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Azacitidine Improves Survival in Myelodysplastic Syndromes

Key Words

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


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).


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


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.


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.


“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.


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.”

  • Posted: March 26, 2009

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