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Kidney Function May Not Affect Vidaza’s Safety And Efficacy In Higher-Risk MDS Patients

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Published: Aug 16, 2013 12:46 pm
Kidney Function May Not Affect Vidaza’s Safety And Efficacy In Higher-Risk MDS Patients

The results of a small retrospective study indicate that kidney function may not affect the safety and efficacy of Vidaza when it is used to treat higher-risk myelo­dys­plas­tic syndromes (MDS) patients.

The investigators of the study examined treatment outcomes for a sample of patients treated with Vidaza and found that patients with impaired kidney function had similar response rates, survival, and side effects as patients with normal kidney func­tion.

The study investigators also found, however, that after they controlled for several factors that might affect patient survival, poor kidney function was associated with shorter overall survival.  Kidney function was mea­sured using an estimate of the kidney (glomerular) filtration rate.

The researchers believe the impact of kidney function on survival that they observed may point to kidney health deserving greater attention as a factor affecting MDS patient prognosis.

The study’s lead investigator, Dr. Ioannis Kotsianidis of the Democritus University of Thrace Medical School in Alexandroupolis, Greece, said, “I believe we convincingly show that a patient with [mild or moderate kidney impairment] can (and should) receive the same Vidaza dosing schedule as patients with normal renal [kid­ney] function.”

Dr. Mikkael Sekeres of the Cleveland Clinic, who was not involved with the study, agreed with Dr. Kotsianidis that this study indicates Vidaza is effective and safe in patients with impaired kidney function. “This study reports that patients with abnormal kidney function respond just as well to azacitidine [Vidaza], without any additional toxicities, as those [patients] without kidney abnormalities,” said Dr. Sekeres.

Based on their findings, the study investigators recommend that the prescribing information for Vidaza be reconsidered for patients with impaired kidney function. Currently, the prescribing information recommends that if patients show changes in kidney function that the Vidaza dose should be reduced by 50 percent.

“Our work challenges the validity of this recommendation,” said Dr. Kotsianidis. “First, there is no robust evidence that any other schedule than the seven-day 75 mg/m2 [Vidaza schedule] is equally effective in high-risk patients … Second, we and others show that deterioration [of kidney function], if it occurs, is transient and generally re­cov­ers on the subsequent cycle(s), without the need for treatment delays and/or dose adjustments, which can be detrimental.”

Dr. Sekeres cautioned, however, “This is a retrospective study of a limited number of patients – 42. So, while this provides some evidence supporting the safe and effective use of azacitidine in patients with kidney ab­nor­mal­i­ties, it was not a large, formal, randomized study.”

To determine the optimal use of Vidaza in patients with kidney impairment, a recently completed clinical trial studied different Vidaza dosing schedules in patients with normal and impaired kidney function. Results from this study have not yet been published.

Background

Vidaza (azacitidine) is approved for use in the United States and Europe as a treatment for MDS. However, the interaction between kidney function and Vidaza, which is primarily excreted by the kidneys, was not assessed in the clinical trials that led to Vidaza’s approval.

Preclinical animal studies indicate that Vidaza may affect kidney function, and fatal cases of kidney failure have been reported in patients treated with Vidaza plus chemotherapy.

Findings from a 2010 study indicate that treatment with Vidaza may be possible for patients with higher-risk MDS and kidney disease (see related Beacon news), but no studies have directly compared the safety and efficacy of Vidaza in patients with and without kidney impairment.

Given the limited data on the safety of Vidaza for MDS patients with impaired kidney function, both the U.S. prescribing information (pdf) and European summary of product characteristics (pdf) for Vidaza warn that patients with kidney impairment should be monitored for further kidney damage.  They also warn that elderly patients, a population that is more likely to already have decreased kidney function, should be monitored for kidney function while receiving Vidaza treatment.

In addition, the prescribing information recommends that Vidaza’s dose should be adjusted if, during treatment, signs of reduced kidney function emerge.

Study Design

In the current study, researchers from Greece sought to compare the efficacy and safety of Vidaza treatment for patients with and without impaired kidney function.

They therefore retrospectively studied data from 42 intermediate-2 and high-risk MDS patients with moder­ate, mild, or no kidney impairment who were treated with Vidaza at their institution.

The median patient age was 74 years.  However, patients with moderate kidney damage were older than the patients with mild or no kidney damage.  The median ages were 77 for those with moderate kidney damage, 60 years for those with mild kidney damage, and 70 years for those with normal kidney function.

Patients were given 75 mg/m2 of Vidaza subcutaneously for the first seven days of a 28-day cycle. Dose modifications were made for patients who experienced severe blood-related side effects. Patients com­plet­ed a median of six cycles of Vidaza.

The median follow-up time was 31 months from the start of Vidaza treatment.

Results

The researchers noted small differences in response rates, event-free survival, overall survival, and side effects among MDS patients with moderate, mild, and no kidney impairment.  However, none of the dif­fer­ences were statistically significant.

In particular, the overall response rate appeared to be highest for patients with moderate kidney impairment (50 percent), compared to those with mild kidney impairment (31 percent) or no kidney impairment (35 per­cent).

However, the complete remission rate was highest among patients with normal kidney function.  The com­plete remission rates were 17 percent for those with moderate kidney impairment, 19 percent for those with mild impairment, and 35 percent for those with no impairment.

More patients with moderate kidney impairment experienced improved platelet counts (33 percent) com­pared to those with mild kidney impairment (12 percent) or normal kidney function (0 percent).

The median event-free survival across all patients was 7.8 months.  More specifically, it was 6 months for those with moderate kidney impairment, 7 months for those with mild kidney impairment, and 8 months for those with normal kidney function.

The median overall survival across all patients was 10.4 months, with a median overall survival of 10 months for those with moderate kidney impairment, 14 months for those with mild impairment, and 10 months for those with normal kidney function.

After controlling for several patient characteristics that might affect patient survival – including age, gender, and the presence of chromosomal abnormalities – the researchers found that the only factor that was sig­nif­i­cant­ly associated with a difference in overall survival was kidney filtration rate at the start of treatment.

In particular, a decreased rate of kidney filtration – indicating poorer kidney health – was associated with decreased overall survival.

The most common severe side effects among those with moderate, mild, and no kidney impairment in­clud­ed low white blood cell counts (50 percent, 63, percent, and 57 percent, respectively), low platelet counts (75 percent, 75 percent, and 50 percent, respectively), and infections (58 percent, 56 percent, and 36 percent, respectively).

Approximately a third of the patients in each group required dose reductions due to low blood cell counts or related side effects.

Treatment was discontinued due to side effects in 58 percent of patients with moderate kidney impairment, 25 percent of those with mild impairment, and 29 percent of patients with no impairment.

Patients with mild kidney impairment tended to be hospitalized more often and for longer periods of time.  The median number of hospitalizations was 9 times for a median of 20 days for those with mild kidney im­pairment, compared to a median of 6 times for a median of 16 days or 17 days for those with moderate or no impairment, respectively.

Patients who had moderate or mild kidney impairment at the start of treatment had stable kidney filtration rates throughout treatment, indicating that Vidaza treatment did not make their kidney function worse.  Among the patients who had normal kidney function at the start of treatment, two women experienced declines in kidney filtration rates starting on the seventh day of treatment.  One of these patients regained nearly normal kidney function by the start of the second cycle of treatment, while the other patient’s filtration rate did not return to normal.

The researchers conclude that Vidaza may occasionally cause a mild and transient decline in kidney func­tion between days 7 and 15 after the start of treatment.  They further state that kidney function typically re­covers during later cycles of treatment.

For more information, please see the study in the journal Leukemia Research (abstract).

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