Effects of tamoxifen on the mutant allele burden in MPNs

Claire Harrison, MD, DM, FRCP, FRCPath, Guy’s and St Thomas’ NHS Foundation Trust, London, UK, shares the findings of the TAMARIN study (ISRCTN65011803): A Phase II trial of tamoxifen’s safety and ability to reduce molecular markers of disease burden in patients with myeloproliferative neoplasms (MPNs). Preclinically, estrogen receptor modulation has been shown to normalize apoptosis in JAK2-mutant hematopoietic progenitors, a common causative mutation of MPNs. Therefore, mutant allele burden was measured after 12 and 24 weeks of tamoxifen therapy. The results showed that of 32 patients completing 24 weeks of treatment, 4 patients achieved ≥50% reduction in mutant allele burden, with an additional 6 reaching ≥25% reduction. Baseline analysis of the hematopoietic stem and progenitor cell transcriptome completely segregated treatment responders and non-responders, indicating that clinical benefit could be predicted. This interview took place during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, 2020.

So i’d like to just share with you um a brief summary of the presentation that we made um about the use of tamoxifen and its effects upon mutant allele burden and disease course in patients with mpn so this is a study that was done by a large collaborative group based on previous work from simon mendes ferrer who actually made the presentation at the ash meeting

So the study is called tamarind you can see the lovely animal logo and it’s a therapy acceleration program trial supported by blood cancer uk and run by the cr uk clinical trials unit in birmingham so here is the schema for the study on the right hand side of the slide you can see that the main aim was to aim to reduce the mutant allele burden at 24 weeks by 50

And the secondary outcome was to reduce it by between 25 and 49 also at 24 weeks um to be eligible and patients had to be aged over 60 or postmenopausal if they were women that’s based on the side effects of tamoxifen and they had to have a detectable allele burden so we deemed that to be more than 20 percent we would not include patients who were treated with

Interferon alpha or other new agents we started the patients on 20 milligrams of tamoxifen which is a pretty standard breast cancer type treatment dose and escalated to 40 at 12 weeks if the allele burden hadn’t changed and on the right you can see the schema that we were following for the trial um we recruited a range of patients mostly they were older and the

Majority of them were male they were smattering of all of the different disease types in the classical mpn’s and most of them were at least seven years from diagnosis some shorter 0.4 years and some a long time up to 22 years the majority of patients were previously treated or currently treated with hydroxycarbomide but a range of prior treatments were given

And just to be clear that we were continuing the patient’s current treatment whether that be hydroxycarbomide or just watching weight or ruxolitinib for example and adding the tamoxifen so this is a rather complicated slide but it summarizes beautifully their primary endpoints of the study so you can see we registered 38 patients 37 of them started treatment 35

Completed 12 weeks and 32 so good number competed 24 weeks 31 of those 32 continued on beyond 24 weeks because they felt they were benefiting from the drug importantly related to this side effect profile of tamoxifen we saw two thrombotic events one after discontinuation superficial thrombophlebitis and one dvt after 20 weeks of treatment and if you look at the

Swimmer plots obviously each of these represent a patient you can see that there were actually three major responses one was discarded there were four one was discarded this one here because we couldn’t validate it and there were six minor responses now that’s really interesting in and of itself that you can give um tamoxifen treatment and lower the allele burden

In these patients without altering anything else but the really interesting data from this presentation was the work done in in simon’s laboratory and by the team by his team so here you can see rnac from peripheral blood cd34 cells at baseline and you can see that this perfectly clusters and differentiates the responders here shown in green for the those meeting

Primary endpoint and the here shown in amber for those meeting the secondary endpoint and the non-responders here in red important to note that there’s some variability of course in jack a little burden so it was important to look at week 24. so not only can patients respond to tamoxifen with a reduction in allele burden but you could maybe also predict actually

And this data looks like you can predict pretty well who is going to respond at baseline and who isn’t what about mechanism of action of tamoxifen so look at simon’s presentation for a full explanation of this but basically we could also segregate responders here in red versus non-responders here in blue in terms of activation for stat 3 step 5 and inflammation

And also here you can see responses in terms of starvation reactive oxygen species and apoptosis looking in more detail they evaluated the oxford gene signature and again we’re able to differentiate responders versus non-responders but if you look at this image here you can see that we could also see a difference before and after treatment in respondus in terms

Of the oxfox signature and this was also assessed in cell lines and different up and down regulation of different genes and you can see the variety of work here which has explained it in more detail in his oral presentation this was further investigated um thinking about the effects of tamoxifen on mitochondrial complex one inhibition and the way that this can be

Bypassed by um succinate and here is an image and just displaying a miter mitochondrial complex one it’s part of a complex excuse upon array of different proteins in the mitochondrial membrane and so what the team were able to do in brief was show that the inhibition of um that stat5 activation could be inhibition could be overcome by um succinate demonstrating

That it’s possible that the effects of tamoxifen were actually mediated by its effect on complex one in the mitochondrial membrane so the conclusion of this study which is interesting because it introduces a novel treatment and also scientific rationale and a way of predicting those patients who might be who might respond to tamoxifen is shown on this slide so

Basically we had three patients that’s um a twelfth of the patient so eight percent achieving a 50 reduction of mutant allele burden within six months which is fast faster than perhaps you’d expect with interferon a further five piece patients meeting the secondary endpoint and that we could identify these based on their transcriptomic analysis at baseline so

The plan is to consider taking this forward but we have to be very cognizant of tolerability of tamoxifen and its effect on thrombotic risk because these patients were specifically chosen to have a minimal risk of thrombosis they were all patients who had well-controlled disease with no prior robotic event so we need to think very carefully about it and this slide

Particularly acknowledges the trials teams the steering committee the coordinating team in birmingham the laboratory of simon and the tap network in the uk thanks for the opportunity to share this data with you today so this data is very interesting because it proves that tamoxifen can indeed reduce the allele burden in these patients and furthermore that we

Can predict those patients that will respond the challenge is twofold really looking at a side effect profile and deciding which patients might be suitable for a tamoxifen or tamoxifen-like agent but also in the ongoing quest to really prove the benefit of allele burden reduction in mpn patients which we first did recently in the context of the magic study but

Needs validating so as ever much more work to do but an interesting new avenue in this disease which may also explain some of the gender differences we observe in terms of patients presentation you

Transcribed from video
Effects of tamoxifen on the mutant allele burden in MPNs By VJHemOnc – Video Journal of Hematological Oncology