I will begin by emphasizing the importance and universality of the JAK/STAT signaling pathway.¹ This pathway is active in MF, PV, and ET—the 3 classic Philadelphia chromosome‒negative MPNs—regardless of the driver mutation.^2,3 There are 4 members of the JAK family, including JAK2, which have roles in hematopoiesis.¹ JAK2 transduces extracellular cytokine signals into the cell and, via the STAT proteins, stimulates erythropoiesis and other processes; as such, JAK2 is critical for blood cell production. Therefore, inhibition of the JAK/STAT pathway results in anemia, thrombocytopenia, and, to a lesser extent, neutropenia.

Several driver mutations underlie MPN pathogenesis. These are variously prevalent depending on the specific MPN. JAK/STAT signaling becomes constitutively activated in MPN pathogenesis by 3 main driver mutations (and possibly other mutations that have not yet been identified). PV is almost entirely driven by JAK2 mutations, with >95% of cases having an underlying JAK2 V617F mutation.³ Mutations underlying ET and MF are more heterogeneous compared with PV. In ET and MF, JAK2 V617F mutations are found in approximately 60% of cases. Mutations in CALR, an endoplasmic reticulum chaperone protein, account for approximately one quarter of cases.^4,5 Only approximately 5% of ET and MF cases are driven by mutations in MPL, the thrombopoietin receptor gene.⁶  

Of interest, although different patients have MPL or CALR driver mutations, MPL and CALR are inextricably linked. When CALR, an endoplasmic reticulum chaperone protein, is mutated, it is not properly localized. Consequently, it migrates to the cell surface, where it exerts its oncogenic potential by binding to MPL.⁷ 

According to the WHO, a diagnosis of overt primary MF is confirmed when all 3 major criteria and at least 1 of the minor criteria shown on the slide are met.⁸

Criteria focus on megakaryocyte morphology, the presence of driver mutations, and several additional clinical characteristics.⁸ It should be emphasized that these criteria are for overt primary MF. The criteria for prefibrotic primary MF will be discussed later in this presentation.

MF progresses from early primary MF to overt primary MF.⁹ Early primary MF is characterized by a long latency period during which vascular events such as bleeding and clotting issues are the primary clinical issue of concern.

Overt primary MF, as well as post-ET MF and post-PV MF, are associated with progressive cytopenias, progressive organomegaly, and progressive symptoms. In addition, primary MF and post-ET and post-PV MF are associated with an increased risk of leukemic transformation and shortened survival compared with early primary MF.

Prognostic models for MF have evolved over the years. The classic models include the International Prognostic Scoring System (IPSS), Dynamic International Prognostic Scoring System (DIPSS), and DIPSS Plus. In these models, the primary prognostic factors include age, hemoglobin, white blood cell (WBC) counts, peripheral blood blasts, and constitutional symptoms. Except for anemia, which is given a greater weight in the DIPSS model, the prognostic factors are weighted the same in each of these models.¹⁰ Compared with the IPSS, which is designed only for use at initial diagnosis, the DIPSS and DIPSS Plus may be used at any point in the disease course.^11-13

Compared with the IPSS and DIPSS models, DIPSS Plus incorporates 3 additional variables: unfavorable karyotype, red blood cell (RBC) transfusion need, and thrombocytopenia.¹¹ 

Each model provides an estimated survival for patients in each of 4 risk categories, including low, intermediate 1, intermediate 2, and high risk.^11-13 

The IPSS, DIPSS, and DIPSS Plus models do not include driver mutations as prognostic factors. However, since the publication of these models, it has become apparent that driver mutations can significantly affect prognosis.^14-16

Patients with disease driven by CALR mutations have the best prognosis with regard to overall survival (OS). Those with disease driven by JAK2 or MPL mutations have an intermediate prognosis, and those with triple-negative disease have the worst prognosis.^14-16  

In addition to the identified driver mutations, nondriver mutations can negatively affect prognosis. These include mutations in IDH1 and IDH2, EZH2, ASXL1, SRSF2, U2AF1, and Q157.^15-17 The presence of 2 or more high molecular risk (HMR) mutations further worsens prognosis.¹⁶   

The Mutation-Enhanced International Prognostic Scoring System 70 (MIPSS70)‒Plus risk scoring system is one of several prognostic systems that have been developed to incorporate genomic information with existing clinical information.¹⁸    

The MIPSS70-Plus model incorporates anemia; peripheral blood blasts; constitutional symptoms; the absence of CALR type 1 mutations, which is a favorable prognostic factor; presence of HMR mutations, including ASXL1, EZH2, SRSF2, and IDH1/2; presence of 2 or more HMR mutations; and unfavorable karyotype.

Post-PV MF and post-ET MF often are grouped with overt primary MF and treated similarly. However, these are distinct biologic conditions and therefore require a unique prognostic model. 

The Myelofibrosis Secondary to PV and ET‒Prognostic Model (MYSEC-PM) was developed from a large cohort comprising approximately 800 patients with post-PV or post-ET MF.¹⁹ MYSEC-PM incorporates hemoglobin levels, platelet levels, peripheral blood blasts, constitutional symptoms, and the absence of a CALR mutation, which is a positive prognostic factor.

After summing the total points based on the prognostic variables, the total points and the patient’s age are plotted on a nomogram, which allows healthcare professionals to determine a patient’s relative risk on a spectrum ranging from low risk to high risk.  

Before we discuss treatment options for patients with MF, let’s review a case.

Guidelines have been developed for MF that stratify patients as lower or higher risk and recommend treatment accordingly.²⁰ According to the guidelines, patients who are categorized as lower risk may be observed if they are asymptomatic. For symptomatic patients at lower risk, treatment options include ruxolitinib, peginterferon alfa-2a, or, if the patient requires cytoreduction, hydroxyurea.

Recently, most of the focus has been on patients who are higher risk. For these patients, transplant eligibility is a primary clinical consideration. Patients who are not immediately transplant eligible may be eligible after receiving initial treatment with a JAK inhibitor. For initial JAK inhibitor treatment, recommendations are based on platelet levels and whether the patient also has anemia. The JAK inhibitors ruxolitinib, fedratinib, and pacritinib may be considered for specific patients, as we will discuss below. The availability of 3 FDA-approved JAK inhibitors means that patients who have either failed on or have intolerance to one JAK inhibitor may be switched to an alternative JAK inhibitor.  

It is a common misconception that JAK inhibitors are limited to treating patients with disease characterized by JAK mutations. Remember, the JAK/STAT pathway is activated in all patients, regardless of JAK status. Therefore, JAK inhibitors are appropriate for all patients, regardless of the driver mutation they have. They are even appropriate for patients with triple-negative disease.

It is important to recognize that MF presentation is highly variable. Treatments vary widely depending on the patient’s presentation, and decisions should be guided by and individualized to the patient’s specific clinical needs. When selecting a treatment, the primary determinant—more immediate than considerations such as driver mutation, degree of bone marrow fibrosis, or spleen size—is the patient’s most pressing clinical need. Blast percentage is also important, as the patient could be in an accelerated or blastic phase of MF, for which treatment differs.  

Let’s turn now to some of the relevant clinical trials in MF, beginning with COMFORT‑I and COMFORT-II, the pivotal trials for ruxolitinib. COMFORT‑I was a randomized, double-blind phase III trial in which 309 patients with intermediate-2‒ or high-risk MF received ruxolitinib or placebo.²¹ COMFORT‑II was a randomized phase III trial in which 219 patients with primary MF, post-PV MF, or post-ET MF received ruxolitinib or best available therapy (BAT), which was mostly hydroxyurea.²² The primary endpoint was reduction in spleen volume by ≥35% at 24 or 48 weeks in COMFORT-I and COMFORT-II, respectively.^21,22

In COMFORT-I, a significantly greater 42% of patients receiving ruxolitinib achieved a spleen response compared with 0.7% of patients receiving placebo. Similarly, in COMFORT-II, a significantly greater 28% of patients receiving ruxolitinib achieved a spleen response compared with 0% of patients receiving BAT.^21,22  

Symptom reduction also was assessed. In the COMFORT‑I trial, symptoms were assessed by the symptom assessment form that is frequently used in the United States, which generates a total symptom score. Significantly more patients receiving ruxolitinib experienced symptom reduction of ≥50% compared with patients receiving placebo.²¹ Different symptom assessment tools were used in COMFORT‑II, and the results are not depicted on the slide.

Anemia and thrombocytopenia are established on-target effects associated with JAK inhibitors, including ruxolitinib.²² Therefore, with regard to adverse events, it was not surprising that compared with placebo in COMFORT-I or BAT in COMFORT-II, ruxolitinib was associated with higher frequencies of hematologic toxicities, including anemia and thrombocytopenia.^21,22 

Although the COMFORT‑I and COMFORT-II trials were not powered to show survival differences, survival differences were observed beginning as early as 1 year after trial initiation. At 5 years of follow-up, a pooled analysis of COMFORT-I and COMFORT-II demonstrated that ruxolitinib was associated with superior survival of 5.3 years compared with 3.8 years in the control group.²³ When the rank-preserving structural failure time method was used to correct for crossover, the survival benefit associated with ruxolitinib was more pronounced, as survival in the control group dropped to 2.3 years.

Extent of spleen reduction is the most important biomarker demonstrating survival associated with ruxolitinib. Spleen shrinkage with ruxolitinib is dose dependent; therefore, it is important to optimize ruxolitinib dosing to maximize spleen shrinkage and, consequently, survival outcomes.^24,25

The correlation between spleen shrinkage and survival was demonstrated in COMFORT-I, in which approximately equal numbers of patients experienced spleen length reduction of ≥50%, 25% to <50%, and <25%. Patients with ≥50% spleen length reduction had the best OS probability, followed by patients with 25% to <50% spleen length reduction. Patients with <25% spleen length reduction had the worst OS probability.

As described earlier, COMFORT-I demonstrated that spleen response with ruxolitinib is dose dependent, with higher doses inducing better spleen responses. In turn, better spleen responses are associated with increased survival.^24-26

A similar dose-dependent response was not observed with regard to symptom improvement. Results from COMFORT-I demonstrated that ruxolitinib 10 mg twice daily is sufficient for symptom reduction.²⁶  

As mentioned earlier, established on‑target toxicities associated with JAK inhibitors include anemia and thrombocytopenia. In COMFORT-I, hemoglobin levels declined steeply during the first few weeks of ruxolitinib treatment and then partially recovered, with levels plateauing at slightly lower than baseline without fully normalizing.²⁷ Like hemoglobin levels, platelet levels initially declined and then plateaued at below-baseline levels following ruxolitinib treatment initiation.

In practice, managing early-onset, ruxolitinib-induced anemia is difficult. However, ruxolitinib-induced anemia is not prognostically detrimental; therefore, it is important to be aware of the anemia and treat it with appropriate therapies without discontinuing ruxolitinib treatment or reducing the dose.

The REALISE trial was a single-arm phase II trial in which 51 patients with MF and anemia—defined as hemoglobin <10 mg/dL—received alternative ruxolitinib dosing to mitigate anemia-related issues, including the need for transfusions. The alternative dosing strategy consisted of ruxolitinib 10 mg twice daily for the first 12 weeks regardless of baseline platelet counts, followed by uptitrations to a maximum of 25 mg twice daily based on platelet counts and efficacy.²⁸ The alternative dosing strategy was efficacious and well tolerated.

Ruxolitinib failure may variably manifest as resistance, intolerance, or refractoriness. Regardless of how it manifests, ruxolitinib failure is associated with a poor prognosis. Several studies, including a retrospective analysis of an open-label phase I/II study, indicate that median survival following discontinuation is 13-14 months.²⁹ This study also demonstrated that survival is worsened when there is clonal evolution or if platelet counts continue to decline while receiving ruxolitinib.

Because 3 JAK inhibitors currently are commercially available for treating MF—and more are under investigation—there is growing interest in understanding how to identify patients who will have poor outcomes with these therapies. To this end, a recent study assessed potential predictors of survival in patients with intermediate-1‒risk or higher MF who had received ruxolitinib for ≥6 months in an observational study.³⁰ Based on multivariate analyses, 4 factors were associated with shorter survival with ruxolitinib treatment: ruxolitinib dosing of <20 mg twice daily at baseline, Month 3, and Month 6; palpable spleen length reduction of ≤30% from baseline at Months 3 and 6; RBC transfusion requirement at Month 3 and/or 6; and RBC transfusion requirement at all time points (baseline, Month 3, and Month 6). The resulting model—Response to Ruxolitinib After 6 Months (RR6)—integrates the clinical parameters of dose, spleen response, and transfusion requirement into a prognostic tool that categorizes patients as low, intermediate, or high risk, with each category having increasingly worse survival. Results of the RR6 model may influence a healthcare professional’s treatment strategy for a given patient by informing them that the current treatment strategy is not working well and a change may be warranted—even though there is no guarantee that switching to a different JAK inhibitor will improve outcomes.

Fedratinib was approved in the United States in 2019 and has a broad indication for adults with intermediate-2‒ or high-risk MF. The indication does not specify a line of therapy.³¹ Fedratinib has been investigated in patients who are JAK inhibitor naive and in patients with previous exposure to ruxolitinib—in other words, as a first- and second-line therapy.

JAKARTA was a randomized, double-blind, placebo-controlled phase III trial in which 289 patients with intermediate-2‒ or high-risk MF who were JAK2 inhibitor naive received fedratinib 400 mg or 500 mg or placebo once daily (NCT01437787).³² JAKARTA-2 was a single-arm, nonrandomized phase II trial in which 97 patients with intermediate- or high-risk MF who were ruxolitinib resistant or intolerant received fedratinib 400 mg once daily.³³

In the JAKARTA trial, among patients receiving the recommended dose of fedratinib 400 mg once daily, 36% experienced a spleen response, and 36% experienced a symptom response.³² Fedratinib 500 mg once daily demonstrated similar efficacy but was more toxic.  

 In the JAKARTA-2 trial, the primary analysis was based ruxolitinib failure that was defined as ruxolitinib resistance or intolerance following ≥2 weeks of treatment.³³ A reanalysis using a more stringent definition of ruxolitinib failure demonstrated that fedratinib was associated with a 30% spleen response rate and a 27% symptom response rate.³⁴ To date, these are the best results for any agent in the second-line setting.  

Known toxicities associated with fedratinib include Wernicke encephalopathy, which is included in a boxed warning in the fedratinib label and which initially resulted in the withdrawal of fedratinib from the market before it was later reintroduced.^31,32 Although rare, this is a serious complication, and it is important to measure patients’ thiamine levels before initiating fedratinib therapy and as necessary during treatment, as well as to avoid malnutrition and other situations that may result in thiamine deficiency.

Other adverse events associated with fedratinib include gastrointestinal toxicity, nausea, vomiting, and diarrhea, as well as the JAK inhibitor class‒specific adverse events of anemia and thrombocytopenia.

In addition to ruxolitinib and fedratinib, a third JAK2 inhibitor, pacritinib, received FDA approval in February 2022. Pacritinib is indicated for patients with intermediate- or high-risk MF with severe thrombocytopenia, defined as platelet levels of <50 x 10⁹/L.³⁵ Neither ruxolitinib nor fedratinib has been studied in patients with severe thrombocytopenia.

Pacritinib is a nonmyelosuppressive JAK2 inhibitor, which makes it a very attractive therapy for patients with cytopenias.³⁶ Although the exact mechanism is not fully elucidated, the lack of myelosuppression with pacritinib may be explained by its inhibition of IRAK1, which has roles in toll‑like receptor and innate immunity pathways.^36,37 In addition, although fedratinib is mostly selective for JAK2 with a relatively small affinity for JAK1, pacritinib is relatively more selective for JAK2 and does not target JAK1.^36,38  

Pacritinib was approved for treating patients with higher-risk MF and a platelet count of <50 x 10⁹/L based on results from the pivotal PERSIST-2 trial, which was an open-label, randomized phase III trial in which 311 patients with intermediate-1‒, intermediate-2‒, or high-risk MF and a platelet count of ≤100 x 10⁹/L received pacritinib 200 mg or 400 mg twice daily or BAT (NCT02055781).³⁹

Results from PERSIST‑2 demonstrated that in the intention-to-treat population, all of whom had platelet counts of ≤100 x 10⁹/L, pacritinib 200 mg twice daily was associated with a significantly higher spleen response rate of 22% vs 3% with BAT. Similarly, pacritinib 200 mg twice daily was associated with a significantly higher symptom improvement rate of 32% vs 14% with BAT.³⁹

In a subgroup analysis of patients with baseline platelet counts <50 x 10⁹/L, pacritinib 200 mg twice daily resulted in spleen and symptom response rates of 29% and 23%, respectively, vs 3% and 13% with BAT.

Of importance, in this study, BAT included ruxolitinib, which was given to 45% of patients. In addition, prior ruxolitinib treatment was allowed; depending the treatment group, 41% to 46% of patients had prior ruxolitinib exposure.

This slide details adverse events with pacritinib, some of which were discussed earlier.

Very recent evidence has shown that pacritinib is a potent ACVR1 inhibitor.⁴⁰ ACVR1 inhibition decreases hepatic hepcidin production, which, in turn, can improve anemia by increasing iron availability for erythropoiesis and reducing iron sequestration in the reticuloendothelial system.⁴¹ 

The translational relevance of ACRV1 inhibition by pacritinib was illustrated in the transfusion independence results from PERSIST-2. In this trial, 24% of patients receiving pacritinib who were transfusion dependent at the beginning of the trial achieved transfusion independence. This was a significantly higher rate compared with the group receiving BAT (45% of whom were receiving ruxolitinib), in which 5% of patients achieved transfusion independence.⁴⁰     

The efficacy of pacritinib in achieving transfusion independence was demonstrated using 2 sets of criteria—Gale criteria and SIMPLIFY trial criteria. The Gale criteria define transfusion independence as no transfusions in a 12-week period but do not specify a minimum hemoglobin level. By contrast, the SIMPLIFY criteria are more rigorous, defining transfusion independence as no transfusions in a 12-week period and no hemoglobin levels <8 mg/dL.

Note that CCO has created an online treatment decision support tool, for which 5 MF experts, including myself, provided treatment recommendations for numerous case scenarios in MF. Healthcare professionals can enter case-specific characteristics into the tool, along with planned treatment, and receive expert recommendations. The current version of this tool can be found at clinicaloptions.com/MFtool. 

Now, let’s return to our earlier case of a higher-risk patient with MF and low platelets.

Let’s now discuss anemia in MF in more detail. When treating anemia, which is an important aspect of MF management, 3 drug classes are typically used. These include androgens such as danazol, erythropoietin‑stimulating agents for patients whose endogenous erythropoietin is low, and immunomodulatory drugs with or without prednisone.²⁵

Danazol and erythropoietin‑stimulating agents are generally the most effective among these therapy classes. Considerations when choosing a therapy, especially when using danazol, include the potential for hepatoxicity, liver tumors, and prostate cancer and the consequent need to monitor prostate-specific antigen, liver function, and other relevant parameters.

Luspatercept is currently indicated for treating anemia associated with myelodysplastic syndromes.⁴² Based on encouraging results from a phase II trial, this therapy is currently being investigated for treating anemia associated with MF in the INDEPENDENCE trial, a randomized, double-blind phase III trial in which an estimated 309 patients with MF receiving concomitant JAK inhibitor therapy who require RBC transfusions will receive luspatercept or placebo (NCT04717414).⁴³

Luspatercept is currently recommended by national guidelines as a category 3 option for patients with MF and anemia.²⁰

Momelotinib is a JAK inhibitor that, like ruxolitinib, inhibits JAK1 and JAK2. However, unlike ruxolitinib, momelotinib also inhibits ACVR1.^40,41 As described earlier, ACVR1 inhibition affects hepcidin and iron availability, which translates to improved hemoglobin levels.^41,44 

Momelotinib was previously studied in 2 phase III trials, SIMPLIFY-1 and SIMPLIFY-2. Momelotinib failed to meet noninferiority for symptom control vs ruxolitinib in the SIMPLIFY-1 trial in MF with no prior JAK inhibitor treatment (although it was noninferior for spleen response) and superiority for spleen response vs best available therapy in the SIMPLIFY-2 trial in previously treated MF.^46,59

MOMENTUM was the third phase III trial conducted with momelotinib. This was a randomized, double-blind phase III trial in which 195 patients with symptomatic MF and anemia who had previously received a JAK inhibitor were randomized to receive momelotinib 200 mg once daily or danazol.⁴⁵

Notably, the primary endpoint was symptom response and not spleen response. Spleen response and transfusion independence were key secondary endpoints.

Data from MOMENTUM showed that momelotinib was superior to danazol with regard to symptom response, spleen response, and other endpoints and was noninferior to danazol with regard to transfusion independence.⁴⁵  

 In addition to the agents already described in this presentation, myriad other targets are being investigated in MF. The agents listed in this table are currently being studied in phase III trials. These include navitoclax, a BCL-XL/BCL-2 inhibitor being assessed in combination with ruxolitinib for JAK2 inhibitor‒naive and relapsed/refractory MF, as well as pelabresib, a BET inhibitor also being assessed in combination with ruxolitinib for JAK inhibitor‒naive MF. Navtemadlin is an MDM2 inhibitor being investigated in relapsed/refractory MF following JAK inhibitor therapy.

Imetelstat, a telomerase inhibitor, is another investigational therapy.^47,48  Imetelstat was investigated in IMBark, a phase II trial in which 107 patients with relapsed/refractory MF following JAK inhibitor therapy received imetelstat 9.4 mg/kg or 4.7 mg/kg every 3 weeks.

Typical survival of patients following JAK inhibitor failure is 13-14 months; results from IMBark showed a median OS of 28.1 months with imetelstat 9.4 mg/kg, which was striking.⁴⁷ Imetelstat currently is being investigated in IMpactMF, a randomized phase III trial in which patients with relapsed/refractory intermediate-2‒ or high-risk MF following JAK inhibitor therapy will receive imetelstat 9.4 mg/kg every 3 weeks or BAT (NCT04603495). The primary endpoint is OS, which is unprecedented and very welcome in the MF field as the primary endpoint in a pivotal trial. It will be interesting to see if the OS observed in IMBark is also observed in IMpactMF.

Let’s return to one of our presurvey questions.

We will turn now to our discussion of PV, beginning with 2 cases.

The updated diagnostic criteria include bone marrow biopsy as a major criterion for a PV diagnosis. The lowered hemoglobin and hematocrit cutoffs made bone marrow results more important. A PV diagnosis requires that all 3 major criteria or the first 2 major criteria and the minor criterion be met.⁸  

Patients who meet the earlier criteria that included higher hemoglobin and hematocrit cutoffs do not necessarily need a bone marrow biopsy. However, if a bone marrow biopsy is not performed, initial fibrosis, which is indicative of a higher risk of post-PV MF, may be missed. In addition, bone marrow biopsies may help differentiate PV from JAK2‑mutated ET.

The classic guideline management schema for PV recognizes 2 risk categories. Low-risk patients are younger than 60 years of age and have no history of blood clots. High-risk patients are 60 years of age or older and/or have a history of clots. For high-risk patients and some low-risk patients, guidelines recommend cytoreductive therapy with hydroxyurea, peginterferon alfa-2a, or ropeginterferon alfa-2b as first-line options and ruxolitinib as a second-line option.²⁰

The CYTO‑PV study is arguably the most important PV-related trial performed to date. This was a large-scale, randomized phase III trial in which 365 patients with PV underwent phlebotomy, received hydroxyurea, or both. One treatment group received aggressive therapy for a hematocrit target of <45%, and the other group received less aggressive therapy for a target of 45% to 50%.⁴⁹ There was a significant difference in cardiovascular/thrombotic events and mortality between the 2 groups, but the absolute difference in the hematocrit percentage was fairly small. Ultimately, the trial demonstrated that the hematocrit needs to be maintained under 45%.

Results from the final analysis at 6 years of follow-up in the PROUD-PV/CONTINUATION-PV trial demonstrated that ropeginterferon alfa-2b was associated with significant improvements in hematologic and molecular response rates compared with control treatment.⁵² At 6 years, the control arm primarily included treatment with hydroxyurea because patients in the hydroxyurea group largely continued receiving hydroxyurea in the extension study.

Ropeginterferon alfa-2b is unique in that it has demonstrated efficacy in reducing JAK2 V617F allele burden. At 6 years of follow-up in the PROUD-PV/CONTINUATION-PV trial, ropeginterferon alfa-2b was associated with much higher rates of JAK2 V617F allele burden reduction compared with the control group.

Results were recently presented from an open-label phase II study of ropeginterferon alfa-2b plus phlebotomy vs phlebotomy alone in patients younger than 60 years of age with no history of thrombosis (N = 127).⁵³ This study found that the addition of ropeginterferon alfa-2b was associated with improved hematocrit control and a decrease in the number of phlebotomies required per year.

So how do we manage patients with PV who require new treatment after first-line failure? The European LeukemiaNet criteria for hydroxyurea resistance or intolerance are relatively intuitive. Resistance may be defined as having uncontrolled myeloproliferation despite receiving an adequate dose of hydroxyurea. Intolerance is defined as the patient experiencing hematologic or nonhematologic toxicity at the lowest dose required to maintain a clinical hematologic response.^54,55 

Two trials examined the use of ruxolitinib in treating PV in patients with resistance or intolerance to hydroxyurea. RESPONSE and RESPONSE-2 were randomized, open-label phase III trials in which patients with PV and resistance or intolerance to hydroxyurea received ruxolitinib or BAT.^56,57 In RESPONSE, patients had splenomegaly, whereas RESPONSE-2 excluded patients with splenomegaly. In both trials, the endpoints were similar, and because treatment options are limited, the BAT was primarily hydroxyurea, even though patients had previously experienced treatment failure with hydroxyurea. In both trials, ruxolitinib was superior to BAT for endpoints including hematocrit control, complete hematologic remission, symptom response, symptom resolution, and spleen response.

Ruxolitinib currently is approved for polycythemia vera in adults who have had an inadequate response to or are intolerant to hydroxyurea.

The final PV therapy that I want to discuss belongs to the hepcidin mimetic drug class. These agents currently are of great interest among healthcare professionals in the PV field. As opposed to MF-associated anemia, in which the goal is to inhibit hepcidin and increase the amount of iron available for erythropoiesis, the goal of using hepcidin mimetics in PV is to sequester iron in the reticuloendothelial system, thereby reducing bone marrow iron that is available for erythropoiesis.^41,58

The hepcidin mimetic rusfertide is being investigated in 2 trials. REVIVE is a randomized phase II trial comprising a dose-escalation phase; a randomized, blinded, withdrawal phase; and a 3-year open-label extension phase (NCT04057040). In this study, 63 patients with PV who had required ≥3 phlebotomies in the previous 6 months with or without concurrent cytoreductive therapy either initiated therapy with rusfertide or received rusfertide in addition to their current regimen.⁶⁰

Results from the REVIVE trial demonstrated that rusfertide dramatically reduced the phlebotomy requirement and improved the proportion of patients meeting hematocrit goals.

The second trial or rusfertide72, VERIFY, is an ongoing, 2-part phase III trial comprising a randomized, double-blind, placebo-controlled phase and an open-label phase (NCT04576156).

Let’s return now to our PV case discussions.

Finally, we will discuss ET.

It is important to distinguish ET from prefibrotic primary MF because these conditions may appear similar.⁶¹ ET and prefibrotic primary MF can be distinguished by their bone marrow appearance. In addition, these conditions can be distinguished via subtle abnormalities in their major and minor criteria, with prefibrotic primary MF having some features that are more closely associated with MF than with ET.⁸ Distinction between these 2 conditions is important because prefibrotic primary MF is associated with worse survival, higher rates of leukemic transformation, and relatively more bleeding compared with ET.⁶¹ 

In patients with ET, the presence of a CALR mutation is associated with the lowest risk of thrombosis compared with other mutations. This is an important factor in ET management.^14,62-64

The traditional thrombosis risk stratification for ET is similar to that for PV, with cardiovascular risk factors being a consideration in both conditions.⁶⁵ Based on data from the randomized PT1 trial comparing treatment with hydroxyurea vs anagrelide, hydroxyurea is the preferred first-line cytoreductive agent for treating ET, although interferon also may be an option.^65,66 Anagrelide may be considered sometimes as a second‑line agent in patients with hydroxyurea resistance or intolerance.

A common misconception is that platelet count correlates with thrombosis risk—this is inaccurate. Although high platelet counts >1500 may correlate with an increased bleeding risk, there is no correlation between platelet count and clotting risk.

The revised International Prognostic Score of Thrombosis for ET (IPSET-Thrombosis) risk stratification model categorizes patients into 1 of 4 risk groups: very low risk, low risk, intermediate risk, and high risk.⁶⁷ The IPSET-Thrombosis risk groups are differentiated based on 3 factors, including the presence or absence of a JAK2 mutation, age younger than or older than 60 years, and prior thrombosis. In practice, when using this model, it is important to consider cardiovascular risk factors in addition to the 3 main factors.

A particularly compelling trial randomized patients aged 40-59 years with ET and no high-risk factors (such as history of blood clots, disease-related bleeding, or platelet levels >1500 x 10⁹/L) to receive hydroxyurea plus aspirin or aspirin alone.⁶⁸ Trial results demonstrated that adding hydroxyurea to aspirin had no effect on any of the trial endpoints, which included reduction in risk of vascular events, myelofibrotic progression, or leukemic transformation.

Although current therapies used for treating ET—including hydroxyurea and anagrelide—are efficacious in reducing blood counts, they are only minimally effective in reducing symptoms.⁶⁹

 Ruxolitinib is not indicated for treating ET and has not been studied in a randomized, controlled phase III trial. However, it has been investigated in earlier-phase trials, including MAJIC-ET, a randomized phase II trial in patients with ET who were resistant or intolerant to hydroxyurea and who received ruxolitinib or BAT.⁷⁰ In this trial, ruxolitinib and BAT were associated with similar rates of complete response within 1 year of treatment, which was the primary endpoint.

Long-term follow-up results from a second open-label phase II trial of ruxolitinib enrolling 39 patients with ET who were refractory or intolerant to hydroxyurea demonstrated that many patients experienced rapid decreases in platelet and WBC counts that remained relatively stable over time and sustained reductions in splenomegaly.⁷¹

Trial results also demonstrated that—as expected based on its cytokine effects—ruxolitinib was effective in controlling symptoms, inducing rapid reductions in symptom scores that were sustained over time.⁷¹ Of note in the MAJIC-ET trial, ruxolitinib demonstrated superior symptom reduction compared with BAT—but otherwise did not show benefit.⁷⁰ This is important because, as discussed, most current therapies commonly used for treating ET are relatively ineffective at treating symptoms.⁶⁹

Finally, ropeginterferon alfa‑2b, which already is indicated for PV, is being investigated in the hydroxyurea-resistant/intolerant ET setting. SURPASS‑ET is an ongoing randomized phase III trial in which patients with hydroxyurea-resistant/intolerant ET will receive ropeginterferon alfa‑2b or anagrelide (NCT04285086).