Second-Line Treatments Still Needed In Myelofibrosis

Srdan Verstovsek, MD, PhD

Myelofibrosis is known to have the highest morality rate among the myeloproliferative neoplasms, with an average survival of 5 to 7 years. However, new therapeutic approaches are being developed in this patient population.

For patients with myelofibrosis, little treatment options exist beyond JAK inhibitors, which often cause anemia. However, no treatment currently exists for myelofibrosis-induced anemia. Additionally, while the JAK inhibitors available in the first-line setting, ruxolitinib (Jakafi) and fedratinib (Inrebic), can be used one after the other, this is in a minority of patients.

Currently, a number of phase 3 clinical trials are underway to help fill these clinical gaps, in the first-line setting, the second-line setting, and for symptom management. These drugs are being investigated as both monotherapy and in combination with ruxolitinib or fedratinib.

Srdan Verstovsek, MD, PhD, a professor of Medicine and a hematologic oncologist at the University of Texas MD Anderson Cancer Center, discussed the future of myelofibrosis treatment, unmet clinical needs in this patient population, and new therapy options in an interview with Targeted Oncology™. 

TARGETED ONCOLOGY: What are some new therapeutic approaches in myelofibrosis?

VERSTOVSEK: Myelofibrosis is the deadliest of the myeloproliferative neoplasms. The average survival is 5 to 7 years, and we do not have medications that would be eliminating disease and curing the patients. That's only possible through bone marrow transplant, but less than 10% of the patients go to transplant. So, there is a need for therapies that would be controlling the signs and symptoms of the disease, at least, for a very, very long period of time to extend the life of the patients. Now we have approved therapies, in terms of two drugs that are called JAK inhibitors on the market. These are ruxolitinib and fedratinib, which are good for a duration of maybe 1 to 3 years in myelofibrosis patients to control their symptoms and control their enlarged spleen. Beyond that we don't have any other therapies. So, what therapies can we do or provide our patients after JAK inhibitors failure? Not much we can do. What about the third hallmark of myelofibrosis, anemia? If we have JAK inhibitors to control the symptoms and spleen, what about the anemia, which can worsen even on the therapy? As a side effect of these therapies? We don't have any therapy. Twenty percent of the patient's progress to acute myeloid leukemia. JAK inhibitors do not have effect on that risk at all. So, areas of unmet needs are number 1, a second line therapy after JAK inhibitors. After JAK inhibitors, life is usually short, terrible, very bad bone marrow function. Number 2 would be anemia. That can occur patients in frontline setting, second-line setting, in any setting because there is nothing, we can do about it. And the patients that are progressive to acute myeloid leukemia, and not forget a smaller group of people that have low platelets. This is another problem, because current JAK inhibitors do nothing for these patients. They're not even supposed to be given to patients with platelet droplets because they can worsen platelet numbers.

Can you go into a little bit more in-depth of what the current myelofibrosis treatment landscape looks like?

Myelofibrosis patients have 3 hallmarks that require intervention. Remember, not everybody actually needs therapy from day one. We look at the prognosis, which is the one that will determine where the patient has bad enough disease to intervene with a transplant. That's one part of it. Then once you're done with prognostication, you say, 'is there something that bothers the patient that I need to correct?' And the 3 main reasons are anemia, symptomatic splenomegaly, and general systemic symptoms. Night sweating, low grade fevers, itching, bone exit pains, fatigue, weakness, weight loss. So, three areas of concern. And currently, we have ruxolitinib and fedratinib, JAK inhibitors approved as a therapy for patients that have platelets about 50 and required control of the spleen and symptoms. This is what they're good for. They're anti-proliferative, and to degree, anti-inflammatory agents. So, the quality of life improves, the spleen becomes smaller, but it doesn't last forever. It lasts an average of 3 years. We know that they worsen the anemia, so anemia is a problem. Our guidance would say to add anemia drugs to JAK inhibitors, but we don't have any approved, so we scramble and use some off-label drugs for it. You can use one JAK inhibitor after the other. In NCCN guidelines, fedratinib is listed as a second line choice. But it's applicable only to a minority of the patients because most people also have anemia and thrombocytopenia in the course of the therapy. So, we are limited to JAK inhibitors, 2 of them for a large group of people in frontline setting for a limited duration, unfortunately. And we don't tackle anemia at all. So, a lot of issues here that we need to develop new drugs for.

What are the potential treatments currently in the pipeline to fill unmet needs?

There are a number of medications in pipelines, for addressing the issues in different ways for patients with myelofibrosis. For example, if we are saying that in a frontline setting, the majority of the patients are exposed to JAK inhibitors, either ruxolitinib and fedratinib because they do suffer from general systemic symptoms and the symptomatic splenomegaly. We would then say, what about the anemia? It can be worsened by JAK inhibitors. There is a phase 3 randomized study underway with a medication called luspatercept-aamt (Reblozyl). Luspatercept is an anemia drug approved for some patients with myelodysplastic syndrome. It is already on the market for those patients. This is a phase three randomized studies underway in patients who are on a JAK inhibitor and are benefiting from that therapy for symptoms but have anemia. Luspatercept is being studied in a blinded randomized phase 3 study to see whether it will help them to eliminate transfusions. That may, if it's successful, in the future, be a standard practice combination. You have a patient with myelofibrosis, patient has symptoms in the spleen, and you start JAK inhibitors. Anemia is present at the same time, or it may become worse through side effects of JAK inhibitors. You would add luspatercept, so this is really something to follow, because it may have impact on the practice right away from the beginning for these patients in the frontline setting. The next drug that I want to highlight is pacritinib. Pacritinib is a non-myelosuppressive JAK inhibitors that is being developed for patients with platelets below 50. In fact, the application for its approval is under review, and we may expect this drug to be approved by the end of this year. Remember, ruxolitinib and fedratinib are not approved or not suggested to be used, in patients with platelets below 50. This is the indication for pacritinib, a JAK inhibitor that can improve the spleen and symptoms without myelosuppression in patient low platelets. So, this is very exciting. 

Momelotinib is another JAK inhibitor. This is again a little but different from ruxolitinib and fedratinib. Momelotinib can control the symptoms and it can apparently improve the anemia. So, it's kind of conterintuitive, but it seems that momelotinib has a different mode of action. It inhibits the JAK pathway, but it also inhibits the protein called ALK2, which is important for hepcidin, which is the master regulator for iron metabolism. And through this inhibition and decrease of hepcidin in the body of the patients, you have more iron available for erythropoiesis and the anemia improves. So, it's being developed as a second line drug after ruxolitinib or fedratinib as a drug to counteract the symptoms and the anemia, which is the main reason for stopping the frontline JAK inhibitors. The main reason for failing frontline JAK inhibitors is anemia. So, momelotinib might be the preferred second-line drug in the future if it's successful. And then there are a number of other drugs that are non- JAK inhibitors. you have a drug called imetelstat. It is a telomerase inhibitor. It appears from past experience in phase 2studies, that it may prolong the life of the patients. Prolongation of life is the number one goal of the therapy with imetelstat. The phase 3 studies underway comparing imetelstat to best valuable therapy for patients failing ruxolitinib, or the MDM2 inhibitor KRT232, another novel agent with a completely different mode of action that is being studied in a phase 3 study in the second-line setting for control of spleen and symptoms in hose that fail ruxolitinib. That's another phase 3 study. So, there are a number of new agents here that are being studied as a single agent or adding it to ruxolitinib. And there are 3 different other medications that are just trying to boost what the JAK inhibitors do. So, adding an agent to ruxolitinib in the frontline setting, for more spleen control, more symptom control. One is called pelabresib. The other one is called navitoclax. And the third one is parsaclisib. These are 3 different drugs, all pills, all trying to synergize with the JAK inhibitors, to enhance what the JAK inhibitors do.

What clinical need will these drugs fill?

We are at the point in the drug development field for myelofibrosis where we are looking at the subset of patients. Traditionally you would look at the frontline setting and you would say okay, we have JAK inhibitors here, ruxolitinib and fedratinib can possibly be given after the other, but that is for the control of spleen and symptoms, and we need an anemia drug. So, we are developing drugs for anemia, maybe they can be combined with JAK inhibitors, excellent. Then you have a second line setting, where you develop drugs for the second-line setting. But again, it's not all inclusive. It is divided based on what the need is. You have drugs in the second line setting for the spleen and symptoms. You have a drug in the second line setting for the anemia and symptoms. And then you also have to look at the characteristics of the patients. So, it's not just the first line and second line, there are patients that are suffering from low platelets, what can I do for them? So that's another area of need. And I would envision in the very near future, that you will have studies for patients that are progressing to acute myeloid leukemia. Acute myeloid leukemia is the one that you call when you have more than 20% blasts in the blood or bone marrow. But nothing really happens overnight. So, people are in transition from the chronic phase to the blastic phase. We call this the accelerated phase. That's area of unmet need on its own, where I expect the drugs to be given.

Concept number one, do the better job from the beginning. Maybe adding an agent to boost what the JAK inhibitors do, maybe add an agent for anemia. Concept number 2 develop drug for anemia alone, there are patients that are just suffering from anemia. Concept number 4, second line setting for the spleen and symptoms. Another concept second line setting for anemia symptoms, and then the progressive accelerated blasting phase patients that need help. Patients, we don't have a study for yet or drugs, but I think that's the next wave that I can see coming. We are very excited to have so many drugs in the pipeline. And I would say we have at least 8 different phase 3studies in myelofibrosis, from combinations in the frontline setting to combinations where we add another agent to people who are already on the standard practice therapy, an add on approach. To the second line setting and then specific subgroups of patients. We can only succeed if we work together. That means there needs to be a role for a physician to think about studies, and not to be confined to standard practice therapies. Even from day one, we have studies for patients newly diagnosed in need of therapy to be engaged in a phase 3 randomized study for the approval of new combinations over a single agent use. Any patient that is not deriving benefit to the maximum with standard practice therapy can be engaged in a study, not really changing what they're on but adding something to it. Or if you need to change, there are studies to be included in that area, as well. So, engagement with the referring doctors, practicing doctors, academics is essential to succeed. And of course, the patients have their own primary interest in getting better by participating in study, being ahead of everybody else. So, it's after all, a team effort. So, I encourage everybody at any juncture, from day one, to look for the clinical study for their patients to participate in.