Ongoing Unmet Needs and New Approaches in Myelofibrosis

Ruben A. Mesa, MD: Important unmet needs for myelofibrosis [MF] include managing the challenging anemia, which is important because therapies are being looked at. Luspatercept is an add-on to current therapies, perhaps momelotinib, which might—with its inhibition of ACVR1 and inhibiting hepcidin—improve anemia along with splenomegaly and symptoms. Second, better biological markers of progression-free and overall survival. I do believe that therapies that are effective have an impact on survival in MF. We’ve seen that with ruxolitinib as we’ve discussed. We saw data with imetelstat and momelotinib at ASH [American Society of Hematology Annual Meeting], suggesting they might have an impact on survival, indeed decreasing progression in the disease. Improving progression-free and overall survival are important goals, but we need better surrogate biomarkers of these goals so we can have realistic trials that don’t anticipate patients remaining on control arms indefinitely.

Pankit Vachhani, MD: There are several unmet needs in myelofibrosis. One area that needs significant attention is patients who have myelofibrosis and thrombocytopenia. We know that these patients have worse overall survival compared with those who do not have thrombocytopenia. But in addition to having worse overall survival, these patients do not have good treatment options. For example, ruxolitinib, an FDA-approvedJAK inhibitor, is most used in myelofibrosis. The clinical trials that led to it, the COMFORT-I and COMFORT-II studies, included patients who had platelets more than 100,000 mm3 at the time of enrollment.

Even the FDA-approved label does not talk about doses to use in those who have platelets less than 50,000 mm3. This is an area that clearly deserves some attention. To that add pacritinib, also a JAKinhibitor that is being studied in a phase 3 clinical trial, PACIFICA. It is randomizing patients with newly diagnosed myelofibrosis and thrombocytopenia, a concurrent event to either pacritinib or physician’s choice of drug. Another area that needs more attention is of course what to do after someone has failed ruxolitinib. For example, we know that the median survival is somewhere between 8 and 12 months. Many new clinical agents have been tested in various clinical trials, some of which are the MDM2 inhibitor, which is KRD-232 or the BCL2/BCLX inhibitor navitoclax, and various other agents. Hopefully, some of these will show significant benefit for patients who are beyond ruxolitinib and have failed that drug at some point in their myelofibrosis journey.

Another area of unmet needs is patients with myelofibrosis and concurrent anemia, whether they are on JAKinhibitor therapy or another. Two drugs in this space are looking promising and are under investigation. One is momelotinib, and the second is luspatercept. Luspatercept is FDA approved in thalassemia and in low-grade MDS [myelodysplastic syndrome]. Momelotinib has been previously studied in the simplified trials. The mechanism of action there appears to be possibly related to ALKinhibition in terms of anemia amelioration.

Srdan Verstovsek, MD, PhD: We have medications in a first-line setting, in untreated patients, who can do very well for control of the spleen and control of the systemic symptoms. These are JAK inhibitors.One can use 1 after the other, so we can say ruxolitinib perhaps in the frontline setting and then, if that doesn’t work very well for patients who have still spleen and symptoms, you can use fedratinib.Not much else has been approved.

Anemia is a major problem. It can be present on its own. It’s present at the beginning of life with myelofibrosis already in about a third of patients. Through life, when you see patients after 1 year, two-thirds are already anemic. I don’t have a good medication to give them. Patients may have exacerbation of anemia while onJAK inhibitors. Anemia is a target for new medication to develop.

In terms of how many patients will benefit from such a drug, you can have it in combination withJAK inhibitors in the frontline and second line. You can have it in patients who are only anemic—a small portion of the patients, but they can still benefit. Luspatercept is being developed as a medication and is being studied. That’s an anemia drug approved for myelodysplastic syndrome. It is being studied in myelofibrosis in patients who are onJAK inhibitor and are transfusion dependent and therefore severely anemic. In these patients, luspatercept is being compared with best-available therapy. This study is about to start for possible approval of this drug.

But in terms of the aggressiveness of the disease, an unmet need, when we talk about people dying from the disease, is the second-line setting. Fedratinib can help. Rechallenging patients with ruxolitinib has been done, and it can help in patients in a second-line setting. But there is not much more you can do, and patients have anemia and have a bad quality of life.

We are carefully monitoring the MOMENTUM study, which is the phase 3 study for possible approval of momelotinib, anothernonmyelosuppressive JAK inhibitor that is possibly good for anemia and symptoms. It is a randomized study, blinded, comparing momelotinib with danazol, an anabolic steroid, in a second-line setting for patients who are anemic or have a bad quality of life.

There are combinations with ruxolitinib, CPI-0610. It’s an investigational agent in the frontline setting to boost what ruxolitinib does, more of the spleen and symptoms. It’s a BET inhibitor, an epigenetic modifier in a simple way. There is navitoclax, a BCLXL inhibitor in a phase 3 study in a frontline setting that is about to start, to boost what ruxolitinib does—more of the spleen and symptom control. The study in in second line with imetelstat, a telomerase inhibitor, is a phase 3 study, with the goal to prolong the life of the patients, to control the symptoms and signs to some degree if possible, but make them live longer. It is first study in myelofibrosis with that particular goal in a situation where there is not much you can do.

There is a spectrum of studies. You see anemia drugs, in frontline, in combination, in patients with bad outcomes who would be studied for prolongation of life. You have combinations to boost what theJAKinhibitors do—different attempts and several different drugs with different mechanisms of action that are being studied in myelofibrosis. We are branching out a lot fromJAK inhibitors in different directions.

Ruben A. Mesa, MD: There is a robust pipeline of exciting new therapies that being looked at for the front line to deepen or broaden initial response: the BET inhibitor CPI-0610 and navitoclax, either in combination up front for better frontline therapy. There are numerous options in the second line, either added on or as a single agent: either of those 2 agents, imetelstat, the LST1 inhibitor IMG-7289, MDM2 inhibitors, or PI3 kinase inhibitors, alone or in combination with JAKinhibition. The pipeline is robust. Our goals for the future are to expand the breadth of response, beyond spleen and symptoms, but to include progression-free and overall survival, potentially improve issues such as genetic mutation burden or fibrosis, and to improve anemias or cytopenias. So we’re excited by the robust pipeline of new therapies. Indeed, we even hope to treat individuals whom we otherwise weren’t able to—with marked thrombocytopenia—with agents such a pacritinib. There are many more options, many more nuances as we manage these patients moving forward into the future.

Transcript edited for clarity.