Epival

[LynnI]

I saw my Dr. today, good news, the last BMB still showed no chromesome changes and my C-Kit gene is normal as well.

Since I have been denied Rivlimid from our insurance company, they have decided to try a new drug on me. Apparently, my Dr. just went to a conferance with a Specialist in MDS from Germany, they have been having great luck with Eqival a anti seizure med for MDS RA, low risk patients.
Weekly CBC's and few side effects. I have to have another transfusion next week, hopefully that is the last one for a very long time. Back to see my Dr. in Sept, unless he sees a problem from the CBC reports.

Anyone heard of this treatment?

Lynn

[Zoe's Life]

Lynn,

Haven't heard of it. Is is a pill? Do you have chromosome damage? I will try to look around.

Zoe

[LynnI]

Hi Zoe's Life;
Yes its a pill, its an anti seizure med. No I don't have an chromosome damage.
I start it tomorrow, even the local small town pharmacist says there should be any side effects.
Thanks
Lynn

[Birgitta-A]

Hi Lynn,
Epival is the same as valproic acid. Valproic acid is a histone deacetylase inhibitor (HDAC inhibitor) and these kind of drugs seem to be good when you treat MDS.

The best of the HDAC inhibitors is MGCD0103 (yet - better drugs are coming) but MGCD0103 is not approved for any disease so other HDAC inhibitors are used.

The problem with Epival is that you can get tired but if you take the drug in the evening that could perhaps be a "good adverse effect".

Good luck with your treatment !
Kind regards
Birgitta-A

[Margie]

Does anyone know how Epival works or what effect it has on the low blood counts caused by myelodysplasia? Is it used often?

[LynnI]

Birgitta;
Thanks, wow I am impressed by your knowledge (along with a few others on here
I hope it works too, took my first pill this morning, already feeling tired, but then my Hem's are also very low at this time, so that doesn't help.

Thanks again
Lynn

Originally Posted by Birgitta-A

Hi Lynn,
Epival is the same as valproic acid. Valproic acid is a histone deacetylase inhibitor (HDAC inhibitor) and these kind of drugs seem to be good when you treat MDS.

The best of the HDAC inhibitors is MGCD0103 (yet - better drugs are coming) but MGCD0103 is not approved for any disease so other HDAC inhibitors are used.

The problem with Epival is that you can get tired but if you take the drug in the evening that could perhaps be a "good adverse effect".

Good luck with your treatment !
Kind regards
Birgitta-A

[LynnI]

Originally Posted by Margie

Does anyone know how Epival works or what effect it has on the low blood counts caused by myelodysplasia? Is it used often?

Margie,
I don't know how it works other than it is suppose to raise my hemoglobins and that if it does work, I should be transfusion free for at least a year (that is what my Dr. is hoping for, me too).

Lynn

[Birgitta-A]

Hi Lynn and Margie,
I can only find very difficult articles about Epival (valproic acid). In short it is a drug that affects the growth of malignant cells due to its capability to inhibit histone deacetylation. Aberrant histone deacetylase activity in malignant cells leads to silencing of tumor supressor genes and the malignant cells increases.

"Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia
Kuendgen, Andrea1; Knipp, Sabine; Fox, Frank; Strupp, Corinna; Hildebrandt, Barbara; Steidl, Christian; Germing, Ulrich; Haas, Rainer; Gattermann, Norbert

Annals of Hematology, Volume 84, Supplement 1, December 2005 , pp. 61-66

Abstract:
Valproic acid inhibits histone deacetylase activity and induces differentiation of acute myeloid leukemia (AML) blasts in vitro. We observed clinical responses to valproic acid in patients with myelodysplastic syndrome and AML.

Here, we report follow-up data on 75 patients. Of these, 66 were started on valproic acid monotherapy, with later addition of all-trans retinoic acid in patients who did not respond or relapsed. Nine patients were treated with valproic acid + all-trans retinoic acid from the start. Median treatment duration was 4 months for valproic acid and 2 months for all-trans retinoic acid.

Hematological improvement, according to international working group criteria for MDS, was observed in 18 patients (24%). Median response duration was 4 months. All-trans retinoic acid exerted no additional effect in patients receiving the combination from the start or benefited primary valproic acid nonresponders.

However, of ten valproic acid responders who relapsed, four achieved a second response after addition of all-trans retinoic acid. Response rates were strongly dependent on disease type according to WHO classification.

We found a response rate of 52% in MDS patients with a normal blast count (refractory sideroblastic anemia, refractory cytopenia with multilineage dysplasia, and refractory sideroblastic cytopenia with multilineage dysplasia).

The response rate was 6% in refractory anemia with excess blasts (I + II), 16% in AML, and 0% in chronic myelomonocytic leukemia. Bone marrow blast count was the only variable that predicted responses.

We conclude that valproic acid is clinically useful in low-risk MDS. For patients with high-risk MDS, valproic acid may be combined with chemotherapy or demethylating drugs (for example Vidaza). If patients relapse after an initial response to valproic acid, all-trans retinoic acid has the potential to induce a prolonged second response."

Kind regards
Birgitta-A

[Margie]

Many thanks Birgitta A for the info.
I was interested in this drug as a possible treatment to ask my doctor about. The Annals of Hemotology article indicates that Valporic Acid has been used successfully with multilineage dysplasia. (At least I think that is what it said.) However, one drug report I read today said that this drug "could change the time it takes blood to clot and may increase chance of bleeding". Another also mentioned the negative effect on clotting. This would not be a problem for Lynn as her platelets have not been affected. But since my platelets are already in the lower 20's, would this treatment be viable? Would the platelets come back up after treatment is stopped? I really don't expect any of you to actually know all the answers, but am just kicking around the questions?

[Birgitta-A]

Hi Margie,
You know you live in US and can get Vidaza, that is the best treatment for MDS as far as I understand. Low platelets is a common adverse reaction in connection with almost all treatments. If you look at Vidaza 65 % of the patients gets low platelets for a period after treatment.

This is the result from one trial:
1-Year Survival in Azacitidine Subgroups and Conventional-Care Regimen in MDS
Response to Treatment 1-Year Survival
Azacitidine (Vidaza)
Complete remission 96.7%
Partial response 85.5%
Hematologic improvement 96.0%
Stable disease 73.3%
Disease progression 28.6%
Conventional care 55.6%

Then there is one drug - a histone deacetylase inhibitor called Zolinza - that is approved in US for cutaneous leukemia. This drug is more effective than Epival but not as good as MGCD0103. Perhap you could get Zolinza off record?

"Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes
Guillermo Garcia-Manero, Hui Yang, Carlos Bueso-Ramos, Alessandra Ferrajoli, Jorge Cortes, William G Wierda, Stefan Faderl, Charles Koller, Gail Morris, Gary Rosner, Andrey Loboda, Valeria R Fantin, Sophia S Randolph, James S Hardwick, John F Reilly, Cong Chen, Justin L Ricker, Paul J Secrist, Victoria M Richon, Stanley R Frankel, Hagop M Kantarjian
Blood, Vol. 111, No. 3. (1 February 2008), pp. 1060-1066.

Abstract
Vorinostat (suberoylanilide hydroxamic acid, SAHA, Zolinza) is a histone deacetylase inhibitor active clinically in cutaneous T-cell lymphoma and preclinically in leukemia.

A phase 1 study was conducted to evaluate the safety and activity of oral vorinostat 100 to 300 mg twice or thrice daily for 14 days followed by 1-week rest. Patients with relapsed or refractory leukemias or myelodysplastic syndromes (MDS) and untreated patients who were not candidates for chemotherapy were eligible.

Of 41 patients, 31 had acute myeloid leukemia (AML), 4 chronic lymphocytic leukemia, 3 MDS, 2 acute lymphoblastic leukemia, and 1 chronic myelocytic leukemia.

The maximum tolerated dose (MTD) was 200 mg twice daily or 250 mg thrice daily. Dose-limiting toxicities were fatigue, nausea, vomiting, and diarrhea. Common drug-related adverse experiences were diarrhea, nausea, fatigue, and anorexia and were mild/moderate in severity. Grade 3/4 drugrelated adverse experiences included fatigue (27%), thrombocytopenia (12%), and diarrhea (10%). There were no drug-related deaths;

7 patients had hematologic improvement response, including 2 complete responses and 2 complete responses with incomplete blood count recovery (all with AML treated at/below MTD). Increased histone acetylation was observed at all doses. Antioxidant gene expression may confer vorinostat resistance. Further evaluation of vorinostat in AML/MDS is warranted."

I have low platelets too (last count 45) and dare not try any drugs now. I am waiting for the new drug Eltrombopag/Promacta/Revolade for low platelets to be approved but there will probably be restrictions so perhaps I won´t be able to get that drug on license off record.
Kind regards
Birgitta-A

[Zoe's Life]

Originally Posted by Birgitta-A

[Here, we report follow-up data on 75 patients. Of these, 66 were started on valproic acid monotherapy, with later addition of all-trans retinoic acid in patients who did not respond or relapsed. Nine patients were treated with valproic acid + all-trans retinoic acid from the start. Median treatment duration was 4 months for valproic acid and 2 months for all-trans retinoic acid.

Hematological improvement, according to international working group criteria for MDS, was observed in 18 patients (24%). Median response duration was 4 months. All-trans retinoic acid exerted no additional effect in patients receiving the combination from the start or benefited primary valproic acid nonresponders.


Birgitta-A

Birgitta,

So median response time is 4 months? Am I understanding this correctly? That isn't very long. Are you a medical professional? You are quite knowlegeable. I am always impressed by what you find.

Zoe

[Zoe's Life]

"Valproic acid has been previously associated with hematologic toxicity, including a reversible myelodysplasia-like syndrome without chromosomal abnormalities. We now report three cases of acute leukemia with features of secondary leukemia associated with valproic acid therapy: two cases of acute myelogenous leukemia with multilineage dysplasia, one with trisomy 8 and one with monosomy 7, and one case of secondary acute lymphoblastic leukemia with del (7) (q22q34), del (9) (q21.11q22), del (11) (q12q23). One patient had a previous myelodysplastic syndrome while on valproic acid. Valproic acid has been previously shown to be a histone deacetylase inhibitor. Inhibition of histone deacetylase causes a relaxation of chromatin structure and thus increases susceptibility to DNA damage and sensitizes cells to radiation. We propose that valproic acid therapy may lead to secondary leukemia by increasing DNA damage through chronic inhibition of histone deacetylase. Am. J. Hematol. 78:256-260, 2005. © 2005 Wiley-Liss, Inc."

So it causes hematological problems, but if you have them it helps?

Zoe

[Ruth Cuadra]

Originally Posted by Zoe's Life

So it causes hematological problems, but if you have them it helps?

Good question, Zoe. I would also like to know why the clinical trial for titled "Phase I/II Study of Decitabine and Valproic Acid in Relapsed/Refractory Leukemia or Myelodysplastic Syndromes" that was to have been conducted at MD Anderson Cancer Center was cancelled. Lynn, I think you need to be sure that your counts are monitored very closely while you're taking Epival because even though it has a good reputation as a drug for managing seizures, its effects on the blood and marrow do not seem to be well understood.

Regards,
Ruth

[LynnI]

Agreed, now more confused that ever. 4 months is not very long especially if the cost is possible chromosome damage. Did I understand that correctly???

Lynn

[Birgitta-A]

Hi Zoe, Ruth and Lynn,
All the new epigenic drugs like Vidaza and histone deacetylase inhibitors have a long response time – you often need at least four treatment cycles.

Yes, Epival like Vidaza, Revlimid and all other drugs for MDS as I have read about have haematological adverse effects because they damage healthy blood cells too .

I don´t know why the trial with Decitabine and Valproic acid at MD Anderson Cancer Center was cancelled but it can depend on that Vidaza seems to be a better drug than Decitabine and MGCD0103 really is a much better histone deacetylase inhibitor than Valproic acid, so it´s better for the patients to get the best drugs.

Here is a link about the new epigenic drugs – hypomethylating drugs like Vidaza and histone acetylase inhibitors like Epival, Zolinza and MGCD0103: http://tinyurl.com/5fyzsf
Kind regards
Birgitta-A

[LynnI]

I started the Epival on July 11, had my last tx on July 17th. A couple days after the tx, I felt great.
My Hemoglobins are climbing!! I have not felt this awesome since last Sept.
My Spleen has also stopped bothering me.
I have started to work again, also training my dogs and competing in Agility (winning too!!)
I expect to start riding again in a couple of weeks. I have my life back and I am going strong while it lasts!!

CBC results for the past 4 wks.

1st wk- after tx/meds;
HGB- 107, WBC-6.7, PLTS- 3.08
2nd
HGB- 113, WBC-7.7, PLTS- 3.63
3rd
HGB- 108, WBC- 6.3, PLTS- 3.33
4th
HGB- 116, WBC- 6.4, PLTS- 3.09

My hemoglobins even after a tx have not been higher than 90 since last October.

[Birgitta-A]

Congratulations to the good treatment results !
Kind regards
Birgitta-A

[LynnI]

New update;
My hemoglobins as of today are a whoping 127!!!!!!!! after 2 months of taking the pills and 2 months since my last tx. WBC's and PLTS continue to be normal and constant in their numbers.
My doctor continues to monitor me closely with weekly CBC's. It wouldn't surprise me to have to have another BMB in the near future..........
I am on a low dose at this time. Hopefully this treatment continues to work for me and for a long time........and without risks.

Lynn

[Birgitta-A]

Hi Lynn,
It is very interesting to learn that one of the histone deacetylase inhibitors (valproat, Epival) that already is on the market have so good effect !
Kind regards
Birgitta-A