Pillar 3 - AML, page-12

An overview of EM AML:

Extramedullary (outside the bone barrow) AML is defined as an extramedullary mass composed of myeloid blasts occurring in anatomical sites outside of the bone marrow.¹ Two well-known EM manifestations are Myeloid sarcoma (MS) and leukemia cutis (LC).¹ MA is also known as granulocytic sarcoma or chloroma and is a rare EM tumour of immature myeloid cells. ¹ LC is the infiltration of the epidermis, dermis, or subcutis (layers of the skin) by neoplastic leukocytes (leukemia cells) resulting in clinically identifiable cutaneous lesions. Interestingly, both subtypes of EM were seen in RAC’s recent phase II AML trial:²

Research has suggested the occurrence of the MS (2.5-9.1%) and LC (~3%) subtypes,¹ however, more recent research states the prevalence of EM AML is roughly ~20% of all AML cases.³ Comparing that to the table I have recently used:

While data is limited, survival rates for EM AML and AML are similar. ^4-5 Given that MS can develop in a wide range of sites, imaging is used to diagnose as well as monitor treatment.¹ While molecular mutations and genetic aberrations have recently become an important tool in evaluating acute leukemia and assessing prognosis, there is currently limited data available regarding the role of genetic mutations in MS.¹

Prognostic genetic markers in MS:^(1,6)

Currently, there is evidence that suggests FTO is overexpressed in AML and subtypes of AML, of particular importance is the NPM1 and FLT3 mutations. ⁷ Where FTO is expressed at a significantly higher level in AML with the NPM1 and FLT3 mutations compared to those without.⁷ FTO promotes cell proliferation/transformation and supresses apoptosis (cell death) in AML.⁷ The following is a piece of text taken from the phase II AML trial for Bisantrene discussing the impact of Bisantrene on FTO and the importance of targeting the molecule.²



Assuming that the impact of Bisantrene on FTO inhibition is as the City of Hope has said it is, we can assume that Bisantrene has the opportunity to be effective in roughly 29% of MS cases (14 + 15) and 85% of AML cases (50 + 35). While recent studies have explored the genetic marker IDH1 for FTO expression in wild mice, I cannot make sense of it, so Dr. T may have to investigate that. However, I did find that a patient who achieved a partial response from the phase II AML Bisantrene trial had a high level of IDH1 gene, which was higher than the NPM1 gene.2

Treatment options available:

Treatment strategies for MS are largely dependent on whether they develop at initial diagnosis or at relapse. LC almost always represents a local manifestation of underlying systemic disease and therefore should be managed as such.¹

Terms: RT,radiation therapy; HCT, hematopoietic cell transplantation; TSEB, total skin electronbeam therapy

I have covered intensive AML chemotherapy in a previous post and have outlined the advantages of Bisantrene as a therapeutic agent used singularly or in combination with cytarabine. Briefly, Bisantrene is much safer for the heart than the main treatment options available – anthracyclines. Because of the cardiotoxicity associated with anthracycline use, there is a limited total dose that can be given to one person over the course of their life. This influences future consolidation treatments, potentially undermining the effectiveness. Since Bisantrene has been proven to be a better option, it could replace anthracyclines both in induction as well as consolidation treatments.

Here is a table summarising the drugs used for prognostic genetic markers: ^1,6

CR, complete remission; CRh, complete remission with partial hematologic recovery; *, MS specific; LSC/LIC, leukemia stem cells/leukemia-initiating cells.
It is important to note that Bisantrene has historic data from multiple phase I and II data in 111 patients with an average complete response rate of 47%.



And of course, we need to also factor in the incredible imaging results obtained from the recent phase II AML trial:



Value:

I am not an expert when it comes to making assumptions about buyout prices, but here goes…I am going to compare Bisantrene to ivosidenib (IV), because IV has been FDA approved for use in newly diagnosed AML as well as R/R AML. Ivosidenib achieved a CR + CRh response rate of 43% in their phase I/II clinical trial, like that of the complete response rate seen in RAC from historic as well as recent phase II AML trials.^2,6 Also, IV is an IDH1 inhibitor, which accounts for 16-20% of all AML cases and roughly 31% of MS (EM AML subtype) cases.⁶

Keeping in mind that I do not have any experience with valuing companies, and this is not financial advice, but it is nice to have some numbers on my post for once. I have assumed full share dilution and that expected value for Bisantrene would be the same as 4.5x the average yearly sales of Ivosidenib.

Important final point for thought:

I am wondering if the success that Bisantrene has hadwith AML is in part due to the inhibition of FTO.

The relationship between FTO and AML is quitestrong, and now with an identified mechanism, is it too optimistic to begin to bringthe puzzle pieces together and assume that the efficacy of Bisantrene on FTO isbecause it is an effective FTO inhibitor. Could this classify as additional,conformational information improving the likelihood of inhibitory effects of Bisantreneon FTO. Certainly, exciting times ahead, and I have no doubt that Dr. T has hisfinger on the pulse with regards to this.