Azacitidine and Decitabine "Important" in Myelodysplastic Syndromes

Zosia Chustecka

April 20, 2010

April 20, 2010 — The hypomethylating agents azacitidine (Vidaza, Pharmion) and decitabine (Dacogen, MGI Pharma) are an "important addition" to the therapeutic armamentarium for myelodysplastic syndromes (MDS), say 2 experts writing in the April issue of the Hematology/Oncology Clinics of North America, which focuses on the syndrome.

However, many of the practical decisions about using these drugs "must be made in the absence of high-quality data," write David Steensma, MD, and Richard Stone, MD, from the Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts.

There is still some uncertainty over some issues with this therapy — such as which drug to choose, which patients to treat, and how long to continue treatment, they note. "Ideally, such questions should be addressed individually in well-designed clinical trials," they continue, but this is not likely to happen because of the relatively short duration of the remaining patent life and marketing exclusivity for both agents in the United States (where azacitidine was approved for MDS in 2004 and decitabine in 2006).

Hence, in their review, Drs. Steensma and Stone discuss their own clinical experience with these agents, and offer practical recommendations.

Excellent Candidates for Therapy

Excellent candidates for hypomethylating agent therapy are patients with higher-risk MDS, the authors explain.

In such patients, azacitidine demonstrated a survival benefit of 9 months, compared with supportive care (i.e., 24 vs 15 months), in the AZA-001 trial (Lancet Oncol. 2009;10:223-232). These results were welcomed enthusiastically when they were announced in 2007, which was the first time that any therapy has shown an improvement in survival in MDS.

Along with high-risk MDS patients, the AZA-001 trial included patients with International Prognostic Scoring System intermediate-2 rating. In addition, there were patients with 20% to 30% bone marrow blasts (currently classified as acute myeloid leukemia by the World Health Organization, but formerly classified as MDS subtype refractory anemia with excess blasts in transformation); these patients also experienced a survival benefit, the authors note.

In contrast, however, decitabine has not shown a survival benefit. This lack of survival benefit — reported in the European EORTC 06011 trial (American Society of Hematology 50th Annual Meeting and Exposition abstract 226) — could be to due to several things, the authors suggest. The drug was used in a suboptimal manner (in a 3-day inpatient regimen instead of the widely used 5-day outpatient regimen developed at the University of Texas M.D. Anderson Cancer Center in Houston). In addition, it might not have been used for long enough (patients received a median of 4 cycles, with 40% receiving 2 cycles or less, compared with the 9 cycles of azacitidine in AZA-001). Last, salvage chemotherapy was administered to more than 20% of patients who were randomized to the supportive-care control group.

"It is not known whether decitabine, when optimally administered, has an impact on survival comparable to azacitidine," the authors note, adding that another large trial is now unlikely.

A preference for azacitidine seems appropriate.

In view of this, "a preference for azacitidine seems appropriate, especially for patients who would have qualified for the AZA-001 trial," they explain.

Azacitidine is listed as the preferred drug for high-risk MDS patients, and decitabine is listed as an alternative in the 2009 National Comprehensive Cancer Network guidelines, on the basis of survival data, the authors note.

Despite this, decitabine continues to be used, driven by the fact that this drug has achieved the highest ever complete response rate in MDS reported to date (37%), they note. However, they also point out that this report comes from a single-institution M.D. Anderson study using the 5-day regimen developed at that center (Blood. 2007;109:52-57), and it was not replicated in a multicenter study using the same regimen (where the complete response rate was 15%, which is only slightly better than the 9% to 13% reported with the 3-day regimen).

Drs. Steensma and Stone add that their impression is that the "intensity of therapy" is greater with 5-day decitabine than with azacitidine (which is given over 7 days). In addition, "the rate of response to decitabine seems to be somewhat more rapid," they note.

Therefore, in their own practices, they "tend to prefer 7-day azacitidine in patients who would have been eligible for AZA-001 and for frailer patients, and 5-day decitabine in patients who have more rapidly progressive disease."

If a patient fails on one of these agents, it might be worth trying the other, the authors suggest, because there are differences in cellular metabolism. There is only 1 report of patients who were treated with decitabine after having failed on, or been intolerant of, azacitidine, but in that series of 14 patients, 3 achieved complete remission and 1 experienced a hematological improvement (Leuk Lymphoma 2008;49:690-695).

Lower-Risk MDS Patients

It is not clear whether lower-risk MDS patients would have a survival benefit similar to that seen in high-risk patients, but data so far show that low-risk patients experienced similar overall hematopoietic response rates to those seen in the high-risk patients, the authors note.

Among the low-risk patients, the ones who have the most compelling indication for hypomethylating agents are those who are transfusion dependent, and for whom hematopoietic growth factors, such as recombinant erythropoietin, have failed, they write.

However, it "seems prudent to withhold this therapy" from asymptomatic and minimally symptomatic patients with lower-risk disease, especially those who do not yet require transfusions.

"It is not known yet whether early treatment is better than late treatment in MDS," they explain.

Another group for whom treatment with these agents might be appropriate is those with MDS who are candidates for allogeneic stem-cell transplantation. The delays inherent in organizing such a procedure make pretransplant hypomethylating therapy reasonable, with the goal of temporary disease stabilization rather than cytoreduction, the authors point out.

Don't Give Up Too Soon

"Because response to hypomethylating agents can be delayed, it is important not to give up too soon when administering these drugs," the authors write. They follow the prescribing information, which for azacitidine is at least 4 to 6 cycles and for decitabine is at least 4 cycles.

However, how long treatment should be continued is unclear. These drugs do not appear to be curative; continued therapy is necessary to maintain a response, but resistance eventually emerges, the authors note.

Some clinicians argue for continuing with therapy indefinitely, whereas others allow patients to take a break and retreat at the time of relapse. Drs. Steensma and Stone favor the first approach, and "tend to continue to treat responding patients until the time of disease progression, as long as they tolerate the drug."

There is even an argument for continuing with this therapy, if it is being tolerated, in patients who have not shown a measurable response to treatment; a post hoc analysis of data from the AZA-001 trial suggests that a complete response is not necessary for a survival benefit, as reported previously by Medscape Oncology.

However, the authors realize that, "in practice, it is often difficult to convince a patient to receive a therapy indefinitely in the absence of measurable benefit, and many patients are not persuaded by the argument that their disease might be worse if they were not taking the drug."

Their approach, in patients who have not shown a response after 4 to 6 cycles, is to discontinue and try something else. But if the patient does respond, they continue with the hypomethylating agent until either disease progression or the patient can no longer tolerate the treatment.

"The benefit that these agents offer to appropriately selected patients makes their use worthwhile, and the responses are often quite satisfying," the authors conclude.

Hematol Oncol Clin North Am. 2010;24:389-406. Abstract

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