Decitabine - Clinical Trials in Thalassemia Intermedia

Clinical Trials using Decitabine a possible fetal hg inducer in thalassemia intermedia, it would be interesting to see the outcome. 

http://clinicaltrial.gov/ct2/show/locn/NCT00661726

see also http://prsinfo.clinicaltrials.gov/ct2/show/NCT00661726?cond=%22Beta-Thalassemia+Major%22&rank=24

Actually Sharmin, i heard about this study a year and more ago and i am very much interested in. I emailed the people in charge and will post if i get any feedback . Thanks for sharing

manal

Hi Manal

How is Decibatine different from hydro oxy urea?

Both looks to be used for chemotherapy.

Thanks
 

Hi Puja,

I am not sure whether it is chemotherapy or not but this is one of my questions to them and i will post their reply once i receive it

manal

Hi Puja

I received their reply and yes as you said it is a chemotherapy that helps in raising the Hb in thal intermedia. This trail is a very preliminary on a very small number of patients (adults only), to determine the drug safety. It is not generally available for children.
Also, eligibility is for healthy intermedias  and currently this small study is being completed at 3 hospitals in Canada and the United States

Manal
 

Hi Manal

I came across another study of NHLBI, chk this out


http://wwwlb.aub.edu.lb/news/dynamic/61700.html

Thanks

Puja

From   http://asheducationbook.hematologylibrary.org/cgi/content/full/2006/1/58

Decitabine

In 2006, the FDA approved the use of decitabine, an analogue of 5-azacytidine, for the treatment of patients with myelodysplastic syndromes. As a result of the recent introduction of decitabine as a new DNA hypomethylating agent and follow-up animal studies which showed that hypomethylating agents could reduce the incidence of tumors, there has been a renewed interest in the use of DNA hypomethylation therapy for inducing HbF in patients with SCD. Three clinical trials have been reported in which decitabine was administrated to patients with SCD by either intravenous or subcutaneous injections.19–21 This resulted in significant increases in mean -globin synthesis, HbF levels and the fraction of F cells in the treated patients. Moreover, decitabine treatment resulted in an increase in total hemoglobin levels of 2 g/dL while reticulocyte counts decreased, suggesting decreased hemolysis. The increase in the level of HbF was associated with significant improvement in several parameters that are important in the pathophysiology of vaso-occlusion such as red blood cell adhesion, endothelial damage and activation of the coagulation pathway. The increase in HbF levels was shown to be associated with decreased DNA methylation at the promoters of the -globin genes. Interestingly, 100% of patients with SCD responded with an increase in HbF levels, including patients who had previously failed to respond to hydroxyurea.

The major dose-limiting toxicity that was observed in studies of decitabine in patients with SCD was reversible neutropenia. Interestingly, decitabine treatment resulted in an increase rather than a decrease in platelet count. In spite of the encouraging findings of these short-term studies, the long-term risks of treatment with decitabine are not known at this stage. A relatively short-term study of decitabine in patients with leukemia did not show an increase in incidence of secondary tumors after 2 to 5 years of therapy.22 An early study reported that this agent was not carcinogenic in the rat model.7 More interestingly, recent studies have shown that treatment of mice with a genetic disposition for colon or lung cancer with decitabine results in a marked reduction in tumor formation.23,24 It is believed that this reduction in tumorogenesis may reflect demethylation of tumor suppressor genes. Thus, these studies suggested that decitabine may provide potential chemoprevention for certain cancers. Larger and longer-term studies are clearly needed to confirm the safety and efficacy of decitabine in patients with SCD.

Zaini.

great find Zaini - I hope that this drug offers new hope for intermedias and maybe even majors one day. 

Thanks Puja for the link.

In addition the group of Dr. Ali Taher will also conduct the clinical trail of Hemaquest ( new oral drug that is a fetal Hb inducer but is not a chemotherapy) This trail is supposed to start by the end of this year on adults and i am following it.


Zaini, thanks a lot for your efforts that is an excellent update

manal

Manal, Puja - this is the fetal hg inducer that Dr. Vichinsky was talking about during our visit if I remember correctly. 

Sharmin

Thanks Sharmin, but i hope they start approving it for children

manal

Manal,

Let me find out for you.

Sharmin

Decitabine Side effects:

Important things to remember about the side effects of Decitabine:

You will not get all of the side effects mentioned below.
Side effects are often predictable in terms of their onset, duration, and severity.
Side effects are almost always reversible and will go away after therapy is complete.
Side effects are quite manageable. There are many options to minimize or prevent them.

The following side effects are common (occurring in greater than 30%) for patients taking Decitabine:

Low blood counts. Your white and red blood cells and platelets may temporarily decrease. This can put you at increased risk for infection, anemia and/or bleeding, and may increase need for blood or platelet transfusions.
Fatigue
Fever
Nausea
Cough
Petechiae  (Tiny red dots on your skin, called petechiae [pe- TEEK- ee- ay].  Can occur with low platelet count.)
Constipation
Diarrhea
Hyperglycemia - high blood glucose levels

These are less common side effects for patients receiving Decitabine:
Headache
Difficulty sleeping
Swelling
Low albumin
Low magnesium
Chills
Low potassium
Bruising
Rash
Low sodium
Dizziness
Generalized aches and pains
Cardiac murmur
Poor appetite
Sore throat
Abdominal pain
High bilirubin blood level
High potassium
Mouth sores
Drowsiness
Abnormal liver function blood tests
Confusion
Anxiety
Itching
Heartburn 

This list includes common and less common side effects for those taking Decitabine. Side effects that are very rare -- occurring in less than about 10 percent of patients -- are not listed here. But you should always inform your health care provider if you experience any unusual symptoms.

http://www.chemocare.com/bio/decitabine.asp

Thanks Sharmin 

Andy, in explaining how Decitabine works, they mention that

Decitabine is a member of a new class of drugs known as DNA "demethylating" agents.  Methylation of DNA is a major mechanism that regulates gene expression in cells.  When there is an increase in DNA methylation this can result in the blockage of the activity of "suppressor genes" that regulate cell division and growth.  When suppressor genes are blocked, cell division becomes unregulated, allowing or promoting cancer. 

any idea how does this affect the process of growth especially that i think hydroxyurea works with the same mechanism???

manal

Hi Manal,

I don't think Decitabine has been studied to see if it affects growth in children, but hydroxyurea has been studied.

http://www.ncbi.nlm.nih.gov/pubmed/11865275

CONCLUSIONS: Hydroxyurea treatment had no adverse effect on height or weight gain or pubertal development in school-aged children with SCA.

Both of these drugs are used in smaller doses than when used as chemotherapy in cancer patients. Interestingly, cancer patients who need transfusions often become transfusion independent after using Decitabine. Hopefully, the questions about the use of Decitabine for thalassemics will be answered by the coming trial.