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Old Thu Apr 22, 2010, 04:57 AM
Birgitta-A Birgitta-A is offline
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Join Date: Oct 2007
Location: Stockholm, Sweden
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Vidaza and Dacogen

Hi Neil,
Here is a short version of the article in Medscape:
Azacitidine and Decitabine "Important" in Myelodysplastic Syndromes
April 20, 2010 David Steensma, MD, and Richard Stone, MD,Hematol Oncol Clin North Am. 2010;24:389-406.

Excellent Candidates for Therapy
Excellent candidates for hypomethylating agent therapy are patients with higher-risk MDS. In such patients, azacitidine demonstrated a survival benefit of 9 months, compared with supportive care (i.e., 24 vs 15 months).

In contrast, however, decitabine has not shown a survival benefit. This lack of survival benefit could be to due to several things. The drug was used in a suboptimal manner (in a 3-day inpatient regimen instead of the widely used 5-day outpatient regimen). 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.

A preference for azacitidine seems appropriate.
A preference for azacitidine seems appropriate. 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.

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%). However this report comes from a single-institution M.D. Anderson study using the 5-day regimen developed at that center, 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).

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. 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 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.

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.

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. It is not known yet whether early treatment is better than late treatment in MDS.

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. 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.

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 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.
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