Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial.

PURPOSE: Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and improves symptoms. PATIENTS AND METHODS: MAJIC-PV is a randomized phase II trial of ruxolitinib versus best available therapy (BAT) in patients resistant/intolerant to hydroxycarbamide (HC-INT/RES). Primary outcome was complete response (CR) within 1 year. Secondary outcomes included duration of response, event-free survival (EFS), symptom, and molecular response. RESULTS: One hundred eighty patients were randomly assigned. CR was achieved in 40 (43%) patients on ruxolitinib versus 23 (26%) on BAT (odds ratio, 2.12; 90% CI, 1.25 to 3.60; P = .02). Duration of CR was superior for ruxolitinib (hazard ratio [HR], 0.38; 95% CI, 0.24 to 0.61; P < .001). Symptom responses were better with ruxolitinib and durable. EFS (major thrombosis, hemorrhage, transformation, and death) was superior for patients attaining CR within 1 year (HR, 0.41; 95% CI, 0.21 to 0.78; P = .01); and those on ruxolitinib (HR, 0.58; 95% CI, 0.35 to 0.94; P = .03). Serial analysis of JAK2V617F variant allele fraction revealed molecular response was more frequent with ruxolitinib and was associated with improved outcomes (progression-free survival [PFS] P = .001, EFS P = .001, overall survival P = .01) and clearance of JAK2V617F stem/progenitor cells. ASXL1 mutations predicted for adverse EFS (HR, 3.02; 95% CI, 1.47 to 6.17; P = .003). The safety profile of ruxolitinib was as previously reported. CONCLUSION: The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to EFS, PFS, and OS.

Tobacco use in the Myeloproliferative neoplasms: symptom burden, patient opinions, and care.

BACKGROUND: Patients with Philadelphia-negative Myeloproliferative Neoplasms (MPN) suffer from numerous symptoms and decreased quality of life. Smoking is associated with an increased symptom burden in several malignancies. The aim of this study was to analyze the association between smoking and MPN-related symptom burden and explore MPN patients' opinions on smoking. METHODS: A total of 435 patients with MPN participated in a cross-sectional internet-based survey developed by the Mayo Clinic and the Myeloproliferative Neoplasm Quality of Life Group. Patients reported their demographics, disease characteristics, tobacco use, and opinions on tobacco use. In addition, MPN-related symptoms were reported via the validated 10-item version of the Myeloproliferative Neoplasms Symptom Assessment Form. RESULTS: Current/former smokers reported worse fatigue (mean severity 5.6 vs. 5.0, p = 0.02) and inactivity (mean severity 4.0 vs. 3.4, p = 0.03) than never smokers. Moreover, current/former smokers more frequently experienced early satiety (68.5% vs. 58.3%, p = 0.03), inactivity (79.9% vs. 71.1%, p = 0.04), and concentration difficulties (82.1% vs. 73.1%, p = 0.04). Although not significant, a higher total symptom burden was observed for current/former smokers (mean 30.4 vs. 27.0, p = 0.07). Accordingly, overall quality of life was significantly better among never smokers than current/former smokers (mean 3.5 vs. 3.9, p = 0.03). Only 43.2% of the current/former smokers reported having discussed tobacco use with their physician, and 17.5% did not believe smoking increased the risk of thrombosis. CONCLUSION: The current study suggests that smoking may be associated with increased prevalence and severity of MPN symptoms and underscores the need to enhance patient education and address tobacco use in the care of MPN patients.

How I treat pain in hematologic malignancies safely with opioid therapy.

The field of malignant hematology has experienced extraordinary advancements with survival rates doubling for many disorders. As a result, many life-threatening conditions have since evolved into chronic medical ailments. Paralleling these advancements have been increasing rates of complex hematologic pain syndromes, present in up to 60% of patients with malignancy who are receiving active treatment and up to 33% of patients during survivorship. Opioids remain the practice cornerstone to managing malignancy-associated pain. Prevention and management of opioid-related complications have received significant national attention over the past decade, and emerging data suggest that patients with cancer are at equal if not higher risk of opioid-related complications when compared with patients without malignancy. Numerous tools and procedural practice guides are available to help facilitate safe prescribing. The recent development of cancer-specific resources directing algorithmic use of validated pain screening tools, prescription drug monitoring programs, urine drug screens, opioid use disorder risk screening instruments, and controlled substance agreements have further strengthened the framework for safe prescribing. This article, which integrates federal and organizational guidelines with known risk factors for cancer patients, offers a case-based discussion for reviewing safe opioid prescribing practices in the hematology setting.

Relationship between symptom burden and disability leave among patients with myeloproliferative neoplasms (MPNs): findings from the Living with MPN patient survey.

Patients with myeloproliferative neoplasms (MPNs) experience burdensome symptoms that negatively affect their quality of life. How MPN symptoms relate with medical disability leave (MDL) among patients with the disease has not been previously examined. Using data collected from the Living with MPNs patient survey, symptom burden and functional status were compared in patients who reported taking MDL due to their MPN versus patients who reported no changes in employment status. Among 592 patients who were employed full- or part-time at diagnosis, 24.8% reported taking ≥ 1 MDL and 49.4% reported no change in employment status as a result of their MPN. Of the patients who took MDL, 29.9% took ≥ 2 MDLs, and most patients (62.6%) did not return to work. All 10 symptoms comprising the MPN Symptom Assessment Form were significantly more frequent and severe in patients who took MDL compared with those who had no employment change. Furthermore, functional impairments were also significantly more frequent among patients who went on MDL versus those with no employment change. Effective management of MPN-related symptoms may reduce disability leave among patients with high symptom burden.

Item nonresponse on the Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF): a comparison of missing data strategies.

Administering questionnaires to patients is an efficient and effective method for assessing patients' symptoms. However, item nonresponse (skipped questions) potentially compromises the utility of these questionnaires. Using an international sample of 2,067 patients with myeloproliferative neoplasms, we evaluated the impact of item nonresponse on scoring of the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS or MPN-10). We characterized item nonresponse on the MPN-10 and compared strategies for addressing item nonresponse (available-case analysis, proration, and multiple imputation) on the MPN-10 (multi-symptom assessment) and Brief Fatigue Inventory (BFI; single-symptom assessment). Characteristics of multi-symptom assessments would be expected to adversely affect proration, yet proration and multiple imputation provided very similar results for both the MPN-10 and BFI. This is likely because the MPN-10 item missing data rates were low, consistent with prior clinic- and internet-based studies. These results support the published scoring method for the MPN-10 (proration).

Associations between gender, disease features and symptom burden in patients with myeloproliferative neoplasms: an analysis by the MPN QOL International Working Group.

The myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia and myelofibrosis, are distinguished by their debilitating symptom profiles, life-threatening complications and profound impact on quality of life. The role gender plays in the symptomatology of myeloproliferative neoplasms remains under-investigated. In this study we evaluated how gender relates to patients' characteristics, disease complications and overall symptom expression. A total of 2,006 patients (polycythemia vera=711, essential thrombocythemia=830, myelofibrosis=460, unknown=5) were prospectively evaluated, with patients completing the Myeloproliferative Neoplasm-Symptom Assessment Form and Brief Fatigue Inventory Patient Reported Outcome tools. Information on the individual patients' characteristics, disease complications and laboratory data was collected. Consistent with known literature, most female patients were more likely to have essential thrombocythemia (48.6% versus 33.0%; P<0.001) and most male patients were more likely to have polycythemia vera (41.8% versus 30.3%; P<0.001). The rate of thrombocytopenia was higher among males than females (13.9% versus 8.2%; P<0.001) and males also had greater red-blood cell transfusion requirements (7.3% versus 4.9%; P=0.02) with shorter mean disease duration (6.4 versus 7.2 years, P=0.03). Despite there being no statistical differences in risk scores, receipt of most therapies or prior complications (hemorrhage, thrombosis), females had more severe and more frequent symptoms for most individual symptoms, along with overall total symptom score (22.8 versus 20.3; P<0.001). Females had particularly high scores for abdominal-related symptoms (abdominal pain/discomfort) and microvascular symptoms (headache, fatigue, insomnia, concentration difficulties, dizziness; all P<0.01). Despite complaining of more severe symptom burden, females had similar quality of life scores to those of males. The results of this study suggest that gender contributes to the heterogeneity of myeloproliferative neoplasms by influencing phenotypic profiles and symptom expression.

The role of sexuality symptoms in myeloproliferative neoplasm symptom burden and quality of life: An analysis by the MPN QOL International Study Group.

BACKGROUND: Patients with myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia, and myelofibrosis, are faced with oppressive symptom profiles that compromise daily functioning and quality of life. Among these symptoms, sexuality-related symptoms have emerged as particularly prominent and largely unaddressed. In the current study, the authors evaluated how sexuality symptoms from MPN relate to other patient characteristics, disease features, treatments, and symptoms. METHODS: A total of 1971 patients with MPN (827 with essential thrombocythemia, 682 with polycythemia vera, 456 with myelofibrosis, and 6 classified as other) were prospectively evaluated and patient responses to the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ C30) were collected, along with information regarding individual disease characteristics and laboratory data. Sexuality scores were compared with an age-matched, healthy control population. RESULTS: Overall, patients with MPN were found to have greater sexual dysfunction compared with the healthy population (MPN-SAF score of 3.6 vs 2.0; P<.001), with 64% of patients with MPN describing some degree of sexual dysfunction and 43% experiencing severe symptoms. The presence of sexual symptoms correlated closely with all domains of patient functionality (physical, social, cognitive, emotional, and role functioning) and were associated with a reduced quality of life. Sexual problems also were found to be associated with other MPN symptoms, particularly depression and nocturnal and microvascular-related symptoms. Sexual dysfunction was more severe in patients aged >65 years and in those with cytopenias and transfusion requirements, and those receiving certain therapies such as immunomodulators or steroids. CONCLUSIONS: The results of the current study identify the topic of sexuality as a prominent issue for the MPN population, and this area would appear to benefit from additional investigation and management. Cancer 2016;122:1888-96. © 2016 American Cancer Society.

Comprehensively understanding fatigue in patients with myeloproliferative neoplasms.

BACKGROUND: Patients with myeloproliferative neoplasms (MPNs) experience a high persistence, prevalence, and severity of fatigue. There is currently only limited information regarding factors that contribute to fatigue in patients with MPNs. METHODS: A 70-item, Internet-based survey regarding fatigue was developed by MPN investigators and patients/advocates and hosted by the Mayo Clinic Survey Research Center. RESULTS: Fatigue was found to be prevalent and severe among international survey respondents (1788 respondents). Higher body mass index (P<.001), current use of alcohol (P<.001), and current tobacco use (P = .0025) were found to be significantly associated with greater fatigue. Moderate/severe fatigue was present more frequently in those individuals who did not exercise compared with those who reported exercising at least once per week (P<.001). Medical comorbidities found to be significantly associated with greater fatigue included restless leg syndrome (P = .006), diabetes mellitus (P = .045), fibromyalgia (P < 0.001), chronic fatigue syndrome (P = .006), and chronic kidney disease (P = .02). Current use of antidepressants (P<.001), antihistamines (P = .0276), antianxiety medications (P = .0357), and prescription pain medications (P<.001) were found to be associated with worsened fatigue. Nearly 25% of respondents scored > 2 on the Patient Health Questionnaire, indicating a high probability of depression. Higher Brief Fatigue Inventory score, Myeloproliferative Neoplasm Total Symptom Score, and individual symptom items were all associated with a higher likelihood of depressive symptoms (P<.0001). CONCLUSIONS: The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. Patients with MPNs likely have a higher prevalence of mood disturbances compared with the general population, suggesting the need to assess and intervene in this domain.

Management of symptoms in polycythemia vera and essential thrombocythemia patients.

The BCR-ABL-negative myeloproliferative neoplasms (MPNs) are clonal stem cell derived malignancies, which include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). The MPNs are characterized by dysregulated JAK-STAT signaling pathways. PV and ET are associated with an increased risk of thrombo-hemorrhagic complications, risk of progression to MF and leukemia. Presentation of patients with PV and ET is variable and usually as a result of abnormal full blood count indices (raised hemoglobin and hematocrit, leukocytosis, and thrombocytosis). Presentation with thrombosis or splenomegaly occurs in ~30% of patients. Historically thought of as indolent compared with MF, patients with PV and ET have significant disease symptom burden which does not directly correlate to the current clinical prognostic classifications. The mainstay of therapy is reserved for patients with high-risk disease and thus excludes a population of patients with significant symptom related morbidity impacting their quality-of-life and survival. Recent treatment strategies have aimed to incorporate disease burden assessment into the selection of therapeutic interventions such as JAK2 inhibitors and HDAC inhibitors. We will review the advances in the field of MPN symptom assessment and symptom burden experienced by ET and PV patients. We will also discuss the risk-stratified management of ET and PV patients alongside symptom assessment and the impact of potential novel therapies, for patients who fail to respond to conventional treatment.

Impact of Inflammation on Myeloproliferative Neoplasm Symptom Development.

Myeloproliferative neoplasms (essential thrombocythemia, ET; polycythemia vera, PV; myelofibrosis, MF) are monoclonal malignancies associated with genomic instability, dysregulated signaling pathways, and subsequent overproduction of inflammatory markers. Acknowledged for their debilitating symptom profiles, recent investigations have aimed to determine the identity of these markers, the upstream sources stimulating their development, their prevalence within the MPN population, and the role they play in symptom development. Creation of dedicated Patient Reported Outcome (PRO) tools, in combination with expanded access to cytokine analysis technology, has resulted in a surge of investigations evaluating the potential associations between symptoms and inflammation. Emerging data demonstrates clear relationships between individual MPN symptoms (fatigue, abdominal complaints, microvascular symptoms, and constitutional symptoms) and cytokines, particularly IL-1, IL-6, IL-8, and TNF-α. Information is also compiling on the role symptoms paradoxically play in the development of cytokines, as in the case of fatigue-driven sedentary lifestyles. In this paper, we explore the symptoms inherent to the MPN disorders and the potential role inflammation plays in their development.

Emerging drugs for the treatment of myelofibrosis.

INTRODUCTION: Myelofibrosis (MF) is a myeloproliferative neoplasm associated with significant disease burden composed of splenomegaly, constitutional symptoms and a reduced life expectancy. The advent of targeted treatments has provided new means by which to improve MF associated splenomegaly, symptoms, health-related quality of life and even mortality. AREAS COVERED: We discuss the spectrum of targeted treatments currently under investigation for MF. We furthermore compare their effects on improving anemia, reducing fibrosis and splenomegaly and enhancing symptom control. EXPERT OPINION: MF is a complex disorder, partly attributable to its heterogeneity. Although the severity of patient symptoms correlates with risk category, high symptom burden may also be observed in low-risk patients. Serial use of PRO tools allows clinicians to objectively evaluate the MF symptom burden, compare efficacy of therapies and adjust medications to improve symptom control. Novel targeted agents have proven superior to historic treatment regimens for symptom management. Promising treatment categories include JAK2 inhibitors, histone deacetylase inhibitors, hypomethylating agents, heat shock protein-90 inhibitors, hedgehog inhibitors, PI3-AKT-mTOR inhibitors, antifibrosing agents and telomerase inhibitors. The majority of therapies remain under investigation, either alone or in combination with other treatments. It is anticipated that these agents will be increasingly integrated into standard treatment algorithms for MF symptom management.

Reducing symptom burden in patients with myeloproliferative neoplasms in the era of Janus kinase inhibitors.

Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are clonal stem cell-derived malignancies that include primary myelofibrosis, polycythemia vera and essential thrombocythemia and are characterized by dysregulated Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling. Clinical manifestations include splenomegaly, cytopenias and/or systemic inflammation. Patients have a heterogeneous symptom profile that includes fatigue, loss of appetite, pruritus and night sweats, which significantly impact quality of life (QoL) and lead to poor survival outcomes. With the introduction of JAK inhibitors, improvement in disease-related symptoms has emerged as a realistic expectation of therapy and an integral measure of clinical efficacy. The JAK1/JAK2 inhibitor ruxolitinib is approved for the treatment of myelofibrosis and is currently under clinical development for polycythemia vera. Ruxolitinib has demonstrated significant reductions in symptom burden, with consequent improvements in QoL measures. With the potential to improve QoL, recognition of the impact and burden of symptoms on patients with MPNs is critical.

Therapy for myeloproliferative neoplasms: when, which agent, and how?

Myeloproliferative neoplasms, including polycythemia vera (PV), essential thrombocythemia, and myelofibrosis (MF) (both primary and secondary), are recognized for their burdensome symptom profiles, life-threatening complications, and risk of progression to acute leukemia. Recent advancements in our ability to diagnose and prognosticate these clonal malignancies have paralleled the development of MPN-targeted therapies that have had a significant impact on disease burden and quality of life. Ruxolitinib has shown success in alleviating the symptomatic burden, reducing splenomegaly and improving quality of life in patients with MF. The role and clinical expectations of JAK2 inhibition continues to expand to a variety of investigational arenas. Clinical trials for patients with MF focus on new JAK inhibitors with potentially less myelosuppression( pacritinib) or even activity for anemia (momelotinib). Further efforts focus on combination trials (including a JAK inhibitor base) or targeting new pathways (ie, telomerase). Similarly, therapy for PV continues to evolve with phase 3 trials investigating optimal frontline therapy (hydroxyurea or IFN) and second-line therapy for hydroxyurea-refractory or intolerant PV with JAK inhibitors. In this chapter, we review the evolving data and role of JAK inhibition (alone or in combination) in the management of patients with MPNs.

Quality of life in MPN comes of age as a therapeutic target.

BCR-ABL-negative myeloproliferative neoplasms include primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Clonal stem cell proliferation and dysregulated JAK/STAT molecular pathways characterize these hematologic malignancies. Symptoms experienced by patients are heterogeneous including excessive and disabling fatigue, early satiety, anorexia, pruritus, bone pain, night sweats, cachexia, abdominal pain and discomfort, and cognitive complaints. Patients also experience impaired quality of life along with decreased overall survival. New targeted drug therapies, including JAK2 inhibitors, have demonstrated remarkable success in alleviating the myeloproliferative neoplasm (MPN) symptomatic burden, reducing splenomegaly and improving quality of life while offering overall survival benefit. Within the USA, FDA approval has only been granted to use JAK2 inhibitors in intermediate- to high-risk myelofibrosis. However, given that low-prognostic-scoring patients have been shown to have considerable symptomology, there is a possibility that lower-risk patients may benefit from therapy. More than ever, the need for accurate MPN symptom burden assessment and subsequent addition of targeted therapies is critical in the treatment of MPNs. This article discusses the role of MPN symptom burden and quality of life as therapeutic targets in the context of recent MPN clinical advances.

Distinct clustering of symptomatic burden among myeloproliferative neoplasm patients: retrospective assessment in 1470 patients.

Symptom burden in myeloproliferative neoplasms (MPNs) is heterogeneous even among patients within the same MPN diagnosis. Using cluster analysis from prospectively gathered symptom burden data in 1470 international patients with essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF), we assessed for the presence of clusters and relationship to disease features and prognosis. In MF (4 clusters identified), clusters significantly differed by Dynamic International Prognostic Scoring System (DIPSS) risk (P < .001), leukopenia (P = .009), thrombocytopenia (P < .001), and spleen size (P = .02). Although an association existed between clusters and DIPSS risk, high symptom burden was noted in some low and intermediate-1-risk MF patients. In PV (5 clusters identified), total symptom score increased across clusters (P < .001), but clusters did not significantly differ by PV risk or the risk assessment variable of age. Among ET patients (5 clusters identified), clusters differed by gender (P = .04), anemia (P = .01), and prior hemorrhage (P = .047). Total symptom score increased across clusters (P < .001), but clusters did not significantly differ by International Prognostic Score for ET risk including the risk assessment variables. Significant symptom heterogeneity exists within each MPN subtype, sometimes independent of disease features or prognosis.

Therapy for myeloproliferative neoplasms: when, which agent, and how?

Myeloproliferative neoplasms, including polycythemia vera (PV), essential thrombocythemia, and myelofibrosis (MF) (both primary and secondary), are recognized for their burdensome symptom profiles, life-threatening complications, and risk of progression to acute leukemia. Recent advancements in our ability to diagnose and prognosticate these clonal malignancies have paralleled the development of MPN-targeted therapies that have had a significant impact on disease burden and quality of life. Ruxolitinib has shown success in alleviating the symptomatic burden, reducing splenomegaly and improving quality of life in patients with MF. The role and clinical expectations of JAK2 inhibition continues to expand to a variety of investigational arenas. Clinical trials for patients with MF focus on new JAK inhibitors with potentially less myelosuppression (pacritinib) or even activity for anemia (momelotinib). Further efforts focus on combination trials (including a JAK inhibitor base) or targeting new pathways (ie, telomerase). Similarly, therapy for PV continues to evolve with phase 3 trials investigating optimal frontline therapy (hydroxyurea or IFN) and second-line therapy for hydroxyurea-refractory or intolerant PV with JAK inhibitors. In this chapter, we review the evolving data and role of JAK inhibition (alone or in combination) in the management of patients with MPNs.

Myeloproliferative neoplasm (MPN) symptom assessment form total symptom score: prospective international assessment of an abbreviated symptom burden scoring system among patients with MPNs.

PURPOSE: Myeloproliferative neoplasm (MPN) symptoms are troublesome to patients, and alleviation of this burden represents a paramount treatment objective in the development of MPN-directed therapies. We aimed to assess the utility of an abbreviated symptom score for the most pertinent and representative MPN symptoms for subsequent serial use in assessing response to therapy. PATIENTS AND METHODS: The Myeloproliferative Neoplasm Symptom Assessment Form total symptom score (MPN-SAF TSS) was calculated as the mean score for 10 items from two previously validated scoring systems. Questions focus on fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. RESULTS: MPN-SAF TSS was calculable for 1,408 of 1,433 patients with MPNs who had a mean score of 21.2 (standard deviation [SD], 16.3). MPN-SAF TSS results significantly differed among MPN disease subtypes (P<.001), with a mean of 18.7 (SD, 15.3), 21.8 (SD, 16.3), and 25.3 (SD, 17.2) for patients with essential thrombocythemia, polycythemia vera, and myelofibrosis, respectively. The MPN-SAF TSS strongly correlated with overall quality of life (QOL; r=0.59; P<.001) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) functional scales (all P<.001 and absolute r≥0.50 except social functioning r=0.48). No significant trends were present when comparing therapy subgroups. The MPN-SAF TSS had excellent internal consistency (Cronbach's α=.83). Factor analysis identified a single underlying construct, indicating that the MPN-SAF TSS is an appropriate, unified scoring method. CONCLUSION: The MPN-SAF TSS is a concise, valid, and accurate assessment of MPN symptom burden with demonstrated clinical utility in the largest prospective MPN symptom study to date. This new prospective scoring method may be used to assess MPN symptom burden in both clinical practice and trial settings.

JAK2 inhibitors in the treatment of myeloproliferative neoplasms.

INTRODUCTION: Dysregulation of JAK-STAT signaling is a pathogenetic hallmark of myeloproliferative neoplasms (MPNs) arising from several distinct molecular aberrations, including mutations in JAK2, the thrombopoietin receptor (MPL), mutations in negative regulators of JAK-STAT signaling, such as lymphocyte-specific adapter protein (SH2B3), and epigenetic dysregulation as seen with Suppressor of Cytokine Signaling (SOCS) proteins. In addition, growth factor/cytokine stimulatory events activate JAK-STAT signaling independent of mutations. AREAS COVERED: The various mutations and molecular events activating JAK-STAT signaling in MPNs are reviewed. Detailed inhibitory kinase profiles of the currently developed JAK inhibitors are presented. Clinical trial results for currently developed JAK targeting agents are comprehensively summarized. The limitations of JAK-STAT targeting in MPNs, as well as potential rational combination therapies with JAK2 inhibitors, are discussed. EXPERT OPINION: Aberrant JAK-STAT signaling is an underlying theme in the pathogenesis of MPNs. While JAK2 inhibitors are active in JAK2V617F and wild-type JAK2 MPNs, JAK2V617F mutation-specific or JAK2-selective inhibitors may possess unique clinical attributes. Complimentary targeting of parallel pathways operating in MPNs may offer novel therapeutic approaches in combination with JAK inhibition. Understanding the intricacies of JAK-STAT pathway activation, including growth factor/cytokine-driven signaling, will open new avenues for therapeutic intervention at known and novel molecular vulnerabilities of MPNs.

JAK2 inhibitors and their impact in myeloproliferative neoplasms.

The BCR-ABL-negative myeloproliferative neoplasms (MPNs) include essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Historically, complex biochemical alterations defining these heterogeneously distinct malignancies have remained elusive and constrained available therapy options. The discovery of Janus kinase (JAK) mutations collectively present in BCR-ABL-negative MPNs has led to a resurgence of medical interest in JAK-STAT targeted treatment modalities, as well as provided a unique platform for inhibiting symptom-directing proinflammatory cytokines. INCB018424, CYT387, SB1518, and TG101348 are among the most propitious JAK2 inhibitors under investigation, providing substantial improvement in constitutional symptoms, transfusion-dependent cytopenias, and reduction in spleen size. Despite their attributes, evidence of complete or partial remission has yet to be observed with therapy. Many uncertainties surrounding the full clinical potential of JAK2 inhibitors persist. Treatment guidelines addressing optimal stages for drug implementation, ideal dosing parameters and criteria for medication continuation/withdrawal may effectively resolve these ongoing concerns and provide advancements in the morbidity and mortality of these multifaceted disease processes.