Innovative Developments in Myelofibrosis Treatment Options

Prithviraj Bose, MD, MD Anderson Cancer Center, Houston, Texas, shares expert insight on recent developments in myelofibrosis treatment, briefly reviewing BET inhibitors, PIM kinase inhibitors, type II JAK inhibitors, and phase 3 trial data on imetelstat and luspatercept.

“This is an exciting era for drug development in myeloproliferative neoplasms, especially in myelofibrosis, some [studies] coming down the pipe [and] some that we have some results on,” concluded Dr Bose.

Transcript:

Hi, I'm Prithviraj Bose. I'm a professor in the department of leukemia at MD Anderson Cancer Center in Houston, Texas, and I focus on myeloproliferative neoplasms. This is an exciting era for drug development in myeloproliferative neoplasms, especially in myelofibrosis. I'll very briefly touch on some of the things that are exciting in the field; some coming down the pipe, and some that we have some results on.

Our audience knows that there's been tremendous excitement about pelabresib, the BET inhibitor, results of which in the phase 3 setting were presented at (the American Society of Hematology) ASH [meeting] 2023 and then at (the American Society of Clinical Oncology) ASCO [meeting] and (the European Hematology Association) EHA 2024 [meeting]. But there are other BET inhibitors that are not quite as far along in their development, but certainly things to watch. I would direct folks' attention to the INSITE compound INCB057643, which is in the LIMBER-103 trial. This is a BET inhibitor that's coming along nicely with some good tolerability, some early clinical efficacy, both in the frontline setting and in the add -on setting.

Moving on then to other targets, there is a PIM kinase inhibitor that has generated quite a bit of excitement. This is from a company called Sumitomo and it's called TP3654. This drug is novel because its target is PIM and it manages to spare the platelets, which is clearly an advantage in drug development in myelofibrosis. One can give this to patients that are fairly thrombocytopenic. The trial has gone down to platelets of 25 as the lower limit. This is because it's PIM-1 selective. The key message from this trial is that this is an active drug, thus far studied only in monotherapy, but it's an active drug, especially for symptoms. We've learned from recent phase 3 trials that symptoms can be a high bar to overcome, especially when you're trying to beat ruxolitinib [treatment] alone. We're not there with this drug—just to clarify, it's only been studied as monotherapy, but there is a clear symptom signal. What's nice about it is that it's also correlated with cytokine downregulation. So, there is perhaps some biologic plausibility there that explains the symptom benefit.

Those are 2 exciting, non- (Janus kinase) JAK targets. There are also a whole slew of new approaches looking at a JAK itself. For example, the mutant-selective JAK inhibitors. There's also the type II JAK inhibitor. These are 2 different concepts. The mutant selective, as the name suggests, targets JAK2V617F and not wild type JAK. So, the idea [is to] spare the cytopenias and be able to hit the target harder.

Whereas with the type II, they attempt to overcome persistence, which is a mechanism of resistance to type 1 JAK inhibitors, which all 4 commercially available ones are. The type II [inhibitors] would be something completely novel and clearly looking forward to these trials, [because there is] no clinical data on either of these compounds yet.

There is also targeting mutant (Calreticulin) CALR. Mutant CALR, because of its biology, lends itself particularly well to targeting by the immune system. So, we have a monoclonal antibody against mutant CALR, and we have a T-cell redirecting by specific antibody against mutant CALR. Again, [there is] no data on these in the public domain, but very, very interesting targets.

Finally, there are some phase 3 [trials] which are coming along nicely and approaching end of accrual,  or at least more than half accrued. I'll make quick mention of imetelstat, a telomerase inhibitor that was just approved for myelodysplastic syndromes (MDS). The myelofibrosis trial is underway. It's phase 3 overall survival is the primary end point uniquely to this trial and it's compared against best available therapy excluding JAK inhibitors and this is in the second-line setting. The trial is called the IMpactMF trial.

Finally, there's luspatercept, which is an anemia drug approved for MDS, but they have a phase 3 trial; the trial is called INDEPENDENCE, [a] phase 3 trial versus placebo in transfusion requiring subjects who are on a JAK inhibitor, a stable dose of a JAK inhibitor with myelofibrosis. This is another phase 3 trial nearing completion of accrual, and the readout of this is highly anticipated.