The first JAK inhibitor to make its debut in the MPN treatment landscape was ruxolitinib (Jakafi), followed by the FDA approval of fedratinib (Inrebic) in 2019. Since then, experts have continued to make advancements with novel therapeutic strategies.

With now over 10 ongoing phase 3 trials around the world, investigators are combining novel treatments with JAK inhibitors to develop new options to use when treating patients with MPNs, including polycythemia vera (PV), essential thrombocytopenia (ET), and myelofibrosis.

“We are looking first to see whether the combinations that are exploring enhancement of the control of the sign symptoms on top of JAK inhibitors will do that well, well enough to be approved and then considered in everyday practice. We are also looking in the near future to see whether any of these therapies can prolong life,” said Srdan Verstovsek, MD, in an interview with Targeted Oncology^TM.

In the interview, Verstovsek, associate professor of medicine in the Leukemia department at the University of Texas MD Anderson Cancer Center, discussed the current MPN treatment landscape and where the field is shifting.

Targeted Oncology: Can you describe the current treatment landscape for essential thrombocytopenia?

Verstovsek: In essential thrombocythemia or ET, we worry about the thrombotic risk and our priority is to decrease it. We define the patients that are at an increased risk of blood clotting by applying certain prognostic factors. A significant change in the prognostication happened several years ago, which is now incorporated in United States based guidance, the NCCN guidelines. This is to say that in addition to historical factors of age over 60, or history of blood clotting, now, we also account for a presence or absence of a JAK2 mutation, which is present in about 60% of ET patients and it drives the disease process.

Therefore, there is a significant shift in identifying those that are at high risk of blood clotting by adding a JAK2 mutation presence to age. So, patients that are older than 60 and have a JAK2 mutation are the high-risk patients or of course, those that have a history of blood clotting. There is also an attempt to improve our management of these patients. Standard practice is to prescribe hydroxyurea, which is chemotherapy by mouth, to decrease the blood cell count. Then anagrelide is a second-line agent which inhibits the growth of the cells in the bone marrow that make platelets, so it lowers the platelets.

There is a phase 3 randomized study underway comparing anagrelide to a new agent that has the potential to be active in ET as it is in PV for which is already approved. I’m talking about ropeginterferon alfa-2b-njft [Besremi]. That study is a global randomized study comparing ropeginterferon to rusfertide, to prove the point that ropeginterferon might be better in controlling the platelets and the white cells that may be elevated sometimes in his patients. Hopefully, we are not going to have only to implement a prognostication and identification of the patients that need to be treated, otherwise, you just give them aspirin, but also more therapies to offer. Right now, it’s hydrea. And for interferon if we can get it off label, this will be onlabel as a second-line choice in the near future if the study is successful.

What has recently been seen in the polycythemia vera and myelofibrosis spaces?

Where in essential thrombocythemia we worry about thrombotic risk, we phlebotomize the patients to decrease the hematocrit, which is a measure of the percent of blood made from red blood cells in polycythemia vera and we give patients aspirin to make a blood flow easier. In some patients older than 60 or those that have a history of blood clots, we give them cytoreductive therapy to decrease the red blood cells, white cells, and platelets. Again, we use hydroxyurea for ET. But now ropeginterferon was approved last November for PV. It is a long acting interferon and the guidance now says that one could consider 1 or the other meaning, hydrea or ropeginterferon as a frontline choice. Then in a second-line, we have standard practice drug ruxolitinib, a JAK inhibitor, which is actually approved for hydroxyurea-resistant, -refractory, or -intolerant patients.

In this setting, there is another drug that is being developed in a phase 3 randomized study for possible approval. It’s called rusfertide. It’s a hepcidin mimetic and hepcidin is an important protein in the blood that modulates the iron metabolism. That medication would mimic what it does and keep the iron inside the liver, for example, or spleen, or a lining of the [gastrointestinal] tract. That’s called a radical endothelial system in the body. That would decrease the iron availability for the red blood cells and that would lead to elimination of the need for phlebotomy, which is very important, and people may feel better. At the moment, there is a phase 3 randomized placebo-controlled study in patients that need too many phlebotomies with a goal to approve rusfertide in the near future as another agent for these patients with PV.

Then, myelofibrosis is the most aggressive of MPNs with a shorter life expectancy. Here we have a plethora of different studies underway. The most important part is that in addition to ruxolitinib and fedratinib, this year, we have also pacritinib approved which is another JAK inhibitor and it can be given to patients with low platelets. Then, there is the recent application for possible approval of another JAK inhibitor called momelotinib, which is quite different from the others. It can improve anemia and eliminate the need for transfusions. The phase 3 randomized study of momelotinib vs danazol has completed and the results are good, and an application for approval is in place. By next summer, we may have momelotinib the fourth drug approved from myelofibrosis which will be perfect for patients who have suffered from anemia.

Can you further explain ruxolitinib and its mechanism of action?

Ruxolitinib inhibits JAK1 and JAK2, 2 of 4 members of JAK enzymes that are important in the body for function relative to blood making inflammation in the immune system. In particular, the JAK2 enzyme is associated with the growth factors and mechanisms of cell growth for red blood cells and platelets. JAK1 and JAK2 are also involved heavily in inflammation.Ruxolitinib will inhibit the proliferation and inflammation. People with myelofibrosis, for example, have a smaller spleen because of therapy, and that is why people feel much better, because it’s anti-inflammatory. On the other hand, it can lower the platelets through myelosuppression and that’s why we need to balance when we can give it. We like to give it as early as possible in the life of the patients and when the patients are not too sick. It’s easier to give it, it is a good dose, and the results are much better with earlier intervention.

In polycythemia vera, ruxolitinib is valuable as a second-line choice when things don’t go well with hydroxyurea. Patients then have much higher white blood cell counts, may have a big spleen, and of course, require phlebotomy. In that setting, it has been proven in 2 randomized studies that ruxolitinib provides a significant clinical benefit in normalizing blood cell count, improving quality of life, and decreasing spleen in those that have a big spleen. It appears after many years of follow-up that this is very durable, and possibly decreases the risk of early death from the complications of uncontrolled polycythemia vera. We use it often in the second-line setting, and it is a number 1 choice in PV.

What unmet needs still exist regarding MPNs?

In any of these three conditions, ET, PV, or myelofibrosis, we are talking about decreasing thrombotic risk, controlling the blood cell count, improving the quality of life, and decreasing the spleen. We don’t really have drugs that would eliminate disease or make it controllable forever. More active drugs that will be much more durable and perhaps that can be achieved by combinations [are needed]. For example, in myelofibrosis, we’re witnessing a flurry of phase 3 randomized studies where novel agents are combined with the JAK inhibitor ruxolitinib to make it even better and perhaps longer lasting in controlling signs and symptoms. I would like to see agents like interferon that have a potential that can lower, and perhaps eliminate malignant clones.

What are the future directions in this space?

We are looking first to see whether the combinations that are exploring enhancement of the control of the sign symptoms, on top of JAK inhibitors, will actually do that well or well enough to be approved and considered everyday practice. We are also looking in the very near future to see whether any of these therapies can prolong life. Overall survival is already in 1 study with a possible approval with the drug called imetelstat, which is a telomerase inhibitor, a primary goal. This is a phase 3 randomized study in a second-line setting.

Then to enhance that, perhaps not in a year but in 3-5 years, that effect of the potential targeted agents to bring about the molecular response, and that would mean possibly a complete response and partial response. We are at the beginning of the new phase in developing the drugs, not just to talk about improvement in the number or the size of the spleen or a blood cell count, but also to talk about affecting the malignant clone.

Raajit K. Rampal, MD, PhD
Hematologic Oncologist
Associate Attending Physician
Memorial Sloan Kettering Cancer Center
New York, NY

Targeted Oncology^TM: What nontransplant therapies do the National Comprehensive Care Network (NCCN) guidelines recommend for the management of higher-risk myelofibrosis (MF)?

RAMPAL: In the current NCCN guidelines, for patients with a platelet count of at least 50,000/μL, fedratinib [Inrebic], ruxolitinib [Jakafi], and [clinical trial are options].¹ Ruxolitinib and fedratinib are supported by category 1 data, and I think a clinical trial is always a reasonable option. We’re fortunate these days because there are 3 phase 3 registration trials going on, where patients are randomly assigned to either ruxolitinib or ruxolitinib plus an investigational agent. The investigational agents are a BET inhibitor, a BCLX/BCL2 inhibitor, or a PI3K inhibitor. In this day and age, a clinical trial is absolutely a reasonable first-line consideration.

For patients with a platelet count of less than 50,000/μL, [the NCCN guidelines recommend a clinical trial or pacritinib [Vonjo] if the patient is not transplant eligible].¹ The landscape changed with the approval of pacritinib,² which has been studied as first-line and second-line [therapy] in MF, but has also been studied selectively in a patient population very different from those in the COMFORT-I [NCT00952289], COMFORT-II [NCT00934544], and JAKARTA [NCT01437787] studies, [whose data supported] the approvals of ruxolitinib and fedratinib, respectively.^3,4

For patients [with a platelet count of 50,000/μL or greater] who get ruxolitinib or fedratinib as a first-line therapy [and then] lose response or have some degree of progression, you can switch to an alternative JAK inhibitor.¹

What data support the management of MF with ruxolitinib?

Ruxolitinib was approved based on the COMFORT-I and COMFORT-II trials.³ These were randomized trials of ruxolitinib vs either placebo or best available therapy. Included in these trials were symptomatic patients with intermediate- or higher-risk disease and platelet counts of 100,000/μL or greater.

It’s important to remember the platelet count of these patients when [you consider the] data from these trials.^5,6 The top-line data from the COMFORT-I and COMFORT-II studies were essentially similar, showing that [the rate of] spleen volume reduction by at least 35% was superior with ruxolitinib vs the comparator arm in each study with COMFORT-I: 41.9% vs 0.7%, respectively [odds ratio, 134.4; 95% CI, 18.0-1004.9; P < .001] and COMFORT-II: 28% vs 0%, respectively.

In both studies, almost all of the patients in the ruxolitinib arms experienced spleen volume reduction [COMFORT-II: 97% vs 56% in the experimental and control arms, respectively]. In the comparator arms, there was [more] spleen volume increase, although some patients in the COMFORT-I placebo arm, strangely enough, had a spleen volume reduction, which I still don’t understand.^5,6 The [parameter of] spleen volume reduction by 35% is an FDA-mandated end point; there’s nothing particularly magical about 35%. But the degree of spleen size reduction does matter, and there are data that demonstrate that the amount of spleen volume [reduction] does influence a patient’s overall survival [OS].⁷

Is that because we are saving lives by shrinking spleens? I don’t think so. I think spleen volume reduction is a marker of disease responsiveness to the JAK inhibitor, but it is important to remember that the amount of spleen reduction does correlate with patient survival. These patients can be terribly symptomatic, as [we] know. In the COMFORT-I study, the symptom burden reduction [was measured by] the Total Symptom Score, a validated tool, and the majority of patients treated with ruxolitinib showed symptom improvement.

Night sweats, early satiety, itching, bone pain, inactivity, and abdominal discomfort all [improved] in the patients who received ruxolitinib and worsened in patients who received the placebo.⁵ The same pattern was observed in the COMFORT-II study, wherein symptom response was measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire.⁶

Survival was not an end point of the COMFORT studies. In the ad hoc analysis, there appeared to be a survival benefit in the COMFORT-I but not in the COMFORT-II study. This prompted a pooled analysis of the COMFORT-I and COMFORT-II data [that reflected] the patients in the intention-to-treat arm.

The data showed that there did seem to be a survival benefit. The median OS was 5.3 years vs 3.8 years in the ruxolitinib and control arms, respectively [HR, 0.70; 95% CI, 0.54-0.91; P < .0065].^8,9 We have to take into account that this was a pooled analysis and this was not a primary end point of the studies. But these data suggest that there is improved survival [in treated patients].

The question is why: [Did the treatment] change the natural history of the disease or [did it] just change patients’ overall performance status? If a patient is terribly symptomatic and cachectic from their disease, are they living longer because they’re responding to treatment? I think there are 2 answers. There’s the real-world answer, which is that it [doesn’t] matter. If patients are living longer, they’re living longer. And then there’s the academic question as to why [we are seeing this survival benefit]. I don’t think we know the answer to that.

Of the patients who did die, death was most often caused by progression to acute myeloid leukemia [86 of 1054 patients]. [Other causes of death included] thrombosis, bleeding, infection, and portal hypertension, which can be a byproduct of the disease process itself.^8,9 Infection is an important adverse event to remember. There are signals from other studies that ruxolitinib treatment may increase the risk of Herpes zoster infection or [tuberculosis] reactivation.

What data support the idea that spleen response correlates with OS among ruxolitinib-treated patients?

An important [analysis addressed this relationship,] treating spleen response as a binary variable of response vs no response at 6 months, with response defined as a 35% spleen volume reduction. Patients who had a spleen response also had a better OS outcome [P = .04].

The OS [also correlated with] the durability of the spleen response. In that analysis, the nonresponders had the worst OS. [Separate analyses were performed for] patients who had a stable response and for patients who had an unstable response, [and these groups] had overlapping OS curves [P = .04].¹⁰ Those data might suggest that patients’ quality of life is being improved and that’s why they’re living longer.

What factors are associated with a lower spleen response?

The factors associated with a lower spleen response include high-risk disease, spleen size of at least 20 cm, high white blood cell count, delay in starting ruxolitinib after diagnosis, and using a dosage of less than 10 mg twice daily.^11,12 I think that [the influence of dosage and of spleen size are both] important concepts. Both the patient and the physician are often reluctant to start therapy if the patient is not symptomatic, but [I think] you have to keep this warning in mind.

If [the spleen] is getting progressively larger, you’re going to reach a point where even a high dose of ruxolitinib may not achieve the optimal response. That could affect the patient’s OS. [Another way to look at this is that] if the maximal effect of the drug is going to be to reduce the spleen by a certain percentage volume, the bigger the spleen gets [before you start treatment], the larger the residual spleen will be even if you get a maximal percentage reduction.

How does ruxolitinib efficacy correlate with dosage?

[Analysis revealed that] spleen volume reduction correlated with ruxolitinib dosing. Maximal efficacy was achieved at a dose of at least 10 mg twice daily. There was some [efficacy] difference between the 10- and 15-mg doses, but not much of a difference between the 20- and 25-mg doses. There was a clear efficacy difference between a dose of less than 10 mg and the higher doses.13 One needs to try to optimize the dosing of ruxolitinib to achieve the best spleen response. The symptom response [showed a similar trend].

[Patients achieved] some degree of response at a dose of less than 10 mg twice daily, but doses of 10 mg twice daily and higher [conferred maximal] symptom response. We always worry about the hematologic parameters. When we start a patient on therapy, their blood counts start to decrease and we have to begin transfusing them, [we have to decide whether to dose reduce].

Do we reduce to 5 mg twice daily because the blood counts are more stable [at that dosage]? Sometimes when you reduce to that dose, the patient instantly feels better. They’re not completely better, but they are relatively better. That can give us a false sense of security, and [we] have to be careful of that. I think it is useful to start at a low [dose] and titrate up. I always start at 5 mg twice daily and titrate the dose up to [the target dose], which is usually approximately 10 mg twice daily. If you start at 20 mg twice daily, often that patient’s hemoglobin level or platelet count crashes, and then you have to back off and you don’t end up with the optimal dose.

What data can guide the use of ruxolitinib, with respect to patients’ platelet counts?

The dose of ruxolitinib is based on the patient’s platelet count. Per the package insert, the starting dose for patients with platelet counts of 50,000/μL to 100,000/μL is 5 mg twice daily. For patients with higher platelet counts, you can [start with] 10 mg twice daily.¹⁴ The problem is that if you leave patients with low platelet counts at 5 mg twice daily, they’re going to have an inferior outcome. [Keep in mind that, according to the] Dynamic International Prognostic Scoring System [DIPSS] and the DIPSS-Plus, patients with platelet counts under 100,000/μL are already prone to inferior outcomes, [which can be exacerbated by suboptimal dosing]. There are data to support the idea that you can safely increase the dose of ruxolitinib if the platelet count is between 50,000/μL and 100,000/μL. In the EXPAND study [NCT01317875], patients were divided into 2 strata, defined by a platelet count of either 50,000/μL to 74,000/μL or 75,000/μL to 99,000/μL.

All patients were started at a dose of 5 mg twice daily, and the dose was [gradually increased to] 15 mg twice daily. The safe dose was determined to be 10 mg twice daily in both strata.^15,16 That’s an important thing to remember, because leaving patients at 5 mg twice daily can lead to suboptimal outcomes. In the EXPAND study, grade 3 and 4 thrombocytopenia was observed in 40% of patients with a higher platelet count and in 78% of patients with a lower platelet count. Platelet count decrease occurred in 25% vs 6% of the patients in those respective groups, and anemia occurred in 25% vs 17%, respectively.¹⁶ Most of the patients [in both strata] had some degree of spleen volume decrease, and some achieved 35% spleen volume reduction. That is an important end point that correlates with survival, so pushing the dose can be beneficial. The symptom score [data exhibited a similar trend] in both strata.¹⁵

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