Photo by Clay Eals
Imagine that you're at retirement age and you decide to hire a private security guard to keep your enemies away. All may go well at first, but how would you feel if your protector mistakenly aimed his weapon at you?
That may be the case with myelodysplastic syndrome (MDS), a disease of the bone marrow that few have heard of but afflicts about 15,000 Americans each year.
In MDS, one culprit is an outpouring of molecules known to cause inflammation, a process typically initiated to help the body heal. What ensues is a cycle of marrow cell death and, in some cases, a rapid takeover by pre-cancerous cells.
Researchers don't know the identity of the initial trigger that eventually leads to the destruction of marrow and blood cells in MDS. But the molecular trail left by the inflammatory response and other immune reactions may provide targets for new treatments for what is typically a fatal disease.
Hematopoietic (blood) stem-cell transplantation is the only therapy that can cure MDS, yet such an aggressive therapy can be toxic for people over age 65, the average age of those diagnosed with MDS.
That's why researchers like Dr. Joachim Deeg and his Clinical Research Division colleagues have initiated studies on alternate strategies based on insights into the mechanisms of the disease process.
Drugs that block the chain of events triggered by inflammation show some promise, said Deeg, who leads laboratory studies and clinical trials to test this and other forms of therapy.
Drug called Enbrel
One study enrolling patients at the Seattle Cancer Care Alliance uses an anti-inflammatory drug called Enbrel?, developed by Immunex Corporation and typically prescribed for rheumatoid arthritis.
"In the mid-1990s, published studies showed that MDS marrow cells produce high levels of tumor necrosis factor-alpha (TNF-alpha), which is an inflammatory response signal that also can initiate cell death," he said.
"We showed that neutralization of TNF-alpha in cultures of MDS marrow in the laboratory increases the formation of normal marrow cells. This led us to develop a clinical trial to examine whether a drug that interferes with the TNF receptor might offer some therapeutic benefit, and indeed, we observed improvements in blood-cell counts in some patients."
Patients in a current follow-up study are treated with a combination of Enbrel?, which blocks binding of TNF alpha to its receptors, and antithymocyte globulin (ATG), an immunosuppressive agent.
"It's not a home run in terms of a cure," Deeg said. "But some patients do show improvements, and in two patients, we saw a normalization of peripheral blood cell counts. Our goal now is to learn more about specific inflammatory signaling molecules other than TNF alpha and their receptors and how to distinguish responses in normal cells from those in abnormal marrow cells."
Unlike aplastic anemia, in which the marrow is devoid of blood-forming cells, MDS marrow produces a mixture of normal and abnormal cells. Most of these cells are destroyed via programmed cell death (apoptosis) before they reach the blood due to the action of TNF-alpha and other "cell-death molecules."
The patient is left with shortages of one or multiple cell types in the circulating blood. This discrepancy of a cellular marrow and low cell counts in peripheral blood serves as a diagnostic marker for the disease, which initially may present with anemia-like symptoms of fatigue and bruising.
Some 30 percent of all MDS cases eventually develop into acute leukemia as the population of abnormal cells takes over, which originally gave rise to the disease monikers "pre-leukemia" or "smoldering leukemia."
Most perplexing for doctors is the nature of the signal that triggers the process resulting in the release of TNF-alpha and other pro-inflammatory or cell death signals. Deeg said evidence is mounting for an autoimmune component, at least in a proportion of patients, and a higher-than-expected incidence of other autoimmune disorders is showing up in patients who develop MDS.
Recent studies have shown that MDS patients with specific variants of HLA genes, which specify tissue type, are associated with increased response to treatment with immunosuppressive drugs. The same HLA variants also are common in patients with autoimmune diseases, a wide range of disorders in which the immune system attacks the body's own tissue.
Patients with MDS account for about one quarter of all patient consults by Hutch physicians, Deeg said. Although transplantation is the only cure at the present time, many older patients don't fare well with this therapy or are reluctant to undergo that treatment, given that they may have a life expectancy of several years with more conservative management.
"Reduced-intensity regimens for transplantation (mini-transplants), used quite successfully in older patients with other diagnoses, have met with some problems in patients with MDS, and further research is needed," he said.
For this reason, Deeg has focused research efforts on non-transplant therapies that could halt the progression of MDS in its early stages. In addition to TNF-alpha and its receptor, other cell death-inducing molecules and their receptors could serve as potential therapeutic targets.
Paucity of markers
Part of the difficulty in treating MDS results from the broad spectrum of disorders listed under one heading and the paucity of clinical and molecular markers to classify and stage the different forms, Deeg said. Patients are classified using what is known as the FAB (French, American, British) system, based largely on the number of immature (abnormal) cells, or blasts, in the marrow.
"One of the most frustrating things for MDS patients and their doctors is when patients ask, 'What treatment is right for me?,' and frequently there isn't a definitive answer," he said.
Deeg collaborates with an international group of scientists whose work to refine the MDS classification system has become known as the International Prognostic Scoring System. In addition to the number of blasts, the system scores the reduced counts of peripheral blood cells and chromosomal abnormalities.
The group, he said, aims to develop measurable markers to enhance doctors' ability to make an accurate prognosis that would enable treatment to be tailored to each patient.