Vidaza and Dacogen

[Birgitta-A]

Hi all,
Here is an article by experts about Vidaza and Dacogen in MDS patients. No news but still interesting:
http://www.medscape.com/viewarticle/720525
Kind regards
Birgitta-A

[Neil Cuadra]

Only Medscape members can view the article. Can you tell us the title and authors?

[Birgitta-A]

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.

[mausmish]

Good article - thanks for posting, Birgitta!

[Birgitta-A]

Hi Karen,
You have really had a very good response to Vidaza ! Still when you had 17% blasts before treatment a SCT perhaps is the best way to continue even if it is a very risky treatment.
Kind regards
Birgitta-A

[Neil Cuadra]

What's surprising about the "Azacitidine and Decitabine" article is how many questions still can't be answered:

• Would decitabine have a more significant benefit if it was tested under a different protocol?
• What should change?: days per cycle, inpatient vs. outpatient, number of cycles.
• Why were the M.D. Anderson results different?
• Which lower-risk MDS patients should receive the drugs?
• If so, how soon should their treatment begin?
• How long should drug therapy continue if there is no response?

We're certainly keeping the researchers busy. In the meantime, doctors make treatment decisions based on all available information.

[Birgitta-A]

Hi Neil,
The most important of your questions is "Which lower risk MDS patients should receive Dacogen?" Actually we don't know which high risk patients that will respond either.

The truth is that we don't know much about administration of treatment with Dacogen or Vidaza. In PubMed there are 173 reports about Dacogen in MDS patients (some of them are really AML patients).

Then clin trials gov reports about 39 trials with Dacogen in MDS – about 16 of them are recruiting patients. In most of these trials Dacogen is combined with other drugs for better effect.

Since Dacogen is a hypomethylating drug the researcher try to study the patients DNA methylation levels. They found that patients with higher levels of methylation, compared with patients with lower levels, had a shorter median overall survival and shorter median progression-free survival but methylation at baseline did not correlate with clinical response to decitabine.
http://www.ncbi.nlm.nih.gov/pubmed/20038729

So today we still don’t know which MDS patient should receive the drug but we can hope that they will find other important differences between responders and nonresponders. Remember how the drug Gleevec (and now still more effective drugs) has changed the future for patients with CML.
Kind regards
Birgitta-A

[lotusbud]

How do they test for methylation?

[Birgitta-A]

Hi lotusbud,
I am afraid it is quite complicated to really understand our disease , symptoms and treatment but we can all learn something from the reseachers.

DNA methylation involves the addition of a methyl group (CH3OH) to the 5 position of the cytosine pyrimidine ring or the number 6 nitrogen of the adenine purine ring (cytosine and adenine are two of the four bases of DNA).

Patients with myelodysplastic syndromes show a high prevalence of tumor-suppressor gene hypermethylation. DNA methyltransferase inhibitors, such as Vidaza and Dacogen, are therapeutic options for the treatment of MDS.

There are several methods to analyze DNA hypermethylation. This one - called pyrosequencing - is often used in trials:
http://www.nature.com/nprot/journal/....2007.314.html

I suppose it is very expensive to make this type of DNA methylation quantification so it is only done in trials.

Here are the results from a study of very low dose subcutaneous Dacogen administered daily or weekly times three in patients with lower risk myelodysplastic syndrome. The overall response rate was 32% for the daily arm and 19% for the weekly (p=0.3).
http://ash.confex.com/ash/2009/webpr...aper20889.html
Kind regards
Birgitta-A

[lotusbud]

Thankyou Birgitta.
I read both of them, and it appears each time the complex text is a bit easier to read! Yes I know it seems the syndrome is so very complicated. Also it seems in the same individual the situation changes with time.
What does it actually mean to have the tumor-suppressing gene hypermethlyation - does it mean that the proliferation is checked, that the proliferated cells quickly die, or the sequence/rate of cell division to cell death is out of order, or something like this?
But is this the cause or the symptom?

[Birgitta-A]

Hi lotusbud,
You know when the tumor suppressing genes are hypermethylated they are inactivated - the tumor cells get a growth advantage. Read page 20 in this dissertation abour Vidaza in MDS:
http://diss.kib.ki.se/2007/978-91-7357-419-8/thesis.pdf
This is one of the causes of MDS and other cancer diseases.

Another important cause of MDS and other cancer diseases is histone acetylation. Histones are the chief component of chromatin and acts as spools around which DNA is coiled. Some MDS patients get so called histone deacetylase inhibitors (HDAC inhibitors) - like Epival - with good results because histone deacetylation is connected with gene silencing (page 18). If we get an inhibitor of histone deacetylase the genes can sometimes function again.
Kind regards
Birgitta-A