The MDS Beacon™

Researchers have published results of a clinical study examining a five-day intravenous (IV) dosing regimen for Vidaza (azacitidine), a common treatment for myelodysplastic syndromes (MDS).

The researchers, based at Washington University in St. Louis, find that a five-day IV regimen yielded response rates and response durations similar to those reported for the standard seven-day subcutaneous Vidaza dosing regimen. At the same time, overall survival times for the five-day regimen were lower than observed in studies using the standard regimen.

Vidaza is typically administered by two or three subcutaneous injections each day over the course of seven consecutive days. The drug’s overall treatment cycle is 28 days — seven days of injections, and 21 days without injections. This regimen matches the one in two key clinical trials that established the efficacy of Vidaza. However, the regimen often results in pain and bruising around injection sites, and the need for weekend injections is inconvenient for some patients.

Vidaza also can be administered by IV infusion, but the efficacy and safety of this approach is not clearly established because clinical trials have not tested it in comparison to subcutaneous injection.

This Washington University study was carried out to determine if a five-day course of IV infusions could have outcomes similar to those of the standard seven-day subcutaneous regimen, while also offering greater convenience and fewer injection site side effects.

During the Washington University study, 22 patients with primarily intermediate- to high-risk MDS received one 20-minute IV infusion of Vidaza daily for five consecutive days. Patients received a median of 4.5 treatment cycles.

Six of the 22 patients in the study, or 27 percent, achieved complete or partial remission. Another nine patients, or 41 percent, showed no signs of disease progression.

The patients who achieved a complete or partial remission responded to treatment after a median of 108 days, and the median duration of their response was 15 months.

Across all patients in the study, median overall survival was just short of 15 months.

Side effects with the five-day regimen included those usually associated with Vidaza. Patients reported reduced red and white blood cell counts, and they also experienced fatigue, fever, low platelet counts, nausea, and cardiac events due to infection.

Nausea, however, was unusually common among the patients in the Washington University study. Fully 100 percent of the patients required anti-nausea medication by the third 28-day treatment cycle in the study. The authors note that, among patients treated with Vidaza according to the standard seven-day regimen, the incidence of nausea is about five percent.

In the discussion of their results, the study authors note that the response rates observed with the five-day IV Vidaza regimen are similar to those seen in the two major clinical trials that tested the now-standard seven-day subcutaneous Vidaza regimen.

Overall survival time, however, was noticeably lower among the patients in the Washington University study — 15 months, as opposed to 21 and 24 months in the two major trials that used the seven-day subcutaneous regimen.

The difference in survival time would seem to be a clear strike against the five-day IV regimen.

Yet the researchers are not so certain. They note that the patients in their study had noticeably weaker immune systems – based on their absolute neutrophil counts – compared to patients in the two major trials that used the seven-day subcutaneous Vidaza regimen.

And, in fact, a key difference in the survival of the patients in the different studies is that almost one quarter of the Washington University study patients died – primarily due to infections – within two months of starting their Vidaza therapy. In comparison, there were very few early deaths in the two seven-day regimen trials.

Thus, the researchers believe the five-day IV Vidaza regimen still merits further investigation. They note that the sample size of their study was rather small, and many of the key questions raised by their results could be addressed in a larger trial explicitly comparing the two dosing regimens.

In an email exchange with The MDS Beacon, Dr. Ravi Vij, one of the Washington University researchers, said “One cannot make any firm conclusions from a small set of patients. However, the abbreviated five-day regimen seems to have a shorter survival rate than the seven-day regimen. [Our] study was meant to provide justification for conducting a larger multi-center trial. It met its efficacy end-point in that regard.”

A representative of Celgene, the pharmaceutical company that markets Vidaza, told the Beacon that the firm is not currently planning any clinical trials to further investigate the five-day IV regimen.

For more information about the Washington University study, please see the American Journal of Hematology (abstract).

Additional Notes: (1) The daily Vidaza dose given to the patients in the Washington University study was the same (75 mg/m²) as the daily dose typically administered to patients treated with Vidaza in the standard seven-day subcutaneous regimen. The dose was increased, however, by a third for those patients in the study who failed to respond after two 28-day cycles of therapy. (2) The Washington University study defined “complete remission” based on the modified International Working Group (2006) criteria, which require blood counts of more than 1,000 neutrophils per µL and more than 100,000 platelets per µL. MDS patients in complete remission are not necessarily fully cured or free of cancer cells, but they are considered free of any symptoms of MDS.