess blasts in the marrow as well. The doctors decided to proceed with the transplant right away--during the Christmas holidays--before leukemia had time to develop very far. By the time she was admitted to the hospital on December 19, her overall white cell count (which had been way below normal for months) was above normal and rapidly shooting upward, but the chemotherapy immediately brought it back down to earth (in fact, down to zero). Because the transformation to leukemia was detected at an early stage and an immediate bone marrow transplant was possible, the doctors feel that it did not significantly change her prognosis. The bone marrow transplant should cure the leukemia as well as the MDS that preceded it.

Why? We have no idea what caused Rebecca to develop MDS or when it started. As in 80% of MDS cases, there are no known risk factors for her. She has not had previous chemotherapy or radiation therapy, nor any known over-exposure to toxic chemicals, pesticides, or radiation, nor is there any history of blood disease in either branch of her family. It appears to be simply a cosmic accident. Dr. Sherri Zimmerman, her pediatric hematologist/oncologist who made the original diagnosis, feels it is possible that the initial mutation may have occurred several years ago.  In cases where MDS is known to have been caused by previous chemotherapy or radiation therapy, it has often been 4 or 5 years before the first symptoms were detected..