Nature Article

[mistergern]

I'm not sure if this comprehensive article has been shared on this forum yet.

https://www.nature.com/articles/s43018-023-00653-5

I found the final few paragraphs to be extremely positive:

Using a newly established, comprehensive AML patient-derived xenograft resource that reflects the overall genetic abnormalities found in large clinical cohorts, we demonstrated a proof of concept for the sequential administration of standard induction chemotherapy followed by imetelstat consolidation to induce oxidative stress and sensitize AML patient samples to imetelstat treatment. This approach was able to cause significant delay or prevention of AML relapse. The efficacy of sequential therapy suggests that imetelstat may be particularly useful in preventing relapse after chemotherapy, for example, as a maintenance therapy. Recently, maintenance therapy with oral CC486 has shown a survival benefit in AML; however, there is no survival plateau and therefore, most patients still relapse and die of their disease55. A substantial proportion of AML patient samples tested (14 out of 30 samples) were classified as sustained responders to imetelstat monotherapy and are characterized by genetic lesions in genes involved in cell adhesion, metabolism and signaling, with the most striking result obtained for NRAS. NRAS is the fourth most commonly observed gene with driver mutations in adult AML2. Moreover, AML cell clones harboring mutant NRAS arise in some patients relapsing on targeted therapies, particularly FLT3 inhibition (crenolanib56 and gilteritinib57) and BCL2 inhibition in some cases (venetoclax58,59). The demonstrated sustained responses to imetelstat in NRAS-mutant AML patient samples raise the possibility that imetelstat may be used as salvage therapy or possibly in combination with FLT3 inhibitors or venetoclax to prolong remission and prevent relapse.

In conclusion, imetelstat is a potent inducer of ferroptosis that effectively diminishes AML burden and delays relapse following oxidative stress-inducing chemotherapy.

Clinical trials will address the efficacy of imetelstat in AML and may focus on this compound as a consolidation strategy for preventing relapse or potentially together with targeted therapies to improve outcomes in patients with AML.

[biopearl123]

Mistergern, yes this seminal article article was first posted on YMB (not by me) and subsequently reposted here on Oct 31st. It’s pretty amazing work that reflects 5 years of nonstop hard work by Dr. Lane and his team with special recognition to the lead author Dr. Claudia Bruedigam. While this is a basic science contribution, the subsequent highlights that found their way into the YouTube vids, spotlight a lovely Australian lady in her late 70s with AML. While the actual response to Imetelstat was not mentioned, its seems likely that her gratitude and willingness to share her story reflects a beneficial response. A few other tidbits dropped include that the study is about 50% enrolled and looking for another 25 patients. Clinical trials site suggests some data by 1/24 with primary results by then. Primary end point to be assessed after 4 months of therapy, a pretty short study that should pave the way for the first combination therapy study to start at some as yet undetermined time.

[mistergern]

Thanks for your summary BP. I was particularly struck by what seemed to be the universal applicability of imetelstat to inhibit remission. Do you think there's a possibility that Imetelstat may be utilized for non-hematological cancers to aid in the inhibition of remission?

[biopearl123]

Mr.G, good question. As you can see on clin trials site, there have been many solid tumor studies from over a decade ago that failed. Nonetheless less, new combinations might be tried or new ways up inhibit telomerase (e.g. MAIA or Geron’s as yet to be revealed, oral agent in early development) could hold promise. For now there is so much in the liquid tumor realm, I suspect Geron will be busy for a while.