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Gaining Momentum in MDSby Dianne Witter
Elihu Estey, M.D., gestures to the survival curve on his computer screen as he talks; it’s a cautionary graphic to temper our discussion of the unprecedented recent advances in the treatment of myelodysplastic syndrome (MDS), a rare—and often fatal—disease of the bone marrow. Over the years, the steep downward slope of the curve hasn’t improved much. But recent advances in scientific knowledge about the biology of the disease, which led to important treatment advances, have given even a self-avowed skeptic like Dr. Estey renewed expectations. A professor and section chief for MDS and acute leukemias in the Department of Leukemia at The University of Texas M. D. Anderson Cancer Center, Dr. Estey said, “Historically, MDS has been resistant to treatment, and the prognosis for most patients has been poor. Other than bone marrow transplants or acute myeloid leukemia–type chemotherapy for the small minority of patients who qualified, supportive care or clinical trials were the only treatment options.” What a difference two years can make. Today, there are three new, FDA-approved drugs that are putting many more patients into remission. More very promising drugs—and combinations of drugs—are in clinical trials now. M. D. Anderson has played a key role in these advances, thanks in part to one of the largest MDS patient bases in the world. Here, we give a brief overview of the current state of MDS research and treatment. A new class of drugs An improved understanding of the molecular biology of the disease was key to the development of the first nonintensive therapy to have a significant impact on the course of MDS. A new class of drugs, DNA methyltransferase inhibitors, restores normal function to silenced genes that ordinarily suppress the development of MDS. Azacitidine (Vidaza) was the first such drug to receive approval for use in MDS, in May 2004, ushering in a new wave of scientific interest and generating optimism about a disease that, previously, was known only for its poor outcomes. M. D. Anderson investigators were already conducting studies of decitabine (Dacogen), a similar but more potent drug. Laboratory investigators led by Jean-Pierre Issa, M.D., a professor in the Department of Leukemia, championed the idea that this drug’s mechanism of action might make it more effective when administered at very low doses for a longer period of time. Studies proved the hunch to be correct. “This was a remarkable phenomenon that would have been missed if we had simply focused on identifying the maximum tolerated dose,” said Dr. Issa. Hagop Kantarjian, M.D., a professor and the chair of the Department of Leukemia, agrees. “Decitabine was effective in MDS at a fraction of the chemotherapy dose, and without the hematological toxicity,” he said. The multi-institution studies led by Dr. Kantarjian and his colleagues demonstrated a complete response rate of almost 40% and an objective response in as many as 70% of participants. Decitabine received fast-track approval from the FDA in May, but studies of different dosing schedules continue in an effort to further improve outcomes. “I don’t think the best dosing schedule for either decitabine or azacitidine has been identified yet,” Dr. Kantarjian said. “If we can perfect that, we might see a substantial impact on prognosis.” Another drug recently approved for use in a subtype of MDS is lenalidomide (Revlimid), a thalidomide analogue with fewer side effects. In patients whose bone marrow has the 5q−cytogenetic characteristic, historically one of the subgroups with the poorest prognosis, lenalidomide brought about major hematologic responses in a majority of patients. Currently, the only curative treatment for MDS remains a bone marrow transplant or chemotherapy similar to that typically given to patients with acute myeloid leukemia, but in both cases the risks outweigh the possible benefits for many older patients. The advent of the “mini-transplant,” a nonmyeloablative procedure, has made stem cell transplants viable for more patients, including those over 60 years old. The recent approval of a once-daily oral iron-chelating agent, desferasirox (Exjade), is a welcome quality of life advance for people with iron overload due to repeated blood transfusions. Previously, daily iron chelation was usually self-administered by patients subcutaneously via an external pump worn for 8 to 12 hours—inconvenient and therefore an impediment to compliance over weeks or months of therapy. Continuing the momentum The recent metamorphosis in the treatment of MDS may be just a preview of things to come. With research funding for the disease at an all-time high (although still low compared with other diseases), the pace in this field has quickened considerably.
Last year, M. D. Anderson was awarded the largest-ever federal grant specifically for MDS research, a $10 million commitment that funds an expansive research program and brings together top scientists from a number of institutions in studies ranging from the laboratory to the clinic. “One of our key objectives is to look at what abnormalities come together to develop MDS,” explained Dr. Estey, who is principal investigator for the grant. “One way we’re doing that is by establishing a multi-institution tissue bank that we’ll sample serially over time to look at epigenetic changes and other characteristics.” He noted that the issue of methylation is key in laboratory research on MDS. Also key in laboratory research is a mouse model of the disease—which doesn’t exist yet for MDS. “Once we have more information about the make-up of MDS, another focus will be to develop an accurate mouse model,” Dr. Estey said. Another emphasis of the grant is clinical discovery and testing of new drugs for MDS. For instance, investigators testing a promising vaccine developed at M. D. Anderson will begin enrolling low-risk MDS patients in a phase II study this fall. This proteinase 3 PR1 peptide vaccine initially showed surprising success in patients with refractory acute myeloid leukemia, and it has shown promise for MDS as well. Following up on the success of the hypomethylating agents decitabine and azacitidine, investigators are now looking at other drugs that may work synergistically with these drugs. “MDS is an exciting disease to study right now,” said Dr. Kantarjian. “With our improved understanding of the biology of MDS, we’re looking at using older drugs in a new, more effective way. For instance, the histone deacetylase inhibitor valproic acid is being studied in combination with decitabine, as are suberoylanilide hydroxamic acid and others.” There are a number of new agents under study as well, including the antineoplastic agent clofarabine and AMG531, a platelet stimulator. The field of MDS has undergone unprecedented transformation in recent years. In the lab, scientists are developing a better understanding of how we might alter the genetic underpinnings of the disease. In the clinic, new medications developed as a result of this knowledge are offering patients greater chance of remission, improved quality of life, and freedom from blood transfusions. The stark statistics of MDS are still daunting, and the survival curve is just as steep. But real ground has been gained, and patients now have a fighting chance. The prognostic outlook, as Dr. Estey might say, is ‘cautiously optimistic.’For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789. Other articles in OncoLog, July/August 2006 issue:
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