March 12, 2009 — The first trial ever to show a marked improvement in survival in patients with myelodysplastic syndrome (MDS), which can progress to leukemia, has now been published. But the results have been changing clinical practice since they were first presented at scientific meetings, as early as 2007.
The trial shows that treatment with azacitidine (Vidaza, Celgene) nearly doubled the 2-year survival rate, compared with conventional care (50.8% vs 26.2%; P = .0001).
The company-sponsored phase 3 study involved 358 patients, and was published in the March issue of Lancet Oncology.
"Azacitidine significantly lengthens overall survival and changes the natural history of myelodysplastic syndrome in patients with a higher-risk disease," the researchers report.
"No previous treatment strategies have shown a significant overall survival benefit," they write, "with the exception of allogeneic hematopoietic stem-cell transplantation, which is suitable only for a few patients."
The survival data from this trial have been incorporated into the product's labeling. Azacitidine has been available in the United States since 2004, but that approval was based on response rates supported by reduction or elimination of transfusions. The drug was originally developed by Pharmion, which was acquired by Celgene in March 2008.
Enthusiastic Response When Results First Presented
Lead author Pierre Fenaux, MD, from HÃ´pital Avicenne, UniversitÃ© Paris XIII, in Bobigny, France, presented initial results at the American Society of Hematology meeting in December 2007, as reported by Medscape Oncology.
At the time, an expert in MDS said they were "unexpectedly fantastic." Azra Raza, MD, from the University of Massachusetts, in Worcester, who was not involved in the study, said "the results were good enough to be proclaimed from the rooftops," and added that "every patient should be given the chance to have this drug."
Every patient should be given the chance to have this drug.
Last year, a new analysis of data from the same trial was presented at the American Society of Clinical Oncology; it showed that the improved survival did not depend on having a complete response to the drug. At that time, Jorge Cotes, MD, from the University of Texas MD Anderson Cancer Center, in Houston, who was not involved in the study, also said that all patients with MDS should be offered this therapy
Dr. Fenaux told Medscape Oncology that these reactions were typical of the response that he received from the medical community. "Most comments were indeed very favorable, or even enthusiastic, because this is the first drug to clearly prolong survival."
Impact on Clinical Practice
The results have already changed clinical practice. "Azacitidine is becoming the first-line treatment of higher-risk MDS" in both the European Union and the United States, Dr. Fenaux said. Uptake of the drug "has been pretty quick in many [European Union] countries," he said, and he expects the publication of the final results to stimulate this further. He estimated that "a large majority" of MDS patients in France and western European countries are now taking azacitidine, but budgetary problems have slowed uptake in some of the less affluent countries.
Another effect of the study on clinical practice is that the indications for treatment with intensive chemotherapy have been "much reduced," said Dr. Fenaux. This approach is now restricted to younger patients with normal karyotype, particularly if chemotherapy can be followed by allogeneic stem-cell transplantation, he said.
Intensive chemotherapy has been an option for MDS patients, but one that was not taken up very frequently. Dr. Raza previously explained that doctors were reluctant to expose MDS patients — who are often elderly with comorbidities — to the toxicity of chemotherapy because it did not prolong survival. In the past, about 50% of patients with MDS were not treated at all, she said, adding that, in light of the new results with azacitidine, "there is now very little to justify this complacent approach."
At the time the trial was being set up, there was no consensus on how best to treat patients with high- or intermediate-risk MDS, so investigators were allowed to place patients into 1 of 3 different conventional-care groups, whichever they felt best reflected their own clinical practice. Investigators could choose best supportive care (105 patients), low-dose cytarabine (49 patients), or intensive chemotherapy (25 patients). The proportions of patients in each group were "consistent with treatment practices," the authors comment.
The trial involved 79 sites in 15 countries, including Europe, Australia, and the United States. Treatment decisions were made in light of different treatment practices, which are influenced by regional, national, and local guidelines, and by consensus criteria, the authors explain. "For these reasons, the results are applicable to the improvement of myelodysplastic syndromes internationally," they write.
The most common adverse events were blood cytopenias for all treatments. Treatment discontinuations with azacitidine were similar to those in the conventional-care groups, and were mostly related to hematologic adverse events. In addition, nausea, vomiting, fatigue, and diarrhea were reported with azacitidine, low-dose cytarabine, and intensive chemotherapy.
After a median follow-up of 21 months, the median overall survival was 24.5 months in the azacitidine group and 15 months in the conventional-care groups, a difference of 9.4 months (P = 0.0001). The hazard ratio for overall survival was 0.58 (95% confidence interval, 0.43–0.77).
"The survival benefit with azacitidine was seen across all prognostic subgroups analysed, including patients with poor, intermediate, and good cytogenetics," the researchers comment. "The median number of azacitidine treatment cycles was 9, suggesting that long-term treatment might give the best survival benefit," they added.
Dr. Fenaux noted that another drug that has been used for MDS, decitabine (Dacogen, Eisai), was not approved in the European Union because of a negative study supported by the European Organisation for Research and Treatment of Cancer (EORTC). However, that trial might not have given decitabine "a fair chance, as the median number of courses administered (about 4) was probably too small," he noted.
Dr. Fenaux reports having participated in advisory board meetings for Celgene, Roche, Amgen, GlaxoSmithKline, Merck, Novartis, Johnson & Johnson, and Cephalon. Several coauthors declare relevant financial relationships, and 3 are company employees, as detailed in the paper.
Lancet Oncol. 2009;10:223-232. Abstract
Medscape Medical News © 2009 Medscape
Cite this: Zosia Chustecka . Azacitidine Markedly Improves Survival in Myelodysplastic Syndromes - Medscape - Mar 12, 2009.