ASH 2010 Combining two oral chelators DFX and DFP

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Offline Akita

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ASH 2010 Combining two oral chelators DFX and DFP
« on: December 18, 2010, 07:52:36 PM »
For some reasons and for some persons it can be useful to combine two chelators. This year conference of the American Society of Hematology in Orlando,Florida, presented several studies concerning Thalassemia and Iron chelation.

http://ash.confex.com/ash/2010/webprogram/start.html

2064 Combination of Two Orally Active Iron Chelating Agents: Efficacy and Safety In a Clinical Setting

To find this study abstract and to read more than i wrote here, please go to the link above and type in:

2064  combining therapy with deferasirox (DFX) and deferiprone (DFP)

(Corr. Margarete 19.12.2010)


Citation: "The combination of DFP and deferoxamine (DFO) has been shown to be effective in reducing cardiac iron overload but some patients are unable or unwilling to use DFO. DFP alone has also been reported to be cardioprotective."

So 4 adult patients with thalassemia major with major problems with excessive cardiac iron load, a reduced left ventricular ejection fraction and either severe allergy or intolerance to DFO have been treated with the combination of DFX and DFP for between 6 and 60 months (mean 18 months). The frame was a compassionate-use programme.

The compliance of the patients was not very high, and so the results vary. The results" "indicate that the combined use of the two oral chelators (DFP & DFX) prevented further cardiac iron loading with a tendency for its reduction, significant improvement in left ventricular ejection fraction, maintenance of ferritin levels and LIC."(..) "The combination was well tolerated and easier to manage."

Citation "In particular, a prospective randomized study in patients with excessive cardiac iron will be necessary before this combination could be considered standard therapy."
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« Last Edit: December 19, 2010, 08:19:02 PM by Akita »

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Offline Lena

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Re: ASH 2010 Combining two oral chelators DFX and DFP
« Reply #1 on: December 19, 2010, 11:03:35 AM »
So this combination has proved to work...let's wait for Ferriprox/Exjade results now.

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Offline Dori

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Re: ASH 2010 Combining two oral chelators DFX and DFP
« Reply #2 on: December 19, 2010, 03:01:59 PM »
Lena, I am also waiting for those results. I really want to move on that in the summer so let's hope there is more clearity (not a word?) by then. Do you think fe of 1200+ and 1125mg of Exjade daily is enough?

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Offline Lena

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Re: ASH 2010 Combining two oral chelators DFX and DFP
« Reply #3 on: December 19, 2010, 05:26:48 PM »
Hi Dori,

I am not an expert on exjade really but I would think that the exjade dosage does not depend on ferritin count, it depends on your weight in the first place. You start from there and then adjust the dosage accordingly. I can not advise you further on that. Sorry. Maybe Andy would have to say something.

Lena

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Offline Andy Battaglia

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Re: ASH 2010 Combining two oral chelators DFX and DFP
« Reply #4 on: December 19, 2010, 05:51:11 PM »
We've been talking with Dore on Facebook about Exjade and right now the key issue is overall tolerance of Exjade. If that can be worked out, then the dosage should also be addressed. Dore, hydrate, hydrate, hydrate.
Andy

All we are saying is give thals a chance.

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Offline Akita

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Re: ASH 2010 Combining two oral chelators DFX and DFP
« Reply #5 on: December 19, 2010, 07:59:45 PM »
So this combination has proved to work...let's wait for Ferriprox/Exjade results now.

Hi all,

DFP = Deferiprone = Ferriprox ????

Are there differences between Ferriprox and DFP?

This study is dealing with this combination: Exjade/DFX and DFP/Deferiprone/Ferriprox!

Asking,

Margarete

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Offline Andy Battaglia

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Re: ASH 2010 Combining two oral chelators DFX and DFP
« Reply #6 on: December 19, 2010, 08:00:55 PM »
Deferiprone, L1, Ferriprox and Kelfer are all the same drug.
Andy

All we are saying is give thals a chance.

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Offline Akita

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Re: ASH 2010 Combining two oral chelators DFX and DFP
« Reply #7 on: December 19, 2010, 08:29:06 PM »
Here is the whole abstract. Sorry that i could not copy the table in a right way. As the link in the first posting of this thread did not work, i put an advice there how to come to the study-abstract, so you can see the correct table.

Regards,

Margarete

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2064 Combination of Two Orally Active Iron Chelating Agents: Efficacy and Safety In a Clinical Setting
Oral and Poster Abstracts
Poster Session: Thalassemia and Globin Gene Regulation: Poster I
Saturday, December 4, 2010, 5:30 PM-7:30 PM
Hall A3/A4 (Orange County Convention Center)
Poster Board I-1044

Vasilios Berdoukas, MBBS1, Susan Carson, RN, MSN, CPNP1*, Anne Nord, RN, BSN, CCRP1*, Thomas Hofstra, MD1*, Susan Claster, MD2, John Wood, MD, PhD3* and Thomas D. Coates, MD1

1Department of Hematology, Children's Hospital of LA, Los Angeles, CA
2Hematology Oncology, Children's Hospital Los Angeles, Los Angeles, CA
3Pediatrics and Radiology, Children's Hospital Los Angeles, Los Angeles, CA
For patients with transfusion dependent anemias, in particular thalassemia major, as part of a compassionate –use program that was approved by the hospital’s IRB,  we report the efficacy and safety outcomes of combining therapy with deferasirox (DFX) and deferiprone (DFP).  The combination of DFP and deferoxamine (DFO)has been shown to be effective in reducing cardiac iron overload but some patients are unable or unwilling to use DFO. DFP alone has also been reported to be cardioprotective.  Based on concerns for their welfare in the presence of excessive cardiac iron load, a reduced left ventricular ejection fraction and either severe allergy or intolerance to DFO, 4 adult patients with thalassemia major have been treated with the combination of  DFX and DFP for between 6 and 60 months (mean 18 months). All four patients were initially treated with DFO or DFX but DFP at 75-100 mg/kg/day was initiated because of severe cardiac iron overload.  DFX  at 15-40 mg/kg/day was added based upon high liver iron concentrations(LIC).  Efficacy was evaluated by monthly ferritin levels and semiannual cardiac T2* and LIC estimates (using MRI R2 and R2*).  All 4 patients had at least two MRI assessments. Table 1 shows the changes in ferritin, cardiac T2*, LVEF and mean LIC.  Cardiac T2* improved from 5.8 ±1.5 to 7.0 ± 1.5 ms., (p=0.15).  If the T2* is recalculated as cardiac iron concentration then the change was from 4.1± 1.3 to 3.3± 1.1 mg/g dry weight (p=0.09).  One patient who has been receiving the treatment for 6 months has shown a 1% per month deterioration in T2*.  The patients who have been on the combination for 12, 24 and 60 months, have had reductions of 2.7%, 0.5% and 1.5% per month respectively.  LVEF improved overall from the baseline value of 52.8% to 58.9% (p=0.02).  Ferritin fell from a mean of 5826 to 5544 ng/L (p=0.86). LIC increased from a mean of 20.7 to 28.1 mg/g dry weight (p=0.36).   Table 2 shows the baseline and minimum absolute neutrophil counts and baseline and final ALT (IU/L).  No drug-related neutropenia (ANC of <1.5 x109/L), agranulocytosis or arthralgia were observed. No patients demonstrated significant proteinuria and mean creatinine levels were unchanged.  ALT’s showed fluctuations that were compatible with the degree of LIC.  It is important to note that compliance was extremely variable in that one patient (P3), only took DFX once monthly with many lapses in her DFP treatment as well.  The other patients also had significant lapses in their compliance as well as long vacation periods during which they did not receive treatment.  These results indicate that the combined use of the two oral chelators (DFP & DFX) prevented further cardiac iron loading with a tendency for its reduction, significant improvement in left ventricular ejection fraction, maintenance of ferritin levels and LIC. It is also possible that the DFP cardioprotective effect may be activated even in the presence of poor compliance with it.  The combination was well tolerated and easier to manage.  It is more acceptable for life-long chelation and positively influenced patients’ quality of life. It seems likely that maximum doses of both medications need to be prescribed for better outcomes and longer periods of follow up are essential.  In particular, a prospective randomized study in patients with excessive cardiac iron will be necessary before this combination could be considered standard therapy.

Table 1 showing the starting (1) levels and most recent levels (2) for ferritin (ng/L), cardiac T2* (T2*H in ms.), Left Ventricular Ejection Fraction (LVEF %) and  Liver Iron Concentration (LIC mg/g dry weight).

Identifier

 
   

Ferritin1

 
   

Ferritin2

 
   

T2*H1

 
   

T2*H2
   

%change/month
   

LVEF1%
   

LVEF2%
   

LIC 1

 
   

LIC 2

 

P1
   

1560
   

2050
   

5.6
   

7.8
   

2.7
   

46.5
   

53.6
   

3
   

8.7

P2
   

1892
   

3419
   

7.8
   

7.5
   

-1
   

52.9
   

61.2
   

8.6
   

11.1

P3*
   

8100
   

9570
   

4.1
   

4.7
   

0.5
   

60.5
   

62.5
   

35.5
   

60

P4
   

11754
   

7140
   

5.6
   

7.9
   

1.5
   

51.3
   

58.1
   

35
   

30

*Very poor compliance

Table 2 showing baseline absolute and lowest neutrophil count (ANC x109/L ), baseline and latest ALT (IU/L).

Identifier
   

Baseline ANC
   

Lowest ANC
   

Baseline ALT
   

Latest ALT

P1
   

3.4
   

2.2
   

91
   

64

P2
   

4.8
   

2.1
   

23
   

95

P3
   

3.8
   

2.8
   

72
   

69

P4
   

4.7
   

4.5
   

133
   

64

Disclosures: Berdoukas: ApoPharma Inc.: Consultancy. Wood: Novartis Inc.: Research Funding; ApoPharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Coates: Novartis: Research Funding, Speakers Bureau.

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Offline Lena

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Re: ASH 2010 Combining two oral chelators DFX and DFP
« Reply #8 on: December 20, 2010, 08:24:35 AM »

Silly me!!!
of course, we are talking about the two oral chelators here Ferriprox and Exjade and now I remember that my doctor did mention it to me the other day that Dr. Berdoukas has proceeded with this cilinical trial. Of course in our Thal Unit, we have been taking this combination for 2 years, maybe more and results are good up to now- only our results have not yet been published. Again our patients sample is bigger - some 20 or more patients - while the sample in Dr. Berdoukas' trial is only 4 patients, if I understood it correctly.

This is very hopeful for all thals and the key issue, as Andy put it, is the overall tolerance of exjade.
Let's hope for the best.

Lena

Re: ASH 2010 Combining two oral chelators DFX and DFP
« Reply #9 on: December 20, 2010, 08:45:56 AM »
so lena does this mean that thals all over the world can think the needle for chelating a thing of the past?

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Offline Lena

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Re: ASH 2010 Combining two oral chelators DFX and DFP
« Reply #10 on: December 20, 2010, 10:07:03 AM »
Soon I hope. Soon.

Re: ASH 2010 Combining two oral chelators DFX and DFP
« Reply #11 on: December 20, 2010, 11:20:31 AM »
is it advised to take this combination when a child starts chelating?
it is usually unsuccesful if the liver has been damaged previously?
i just hope and pray that more comfortable and cheaper medication is available!

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Offline Akita

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Re: ASH 2010 Combining two oral chelators DFX and DFP
« Reply #12 on: December 20, 2010, 06:20:58 PM »
Hi Love and Prayers,

is it advised to take this combination when a child starts chelating?

This combination actually is not advised at all. This study describes four patients with special problems with iron in the heart, and it was given by "compassionate use", -not regularly. The combination seems to help to diminuish the danger of heart - problems connected with an iron-overloaded heart in this special constellations/cases and probably in similar ones, if the doctor decides to try this combination with a patient..  As patients with Thal-Major (so i read) usually don`t get a cardiac iron loading problem before age of 9.5, i cannot imagine that is can be advisable to use this combination for a child starting chelation.

it is aimed to prevent dangerous damage for the heart by iron overload for some adult patients, who cannot tolerate another chelation therapy. Maybe there wil be a better outcome in another study on DFX and DFP, where the study - patients where more stabile compliant to the medication.

I cannot advise you at all in this question, as i dont know much more as there is written in the study/s and a doctors clinical experience is necessary to advise you in this serious question.
Maybe the next study, mentionend in this thread, will bring new insights..

it is usually unsuccesful if the liver has been damaged previously?

This is a special topic you should discuss with your doctor.

i just hope and pray that more comfortable and cheaper medication is available!

That is a big problem

The combination of chelators should not be for financial reasons because there exists the danger of failing the necessary theapies that are adjusted for the very patient by advice of the doctors..

Sorry,

Regards,

Margarete
« Last Edit: December 20, 2010, 06:43:15 PM by Akita »

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Offline Akita

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Ferritin Levels in this study DFX - DFP
« Reply #13 on: December 20, 2010, 06:51:02 PM »
The levels for ferritin, as indicated in Table 1 were:

Patient: 1

starting level: 1560
most recent level after the treatment 2050

Patient 2

starting level: 1892
most recent level after the treatment 3419

Patient 3 - very poor compliance

starting level 8100
most recent level after the treatment 9570

Patient 4

starting level 11754
most recent level after the treatment 7140

You see that the ferritin levels only decreased in patient 4, not in the three other patients.

But the combination seemed to prevent further cardiac iron loading "with a tendency for its reduction'" significant improvement in left ventricular ejection fraction, maintainance of ferritin levels and LIC..

Regards,

Margarete

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Offline Dori

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Re: ASH 2010 Combining two oral chelators DFX and DFP
« Reply #14 on: January 05, 2011, 04:20:57 PM »
Lena, I quitted with Exjade. I had no choice. It's so weird one can feel so good without it. I know, I should restart soon. I am completely at a lost. I think I will give every dose a month to get used of it or. Or just go in war and stay 2 months at the same level. Still don't know which, haha. I will bored you on other time with that. Know that any help is more than welcome.

 

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