Search

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm that typically manifests with debilitating symptoms that progressively worsen, negatively impacting patients’ quality of life. Fatigue is a multifactorial and burdensome MF-related symptom due to its severity, persistence, and prevalence, with anemia a contributing factor and major unmet need. Clinical trials of the Janus kinase (JAK)1/JAK2/activin A receptor type 1 inhibitor momelotinib have shown consistent anemia benefits, in addition to improvements in MF-related symptoms. The phase 3 MOMENTUM trial in symptomatic and anemic patients met its primary end point, with a greater proportion having a Myelofibrosis Symptom Assessment Form (MFSAF) Total Symptom Score (TSS) reduction ≥50% at week 24 with momelotinib versus danazol. To support the positive primary end point result, we conducted longitudinal, responder, and time-to-event analyses of patient-reported outcomes from MOMENTUM, as measured by the MFSAF, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and Patient-Reported Outcomes Measurement Information System (PROMIS) assessments. These analyses demonstrated rapid and durable response benefits with momelotinib, with achievement of first TSS response by day 29 and continued improvement over time. Improvements favored momelotinib versus danazol for each MFSAF individual item, and greater improvements were observed for disease- and cancer-related fatigue and physical functioning at week 24, with significant results for multiple items/domains across the 3 assessments. These findings are consistent in demonstrating that momelotinib provides substantial symptom benefit.

Abstract The safety profile of the novel oral JAK2/IRAK1 inhibitor pacritinib in patients with cytopenic myelofibrosis was described in the Phase 2 PAC203 and Phase 3 PERSIST‐2 studies. To account for longer treatment durations on the pacritinib arms compared to best available therapy (BAT), we present a risk‐adjusted safety analysis of event rates accounting for different time on treatment. While the rate of overall events was higher on pacritinib compared to BAT, the rate of fatal events was lower, and there was no excess in bleeding, cardiac events, secondary malignancy, or thrombosis on pacritinib, including in patients with severe thrombocytopenia.

Dasatinib is a multi-kinase inhibitor with activity against the SRC kinase LCK, which plays a critical role in T-cell receptor signaling. Dasatinib, initially developed as an immunosuppressive agent, is by contrast, also noted to result in enhanced tumor immunity in a subset of patients. We studied the impact of dasatinib in chronic myeloid leukemia patients and compared it with patients taking other tyrosine kinase inhibitors (TKI) and healthy controls. We found that patients on dasatinib showed inhibition of both T-cell receptor (TCR) and STAT5 signaling pathways, and reduced expression of Teffector pro-inflammatory cytokines. In addition, dasatinib induced selective depletion of regulatory T cells (Tregs) and effector Tregs, particularly in patients with clonal expansion of effector CD8+ T cells, who demonstrated greater and preferential inhibition of Treg TCR intracellular signaling. In addition, we show that dasatinib selectively reduces Treg STAT5 phosphorylation via reduction of IL-2, in relation with the marked reduction of plasma IL-2 levels in patients taking dasatinib. Finally, patients on other TKI had significantly increased TCR signaling in TIM3+ cells compared to patients taking dasatinib, suggesting that chronic SRC kinase inhibition by dasatinib may play a role in preventing TIM-3-mediated T-cell exhaustion and preserve anti-tumor immunity. These data provide further insight into the selective immunomodulatory effects of dasatinib and its potential use for pharmacologic control of immunotherapies.

Background: Thrombocytopenia is a common feature of myelofibrosis (MF), a myeloproliferative neoplasm driven by dysregulated JAK/STAT signaling; however, pivotal trials assessing the efficacy of ruxolitinib (a JAK1/2 inhibitor) excluded MF patients with low platelet counts (

Abstract In a multicenter European retrospective study including 162 patients with COVID-19 occurring in essential thrombocythemia (ET, n = 48), polycythemia vera (PV, n = 42), myelofibrosis (MF, n = 56), and prefibrotic myelofibrosis (pre-PMF, n = 16), 15 major thromboses (3 arterial and 12 venous) were registered in 14 patients, of whom all, but one, were receiving LMW-heparin prophylaxis. After adjustment for the competing risk of death, the cumulative incidence of arterial and venous thromboembolic events (VTE) reached 8.5% after 60 days follow-up. Of note, 8 of 12 VTE were seen in ET. Interestingly, at COVID-19 diagnosis, MPN patients had significantly lower platelet count (p

Abstract Background Philadelphia chromosome negative myeloproliferative neoplasms (MPNs), including essential thrombocythemia, polycythemia vera, and myelofibrosis, have severe function‐limiting symptom burden that is experienced by the majority of patients. Previous studies have suggested that depression may be present in over a quarter of MPN patients, but to date no studies have evaluated the relationship between depression and other variables such as symptoms. Methods A 70‐item internet based survey regarding fatigue and mood symptoms was developed by a multidisciplinary team of MPN investigators, patients and patient advocates including Patient Health Questionnaire and the Myeloproliferative Neoplasm Symptom Assessment Form was completed by over 1300 patients with MPN diagnosis. Results There were 309 respondents (23%) with PHQ‐2 scores ≥ 3. In this analysis, we found worse systemic symptom burden in individuals reporting depressive symptoms. Conclusion This analysis suggests the importance of depression in contributing to as well as confounding symptomatology in MPN patients, and suggests that this critical variable should also be addressed by clinicians and researchers alike when comprehensively assessing symptom burden etiologies.

Background: Myelofibrosis (MF) is a blood cancer associated with splenomegaly, blood count abnormalities, reduced life expectancy and high prevalence of disease-associated symptoms. Current treatment options for MF are diverse, with limited data on management strategies in real-world practice in the United Kingdom. Methods: The REALISM UK study was a multi-center, retrospective, non-interventional study, which documented the early management of patients with MF. The primary endpoint was the time from diagnosis to active treatment. Discussion: Two hundred patients were included (63% [ n = 126/200] with primary MF; 37% [ n = 74/200] with secondary MF). Symptoms and prognostic scores at diagnosis were poorly documented, with infrequent use of patient reported outcome measures. ‘Watch and wait’ was the first management strategy for 53.5% ( n = 107/200) of patients, while the most commonly used active treatments were hydroxycarbamide and ruxolitinib. Only 5% of patients proceeded to allogeneic transplant. The median (IQR) time to first active treatment was 46 days (0–350); patients with higher risk disease were prescribed active treatment sooner. Conclusion: These results provide insight into real-world clinical practice for patients with MF in the United Kingdom. Despite the known high prevalence of disease-associated symptoms in MF, symptoms were poorly documented. Most patients were initially observed or received hydroxycarbamide, and ruxolitinib was used as first-line management strategy in only a minority of patients. Plain Language Summary Background: Myelofibrosis is a rare blood cancer associated with symptoms that can seriously affect a patient’s daily life, such as enlarged spleen and decreased white and red blood cells. Although several treatments are available for patients with myelofibrosis, it is not clear which ones clinicians use most frequently. Methods: We aimed to review which treatments are usually given to patients with myelofibrosis in the UK, by collecting information from the medical records of 200 patients with myelofibrosis treated in different centres across the UK. Results: The results showed that the symptoms patients experienced were not always written down in the medical records. Similarly, clinical scores based on patient characteristics (which clinicians use to try to predict if a patient will respond to treatment well or not) were also missing from the medical records. Clinicians also rarely asked patients to complete questionnaires that try to measure the impact of myelofibrosis and its treatment on their health. The most common approach for patients with myelofibrosis in the UK was ‘watch and wait’, which over half of patients received. The most common drugs used for treatment were hydroxycarbamide and ruxolitinib; only a very small proportion of patients received a bone marrow transplant. On average, patients waited for 46 days before receiving a treatment, although patients considered to have a more aggressive type of disease received treatment sooner. Conclusion: The results of this study suggest that medical records can be missing key information, which is needed to decide which is the best way to treat a patient with myelofibrosis. They also suggest that clinicians in the UK prefer observation to treatment for a large number of patients with myelofibrosis. This could mean that the approach used for many patients with myelofibrosis does not help them to control symptoms that have an impact on their daily lives.

Abstract Background The goal of the research reported here was to understand the patient experience of living with myelofibrosis (MF) and establish content validity of the Modified Myeloproliferative Neoplasm Symptom Assessment Diary (MPN-SD). Methods Qualitative interviews were performed in patients with MF, including both concept elicitation and cognitive debriefing. Patients with MF were asked to spontaneously report on their signs, symptoms, and impacts of MF, as well as their understanding of the MPN-SD content, and use of the tool on an electronic platform. A supplementary literature review and meetings with MF experts were also performed. Results Twenty-three patients with MF participated in qualitative interviews. Signs and symptoms most commonly reported by ruxolitinib-experienced patients (n = 16) were: fatigue and/or tiredness (n = 16, 100%), shortness of breath (n = 11, 69%), pain below the ribs on the left side and/or stomach pain and/or abdominal pain (n = 9, 56%), and enlarged spleen (n = 9, 56%) and for ruxolitinib-naïve patients (n = 7) were: fatigue and/or tiredness (n = 6, 86%), pain below the ribs on the left side (n = 6, 86%), enlarged spleen (n = 4, 57%), full quickly/filling up quickly (n = 4, 57%), night sweats and/or general sweats (n = 4, 57%), and itching (n = 4, 57%). Patients demonstrated that they were able to read, understand, and provide meaningful responses to the MPN-SD. The final version of the MPN-SD includes the 10 most commonly reported concepts from the MF patient interviews. Conclusions The findings demonstrate the comprehensiveness of the MPN-SD in assessing MF symptoms in both ruxolitinib-experienced and ruxolitinib-naïve patients, while remaining easy for patients to understand and complete.

High-dimensional cytometry is an innovative tool for immune monitoring in health and disease, and it has provided novel insight into the underlying biology as well as biomarkers for a variety of diseases. However, the analysis of large multiparametric datasets usually requires specialist computational knowledge. Here, we describe ImmunoCluster (https://github.com/kordastilab/ImmunoCluster), an R package for immune profiling cellular heterogeneity in high-dimensional liquid and imaging mass cytometry, and flow cytometry data, designed to facilitate computational analysis by a nonspecialist. The analysis framework implemented within ImmunoCluster is readily scalable to millions of cells and provides a variety of visualization and analytical approaches, as well as a rich array of plotting tools that can be tailored to users’ needs. The protocol consists of three core computational stages: (1) data import and quality control; (2) dimensionality reduction and unsupervised clustering; and (3) annotation and differential testing, all contained within an R-based open-source framework.

Background: There is insufficient evidence to support clinical decision-making for cancer patients diagnosed with COVID-19 due to the lack of large studies.Methods: We used data from a single large UK Cancer Center to assess the demographic/clinical characteristics of 156 cancer patients with a confirmed COVID-19 diagnosis between 29 February and 12 May 2020. Logistic/Cox proportional hazards models were used to identify which demographic and/or clinical characteristics were associated with COVID-19 severity/death.Results: 128 (82%) presented with mild/moderate COVID-19 and 28 (18%) with a severe case of the disease. An initial cancer diagnosis >24 months before COVID-19 [OR: 1.74 (95% CI: 0.71–4.26)], presenting with fever [6.21 (1.76–21.99)], dyspnea [2.60 (1.00–6.76)], gastro-intestinal symptoms [7.38 (2.71–20.16)], or higher levels of C-reactive protein [9.43 (0.73–121.12)] were linked with greater COVID-19 severity. During a median follow-up of 37 days, 34 patients had died of COVID-19 (22%). Being of Asian ethnicity [3.73 (1.28–10.91)], receiving palliative treatment [5.74 (1.15–28.79)], having an initial cancer diagnosis >24 months before [2.14 (1.04–4.44)], dyspnea [4.94 (1.99–12.25)], and increased CRP levels [10.35 (1.05–52.21)] were positively associated with COVID-19 death. An inverse association was observed with increased levels of albumin [0.04 (0.01–0.04)].Conclusions: A longer-established diagnosis of cancer was associated with increased severity of infection as well as COVID-19 death, possibly reflecting the effects a more advanced malignant disease has on this infection. Asian ethnicity and palliative treatment were also associated with COVID-19 death in cancer patients.

The bone marrow niche is a complex and dynamic structure composed of a multitude of cell types which functionally create an interactive network facilitating hematopoietic stem cell development and maintenance. Its specific role in the pathogenesis, response to therapy, and transformation of myeloproliferative neoplasms has only recently been explored. Niche functionality is likely affected not only by the genomic background of the myeloproliferative neoplasm-associated mutated hematopoietic stem cells, but also by disease-associated ‘chronic inflammation’, and subsequent adaptive and innate immune responses. ‘Cross-talk’ between mutated hematopoietic stem cells and multiple niche components may contribute to propagating disease progression and mediating drug resistance. In this timely article, we will review current knowledge surrounding the deregulated bone marrow niche in myeloproliferative neoplasms and suggest how this may be targeted, either directly or indirectly, potentially influencing therapeutic choices both now and in the future.

Abstract. Deregulated Janus Kinase 2 (JAK2) activation is central to the pathogenesis of most myeloproliferative neoplasms (MPNs), of which essential thrombocythemia (ET) is the most common entity. Patients with ET are risk-stratified according to their risk of thrombo-hemorrhagic complications. High-risk patients are offered treatments to reduce their platelet count using cytoreductive therapy. The disease course is often long and therapy intolerance is not infrequent. Ruxolitinib, a Janus Kinase (JAK) 1/JAK2 inhibitor, has demonstrated efficacy in patients with both myelofibrosis (MF) and polycythemia vera and is well tolerated. Side effects include predictable cytopenias and an augmented risk of infections. Ruxolitinib has been investigated in a small group of ET patients who were refractory/intolerant to hydroxycarbamide (HC) and demonstrated improvements in both symptoms and splenomegaly. Of note, a proportion of treated patients (13.2%) also had a significant reduction in platelet counts. However, these results require further validation in comparison with conventional therapy. Recently, a randomized-controlled phase 2 study (MAJIC-ET) assessed the role of Ruxolitinib in patients refractory or intolerant to HC. This study revealed that Ruxolitinib demonstrated some clinical efficacy but was only superior in terms of symptom control. In clinical practice, some individuals with ET do exhaust all potential treatment options and there may well be a role for Ruxolitinib in such patients or those with a significant symptom burden. However, in the wider context the goal of therapy with the use of JAK inhibitor therapy in ET needs to be defined carefully and we explore this within this timely review article.

The role of antiplatelet therapy as primary prophylaxis of thrombosis in low-risk essential thrombocythemia has not been studied in randomized clinical trials. We assessed the benefit/risk of low-dose aspirin in 433 patients with low-risk essential thrombocythemia (271 with a CALR mutation, 162 with a JAK2V617F mutation) who were on antiplatelet therapy or observation only. After a follow up of 2215 person-years free from cytoreduction, 25 thrombotic and 17 bleeding episodes were recorded. In CALR-mutated patients, antiplatelet therapy did not affect the risk of thrombosis but was associated with a higher incidence of bleeding (12.9 versus 1.8 episodes per 1000 patient-years, P=0.03). In JAK2V617F-mutated patients, low-dose aspirin was associated with a reduced incidence of venous thrombosis with no effect on the risk of bleeding. Coexistence of JAK2V617F-mutation and cardiovascular risk factors increased the risk of thrombosis, even after adjusting for treatment with low-dose aspirin (incidence rate ratio: 9.8; 95% confidence interval: 2.3–42.3; P=0.02). Time free from cytoreduction was significantly shorter in CALR-mutated patients with essential thrombocythemia than in JAK2V617F-mutated ones (median time 5 years and 9.8 years, respectively; P=0.0002) and cytoreduction was usually necessary to control extreme thrombocytosis. In conclusion, in patients with low-risk, CALR-mutated essential thrombocythemia, low-dose aspirin does not reduce the risk of thrombosis and may increase the risk of bleeding.

Ultra-endurance running provides numerous physiological, psychological, and nutritional challenges to the athlete and supporting practitioners. We describe the changes in physiological status, psychological condition, and nutritional intake over the course of two 100-mile running races, with differing outcomes: non-completion and completion. Athlete perception of pain, freshness, and motivation differed between events, independent of rating of perceived exertion. Our data suggest that the integration of multiple sensations (freshness, motivation, hunger, pain, and thirst) produce performance. Increases in carbohydrate feeding (+5 g·h−1) and protein intake (+0.3 g·kg−1) also likely contributed to successful completion of a 100-mile race, by reducing the fractional utilization of maximal oxygen uptake and satiating hunger, respectively. Nutritional data support the notion that the gut is a trainable, and critical organ with respect to ultra-endurance performance. Finally, we propose future research to investigate the rate at which peak feeding occurs throughout ultra-endurance events, as this may further serve to personalize sports nutrition strategies.

Ruxolitinib, a potent Janus kinase 1/2 inhibitor, resulted in rapid and durable improvements in splenomegaly and disease-related symptoms in the 2 phase III COMFORT studies. In addition, ruxolitinib was associated with prolonged survival compared with placebo (COMFORT-I) and best available therapy (COMFORT-II). We present a pooled analysis of overall survival in the COMFORT studies using an intent-to-treat analysis and an analysis correcting for crossover in the control arms. Overall, 301 patients received ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 patients received placebo (n=154) or best available therapy (n=73). After a median three years of follow up, intent-to-treat analysis showed that patients who received ruxolitinib had prolonged survival compared with patients who received placebo or best available therapy [hazard ratio=0.65; 95% confidence interval (95%CI): 0.46–0.90; P=0.01]; the crossover-corrected hazard ratio was 0.29 (95%CI: 0.13–0.63). Both patients with intermediate-2– or high-risk disease showed prolonged survival, and patients with high-risk disease in the ruxolitinib group had survival similar to that of patients with intermediate-2–risk disease in the control group. The Kaplan-Meier estimate of overall survival at week 144 was 78% in the ruxolitinib arm, 61% in the intent-to-treat control arm, and 31% in the crossover-adjusted control arm. While larger spleen size at baseline was prognostic for shortened survival, reductions in spleen size with ruxolitinib treatment correlated with longer survival. These findings are consistent with previous reports and support that ruxolitinib offers a survival benefit for patients with myelofibrosis compared with conventional therapies. (clinicaltrials.gov identifiers: COMFORT-I, NCT00952289; COMFORT-II, NCT00934544)

Available information is limited regarding the use of cytoreductive combination therapy in high-risk patients with essential thrombocythemia. This analysis aims to evaluate the clinical relevance and patterns of cytoreductive combination treatment in European high-risk patients with essential thrombocythemia in the Evaluation of Xagrid® Efficacy and Long-term Safety study. Of 3643 patients, 347 (9.5%) received combination therapy. Data were recorded at each 6-month update. Of 347 patients who received combination therapy, 304 (87.6%) received hydroxycarbamide + anagrelide. Monotherapies received before this combination were hydroxycarbamide (n=167, 54.9%) and anagrelide (n=123, 40.5%). Median weekly doses of hydroxycarbamide and anagrelide were: 7000 and 10.5 mg when used as prior monotherapy; 3500 and 7.0 mg when used as add-on treatment. Overall, median platelet counts were 581×109/L and 411×109/L before and after starting hydroxycarbamide + anagrelide, respectively. In patients with paired data (n=153), the number of patients with platelet counts less than 400×109/L increased from 33 (21.6%) to 74 (48.4%; P

Prior to Janus kinase inhibitors, available therapies for myelofibrosis were generally supportive and did not improve survival. This analysis compares efficacy outcomes of patients with myelofibrosis in the control arms (placebo [n=154] and best available therapy [n=73]) from the two phase 3 COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment (COMFORT) studies. Spleen volume was assessed by magnetic resonance imaging/computed tomography at baseline and every 12 weeks through week 72; spleen length was assessed by palpation at each study visit. Health-related quality of life and symptoms were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Items at baseline and in weeks 4, 8, 12, 16 and 24 in COMFORT-I and in weeks 8, 16, 24 and 48 in COMFORT-II. The demographic and baseline characteristics were similar between the control arms of the two studies. One patient who received placebo and no patients who received best available therapy had a ≥35% reduction in spleen volume from baseline at week 24. At 24 weeks, neither placebo nor best available therapy had produced clinically meaningful changes in global quality of life or symptom scales. Non-hematologic adverse events were mostly grade 1/2; the most frequently reported adverse events in each group were abdominal pain, fatigue, peripheral edema and diarrhea. These data suggest that non–Janus kinase inhibitor therapies provide little improvement in splenomegaly, symptoms or quality of life as compared with placebo. Both COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544) studies have been appropriately registered with clinicaltrials.gov.

Primary myelofibrosis is a member of the myeloproliferative neoplasms, a diverse group of bone marrow malignancies. Symptoms of myelofibrosis, particularly those associated with splenomegaly (abdominal distention and pain, early satiety, dyspnea, and diarrhea) and constitutional symptoms, represent a substantial burden to patients. Most patients eventually die from the disease, with a median survival ranging from approximately 5–7 years. Mutations in Janus kinase 2 (JAK2), a kinase that is essential for the normal development of erythrocytes, granulocytes, and platelets, notably the V617F mutation, have been identified in approximately 50% of patients with myelofibrosis. The approval of a JAK2 inhibitor in 2011 has improved the outlook of many patients with myelofibrosis and has changed the treatment landscape. This article focuses on some of the important issues in current myelofibrosis treatment management, including differentiation of myelofibrosis from essential thrombocythemia and polycythemia vera, up-dated data on the results of JAK2 inhibitor therapy, the role of epigenetic mechanisms in myelofibrosis pathogenesis, investigational therapies for myelofibrosis, and advances in hematopoietic stem cell transplant. Three myelofibrosis cases are included to underscore the issues in diagnosing and treating this complex disease.

The Philadelphia negative myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia, and myelofibrosis, are associated with substantial vascular and transformative complications. Standard therapy for high-risk disease, particularly in patients that have failed initial therapy, remains controversial. Non-pegylated interferon has previously been shown to be effective in controlling erythrocytosis, thrombocytosis and thrombotic complications, but was found to have poor tolerability and excessive adverse effects. Recently, pegylated interferon alpha-2a was introduced and found to be better tolerated and less toxic than standard interferon. In addition, in recent phase II trials, pegylated interferon alpha-2a therapy was found to induce both hematologic and molecular remissions. We retrospectively analyzed 118 myeloproliferative patients who underwent pegylated interferon alpha-2a treatment. Responses were evaluated by ELN, IWG-MET and EUMNET standardized criteria sets and adverse effects were analyzed.