Essential Thrombocythemia and Polycythemia Vera Treatments Are Moving Toward Disease Modification

Jeanne M. Palmer, MD

Prevention and mitigation of cardiovascular events, such as thrombohemorrhagic complications, have been the main goal of treatment development for patients with essential thrombocythemia (ET) and polycythemia vera (PV).^1,2 An improved understanding of these myeloproliferative neoplasms, including the identification of driver mutations in JAK2, CALR, and MPL, has opened the door to treatments that enable the natural history of these diseases to be altered.

During a recent OncLive Peer Exchange^®, a panel of hematology cancer experts discussed the diagnosis and management for ET and PV. They reviewed the expanding use of interferons, a treatment class that has shown disease-modifying effects and seen recent advancement with the FDA approval of ropeginterferon alpha-2b-njft (Besremi) for patients with highrisk PV. They also discussed several promising agents in clinical development for ET and PV.

Approaching ET

Diagnosis

“[ET] is a disorder in which there are too many platelets…. Generally, patients will present with an elevated platelet count, and they get sent to hematology,” Jeanne M. Palmer, MD, said. According to the National Comprehensive Cancer Network (NCCN) criteria, a platelet counts of at least 450 × 10⁹/L is one of the major criteria for diagnosing ET (TABLE 1).³ She noted that 80% of patients with ET have a driver mutation; however, because 20% do not have these mutations and only bone marrow biopsies can rule out other etiologies, she said biopsies are indicated for all patients. “Patients can sometimes have prefibrotic myelofibrosis or even overt myelofibrosis, and the only presenting sign is thrombocytosis,” Palmer said.

Treatment

A key treatment for ET across risk groups is aspirin (81-100 mg daily),3 which is used to prevent cardiovascular events. “For most, I consider a baby aspirin. There are some data showing that a baby aspirin twice [daily] in patients who are still a little symptomatic [is beneficial],” Ruben Mesa, MD, said. He noted there is some debate about whether patients with CALR mutations derive sufficient benefit from aspirin to warrant its use because their risk of cardiovascular events is lower. Patients with CALR mutations have been observed to have an approximately 50% lower risk of thrombotic events than their counterparts with JAK2 mutations.⁴ Nevertheless, the NCCN guidelines recommend aspirin for all patients with ET, including those classified as very low risk (ie, age ≤ 60 years, no JAK2 mutation, and no prior history of thrombosis).³

Ruben Mesa, MD

In patients with high-risk ET (ie, history of thrombosis, aged > 60 years, and presence of JAK2 mutation), the NCCN guidelines recommend concomitant cytoreductive therapies, which may include hydroxyurea (NCCN preferred), peginterferon alpha-2a (PEG; Pegasys), or anagrelide (Agrylin). Mesa said that although hydroxyurea is not a disease-modifying agent, it helps control blood counts, adding that some patients may not be able to reach sufficient doses to control their blood counts due to the toxicities associated with this treatment.

Regarding PEG, the NCCN guidelines note it could be considered for younger patients, pregnant patients (because of its reduced risks during gestation), and those who defer hydroxyurea. Although interferon-based treatment for ET in the United States has been with PEG, Mesa said that ropeginterferon alpha-2b is currently being explored as an option for high-risk ET in the phase 3 SURPASS ET study (NCT04285086), introducing the potential for this agent to eventually replace PEG as the preferred interferon-based therapy for these patients. SURPASS ET is initiated at approximately 65 sites across North America, Europe, and Asia and is comparing the efficacy, safety, tolerability, and pharmacokinetics of ropeginterferon with that of anagrelide after 12 months of treatment in patients with high-risk ET who have demonstrated resistance or intolerance to hydroxyurea.⁵

Mesa also said that interferons may eventually replace hydroxyurea as the preferred first-line cytoreductive therapy in patients with high-risk ET because of an increasing body of data showing the potential for these agents to alter the natural course of myeloproliferative neoplasms. “Advantages of interferons over hydroxyurea may have a deeper impact on the stem cell clone. [They] may potentially help decrease the risk of movement toward myelofibrosis longer term,” he said.

Mesa was an investigator in a phase 3 randomized clinical trial (NCT01259856) that showed benefit with PEG vs hydroxyurea in patients with ET or PV who were being treated in the first-line setting.6 Both agents were found to be effective; however, with longer treatment (> 24 months), PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas hydroxyurea produced more histopathologic responses.⁶ Both agents had similar efficacy in limiting thrombotic events and disease progression. Based on these findings, Mesa and colleagues concluded that both agents are efficacious and that “the decision to choose one agent over the other must be personalized.”⁶

Despite the NCCN guidelines recommending interferon-based treatments for ET, Mesa noted these agents remain “in a bit of an uncertain state” from a production and regulatory standpoint because PEG has never been advanced for registration as a treatment for ET. Additionally, he said oncologists may have had negative experiences with interferons from the days when they were used to treat other malignancies, such as melanoma and myeloma. He expressed hope that favorable findings in ongoing clinical trials for ropeginterferon, which may eventually lead to its approval for ET, as well as studies showing benefit with PEG, may lead to improved uptake of interferons for patients with ET, particularly by community oncology practices, where PEG has been underutilized.

“Ropegylated interferon at low doses is a dramatically different therapy. If you haven’t tried it, don’t let that prior experience make you hesitate…. It’s quite helpful,” he said.

Regarding anagrelide, Mesa said it’s a good therapy for lowering platelet levels but that it’s not commonly used in clinical practice. Generally, he said patients with difficult-to-control platelet counts tend to respond better when anagrelide is given as a combination therapy vs as a monotherapy.

In patients with high-risk ET who show an inadequate response or loss of response to the currently recommended cytoreductive therapies, other treatments can be considered, including the JAK inhibitor ruxolitinib (Jakafi) for patients with splenomegaly symptoms.³ Mesa also noted that several promising treatments are in various stages of clinical development for these patients, including LSD1 inhibitors, making clinical trial enrollment an important option.

TABLE 1. NCCN Guidelines for Diagnosing ET3

Positive phase 2 data for the LSD1 inhibitor bomedemstat (IMG-7289) were presented at the European Hematology Association Congress 2022.⁷ The study included 44 patients (median age, 68 years) who were resistant or intolerant to at least 1 standard cytoreductive therapy. The primary end point was a platelet count of 400 × 10⁹/L, with secondary end points including durability of response (ie, maintaining primary end point for ≥ 12 weeks), symptom improvement, and reduction in white blood cell (WBC) counts and mutation burden. Among the patients treated with bomedemstat for at least 24 weeks, approximately 80% achieved a durable reduction of platelet counts to less than 400 × 10⁹/L without thrombotic events. Treatment was also associated with symptom improvements and reductions in WBC counts and mutation burden. Overall, bomedemstat was well tolerated, and the most common adverse events (AEs) regardless of causality included dysgeusia, fatigue, constipation, arthralgia, thrombocytopenia, and contusion. Two serious AEs deemed to be related to treatment included thrombocytopenia and mouth hemorrhage.

“There are more things coming. Longer term, there will maybe even be targeted approaches toward calreticulin. We’re seeing a growing list of options for ET,” Mesa said.

Approaching PV

Diagnosis

Jamile Shammo, MD

“We should think about [PV] when someone presents with a high hemoglobin and high hematocrit without a plausible explanation—essentially in someone who doesn’t have any other reason for secondary erythrocytosis,” Jamile Shammo, MD, said. The NCCN criteria for diagnosing PV are summarized in TABLE 2.³

When patients present with a hemoglobin level that raises suspicion for PV, Shammo said the first tests she orders are for JAK2 V617F mutation and serum erythropoietin (EPO). “If the EPO level is low and the JAK2 mutation is positive, then you have a very good reason to believe that this is PV,” she said, adding a confirmatory bone marrow biopsy may not be needed if hemoglobin levels measure higher than 18 g/dL in men and higher than 18.5 g/dL in women. However, she added that biopsy is crucial if the numbers do not correspond with the NCCN criteria. Additionally, if the JAK2 V617F is negative, then the exon 12 mutation test should be ordered.

“Nowadays, the diagnosis of PV is much easier because 95% of the patients will be positive for a JAK2 mutation,” Shammo said. “If you added exon 12 to that, almost 99% [of patients] will be positive. In cases [for which] you’re entertaining the diagnosis of masked PV, in case there’s iron deficiency, you might want to rely on a bone marrow biopsy to make sure you’re also ruling out other “Nowadays, the diagnosis of PV is much easier because 95% of the patients will be positive for a JAK2 mutation,” Shammo said. “If you added exon 12 to that, almost 99% [of patients] will be positive. In cases [for which] you’re entertaining the diagnosis of masked PV, in case there’s iron deficiency, you might want to rely on a bone marrow biopsy to make sure you’re also ruling out other.

Treatment

In patients with PV, aspirin (81-100 mg daily) is a core treatment, regardless of whether the patient is considered at low or high risk of cardiovascular events.3 The benefit of aspirin in PV was established in the European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) study, which showed aspirin to reduce the combined risk of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes by approximately 60%.⁸

Another key treatment for all patients with PV is phlebotomy, which should strive to maintain a hematocrit level of less than 45%.³ “This 45% has been proven in a trial where they looked at keeping it less than 50% or less than 45% and [under] 45% was superior with regard to cardiovascular events,” Palmer said. When treating women, she said she tries to keep their hematocrit level below 42% whenever possible because women tend to have lower hemoglobin and hematocrit levels than men.

TABLE 2. NCCN Guidelines for Diagnosing PV

In low-risk PV, which includes patients younger than 60 years who have no history of any significant thrombotic events, Palmer said that aspirin and phlebotomy are generally considered sufficient but that cytoreductive therapies are needed for those older than 60 years and for those with a history of arterial or venous thrombotic events. “When I approach cytoreductive therapy, this is where it becomes a shared decision-making process,” she said. NCCN preferred options for these patients include hydroxyurea and PEG, with the recently approved ropeginterferon alpha-2bnjft being another recommended option.³

“The most commonly used therapy is hydroxyurea. It’s easy and quick, and it’s a pill,” Palmer said. As with ET, however, she said the toxicities can be problematic. She also explained that many patients have concerns that hydroxyurea will increase their risk of leukemia, despite this never having been “borne out in well-done studies.”

Of the available options, Palmer was most excited about ropeginterferon. Like PEG, it is given as an injection, but administration is every 2 weeks vs weekly for PEG. She noted that very good clinical data from the PROUD-PV (NCT01949805) and CONTI-PV (NCT02218047) studies support the use of ropeginterferon in Jamile Shammo, MD, discusses diagnostic considerations for polycythemia vera including hemoglobin levels and JAK2 mutation status. patients with high-risk PV.⁹ In these studies, patients were treated with hydroxyurea or best available treatment (controls) or ropeginterferon. PROUD-PV provided data for the first year of treatment and its extension CONTI-PV provided data for 3 years of treatment, but more than 5 years of data have now been reported.⁹

Among the patients who continued treatment for up to 5 years, hematocrit levels below 45% were maintained without the need for phlebotomy in 81.8% of patients in the ropeginterferon arm vs 63.2% of those in the control arm.⁹ When considering the causative JAK2 V617F mutation burden, the median allele burden decreased in the ropeginterferon arm, from 37.3% at baseline to 8.5% at 5 years, whereas it increased in the control arm, from 38.1% at baseline to 44.4% at 5 years (P < .0001).

“This suggests, as does a lot of preclinical data, that the interferons in general may have a modifying effect on the disease or change the natural history of disease. There are preclinical data suggesting [that interferons suppress] the JAK2 clone, although there’s probably some advantage even in patients who don’t have the JAK2 mutation,” Palmer said.

Because of the potential for disease modification with interferons, Palmer said she also discusses their use with patients who have low-risk PV. In this setting, the NCCN guidelines list ropeginterferon as an “other recommended regimen,” giving it a category 2B recommendation.³ This recommendation was partially supported by data from the Low-PV study (NCT03003325), which found supplementing phlebotomy with ropeginterferon to be safe and effective in steadily maintaining target hematocrit values in patients with low-risk PV.¹⁰

Another key population for which Palmer said she uses cytoreductive therapy is in patients who may not fall under the high-risk category but who have symptoms related to iron deficiency, which can be exacerbated by phlebotomy. “Iron deficiency has a lot of symptoms. It can cause fatigue and restless leg syndrome. I’ve even found that mood can be impaired. Oftentimes, I’ll choose cytoreductive therapy so I can start to replace the iron very gently and control their hemoglobin and hematocrit through another mechanism,” Palmer said.

In patients with high-risk PV who have an inadequate response or loss of response to their initial cytoreductive therapy, use of ruxolitinib can be considered (NCCN category 1 recommendation).3 Data to support this recommendation came from the RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036) studies, which showed ruxolitinib to be superior to best available therapy in controlling hematocrit levels, improving splenomegaly and reducing symptoms while providing protection against cardiovascular events.11-13 “Ruxolitinib is definitely an option that I consider, especially in patients who don’t tolerate hydroxyurea or have a large spleen and a significant symptom burden,” Palmer said.

A key area of therapeutic development is the identification of PV treatments that can consistently keep hematocrit levels at target range. “If we’re doing phlebotomy and aspirin, your hematocrit goes up. We phlebotomize, and it goes down. It goes up and down repeatedly,” Mesa explained, adding that it is currently impossible to know how long patients stay within the target range. This has spurred the development of noncytoreductive agents that can provide consistent control of hematocrit levels in phlebotomy-dependent patients. One such agent in clinical development is rusfertide (PTG-300), a hepcidin mimetic. “[Hepcidin mimetics] simulate the anemia of chronic disease to create a state where you control the hematocrit without iron deficiency,” Mesa said, adding that this approach may help iron levels rise so that patients have fewer symptoms.

Data from 2 phase 2 trials assessing rusfertide in phlebotomy-dependent patients with PV were presented at the 2022 American Society of Clinical Oncology Annual Meeting.14 The first study, REVIVE (NCT04057040), included 63 patients with excessive erythrocytosis despite phlebotomy, and the second study, PACIFIC (NCT04767802), included 20 patients with poorly controlled PV (hematocrit level > 48% at study entry) despite treatment with phlebotomy with or without concomitant hydroxyurea. In REVIVE, patients consistently maintained a hematocrit level below 45%, which essentially eliminated the need for phlebotomy, and had normalization in their iron stores and an improvement in their symptoms; PACIFIC reported similar benefits. Neither study showed changes to WBC counts.

“[Rusfertide is] going to be moving forward to phase 3 studies,” Mesa said. “The role of rusfertide or other drugs in that pipeline—there are some from Ionis [Pharmaceuticals, Inc] and others that are looking at this pathway—may expand our medical therapy to be more inclusive of all patients with PV.”