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Key Words

Myelodysplastic syndromes, azacitidine ³, DNA methyltransferase inhibitors. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary ⁴.)

Summary

In an international multicenter randomized trial, the DNA methyltransferase inhibitor azacitidine (Vidaza®) improved overall survival in patients with higher-risk myelodysplastic syndromes. At two years, the risk of death for patients treated with azacytidine was nearly half that of patients receiving conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy).

Source

Lancet Oncology, March 2009 (see the journal abstract ⁵).

Background

Myelodysplastic syndromes (MDS) are a group of disorders in which stem cells in the bone marrow do not mature properly into healthy blood cells. Instead, immature blood cells (blasts) accumulate that die in the bone marrow or soon after they enter the bloodstream, reducing the number of normal blood cells in circulation. In approximately one-third of MDS patients, the condition progresses to acute myeloid leukemia.

In MDS patients whose disease is classified as higher risk, various therapeutic approaches have been used, including intensive conventional chemotherapy and low-dose chemotherapy with cytarabine. The intent of these treatments is to kill abnormal blasts.

Patients can sometimes achieve long-term remission or cure with allogeneic hematopoietic stem cell transplantation, but only those who are healthy enough to undergo the procedure can benefit from this type of therapy. However, many patients do not tolerate intensive therapy, and growth factors such as granulocyte-macrophage colony-stimulating factor may be used to stimulate healthy blood cell production in such patients. Transfusions and other supportive treatments have typically been the preferred treatment for many patients. More recently, therapy with lenalidomide (Revlimid®), which affects the immune system, has shown promise.

In 2004, the Food and Drug Administration approved azacitidine for MDS, based in part on the findings of a randomized phase III trial conducted by the Cancer and Leukemia Group B (CALGB), a group sponsored by the National Cancer Institute (NCI). This trial showed that patients treated with azacitidine had better clinical outcomes and quality of life than those who received supportive care. Azacitidine treatment also delayed the progression of MDS to acute myeloid leukemia. DNA methyltransferase inhibitors like azacitidine and decitabine (Dacogen®) appear to work by preventing the inactivation of tumor suppressor genes.

The Study

As part of the International Vidaza High-Risk MDS Survival Study Group, researchers at 79 sites in 15 countries enrolled 358 patients with higher-risk MDS between 2004 and 2006. MDS is found mainly in older adults, and 72 percent of patients were age 65 or older. Before randomization, investigators assigned all patients to one of three conventional care approaches (best supportive care, low-dose cytarabine, and intensive chemotherapy) based on their clinical assessments of the patients. The patients in each of the three groups were then randomly assigned to receive a seven-day course of azacitidine once a month for at least six months or to receive the conventional treatment.

The study’s principal investigator was Pierre Fenaux, M.D., Ph.D., from the Université Paris XIII in Bobigny, France. A number of the study’s authors report financial relationships with pharmaceutical companies, including the trial sponsor, Celgene.

Results

Patients in the azacitidine group had a median overall survival of 24.5 months, compared with 15 months for those in the conventional care group. After two years, the survival rate of those receiving azacitidine was 50.8 percent, nearly twice that of patients receiving conventional care (26.2 percent). The survival advantage became apparent after about three cycles of azacitidine and continued to the end of the study, by which time the patients in the azacitidine group had received a median of nine cycles of treatment.

As in the CALGB trial, azacitidine treatment delayed the onset of acute myeloid leukemia compared with conventional care. Patients in all prognostic subgroups—including those with cytogenetic abnormalities at chromosome 7, who have particularly poor prognosis—benefited from azacitidine.

When the patients in the three treatment preselection groups were analyzed separately, azacitidine was found to improve survival compared with both low-dose cytarabine and best supportive care. Azacitidine did not appear to improve overall survival compared with intensive chemotherapy, but because very relatively few patients had been deemed suitable for intensive chemotherapy the comparison was not statistically meaningful.

Patients in the azacitidine group had more serious blood-related side effects than patients in the best supportive care group, but fewer than patients in the chemotherapy groups. Azacitidine lowered the risk of infection by one-third compared with risk in the conventional care group.

Comments

“This is the first study ever to show a survival benefit from any intervention in myelodysplastic syndromes,” wrote Guillermo Garcia-Manero, M.D., from the University of Texas M. D. Anderson Cancer Center in an accompanying editorial. However, most patients with higher-risk MDS “will still die as a result of their disease . . . and the response rates on azacitidine were low”—only 17 percent had complete remission and another 12 percent had a partial response.

Richard F. Little, M.D., from NCI’s Cancer Therapy Evaluation Program, said that despite the “welcome benefits” of azacitidine, “the improvements in survival are modest” and molecularly targeted treatments, used in combination, will continue to be the goal of researchers.

Also welcome news, said Little, were the relatively modest side effects with azacitidine: fewer bacterial infections and less need for transfusion of blood products. This result further reinforces the idea that this drug improves MDS patients’ quality of life, added to earlier results from the CALGB trial showing “improvement in fatigue, shortness of breath, physical function, psychological distress, and positive affect,” said Little.

The authors of the paper emphasize that the collaborative trial design incorporated treatment practices and clinical guidelines from countries and regions around the world; thus, the demonstrated advantage of azacitidine should apply to the treatment of MDS internationally.

Limitations

The results failed to prove azacitidine superior to intensive chemotherapy, which “might remain the appropriate treatment in some situations in higher-risk” MDS, said the authors. One of those situations might be using intensive chemotherapy as initial treatment to more rapidly and effectively reduce the number of blasts circulating in the blood, in preparation for eventual allogeneic hematopoietic stem cell transplantation.

On the other hand, said Little, patients with a cytogenetic abnormality on chromosome 7 might do better with azacitidine or decitibine to prepare for a stem cell transplant. “The evidence isn’t yet solid, but if their health doesn’t deteriorate, these drugs could help this group of patients stay in better condition and remain eligible for the subsequent transplant.”

Glossary Terms

An aggressive (fast-growing) disease in which too many myeloblasts (immature white blood cells that are not lymphoblasts) are found in the bone marrow and blood. Also called acute myeloblastic leukemia, acute myelogenous leukemia, acute nonlymphocytic leukemia, AML, and ANLL.

Taken from different individuals of the same species. Also called allogenic.

The soft, sponge-like tissue in the center of most bones. It produces white blood cells, red blood cells, and platelets.

A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional therapy.

A drug used to treat certain types of leukemia and prevent the spread of leukemia to the meninges (three thin layers of tissue that cover and protect the brain and spinal cord). It is also being studied in the treatment of other types of cancer. Cytarabine blocks tumor growth by stopping DNA synthesis. It is a type of antimetabolite.

The study of chromosomes and chromosomal abnormalities.

A drug that is used to treat myelodysplastic syndromes and is being studied in the treatment of other types of cancer. It is a type of antimetabolite. Also called Dacogen.

An enzyme (a protein that speeds up chemical reactions in the body) that attaches a methyl group to DNA. A methyl group is a chemical group containing one carbon and three hydrogen molecules. Also called DNA methylase.

A substance that helps make more white blood cells, especially granulocytes, macrophages, and cells that become platelets. It is a cytokine that is a type of hematopoietic (blood-forming) agent. Also called GM-CSF and sargramostim.

Tissue in which new blood cells are formed.

A drug that is similar to thalidomide, and is used to treat multiple myeloma and certain types of anemia. It is also being studied in the treatment of other types of cancer. Lenalidomide belongs to the family of drugs called angiogenesis inhibitors. Also called CC-5013 and Revlimid.

A statistics term. The middle value in a set of measurements.

A group of diseases in which the bone marrow does not make enough healthy blood cells. Also called preleukemia and smoldering leukemia.

A decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. Also called partial remission.

A study to compare the results of people taking a new treatment with the results of people taking the standard treatment (for example, which group has better survival rates or fewer side effects). In most cases, studies move into phase III only after a treatment seems to work in phases I and II. Phase III trials may include hundreds of people.

A situation or condition, or a characteristic of a patient, that can be used to estimate the chance of recovery from a disease or the chance of the disease recurring (coming back).

A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial.

A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although cancer still may be in the body.

A cell from which other types of cells develop. For example, blood cells develop from blood-forming stem cells.

A method of replacing immature blood-forming cells that were destroyed by cancer treatment. The stem cells are given to the person after treatment to help the bone marrow recover and continue producing healthy blood cells.

Care given to improve the quality of life of patients who have a serious or life-threatening disease. The goal of supportive care is to prevent or treat as early as possible the symptoms of a disease, side effects caused by treatment of a disease, and psychological, social, and spiritual problems related to a disease or its treatment. Also called comfort care, palliative care, and symptom management.

The percentage of people in a study or treatment group who are alive for a certain period of time after they were diagnosed with or treated for a disease, such as cancer. The survival rate is often stated as a five-year survival rate, which is the percentage of people in a study or treatment group who are alive five years after diagnosis or treatment. Also called overall survival rate.

The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed.

A type of gene that makes a protein called a tumor suppressor protein that helps control cell growth. Mutations (changes in DNA) in tumor suppressor genes may lead to cancer. Also called antioncogene.