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ASH 2021 | Bomedemstat in JAK inhibitor-resistant myelofibrosis

Harinder Gill, MBBS, MD, FRCP, FRCPath, The University of Hong Kong, Hong Kong, China, presents findings from the ongoing, open-label Phase II trial (NCT03136185) of bomedemstat, a lysine-specific demethylase-1 (LSD1) inhibitor, in patients with myelofibrosis (MF) who are resistant or intolerant to JAK inhibitors. 89 patients were enrolled, with half the patients having primary MF. Once-daily administration of bomedemstat monotherapy successfully resulted in a reduced spleen volume and total symptoms score (TSS) in a majority of patients, and had an acceptable tolerability profile. Dr Gill additionally highlights the reduction of mutant allele frequencies as a result of bomedemstat. This interview took place at the 63rd ASH Annual Meeting and Exposition congress in Atlanta, GA.

Transcript (edited for clarity)

So, just to give you a brief, sort of background to Bomedemstat. So, basically why was that trial designed, and why is that trial so useful? I think the first thing is that LSD1, or, the lysine specific demethylase 1, actually is associated with sustaining the malignant stem cell activity. So, it’s naturally a target for us in the management of myeloid malignancies.

And, obviously as we know about my myelofibrosis, so a lot of the clinical manifestations and disease manifestations are actually secondary to the malignant megakaryocytes and the clonal hematopoiesis involved...

So, just to give you a brief, sort of background to Bomedemstat. So, basically why was that trial designed, and why is that trial so useful? I think the first thing is that LSD1, or, the lysine specific demethylase 1, actually is associated with sustaining the malignant stem cell activity. So, it’s naturally a target for us in the management of myeloid malignancies.

And, obviously as we know about my myelofibrosis, so a lot of the clinical manifestations and disease manifestations are actually secondary to the malignant megakaryocytes and the clonal hematopoiesis involved.

So, inhibiting this particular pathway is a certain sort of target for us. So, that’s the reason this particular trial was designed, based on the preliminary work. So, basically it’s a once daily dosing of treatment. And, so far, in fact, in all other evaluation, has been evaluated in more than 17 myeloid patients with myeloid malignancies with no sort of safety signals observed. And, we’ll update you on the Phase II results.

In fact, some of the results were previously presented at EHA, right, so, basically it’s an ongoing Phase I/II global study. And, the primary endpoints where the safety and tolerability, and the pharmacokinetics, and the screen volume reduction. We had important secondary endpoints that comprised symptom burden reductions, changes in cytokine profiles and the mutant allele frequencies, and also, changes in the marrow fibrosis. So, the key eligibility were primary or secondary myelofibrosis, and patients with resistance to refractoriness, to the existing, available therapies.

And, those were mainly JAK2 inhibitors. So, in other words, most of these patients failed the conventional JAK2 inhibitors, mostly ruxolitinib. And, obviously we ensure these patients had a good performance status of two or less. And, without any evidence of disease acceleration, and baseline splenomegaly was allowed.

So, what we did, we treated these patients with a daily dosing. We started off at a 0.5 mg per kilogram dosing, and then it’s the one steady dosing. And then usually adjust the treatment every two to four weeks until a target platelet of around 50 to 75, as a therapeutic target, for us to achieve the benefits of this particular agent.

So, this was the actual design, it’s Phase II. So, it’s a single arm. So, basically as far as the results that we’ll be presenting, we have actually completed the enrolment of a total of 89 patients. So, I’ll be presenting on the evaluable patients as well. So, 89 patients were enrolled with a median age of 68, mostly men, 52%, and mostly patients with primary myelofibrosis, 46% patients with primary myelofibrosis. The rest were either post-ET MF, or post-PV MF. And, most patients were actually, IPSS the International Prognostic Scoring System, intermediate two, or high risk.

In fact, 39% for intermediate two, and 53% for high IPSS. And, most of these patients were treated with ruxolitinib. 74% of these patients were treated with ruxolitinib, and a median of two prior lines of therapy. And, most were JAK2 mutated, 64%, as you would expect, followed by calreticulin mutations and MPL mutations. And, of note, 38% of this treatment population actually harbor the high molecular risk mutations like ASXL1, especially. And also, the IDH1, IDH2, EZH2, SRSF2, and U2AF1. So, these are … This is the actual background. And, as far as the safety and tolerability is concerned, the commonest non-hematologic toxicity was dysgeusia.

But then, it was mostly tolerable. All other hematologic toxicity was thrombocytopenia, but that was somewhat expected because we aimed at a lower target platelet count. But then, there were no significant safety signals observed or deaths related to treatment observed in these patients. And, I’d like to go over with some of the important primary endpoints.

As far as symptom, total symptom score at 24 weeks was concerned, 74% of patients, available patients had reduction in total symptom score. And, 26% had a 50% or more reduction in total symptom score. So, these were patients who were refractory to ruxolitinib, mostly and, achieved a further reduction in the symptom burden, so that’s quite important. And, the spleen size reduction also occurred in 75% of the available patients.

An important thing I’d like to highlight about this study was that there were hemoglobin improvements in patients. So, in patients who were transfusion independent, the hemoglobin remains stable, even increased in more than 40% for about one gram per deciliter, over time. And, there were a number of patients who actually achieved transfusion independence too.

And, another important secondary endpoint was the reduction in the mutant allele frequency of the important driver genes. Overall, most genes had reduction in their mutant allele frequencies.

And, that is an important thing. And, the other thing is that ASXL1, which is one of the high-molecular-risk mutations, in fact 45% of these patients harboring this particular mutation had reduction in the mutant allele frequency. This actually, points towards a disease modifying effect of this particular agent. So, in conclusion, it’s safe as a monotherapy. And, it also showed an important sort of, achievement in terms of symptom reduction, and also, evidence of disease modifications. So, obviously we need to wait for longer term results of this particular study to see if these effects were sustained. So, I think this is sort of a sum up of this particular study that I’ll be presenting at ASH.

 

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