Pillar 3 - AML

The point of this post is to get some information around this pillar. As it is our home base, I personally wanted to increase my knowledge in the area, as well as create some discussion around the topic. It is important to know who is suffering from AML as well as the comorbidities associated with these groups and then what treatment options are available.

Demographics:

AML can occur at any age, but is most common in adults over the age of 60, with the average age of roughly 68. Unfortunately, survival rates for people above the age of 60 are as low as 5-15%, as they are often not fit enough for intensive therapy. A report evaluating AML stated that incidence (number of occurances) is expected to rise due to an ageing population.

Estimations on the number of new cases per year:

	Europe	~26,000	https://worldcancerinitiative.economist.com/pdf/acute-myeloid-leukaemia/acute-myeloid-leukaemia-report.pdf
1	US	~19,940	https://www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html
2	Australia	~900	https://www.leukaemia.org.au/blood-cancer-information/types-of-blood-cancer/leukaemia/acute-myeloid-leukemia
3	Asia-pacific	4/100,000 to 7/100,000	4.2 billion people make up the Asia pacific, so 168,000 to 294,000 cases: https://www.mordorintelligence.com/industry-reports/asia-pacific-acute-myeloid-leukemia-treatment-market
4	Total	46,840	Excluding Asia pacific

Ageing population and over 60:
In the American Heart Associations 2019 Heart Disease and Stroke Statistical update, the incidence of cardiovascular disease was reported to be approximately 77% of people aged 60-79 years and 90% of people aged over 80 years. With a growing population of older people who are at great risk of cardiovascular diseases as well as AML, it highlights the clinical importance of chemotheraputic agents that reduce the burden on the heart.
Typical treatment of AML:

Treatment of most patients with acute myeloid leukemia (AML) is typically divided into 2chemotherapy (chemo) phases:

1. Remission induction (often just called induction)
2. Consolidation (post-remission therapy)

Remission induction

For those under the age of 60, intensive chemo with two drugs - Cytarabine (ara-C) and an anthracylcine (either daunorubicin or idarubicin). A systematic review evaluating the effectiveness of daunorubicin or idarubicin with cytarabine reported that idarubicin + cytarabine had better efficacy, although adverse events like cardiotoxicity were consistent between groups. Idarubicin has a culmatative dose of 90 mg/m2 associated with a >5% incidence of heart failure. In comparison to bisantrene...

Bisantrene is positioning itself as a compound that can overcome the culmatative dose-dependent cardiotoxicity limitations of anthracycline based therapies.

Patients with heart problems or those above the age of 60 are typically not to be treated with anthracyclines, so are treated with another chemotheraputic agent like etoposide.

Etoposide with Idarubicin in elderly patients unable to undergo intensive chemotherapy:


Efficacy data on cytarbine and etoposide:

My thought is that Bisantrene could replace this group as a safer anthracyline therapy used in those with heart problems or those above the age of 60 years. The average complete response seen in all 6 phase I and II trials was 47%. On par or higher than the 41.7% seen in the trial above.

Consolidation:
Consolidation is the therapy given to destroy any remaining leukemia cells to help prevent relapse.

For younger patients the main options for consolidationtherapy are:
-- Several cycles of chemo with high-dose cytarabine (ara-C) (sometimes known asHiDAC)
-- Allogeneic (donor) stem cell transplant
-- Autologous stem cell transplant

The best option will depend on the individual factors for each person.

Interestingly, LoDAC (low-dose cytarabine) that was approved for AML based off a 18% complete response, is mentioned in the Rediscovery of Bisantrene article.



Article evaluating the role of anthracyclines in AML consolidation.

The article explore the possibility of anthracyclines being used in consolidation therapy. However, as mentioned before, there is a culmatative dose of 90 mg/m2 of Idarubicin, which limits the amount of anthracycline that can be given. The current options are to use more Idarubicin or to use another anthracycline with proven cardiotoxicities. This highlights that Bisantrene could be used within the consolidation periods alongside high-dose cytarabine.

Another interesting piece of research:

This indicates that anthracyclines induce surface calreticulin (calcium-binding proteins involved in gene trasncription) where cytarabine does not. Potentially indicating that cytarabine + anthracycline therapies could provide improved survival over singular cytarabine doses.

For patients above the age of 60 or with heart problems, the choices of consolidation therapy are limited:

-- Higher-dose cytarabine (usually not quite as high as in younger patients)
-- Standard-dose cytarabine, possibly along with idarubicin, daunorubicin, ormitoxantrone
-- Non-myeloablative stem cell transplant (mini-transplant)

I do not think I need to comment about the position that Bisantrene could take in this group. Replacing the anthracyclines due to reduced cardiotoxicity, as well as being used alongside higher-dose cytarabine.

In conclusion, from what I can see Bisantrene has the potential to replace current therapies and even create new therapies for AML. The reduced cardiotoxic profile of Bisantrene is a game changing component in my opinion because I can see it littered everywhere I look. In my opinion, this is the risk-mitigated pillar.

All IMO.