Unmet Needs in Myelofibrosis Treatment


Experts delve into the unmet needs in the myelofibrosis treatment landscape and highlight promising ongoing clinical trials.

John Mascarenhas, MD: Raajit, there are obviously unmet needs that still exist. Srdan nicely laid out the potential approaches for sequencing these JAK inhibitors, but maybe you could highlight some of the unmet needs in which we may need to look outside the JAK inhibitor therapy family. What are some other targets that might help address some of these unmet needs?

Raajit Rampal, MD, PhD: Let’s lay out some of the clinical unmet needs. Things like anemia and thrombocytopenia are common problems that we deal with. We’ve talked a lot about some of the benefits that we see with the different JAK inhibitors. Srdan [Verstovsek] talked about what we do with patients who are more cytopenic vs those who have more proliferative diseases. Do we have drugs that can reverse those things? That’s more of a problematic issue. Certainly, we have things that we’ve used as adjunctive therapies, such as erythropoietin-stimulating agents to try to improve anemia.

More recently, we have drugs in clinical trials that target the TGFB pathway. Drugs that Aaron [Gerds] is leading trials of, for example. Those things are emerging. There are other emerging JAK inhibitors that may have some benefit for anemia, but these are the consistent clinical problems we deal with.

Ultimately, we need therapies that change the natural history of the disease. The only thing we have to offer is allogeneic stem cell transplant, which is the only potentially curative modality that we have, but it comes at a significant risk to the patient. Are we satisfied with what we have? It depends on what the patient’s goals are. All the drugs we have are good at shrinking the spleen and improving patients’ quality of life. For a substantial number of patients, that’s what they need to be able to live their lives. We know most extensively with ruxolitinib that the effects of therapies aren’t necessarily durable. Aaron was talking about this a moment ago. If you’re watching patients over time, you start to see that the maximal effect diminishes over time. The disease is progressive despite these therapies.

When we think about how we improve upon the therapies we have, let’s put anemia and thrombocytopenia aside for a moment. How do we build a better mousetrap? In principle, there are 2 things. One is that we can become better at targeting the JAK-STAT pathway itself or start to target downstream signaling pathways that are inherent to the activation of the pathway. Starting at the top, is the future more powerful JAK inhibitors or more selective JAK inhibitors? There are preclinical published data to support the idea of type 2 JAK inhibitors. Hopefully, those things are on the horizon. We’ll have to test whether they make a difference clinically.

Alternative pathways are pathways that get activated by JAK-STAT, and there are a couple of things to think about. Some of these ideas are both preclinically and clinically validated. We know that the PI3K-AKT pathway is activated by JAK-STAT. There’s a drug called parsaclisib in clinical trials that in phase 2 studies has shown the ability to reduce the size of the spleen and symptom burden when added to ruxolitinib. That’s at least proof of principle that adding a drug that targets a parallel pathway can have efficacy in the disease. There are interesting preclinical studies that have identified that the MAP kinase pathway appears to be of interest, and not necessarily in the same cell as the JAK-STAT activation but potentially in the surrounding cells, and that may play into the disease pathogenesis. As far as cell cycle, several papers that have demonstrated preclinically that CDK4/6 inhibition when added to JAK-STAT inhibition may have therapeutic efficacy.

We’re beginning to see this idea of moving beyond simply targeting JAK-STAT, but the drugs we have are first generation, and whether we’re going to have newer, more selective, more powerful agents that target the pathway is an open question that remains to be seen. But we’re already in the era of targeting other activated pathways that occur in parallel but also downstream, including NF-KappaB, which we know are fundamental to the disease. In phase 2 studies, we’ve seen success with BET inhibitors that play a role in inhibiting that pathway. There are a lot of potential targets here.

John Mascarenhas, MD: Excellent. To leave the audience with some sense of where the field is from a clinical perspective, there are studies looking at single-agent JAK inhibitors. The PACIFICA study is an ongoing randomized phase 3 study in patients with myelofibrosis [MF] and platelet counts less than 50,000 per mm3 that looks to validate and enforce the current FDA label for pacritinib.

A study that used to be ongoing but has completed accrual and the primary analysis is the MOMENTUM study. This is momelotinib, a JAK1/2 ACVR1 inhibitor in patients with myelofibrosis who were previously treated with ruxolitinib and have anemia. The data that have been presented also look favorable in terms of not just hitting the primary end point of symptom improvement but also key secondary end points of spleen and anemia responses. We look forward to seeing those mature results at ASCO [American Society of Clinical Oncology Annual Meeting] and EHA [European Hematology Association Congress].

There are a number of promising combination studies that have phase 2 data that support their phase 3 study. This includes parsaclisib, a PI3 kinase inhibitor, being looked at in a placebo-controlled, double-blinded study. Actually, there are 2 studies: patients who are naïve to ruxolitinib and those who were previously treated with ruxolitinib, in which the drug can be added. Then there’s the BOREAS study with the MDM2 inhibitor KRT-232, or navtemadlin. That’s a randomized phase 3 study in the TP53 wild-type relapsed/refractory MF population.

It’s important to appreciate that as we move forward, we may see more molecularly defined therapeutic approaches. Here’s 1 example of a TP53 wild-type population, but we may see approaches that capitalize on the presence of mutations. In the consortium, we have a combination IDH2 JAK inhibitor study for patients with IDH2 mutations. We also have the MANIFEST-2 study, which looks exciting, with phase 2 data that suggest improvement in not just the degree of symptom and spleen response but hopefully the durability in maintaining those responses. The combination of pelabresib, the pan-BET inhibitor, with ruxolitinib in JAK inhibitor–naïve patients with MF is the MANIFEST study.

The TRANSFORM studies are combining BCL2 inhibitor navitoclax with ruxolitinib in both the up-front and second-line settings. Lastly, a unique study is the IMpactMF study. This is a randomized phase 3 study of patients who are refractory to JAK inhibitor therapy. They get randomized to imetelstat, the telomerase inhibitor, or best-available therapy, which excludes a JAK inhibitor, with a primary end point of overall survival. The clinical trial landscape looks quite different from 5 years ago, and it will continue to evolve as we exploit these vulnerabilities with agents that hopefully will address these unmet needs that Raajit has outlined.

Transcript edited for clarity.

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