Are Traditional Treatments Falling Short in PV? 

Polycythemia vera (PV) is the most frequent of the Philadelphia-negative myeloproliferative neoplasms (MPNs). Median age at PV diagnosis is approximately 65 years old, with a higher prevalence in males. The incidence rate of PV has been estimated at 1.57 per 100,000 person-years (p-y) between 2002 and 2016. 

PV is characterized by excessive myeloid cell production, mostly secondary to mutations in the JAK2 gene. The consequent hyperactivation of the JAK-STAT pathway drives the typical PV phenotype. Clinically, PV is characterized by pruritus, microvascular disturbances, and constitutional symptoms. In the long term, what impacts an outcome is the increased risk of thrombotic events (TEs), and evolution into post-PV myelofibrosis (PPV-MF) or blast phase.  

PPV-MF diagnosis should be confirmed by a bone marrow evaluation and cytogenetics, as they have prognostic relevance. Practicing physicians should be aware that the incidence rate of TEs is 2.3% p-y after transformation, with a suggested protective role of ongoing cytoreductive treatment (CT). 

Treatment Indications and Rationale in 2022 

Patients who report TEs have a significantly reduced overall survival compared with those who do not experience these complications. The main aim of treatment is preventing thrombotic complications given that approximately one-third of contemporary patients with PV die for vascular reasons. Standard therapy includes phlebotomies to maintain hematocrit (Hct) below 45% and low-dose aspirin (if not contraindicated).  

Patients should be distinguished as at high risk (HR) of thrombosis if they are older than 60 years of age or had a previous TE, and at low risk (LR) in the absence of both factors. For HR patients, CT should be added. Patients conventionally defined as LR should start CT if they have confirmed leukocytosis, symptomatic progressive splenomegaly not related to PPV-MF evolution, or intolerance to phlebotomies. Recent studies have shown a correlation with thrombosis, mainly at arterial sites, and persistently high cardiovascular risk, but the decision to start CT in these otherwise LR cases should be made after all preventive measures have been implemented. 

Patients who report a venous TE (including splanchnic vein thrombosis) also require systemic anticoagulation, with retrospective data suggesting a similar protective role for vitamin K antagonists and direct oral anticoagulants. 

First-line Treatments in HR PV  

Hydroxyurea and interferons (IFNs) are the first-line CT options for PV, as defined by international guidelines. Hydroxyurea is preferred in most countries, because conventional IFNs are burdened by numerous side effects, including flu-like symptoms and psychiatric and autoimmune disorders. 

In one study, hydroxyurea did not appear to prevent recurrence of venous events after splanchnic vein thrombosis. Nevertheless, the authors suggest adding CT in the setting of splanchnic vein thrombosis if blood counts are permissive. Pegylated forms of IFNs (PEG-IFNs) have been developed to improve tolerability through less frequent administrations compared with conventional IFNs. Available evidence suggests that there could be a clinical benefit from first-line PEG-IFN if it is continued for the long term, and in instances when it is not necessary to reach complete hematologic response (CHR) quickly.  

Two recent phase III trials compared PEG-IFN-α2a with standard of care (mainly hydroxyurea) in PV. In the MPD-RC 112 trial, the PEG-IFN cohort achieved Hct control without phlebotomies at 12 months at a significantly higher rate (65% vs 43%). In the PROUD PV trial, after six years of follow-up, those patients treated with ropeginterferon (ropeg-IFN) obtained a significantly higher percentage of CHR (55% vs 35%).  

Based on these encouraging results, the authors recommend considering PEG-IFNs in young patients, females of reproductive age, and patients without critical and recent vascular events or massive splenomegaly. A careful screening for psychiatric and autoimmune disorders should be performed before first administration. 

The ongoing MITHRIDATE trial is comparing the JAK1/2 inhibitor ruxolitinib versus the best available therapy (IFNs or hydroxyurea) in treatment-naïve, not resistant, or intolerant PV subjects, with the primary endpoint of event-free survival, including occurrence of major TEs. 

Resistance or Intolerance to Hydroxyurea 

Approximately 15% to 30% of patients with PV develop resistance or intolerance to hydroxyurea, as specified in the 2010 European LeukemiaNet definitions (TABLE 1), with a discontinuation rate of the therapy estimated to be around 4.1% p-y. The most recent LeukemiaNet recommendations strongly suggest switching from hydroxyurea to another CT in case of intolerance, together with the development of nonmelanoma skin cancers or thrombotic-hemorrhagic events. The choice of a second-line CT should be based on the patient’s age and preferences, in addition to the current evidence on alternative treatments.  

To date, ruxolitinib and IFNs are the available options for patients who initially underwent hydroxyurea. Two prospective, randomized studies, RESPONSE and RESPONSE-2, evaluated ruxolitinib in PV patients resistant or intolerant to hydroxyurea and in need of phlebotomies, with (RESPONSE) or without (RESPONSE-2) splenomegaly. In the RESPONSE trial, Hct control was reached in 60% of ruxolitinib-treated patients versus 20% in the control arm, with a 35% reduction in spleen volume achieved in 38% versus 1% of patients, respectively. In the RESPONSE-2 study, Hct control was reached in 62.2% of the ruxolitinib-treated patients versus 18.7% in the control arm. 

Based on available evidence, ruxolitinib appears to be effective as a second-line therapy, particularly in improving Hct or splenomegaly and in terms of thrombotic risk reduction. It is necessary to keep monitoring patients for the development of nonmelanoma skin cancers while receiving ruxolitinib. Data on PEG-IFNs are limited in terms of late events and safety; however, their indications could be similar to the first-line setting. Finally, patients who are nonresponsive to available treatments should be evaluated for inclusion in clinical trials, when available. 

Should Cytoreduction Be Given to Patients with LR PV? 

There is ongoing discussion as to the therapeutic paradigm for “confirmed” patients with LR PV who have been demonstrated to be at increased thrombotic risk compared with the general population, with a rate of 2% p-y. Periodic phlebotomies, with consequent Hct fluctuations and their ineffectiveness in treating leukocytosis, may not be sufficient to prevent vascular events.  

Even though Hct control is often used as a surrogate endpoint of a reduced thrombosis risk, actual years of follow-up and number of patients under study are not enough to prove a protective vascular effect of ropeg-IFN-α2b in LR patients.  

“One might hypothesize its administration in LR young cases if signs of hypermyeloproliferation or uncontrolled symptoms are present, or for curbing the need [for] and side effects of frequent [phlebotomies],” Drs. Mora and Passamonti wrote.  

Considerations for Treatment Approaches 

Current treatment approaches in PV include PEG-IFNs besides hydroxyurea for the first line and ruxolitinib for the second line, with some patients potentially also receiving PEG-IFN treatments in the latter setting.  

The effect of ruxolitinib treatment on thrombosis has been documented. While a benefit of delaying PPV-MF progression is not evident with ruxolitinib, this is most likely due to the need for longer observation.  

The use of ropeg-IFN is safe, and it exerts an important effect on the JAK2 clone, whose significance requires a longer follow-up. Finally, low-dose aspirin continues to be important in PV.  

“Additional efforts to understand disease progression are needed,” the authors concluded.