The Philadelphia chromosome—negative myeloproliferative neoplasms (MPNs) are clonal disorders characterized by common mutations, but with distinct clinical features, treatment considerations, and prognostic outlooks.

 Identification of the JAK2 (Janus Kinase 2) V617F mutation by several groups in 2005 demonstrated that the myeloproliferative diseases are in fact clonal neoplasms.2-5

The MPNs harbor the JAK2 V617F mutation with differing frequencies; approximately 95% of polycythemia vera (PV) patients, and 50% to 60% of essential thrombocytosis (ET) and myelofibrosis patients (MF), are positive for the JAK2 V617F mutation

 Since the discovery of the JAK2 mutation, significant progress has been made in understanding the biology of these diseases. Acquisition of the JAK2 V617F mutation leads to constitutive activation of the JAK-STAT (signal transducer and activator of transcription) signaling cascade and results in cytokine-independent signaling

Patients with MPNs, regardless of their JAK2 mutational status, have dysregulated JAK-STAT signaling.

 Other mutations that alter the JAK-STAT pathway have also been identified. For example, patients with JAK2 V617F-negative PV have been found to harbor JAK2 exon 12 mutation or in LNK, (also known as SH2B3), leading to sustained JAK2 signaling.

 LNK normally inhibits JAK signaling, and loss of function of LNK in turn results in augmented and persistent JAK-STAT signaling.

 LNK mutations are uncommon in PV and ET; however, LNK mutations have been observed in leukemic transformation in 13% of patients.

Activating mutations in myeloproliferative leukemia virus oncogene (MPL), the receptor for thrombopoietin (TPO), which uses JAK2 for intracellular signaling, have also been found in ET and MF patients.12 Most MPL mutations occur in exon 10 on tryptophan 515, which plays an important role in the cytosolic conformation of MPL.7 The most common mutations are W515L, but others such as the W515K and the S505N have also been reported and result in TPO independent activation and downstream activation of JAK-STAT signaling.

Recently, mutations in the calreticulin gene (CALR) were identified in the vast majority of patients without JAK2 V617F mutations in MF and ET, but not PV.

 The mechanism via which calreticulin leads to disease is unclear; however, it appears to mediate its effect via JAK-STAT signaling.

This is supported by in vitro studies which demonstrate that the growth of cells expressing mutant CALR is inhibited by a JAK inhibitor.

In addition to mutations in the JAK-STAT signaling pathway, mutations in genes involved in epigenetic regulation have been observed in patients with MPN. These mutations have also been observed in other myeloid malignancies and include ten-eleven-translocation-2 (TET2), additional sex combs like 1 (ASXL1), DNA methyltransferase 3A (DNMT3A), and Enhancer of Zeste Homolog 2 (EZH2).

The discovery of the JAK2 V617F mutation improved the diagnostic accuracy of MPNs; however, this mutation by itself cannot distinguish between the MPNs, and its absence does not exclude the presence of an MPN. The World Health Organization (WHO) 2008 criteria should be followed to make an accurate diagnosis (Table 1). Testing for LNK and JAK2 exon 12 may be considered in patients who have a hemoglobin level meeting major criteria for diagnosis of PV and 1 minor criteria (ie, low EPO level), but do not have a JAK2 V617F mutation. Testing for LNK and MPL can similarly be considered in patients suspected of having ET or MF and lacking a JAK2 V617F mutation. CALR mutation testing has become commercially available, and integration of CALR mutation status into the WHO diagnostic criteria is likely in the near future.

The risk of thrombosis in PV and ET is approximately 20%; therefore, the main focus of treatment for patients with PV and ET is thrombosis prevention. To this end, most patients should take a low-dose aspirin daily.20,21 Patients with extreme thrombocytosis (>1000 × 109/L) are at risk for acquired von Willebrand syndrome and should not receive aspirin if the ristocetin cofactor activity is less than 30%

Cytoreduction can be considered for patients at high risk for thrombosis,

 with age greater than 60 years and prior episode of thrombosis being the main factors to consider its initiation.

Other factors such as leukocytosis, cardiovascular risk factors, and the presence of a JAK2 V617F mutation, although not formally part of risk stratification, can be considered in decision making as well.

Several useful models of risk stratification exist for MF: IPSS,25 DIPSS,26 and DIPSS-plus27 (Table 2). These prognostic scoring models are similar; however, the IPSS was validated for use at diagnosis only, while the DIPSS and DIPSS-plus can be used throughout the disease course. Overall survival (OS) varies significantly based on risk category, from 2 to 12 years.

With the discovery of additional mutations, these risk stratification systems are likely to keep evolving. Tefferi et al recently reported on 2 large cohorts of patients and utilized CALR and ASXL1 in one study and CALR, JAK2, MPL, or no identifiable mutations in the other, and found that patients can be further subdivided into prognostic scoring categories based on their mutational profiles.

With regard to treatment, asymptomatic, low- and intermediate-1 risk patients may be observed. Symptomatic, intermediate-2 or high-risk (DIPSS-plus 2 to 6 risk factors) patients can consider treatment with a JAK2 inhibitor, a clinical trial, or an allogeneic stem cell transplant.

It should be noted that despite improvement in the understanding of the molecular biology of MF and the approval of ruxolitinib, the only curative treatment approach for this disease is allogeneic stem cell transplantation (the role of transplantation is outside the scope of this article; however, the recent review by Gupta and colleagues provides in-depth discussion on this subject).

Improved understanding of the disease biology of MPNs has led to the development of a variety of JAK2 inhibitors and the 2011 FDA approval of ruxolitinib, the first oral JAK1/2 inhibitor, for the treatment of patients with intermediate- and high-risk myelofibrosis. The approval of ruxolitinib was based on 2 large, international, phase III studies: COMFORT I and II.

In the COMFORT I study, patients with MF were randomized to receive ruxolitinib or placebo.32 Patients in the COMFORT II study were randomized in a 2:1 fashion to receive ruxolitinib or best available therapy (BAT).33 Patients were eligible regardless of their JAK2 mutational status, and importantly, it was noted that patients benefited regardless of their JAK2 mutational status.

The primary endpoint of both studies was spleen volume reduction of 35% at 24 weeks for COMFORT I and at 48 weeks for COMFORT II, by magnetic resonance imaging (MRI). Secondary endpoints in the COMFORT I study included durability of response, improvement in symptom burden as measured by myelofibrosis symptom assessment form,

 and OS. In the COMFORT I study, 42% of patients experienced spleen volume reduction by 24 weeks, and in the COMFORT II study, 28% of patients compared with 0% in the BAT group experienced a 35% spleen volume reduction at 48 weeks. In addition, 45% of patients experienced significant symptom improvement in the ruxolitinib group. The benefits of ruxolitinib were durable and, in addition, both studies reported a significant improvement in OS, an observation confirmed in a pooled analysis of the 2 trials.

 In addition, results of the COMFORT II study were updated in a recent study with 3-year follow-up confirming an OS benefit.

 Based on these results, patients with intermediate- or high-risk MF who have splenomegaly and/or constitutional symptoms can consider the use of ruxolitinib.

Ruxolitinib Dosing and Treatment Considerations

Patients with myelofibrosis often have cytopenias. Unfortunately, common adverse events associated with ruxolitinib are anemia and thrombocytopenia, with grade 3-4 anemia occurring in up to 45% of patients; however it can improve with time and dose reduction. In contrast, however, grade 3-4 thrombocytopenia is less common, occurring in 10% to 15% of cases.

With regard to platelet counts and dosing, guidelines recommend starting at 20 mg twice a day for platelets above 200 × 109/L, and at 15 mg twice a day for platelets between 100 and 200 × 109/L.32 For patients with platelet counts between 50 and 100 × 109/L, an interim analysis of one study suggests that patients can safely be started at 5 mg twice a day and increased to 10 mg twice a day.37 The use of ruxolitinib at doses such as 5 mg daily is limited due to the drug’s short half-life. As well, 5-mg dosing is not as effective as higher doses for symptom or spleen volume control (please refer to ruxolitinib package insert for additional prescribing information).38 If the initial dose is tolerated, the dose should be increased proactively during the first 3 months of treatment, as increasing the dose after that is less effective.

With regard to anemia, the COMFORT II study included 13 patients receiving concomitant erythropoietin stimulating agents (ESAs), and in that small sample the rate of grade 3-4 anemia was decreased without affecting the efficacy of ruxolitinib.

 Further studies are needed to confirm this.

In terms of dosing goals, higher doses (highest dose is 25 mg twice a day) are associated with improved reduction in splenomegaly, which is associated with longer disease control and possibly better OS.40 However, with regard to symptomatic improvement, a lower dose is equally effective.

When ruxolitinib is discontinued, symptoms can recur within 1 week. Some have reported the occurrence of ‘ruxolitinib withdrawal syndrome,’ characterized by rapid recurrence of disease symptoms, splenomegaly, worsening cytopenias, and hemodynamic compromise, including a septic shock—like syndrome.

 To prevent this, the drug can be tapered off, or alternatively, steroids can be administered to lessen symptoms.

Based on ruxolitinib’s success in the treatment of MF, several studies are investigating the use of ruxolitinib in PV and ET patients. A recently published phase II study reported encouraging results of ruxolitinib in PV and ET: of the 

 PV patients enrolled, 97% achieved a hematocrit of <45% and were able to discontinue phlebotomy. Of the 74% of patients with splenomegaly at study entry, 59% achieved a >50% reduction. Leukocytosis, thrombocytosis, and disease-related symptoms also improved in most patients. Of the 39 ET patients, 49% achieved normalized platelet counts, 90% achieved a normal WBC count, and splenomegaly resolved in 75% of patients (clinicaltrials.gov NCT00726232).

Results of the phase III RESPONSE study were recently presented in abstract form. In this study, patients with PV who were phlebotomy dependent, demonstrated splenomegaly, and had resistance/intolerance to hydrea were randomized to ruxolitinib (n = 110) or BAT (n = 112). The primary endpoint was the proportion of patients achieving hematocrit control without phlebotomy and spleen reduction of greater than 35%, which was achieved in 21% of ruxolitinib-treated patients and 1% of BAT patients.

Among ruxolitinib-treated patients 60% achieved hematocrit control and 38% achieved 35% or greater spleen volume reduction versus 20% and 1% in the BAT group, respectively.43 The RELIEF study is also investigating the use of ruxolitinib in PV patients, with a specific focus on symptom improvement (NCT01632904).

Despite the benefits afforded by ruxolitinib, its use is not associated with significant reductions in JAK2 V617F allele burden, cytopenias can be dose limiting, and no complete remissions have been observed.32 In addition, because ruxolitinib does not modify the underlying disease biology, the risk of progression to acute leukemia is not eliminated. Finally, many patients may not be able to tolerate ruxolitinib long term and for those that do remain on ruxolitinib, some may experience loss of efficacy over time. Results from the COMFORT I and II study have since been updated: at 3 years, approximately 50% of patients initially randomized to ruxolitinib remain on therapy and about half of the patients treated with ruxolitinib continued to experience spleen volume reduction.36,44

Although resistance mutations in the JAK2 kinase have been observed, it appears the main mechanism via which ruxolitinib fails is by the development of persistence. Koppikar et al

 demonstrated that although ruxolitinib is capable of abrogating or diminishing JAK-STAT signaling, with increased exposure JAK-STAT signaling can reactivate as a result of JAK heterodimerization with other members of the JAK family of kinases, including JAK1 and TYK2. This suggests that alternative methods to directly target JAK2, and the JAK-STAT pathway in general, are needed to overcome this persistence.

Several other JAK inhibitors are under investigation. Fedratinib (SAR302503), a selective JAK2 inhibitor, appeared to have efficacy similar to that of ruxolitinib but with greater reduction in allele burden. Unfortunately, reports of Wernicke’s encephalopathy in patients treated with fedratinib halted all ongoing studies.

Pacritinib (SB1518) is a dual JAK2/FLT3 inhibitor in clinical trials.

 In the phase II trial, spleen volume reduction of >25% occurred in 57% (n = 17) of patients, a significant percentage of patients also experienced symptom improvement, and patients were less likely to experience grade 3-4 anemia compared with ruxolitinib, although it should be noted that this comparison was from historical data and not in the setting of a prospective study.

 Based on these results, a phase III trial is ongoing (PERSIST I NCT01773187).

Momelotinib (CYT387) is an oral JAK1, JAK2, and TYK inhibitor. The results of a phase I/II study (NCT00935987) showed that 70% of transfusion-dependent patients achieved transfusion independence, a unique finding in this class of drugs. In the study, 37% of patients achieved reduction in splenomegaly and improvement in constitutional symptoms. Reported dose-limiting toxicities were headache, lipase elevations, and peripheral neuropathy.50 NS-018, a selective JAK2 and Src-family kinase inhibitor, has shown efficacy in preclinical models and is now in clinical trials (NCT01423851).

Single-agent therapy with ruxolitinib leads to significant improvement in symptoms and splenomegaly. However, ruxolitinib does not eliminate the mutant clone or lead to complete remissions. Therefore, several combination studies are under way, with the goal of improving efficacy and ameliorating the toxicities of ruxolitinib therapy. In an effort to minimize anemia, ruxolitinib is being tested in combination with danazol (NCT01732445), azacitidine (NCT01787487), lenalidomide (NCT01375140), and pomalidomide (NCT01644110) (Table 3).

Preclinical data demonstrate that heat shock protein 90 (Hsp90) inhibitors selectively block JAK-STAT signaling in MPN cells regardless of the JAK2 mutational status of the cell lines tested. In addition, the combination of JAK2 and Hsp90 inhibition is more effective than either agent alone in murine models.

 These data provide the preclinical rationale for the ongoing phase I study utilizing the Hsp90 inhibitor PU-H71 in combination with ruxolitinib in patients with myelofibrosis (NCT01393509).

The hedgehog signaling pathway plays a role in normal hematopoiesis and tumorigenesis of hematologic malignancies. Inhibitors of this pathway alone or in combination may lead to disease modification in MF, as evidenced by decreased JAK2 mutant allele burden.54 Based on these preclinical data, an ongoing study with the smoothened inhibitor, LDE225 (NCT01787552), is ongoing.

In the case of blast phase MF (>10% blasts), a trial with decitabine and ruxolitinib (NCT02076191) is under way based on reports that have indicated efficacy of hypomethylating agents55 as well as ruxolitinib56 as single agents in post MPN acute myelogenous leukemia (AML).

Significant progress has been made in the field of MPNs since the discovery of the JAK2 V617F mutation. Most recently, the discovery of CALR mutations in JAK2 V617F-negative ET and MF patients has filled a gap for patients without an identifiable clonal marker. The ability to test for this mutation in the clinic will allow for more accurate classification of this group of diseases. The approval of ruxolitinib changed the face of myelofibrosis and has afforded significant clinical benefit to this patient population. As well, ruxolitinib has demonstrated encouraging results in PV. Despite these advances, ruxolitinib does not lead to complete remissions, and mechanisms of persistence have been described for its shortcomings. Additional therapies that change the biology of these diseases are still mostly lacking, with the exception of allogeneic stem cell transplantation. Current studies focusing on the use of JAK2 inhibitors in combination with other agents, and the next- generation of JAK2 inhibitors, along with new agents that successfully and selectively attenuate the JAK-STAT pathway, will hopefully continue to improve therapies for patients with MPNs.

Gabriela S. Hobbs, MD, is an assistant in medicine, Leukemia Service, Massachusetts General Hospital, Boston, MA.

	Raajit K. Rampal, MD, PhD, is an assistant attending physician, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY.

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Articles

The Philadelphia chromosomeâ€“negative myeloproliferative neoplasms (MPNs) are clonal disorders characterized by common mutations, but with distinct clinical features, treatment considerations, and prognostic outlooks.

Gabriela S. Hobbs, MD, Raajit K. Rampal, MD, PhD

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JAK2 Mutations and JAK Inhibitors in the Management of Myeloproliferative Neoplasms