Diagnosis and Classification of Primary Myelofibrosis (PMF)

According to the World Health Organization (WHO), PMF is categorized as either early or prefibrotic stage; or overt, or fibrotic stage, which includes patients with PV or essential thrombocythemia (ET) that progresses to PMF (post-PV and post-ET, respectively).1 The differentiation of early PMF versus ET is based on differences in both their characteristic morphological bone marrow (BM) features and also their characteristic clinical behavior in terms of mortality, venous thrombotic complications, progression to overt PMF, and blast transformation. Compared with ET, early PMF is a less benign disease, with a distinct clinical pattern of progression, with also an increased bleeding tendency. However, although early PMF can transform into overt PMF, Barbui and colleagues1 showed that the transformation risk is 15% after 15 years on follow-up, and the transformation rate to acute myeloid leukemia (AML) is 10% after 15 years of follow up. Early PMF can thus be considered a benign disease compared with overt PMF and can be treated similarly as ET.

Overt PMF is characterized by progressive organomegaly and extramedullary hematopoiesis, progressive cytopenias, and progressive constitutional symptoms.2 Patients with overt PMF have a substantially decreased quality of life (QoL); progressive incapacitation and immobility; and increased risks for disease-related complications; leukemic transformation, and premature death.

Mutational Characteristics of MF

Three oncogenic driver mutations in MF have been identified: JAK2, CALR, and MPL, all which activate JAK-STAT signaling, which ultimately drives MF.3

These mutations are essentially mutually exclusive and have been associated with specific prognoses. For example, CALR mutations occur in 27% of patients with MF and is associated with a decreased risk of thrombosis, and thus confers a favorable prognosis of about 18 years.4 JAK2 and MPL mutations are detected in 65% and 4% of patients, respectively, and are each associated with a prognosis of about 9 years. Triple-negative disease occurs in about 8.6% of patients and has the worst prognosis of 3 years.

Non-driver mutations of high molecular risk have also been identified, such as IDH, EZH2, ASXL1, and SRSF2.5-7 The presence of two or more of these  mutations worsens survival in MF, and may even negatively impact the presence of a favorable driver mutation, which has been observed when both CALR and ASXL1 mutations were present.

Choosing Therapy for MF

Prognostic Tools

Because patients with PMF have a variable outcome, it is important to subclassify them into risk categories, and there are several prognostic models that are available for this. The differences among these models essentially lies in the parameters that are used to determine a patient’s risk category as well as the time point during the patient’s treatment course that these tools can be used. For example, since the International Prognostic Scoring System (IPSS) only uses information obtained at diagnosis, it can only be used at that time.8 By comparison, the Dynamic International Prognostic Scoring System (DIPSS) uses additional information to that obtained at diagnosis and can be used at any time point during the patient’s course of therapy.9 Finally, the DIPSS-Plus enhances the DIPSS by incorporating other indicators of adverse prognostic significance such as cytogenetic abnormalities, thrombocytopenia, and transfusion-dependent anemia.10

Recently, the Mutation-Enhanced International Prognostic Scoring System 70 (MIPSS70) was developed to determine which patients with PMF should undergo transplantation, based on clinical, cytogenetic, and mutation data.11 This model was enhanced in the MIPSS70-Plus, which includes additional mutation and karyotype information.12 The key elements of the MIPSS70 and MIPSS70-Plus are presented in Figure 1.13

Figure 1. Key Elements on the MIPSS70 and MIPSS70-Plus13

JAK Inhibitors in the Treatment of PMF

The goals of therapy for patients with MF are to improve constitutional symptoms, reduce spleen volume, improve survival, and modify disease. Treatment selection for PMF should be based on the patient’s clinical need. As shown in Table 1, the JAK2 inhibitors ruxolitinib and fedratinib should be considered when the goal of therapy is to improve symptomatic splenomegaly, constitutional symptoms, or quality of life, and survival.1

Table 1. Selecting Therapies Based on Clinical Need1

Ruxolitinib

As mentioned, ruxolitinib is standard of care for patients with intermediate- or high-risk PMF, and the survival benefit of this agent was confirmed in the 5-year overall survival (OS) analysis of the pivotal COMFORT-I and COMFORT-II trials.14 For patients who received ruxolitinib, the risk of death was reduced by 30% compared with those in the comparator groups (median OS, 5.3 vs 3.8 years, respectively; P = .0065). After correcting for crossover, this OS benefit was especially more evident among patients who were originally randomized to receive ruxolitinib versus those who crossed over from the control group (median OS, 5.3 vs 2.3 years). Ruxolitinib was also observed to extend OS versus controls in an analysis of OS censoring patients at the time of crossover (median OS, 5.3 vs 2.4 years, respectively; P = .0013). Finally, ruxolitinib provided an OS benefit regardless of anemia status at baseline or transfusion requirements at week 24. 

Other data indicate a correlation between spleen response to ruxolitinib therapy and OS.15 In a multicenter study of 284 patients, the OS of patients who had a spleen response to ruxolitinib at 6 months was significantly longer versus those who did not respond to therapy, and the OS by durability of response was also significantly greater in the latter group (P = .004 for both comparisons). Baseline factors associated with lower spleen response to ruxolitinib include high/intermediate-2 disease severity, spleen size >20 cm; high white blood cell (WBC) count; delay in ruxolitinib start after diagnosis, and titrated doses <10 mg twice daily.16,17 In regard to the application of these findings to clinical practice, it is important to note that these are clinical trial findings, and that spleen responses in these trials are assessed using specific research MRI protocols. In my opinion, obtaining imaging at baseline and over time may not be clinically useful as these may not be as accurate as those done in clinical trials.

The type and number of non-driver mutations also have been shown to predict response to ruxolitinib therapy.18 In one study, patients with mutations in ASX01, EZH2 and DNMT3 were shown to have worse survival versus those without those mutations, and patients with three or more mutations had worse survival than those with fewer mutations.

Although historically, splenectomy was performed prior to stem cell transplantation, current guidelines state that there is not sufficient evidence to support this as a standard pre-transplant procedure, and that this should be decided on a case-by-case basis, preferably in controlled setting such as registries or clinical trials.19 In the pre-transplant setting, ruxolitinib is indicated in patients with a symptomatic spleen and/or constitutional symptoms at least 2 months prior to allogeneic stem cell transplantation. It is recommended to titrate the agent to maximum tolerated dose, then taper over  5-7 days prior to and stop the day before conditioning begins.

At my institution, we often use ruxolitinib in the pre-transplant setting, but caution is warranted when stopping the agent, since if it is stopped too early, there is the risk of the patient developing fever and cytokine release symptoms, in which case transplant would not be possible. In my practice, we continue ruxolitinib towards the beginning of the patient’s conditioning regimen and then stop it. We normally discontinue it on day 4, taper it off over 5 to 7 days, and stop the day before conditioning.  We actually continue it for about 2 days with the regimen that we use.

Fedratinib

Recently, fedratinib was approved for use in patients with intermediate-2 or high-risk primary or secondary (post- PV or post- EV) MF.20 This agent selectively inhibits JAK2/FLT and also RET and was approved based on findings from the JAKARTA-121 and -2 trials.22 Notably, these studies included patients with platelet counts of ≥50 x 109/L, which is lower than the inclusion criterion of ≥100 x 109/L in the ruxolitinib COMFORT trials.14

JAKARTA-1 was a 3-arm trial in which patients (N=289) were randomly assigned to receive fedratinib at a dose of either 400 mg or 500 mg; or placebo.21 At both doses, fedratinib significantly reduced spleen volume versus placebo at 24 weeks and confirmed 4 weeks later. Thirty-six percent of patients in the fedratinib 400 mg group and 40% in the 500 mg group met the primary endpoint, compared with 1% of those who received placebo (P<.001 for comparisons of both doses versus placebo). In addition to these patients, an additional five patients in each fedratinib treatment arm achieved splenic responses of at least 35% at 24 weeks but were not confirmed 4 weeks later. JAK2 mutational status, MF disease subtype, and risk status did not affect spleen responses.

The single-arm phase 2 JAKARTA-2 study evaluated fedratinib in patients with ruxolitinib-resistant or intolerant, high-risk primary or secondary MF.22 Patients were given fedratinib at a dose of 400 mg once daily, for six consecutive 4-week cycles. The primary endpoint was spleen response (≥35% reduction in spleen volume as determined by CT and MRI), which was achieved by 55% of the 83 assessable patients. A recent re-analysis of JAKARTA-2 was conducted to apply the more stringent definitions of ruxolitinib resistance and intolerance to the overall study population.23 In this analysis, results showed that rates of SVR were 28%, 31%, and 29% in patients who had disease that was relapsed, refractory, and intolerant to ruxolitinib, respectively. Toxicities were consistent with prior reports, with no new safety signals identified.

New Agents and Novel Approaches for Myelofibrosis

Several novel approaches are undergoing investigation for MF, with the goal of improving outcomes in these patients. These include the JAK inhibitors momelotinib and pacritinib. The current data supporting their use in this setting are summarized below.

Momelotinib

Momelotinib is a JAK1/2 inhibitor that has been shown to potentially improve anemia in patients with MF, possibly via suppression of hepcidin.24 This agent has been studied in phase 3 trials, SIMPLIFY-125 and SIMPLIFY-2.26 Findings from these trials are presented in Table 2. The ongoing double-blind, randomized, phase 3 MOMENTUM trial (NCT04173494) is investigating momelotinib versus danazol in symptomatic patients with anemia (hemoglobin <10 g/dL) and previous JAK inhibitor experience.27 The primary endpoint of this study is symptom response, and secondary endpoints include transfusion independence and spleen response.

Table 2. Summary of Key Findings from the SIMPLIFY-1 and SIMPLIFY-2 Trials25,26

BAT=best available therapy; MF=myelofibrosis; RCT=randomized clinical trial; SVR=spleen volume response; Wk=week

Pacritinib

Pacritinib is a selective inhibitor of JAK2, JAK2V61F, and FLT3. Development of this agent was halted by the US food and Drug Administration in 2016 due to reports of patient deaths related to intracranial hemorrhage, cardiac failure, and cardiac arrest,28 but this clinical hold was lifted in 2017.29 This agent has been evaluated in phase 3 trials,30,31 as well as in a phase 2 dose-finding trial in patients with higher-risk MF who received previous ruxolitinib (Table 3).32 Pacritinib is currently under investigation in the ongoing randomized phase 2/3 trial, PACIFICA (NCT03165734), in which the agent is compared with physicians’ choice of treatment for patients with intermediate- or high-risk MF and platelet count of <50,000/µL, and who had limited (90 days) or no previous JAK inhibitor therapy.33

Table 3. Summary of Key Findings from the Clinical Trials Investigating Pacritinib in Myelofibrosis30-32

BAT=best available therapy; MF=myelofibrosis; RCT=randomized clinical trial; SVR=spleen volume response; TSS=tumor symptom score; Wk=week