Holly Geyer

Assessment of Myocardial Mechanics Using Speckle Tracking Echocardiography: Fundamentals and Clinical Applications

The authors summarize the recent developments in speckle-tracking echocardiography (STE), a relatively new technique that can be used in conjunction with two-dimensional or three-dimensional echocardiography for resolving the multidirectional components of left ventricular (LV) deformation. The tracking system is based on grayscale B-mode images and is obtained by automatic measurement of the distance between 2 pixels of an LV segment during the cardiac cycle, independent of the angle of insonation. The integration of STE with real-time cardiac ultrasound imaging overcomes some of the limitations of previous work in the field and has the potential to provide a unified framework to more accurately quantify the regional and global function of the left ventricle. STE holds promise to reduce interobserver and intraobserver variability in assessing regional LV function and to improve patient care while reducing health care costs through the early identification of subclinical disease. Following a brief overview of the approach, the authors pool the initial observations from clinical studies on the development, validation, merits, and limitations of STE.

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 (Cronbachs 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.

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.

Acute Lung Toxicity Related to Pomalidomide

Pomalidomide is an immunomodulatory derivative (IMiD) active in multiple myeloma. In this report, we review the course of two patients receiving pomalidomide therapy who subsequently developed dyspnea, fever, hypoxia, and ground-glass opacities on CT scan. An extensive workup for infectious causes was negative. Both patients improved with discontinuation of the medication and/or treatment with corticosteroids. Both patients were restarted on pomalidomide therapy at a lower dose, with one patient experiencing an immediate recurrence of pulmonary symptoms. The combination of symptoms, radiographic findings, clinical course, and response to treatment strongly supports the diagnosis of acute pulmonary toxicity secondary to pomalidomide. We then review previously published pulmonary toxicity data on thalidomide and lenalidomide and compare the described clinical courses, radiographic findings, and responses to treatment with those observed in our patients. We conclude that pulmonary toxicity is a potential adverse effect of pomalidomide therapy and encourage physicians to remain cognizant of its clinical presentation.

Symptomatic Profiles of Patients With Polycythemia Vera: Implications of Inadequately Controlled Disease

PURPOSE Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) associated with disabling symptoms and a heightened risk of life-threatening complications. Recent studies have demonstrated the effectiveness of JAK inhibitor therapy in patients with PV patients who have a history of prior hydroxyurea (HU) use (including resistance or intolerance), phlebotomy requirements, and palpable splenomegaly. We aimed to determine how these features contribute alone and in aggregate to the PV symptom burden. PATIENTS AND METHODS Through prospective evaluation of 1,334 patients with PV who had characterized symptom burden, we assessed patient demographics, laboratory data, and the presence of splenomegaly by disease feature (ie, known HU use, known phlebotomy requirements, splenomegaly). RESULTS The presence of each feature in itself is associated with a moderately high symptom burden (MPN symptom assessment form [SAF] total symptom score [TSS] range, 27.7 to 29.2) that persists independent of PV risk category. In addition, symptoms incrementally increase in severity with the addition of other features. Patients with PV who had all three features (PV-HUPS) faced the highest total score (MPN-SAF TSS, 32.5) but had similar individual symptom scores to patients with known HU use (PV-HU), known phlebotomy (PV-P), and splenomegaly (PV-S). CONCLUSION The results of this study suggest that patients with PV who have any one of the features in question (known HU use, known phlebotomy, or splenomegaly) have significant PV-associated symptoms. Furthermore, it demonstrates that many PV symptoms remain severe independent of the number of features present.

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.

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.

Ruxolitinib in clinical practice for therapy of myelofibrosis: Single USA center experience following Food and Drug Administration approval

Myelofi brosis is a myeloproliferative neoplasm (MPN) characterized by increased bone marrow fi brosis, abnormal blood counts with peripheral cytopenias, extramedullary hematopoiesis, splenomegaly and profound constitutional symptoms [1,2]. Presenting as a primary disease or arising from polycythemia vera or essential thrombocythemia, myelofi brosis incurs a signifi cant symptom burden for patients, and results in a reduced survival of 2 – 11 years [3 – 7]. Amongst MPNs, myelofi brosis has represented a unique challenge to eff orts aimed at palliating symptoms or impacting disease course. Th e 2005 discovery of the gain-of-function JAK2V617F mutation present in a signifi cant proportion of patients with polycythemia vera, essential thrombocythemia and myelofi brosis opened a new avenue of investigation into potential novel therapies [8,9]. Among the various JAK2 inhibitor agents that have been developed, ruxolitinib was the fi rst to receive Food and Drug Administration (FDA) approval in the USA for the treatment of intermediate- and high-risk myelofi brosis. Th e Controlled Myelofi brosis Study with Oral JAK Inhibitor Treatment Trials compared ruxolitinib therapy in patients with intermediate-2 or high-risk myelofi brosis with placebo (COMFORT-I) and with best available therapy (COMFORT-II) [10,11]. In both trials, patients in the ruxolitinib group experienced signifi cant clinical benefi ts, including reduction in spleen size and amelioration of debilitating symptoms coupled with a tolerable side-eff ect profi le. In this study, we report the initial clinical experience with ruxolitinib outside of the clinical trial setting at our high-volume MPN program. Approval for the analysis was obtained from the Mayo Clinic Institutional Review Board. Patients with myelofi brosis including primary myelofi brosis (PMF), post-polycythemia vera (post-PV MF) and post-essential thrombocythemia (post-ET MF) were included. All patients had a Dynamic International Prognostic Scoring System (DIPSS) score of intermediate-1/2 risk or high risk at the start of therapy [12]. Clinical and hematopathological data, including bone marrow biopsy, were reviewed in all cases, and the diagnosis was made in accordance with the 2008 World Health Organization criteria. Baseline patient information, physical examination results, laboratory data, hematopathology reports and interim follow-up information were acquired via chart review, with baseline obtained within 1 month of initiating therapy. All patients were prescribed ruxolitinib within 6 months of FDA approval. Ruxolitinib was started at 20 mg twice daily for patients with platelet counts of 200 10 9 /L or hemoglobin concentrations 10 g/dL. Patients with values below these were started on lower doses at the discretion of the providing physician. Doses were adjusted for lack of effi cacy or excess toxicity. Complete blood counts were checked on a weekly basis for the fi rst 2 months, then monthly thereafter. Drug effi cacy and toxicity were determined at follow-up visits and through telephone conversations with patients. Symptoms were assessed through a verbal response during review of systems questioning. Spleen size was determined by physical examination. Descriptive statistics were determined using means, medians, ranges and standard deviations for continuous variables. Categorical variables were evaluated using frequencies and relative frequencies.

Polycythemia vera: current pharmacotherapy and future directions

Introduction: In the past, management of polycythemia vera (PV) was built upon a cornerstone of control over erythrocytosis, through therapeutic phlebotomy, as well as the use of low-dose aspirin. Historically, selected patients were managed with additional cytoreductive therapies to decrease the risk of vascular events, with the recognition that these therapies likely did not impede progression. Areas covered: Recent clinical trials have demonstrated, in a randomized fashion, that optimal control of the hematocrit to target levels < 45% are important for decreasing the risk of vascular events. We are identifying that our historical set of cytoreductive agents, such as hydroxyurea, may be replaced in the future. The first candidate is pegylated interferon alpha-2a, which is demonstrating the ability to control vascular events and control extended hematopoiesis, while potentially having impact on fibrotic progression and Janus kinase 2 (JAK2) V1617F mutant allele burden. Ruxolitinib, as well as other JAK2 inhibitors in development, are demonstrating that this class of agents is making a very meaningful impact on the risk of vascular events in PV, controlling expanded hematopoiesis, as well as helping with symptomatic burden. Expert opinion: Future goals include attaining a better understanding of the specific roles of JAK inhibitor therapy and whether their use in combination with standard therapies offers greater efficacy than single agents alone.

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.