by Christina T. Loguidice, OncLive
Prevention and mitigation of cardiovascular events, such as thrombohemorrhagic complications, have been the main goal of treatment development for patients with essential thrombocythemia and polycythemia vera.
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
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.
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
“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.
