15 replies to this topic

[survenant]

"RESULTS

Twenty-four patients were included (age range, 24-79 years). No pharmacological interaction was observed between the drugs. The main adverse events were weight gain in 12 patients and a mean decrease of 0.4 g/dL in hemoglobin concentration. The cumulative incidence of MR^4.5 was 56% (95% confidence interval, 37%-76%) by 12 months, despite a wide range of therapy duration (1.9-15.5 months), and 88% of 17 evaluable patients who were still on imatinib reached MR^4.5 by 48 months. The cumulative incidence of MMR to MR^4.5 spontaneous conversions over 12 months was estimated to be 23% with imatinib alone in a parallel cohort of patients."

 

Extract from

Pioglitazone together with imatinib in chronic myeloid leukemia: A proof of concept study

 

Other link Combination of pioglitazone with tyrosine kinase inhibitor

[Red Cross Kirk]

When I first clicked on the link it sent me to this page:  http://www.cancerthe...article/629613/

 

And now it doesn't.  What's up with that?

 

Anyway the above link has a link to the info about the next stage of trials.  It looks like I'd have to move to France to participate.

 

Here's the link to the U.S. National Institutes of Health page about the trial:  https://clinicaltria...how/NCT02767063

[kat73]

Hm.  Link worked for me and I read the whole article.  This really does sound encouraging!  I am only temporarily checking my enthusiasm until we hear from Trey . . .

[Trey]

We discussed Pioglitazone a while back, and the article posted above provides some new information which appears useful. 

 

The new article shows faster response rates when using Gleevec, but probably similar to Tasigna or Sprycel response rates.  So overall it is interesting but needs more study to see if it is useful.

 

Pioglitazone is a Thiazolidinedione antidiabetic which lowers blood sugar, used mainly to treat type II diabetes.  So if someone with CML has type II diabetes maybe they could try it in a clinical trial and see what happens.

 

http://community.lls...n-to-something/

My post in the previous discussion linked above was one of my good ones.  Oldie but goodie alert.

[kat73]

I am most impressed by 88% reaching MR4.5 by 48 months.  Compare that to the approximate 10% of us who ever get to or past MR4.5. That would have gotten me to a much better place and saved me three miserable years.  This specifically targets the stem cell problem; if this pans out in a large randomized trial, then it might, indeed, be a cure.  Plus it's an existing drug with a good SE profile.  C'mon, Trey - what's not to like?

[survenant]

An interesting paragraph:

 

Cytometric cell cycle analysis after propidium iodide staining revealed that 24-h incubation with pioglitazone and TKIs increased cell cycle arrest in G0/G1 from 66 to 73% for ponatinib, from 72 to 80% for nilotinib and from 71 to 86% for dasatinib (results calculated for cell cycle itself excluding subG1 phase). The addition of pioglitazone sensitized CML cells to TKIs as observed by increased number of K-562 cells in subG1 phase in TKI+pioglitazone group (Figure 2a). Cell cycle arrest was confirmed by western blotting analysis of p27 (Figure 2b). In consequence, pioglitazone significantly increased proapoptotic activity of TKIs as observed in increased cleavage of caspase 3 and PARP (western blotting, Figure 2b). To asses functional symptoms of induced cell death, a luminescent caspase 3/7 activity assay was performed on K-562 cells showing ~50% increase in caspase activity after addition of pioglitazone in comparison with TKIs alone (Figure 2c). Pioglitazone alone did not significantly affect cell cycle nor induced apoptosis (Figure 2).

 

Extract from  PPARγ ligands increase antileukemic activity of second- and third-generation tyrosine kinase inhibitors in chronic myeloid leukemia cells

[survenant]

See this new clinical trial

 

Therapies in Combination or Sequentially With Tyrosine Kinase Inhibitors (TKIs) in Chronic Phase Chronic Myelogenous Leukemia Patients in CCR (ACTIW) (ACTIW)

 

Exclusion Criteria:

1. Pregnant or lactating women,
2. Participation in another clinical trial with any investigative drug within 30 days prior to study enrolment,
3. Patient requiring anti-diabetic medication
4. Prior history of hematopoietic stem cell transplantation (autologous or allogenic)

5. Cardiovascular disease:

   • Stage II to IV congestive heart failure (CHF) as determined by the New York Heart Association (NYHA) classification system for heart failure.
   • Myocardial infarction within the previous 6 months
   • Symptomatic cardiac arrhythmia requiring treatment
6. Grade III or IV fluid retention
7. Known BCR-ABL kinase domain mutation
8. CML patient not in chronic phase at diagnosis
9. Individuals with an active malignancy
10. Kown HIV-positivity

[r06ue1]

What will be most interesting about this is if it does in fact eliminate the LSC's.  Hope it works on those in accelerated and blast crisis too, would be a nice alternative to transplant.

[Trey]

FDA Warns of Bladder Cancer Risk From Diabetes Drug
 

"The US Food and Drug Administration (FDA) has concluded that pioglitazone, used to treat type 2 diabetes, may be linked to an increased risk of bladder cancer."

 

http://www.cancernet...k-diabetes-drug

[kat73]

Parade + rain.

[gerry]

A friend of mine sent me some info on a new drug for CLL - Venetoclax. One of the side effects for some was prostrate cancer. The drug is considered a success, due to the percentage of cancer cell reduction plus 20% going into remission.

[Trey]

The difference is when there are no better options, as with some forms of CLL, it is better to take a drug with risks.  When it is not necessary to add a risky drug to control the disease, as with CML, the additional risks should be considered.

[Red Cross Kirk]

Yes, in our context, leukemic stem cell = (LSC).

[survenant]

"The US Food and Drug Administration (FDA) has concluded that pioglitazone, used to treat type 2 diabetes, may be linked to an increased risk of bladder cancer."

 

http://www.cancernet...k-diabetes-drug

 

The FDA noted that there was a trend toward higher risk with increasing duration of pioglitazone, but this did not reach significance. A retrospective cohort study, however, did find a significant association. This study included 145,806 patients newly treated with antidiabetic drugs, including 10,951 "initiators" of pioglitazone. Over a mean follow-up of 4.7 years, there were 622 new cases of bladder cancer, and 54 of those were developed following pioglitazone exposure. The adjusted HR for bladder cancer after pioglitazone use compared with no use of any thiazolidinedione was 1.63 (95% CI, 1.22-2.19). Again, longer use and larger cumulative dose raised the risk, this time significantly.

 

 

This is the reason that in the first clinical trial, 3 patients used  pioglitazone just for one year only. And they had good result.

 

"When pioglitazone was given temporarily to three chronic myeloid leukemia patients in chronic residual disease in spite of continuous treatment with imatinib, all of them achieved sustained complete molecular response, up to 4.7 years after withdrawal of pioglitazone," the authors write.

"This suggests that clinically relevant cancer eradication may become a generally attainable goal by combination therapy that erodes the cancer stem cell pool."

Extract of

http://www.oncologyn...article/437502/

 

 

[elvis]

There is a trial in Emory University on this that is currently recruiting. Search Pioglitazone trials in US.  Looks like an interesting option.

[r06ue1]

If you need it for diabetes, I would say this may be a way to get rid of one disease but the side effect profile doesn't look all that good and as Trey mentioned, can cause bladder cancer.  

 

https://www.drugs.co...de-effects.html

 

Still good to see drugs coming out to eradicate the stem cell population.  Wonder how many of those that took it for one year have been able to successfully stop all CML treatment (if they tried at all).  Three patients isn't a lot but still good to see they all hit CMR.