Újdonságok, aktualitások a polycythaemia vera                     diagnosztikájában és kezelésében

Polycythaemia vera (PV), a condition characterized by blood hyperviscosity due to the expansion of the erythrocyte mass is the most common entity among all Philadelphia chromosome-negative myeloproliferative neoplasms. Arterial and venous thrombotic events are leading determinants of morbidity and mortality but impairment of quality of life due to vasomotor symptoms (erythromelalgia, pruritus) and disease-associated symptoms (tiredness, fatigue, pruritus, night sweats, vision problems, headache, concentration loss, abdominal discomfort, early satiety, fever, weight loss) are also present. The review of polycythaemia vera is actual as the updated WHO 2016 classification of myeloid neoplasms has changed the diagnostic criteria and a new second-line treatment option – JAK1/JAK2 inhibitor ruxolitinib – has been approved for patients who had an inadequate response to or are intolerant of hydroxyurea, which represents a breakthrough in the treatment of this patient population. Orv. Hetil., 2016, 157(44), 1743–1751.

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Haematopathology of classic myeloproliferative neoplasms

Oxford Specialist Handbook: Myeloproliferative Neoplasms ◽

10.1093/med/9780198744214.003.0004 ◽

2020 ◽

pp. 45-62

Author(s):

Hans Michael Kvasnicka ◽

Jürgen Thiele

Keyword(s):

Continuous Improvement ◽

Who Classification ◽

Myeloproliferative Neoplasms ◽

Primary Myelofibrosis ◽

World Health ◽

Polycythaemia Vera ◽

The World ◽

Health Organization ◽

Diagnostic Importance

The classification of the World Health Organization (WHO) continues to advocate the diagnostic importance of bone marrow (BM) morphology in the diagnostic workup of myeloproliferative neoplasms (MPN). In this regard, distinctive histological BM patterns characterize specific subtypes of MPN and are the key to a meaningful clinical and molecular-defined risk stratification of patients. In this regard, the morphological denominator includes a characteristic megakaryocytic proliferation along with variable changes in the granulopoiesis and erythropoiesis. Importantly, diagnosis of MPN requires absence of relevant dysgranulopoiesis or dyserythropoiesis. In terms of clinical practice, the concept of precursor stages provides the possibility of an early intervention by appropriate therapeutic regimens that might prevent fatal complications like thrombosis and haemorrhage, especially in early stages of polycythaemia vera or in primary myelofibrosis. However, the WHO classification is not aimed to capture all biological true cases of MPN or guarantee a complete diagnostic specificity and thus might be in need of continuous improvement following clinical experience.

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RMC-4550, an Allosteric Inhibitor of SHP2, Displays Therapeutic Efficacy in Pre-Clinical Models of Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2019-128937 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4198-4198 ◽

Cited By ~ 1

Author(s):

Garima Pandey ◽

Nathan Horvat ◽

Narmin E. Amin ◽

Afua A. Akuffo ◽

Christelle Colin ◽

...

Keyword(s):

Research Funding ◽

Myeloproliferative Neoplasms ◽

Critical Role ◽

Philadelphia Chromosome ◽

Jak2 V617f ◽

Ras Signaling ◽

Jak2 Inhibitor ◽

Stat Signaling ◽

Drug Naïve

Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) are JAK2-driven disorders resulting from mutations in JAK2, MPL, or CALR. Ruxolitinib, the only FDA-approved JAK2 inhibitor for MPNs, alleviates patient symptomology and improves quality of life, but has little effect on reducing mutant allele burden. This persistent survival of MPN cells in the face of ruxolitinib, as well as other JAK2 inhibitors that have been clinically tested, is a major clinical bottleneck to the development of an effective targeted therapy for MPN patients. Identifying new therapeutic targets which play critical roles in MPN cells and/or in JAK2 inhibitor persistence may lead to improved MPN therapies. SHP2 is an oncogenic tyrosine phosphatase that is an effector of growth factor and cytokine receptor signaling. SHP2 plays a critical role in the activation of the RAS-ERK pathway and regulates JAK-STAT signaling via numerous phosphatase-dependent mechanisms. Activating mutations of SHP2(PTPN11) have been identified in leukemia, including 8% of MPN patients whose disease progressed to acute myeloid leukemia (AML). In addition, SHP2 has been shown to mediate adaptive resistance to targeted therapies in several cancers. Given the role of SHP2 in cytokine and JAK-STAT signaling, we envisaged a potential role of SHP2 in MPN cell growth and/or survival and ruxolitinib persistence. Treatment of JAK2-V617F-driven MPN model cell lines (UKE1, SET2, and BaF3-JAK2-V617F) with ruxolitinib blocked constitutive tyrosine phosphorylation of SHP2, including phosphorylation of Y542, a marker for activated SHP2. This phosphorylation, however, was restored in ruxolitinib persistent cells. Combination treatment of the allosteric SHP2 inhibitor RMC-4550 (Revolution Medicines) with ruxolitinib prevented the development of ruxolitinib persistent cells and pre-established persistent cells remained sensitive to SHP2 inhibition. RMC-4550 treatment led to significantly reduced levels of pERK consistent with the role of SHP2 in RAS signaling. Interestingly, pERK levels in persistent cells were more sensitive to SHP2 inhibition compared to drug naïve cells suggesting pERK was more dependent on SHP2 in ruxolitinib persistent cells. SHP2 inhibitor treatment increased pSTAT5(Y694) in drug naïve cells but this increase was not observed in similarly treated persistent cells. Furthermore, while ruxolitinib inhibited pERK levels in UKE1 and SET2 cells, pERK levels recovered within 24 hrs of treatment. SHP2 inhibition prevented the recovery of pERK in the presence of ruxolitinib. Collectively, these data suggest that signaling pathways in MPN cells treated with ruxolitinib can become rewired, gaining greater dependence on SHP2, concomitant with sustained pERK and cell survival/growth. Interestingly, we identified a known activating SHP2 mutation (F71L) in UKE1 cells obtained from two independent sources - consistent with the presence of PTPN11 mutations in post-MPN AML. The persistent survival of UKE1 cells in ruxolitinib was antagonized by CRISPR-mediated reduction of SHP2 expression, providing further evidence that SHP2 contributes to ruxolitinib persistence. To assess the effects of a SHP2 inhibitor on MPN progression in vivo, we employed the MPLW515Lbone marrow transplant mouse model of MPN. Initial assessment of therapeutic treatment of mice with an established MPN phenotype indicated that once daily treatment of RMC-4550 (10 or 30 mg/kg) antagonized the MPN phenotype. Complete blood counts indicated a significant reduction in white blood cells, monocytes, and neutrophils compared to vehicle treated mice, while flow cytometry analysis indicated RMC-4550 diminished CD11b+ cell numbers to near that observed in mice transplanted with MPLWT-transduced bone marrow. RMC-4550 improved the overall health of diseased mice, as indicated by increased weight, and significantly reduced organomegaly of the spleen and liver compared to vehicle treated MPN mice. Finally, erythropoietin independent erythroid colony formation of JAK2V617F-positive MPN patient cells was suppressed following SHP2 inhibition, which synergized or enhanced the inhibition induced by ruxolitinib in this assay. In summary, our results suggest that SHP2 inhibition may represent a potential MPN therapy in both ruxolitinib naïve and resistant patients and is an attractive therapeutic target for future clinical investigation. Disclosures Epling-Burnette: Incyte Corporation: Research Funding; Forma Therapeutics: Research Funding; Celgene Corporation: Patents & Royalties, Research Funding. Reuther:Incyte Corporation: Research Funding.

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Aktualitások a primer myelofibrosis ellátásában

Orvosi Hetilap ◽

10.1556/650.2016.30531 ◽

2016 ◽

Vol 157 (39) ◽

pp. 1547-1556

Author(s):

Zsófia Simon ◽

Imelda Marton ◽

Zita Borbényi ◽

Árpád Illés

Keyword(s):

Treatment Approach ◽

Myeloproliferative Neoplasms ◽

Primary Myelofibrosis ◽

Spleen Volume ◽

Novel Therapy ◽

Jak2 Inhibitor ◽

Chronic Myeloproliferative Neoplasms ◽

Associated Symptoms ◽

Modifying Effect ◽

Disease Modifying

Primary myelofibrosis is one of the Philadelphia negative chronic myeloproliferative neoplasms. It is a rare disease featured by cytopenias and hepatosplenomegaly. Although the etiology of the disease is still unknown, our knowledge about its pathology and prognosis has been improving in the last few years. Furthermore, the JAK2 inhibitor ruxolitinib has become available in Hungary since 2015. Beside its high efficacy in spleen volume and in reduction of myelofibrosis-associated symptoms, this novel therapy also exerts a disease-modifying effect and, therefore, ruxolitinib may improve the life expectancy too. Treatment approach of myelofibrosis has been changed these years, which gives a reason for this summary. Orv. Hetil., 2016, 157(39), 1547–1556.

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Leukaemic Transformation of Philadelphia-chromosome-negative Myeloproliferative Neoplasms — A Review of the Molecular Background

European Oncology & Haematology ◽

10.17925/eoh.2011.07.01.59 ◽

2011 ◽

Vol 07 (01) ◽

pp. 59

Author(s):

Nils H Thoennissen ◽

H Phillip Koeffler ◽

◽

Keyword(s):

Chromosomal Abnormalities ◽

Myeloproliferative Neoplasms ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Myeloid Cell ◽

Primary Myelofibrosis ◽

Haematopoietic Stem Cell ◽

Polycythaemia Vera ◽

Causative Role ◽

Blast Phase

Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs), including polycythaemia vera (PV), primary myelofibrosis (PMF) and essential thrombocythaemia (ET), are clonal haematopoietic stem cell disorders characterised by proliferation of one or more myeloid cell lineages. They are closely associated with theJAK2V617F mutation, whose detection is used as a clonal marker in the differential diagnosis of MPN. Despite recent improvements in the molecular diagnosis and therapeutic regimen of these chronic disorders, haematological evolution to blast phase remains a major cause of long-term mortality. The mechanism of MPN transformation is still a matter of some controversy because of insufficient insights into the underlying molecular pathogenesis. The purpose of this article is to summarise the increasing data concerning the mechanism of leukaemic evolution of patients diagnosed with chronic MPN. Chromosomal abnormalities and genes that have been shown to play a potential causative role in chronic-phase acceleration are discussed, as are aberrations that may serve as prognostic markers in the blast phase of MPN.

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The Epidemiology of Myeloproliferative Neoplasms in New Zealand between 2010 and 2017: Insights from the New Zealand Cancer Registry

Current Oncology ◽

10.3390/curroncol28020146 ◽

2021 ◽

Vol 28 (2) ◽

pp. 1544-1557

Author(s):

Chris Varghese ◽

Tracey Immanuel ◽

Anna Ruskova ◽

Edward Theakston ◽

Maggie L. Kalev-Zylinska

Keyword(s):

Risk Factor ◽

New Zealand ◽

Cancer Registry ◽

Independent Risk Factor ◽

Myeloproliferative Neoplasms ◽

Demographic Data ◽

Philadelphia Chromosome ◽

Ethnic Disparities ◽

Male Gender ◽

Polycythaemia Vera

Background: There is a paucity of data on ethnic disparities in patients with the classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs): polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF). Methods: This study analysed the demographic data for PV, ET and PMF collected by the New Zealand Cancer Registry (NZCR) between 2010 and 2017. Results: We found that the NZCR capture rates were lower than average international incidence rates for PV and ET, but higher for PMF (0.76, 0.99 and 0.82 per 100,000, respectively). PV patients were older and had worse outcomes than expected, which suggests these patients were reported to the registry at an advanced stage of their disease. Polynesian patients with all MPN subtypes, PV, ET and PMF, were younger than their European counterparts both at the time of diagnosis and death (p < 0.001). Male gender was an independent risk factor for mortality from PV and PMF (hazard ratios (HR) of 1.43 and 1.81, respectively; p < 0.05), and Māori ethnicity was an independent risk factor for mortality from PMF (HR: 2.94; p = 0.006). Conclusions: New Zealand Polynesian patients may have increased genetic predisposition to MPN, thus we advocate for modern genetic testing in this ethnic group to identify the cause. Further work is also required to identify modifiable risk factors for mortality in MPN, in particular those associated with male gender and Māori ethnicity; the results may benefit all patients with MPN.

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Prefibrotic Primary Myelofibrosis As an Entity Distinct from Other Philadelphia-Chromosome Negative Myeloproliferative Neoplasms - Data from the Austrian Reclassification Project

Blood ◽

10.1182/blood.v128.22.4252.4252 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4252-4252 ◽

Cited By ~ 1

Author(s):

Georg Jeryczynski ◽

Bettina Gisslinger ◽

Martin Schalling ◽

Maria Theresa Krauth ◽

Leonhard Muellauer ◽

...

Keyword(s):

Bone Marrow ◽

Myeloproliferative Neoplasms ◽

Survival Rates ◽

Philadelphia Chromosome ◽

Myeloproliferative Neoplasm ◽

Primary Myelofibrosis ◽

Distinct Entity ◽

Bone Marrow Biopsies ◽

Cumulative Rate ◽

Night Sweats

Abstract Introduction: The distinction between essentialthrombocythemia(ET) and early, prefibrotic primary myelofibrosis (prePMF) by strictly applying the criteria of the WHO classification results in a newly defined subgroup of myeloproliferative neoplasm (MPN) in which the frequency and severity of clinical features are currently poorly characterized. Since prePMF was usually summarized under the subgroup of ET in previous classifications, little is known about the frequency of prePMFamong MPN. The importance of accurate diagnosis, however, is underlined by various publications that could demonstrate a significant impact on management and outcome of these patients. Aims: The aim of this study was to describe the clinical characteristics and symptoms at diagnosis of prePMF as a distinct entity and to evaluate the course of the disease in regard to survival, transformation into overt myelofibrosis and acute leukemia. Methods: All patients with representative bone marrow biopsies at presentation and complete clinical data at time of diagnosis and follow up were included in this study. All patients included were recruited from the MPN cohort of the Medical University of Vienna. Results: In total, 807 MPN patients diagnosed according to the WHO 2008 criteria were analyzed. The relative frequency of prePMF in our cohort was 17.6% (n=142) as opposed to 27.4% (221) in ET (Fig. 1). The median age for prePMF patients was 63.4 years (range 26.9-88.1) and 55.1% were female. The majority showed an elevated platelet count (median 770 G/l, range 78-2869), hemoglobin levels were on the lower end of the normal range in both genders (median 13.9, range 8.1-18.4 and 13.2, range 7.9-16.2 in men and women respectively). Leukocyte counts in the upper range of normal were common (median 9.87, range 4.0-46.0). The lactate dehydrogenase levels (LDH) were markedly elevated (median 303, range 153-729 with an institutional cut-off of 250 U/L). Therewasalso a considerate proportion of patients with splenomegaly (39.8%). Further, 22.6% of patients reported constitutional symptoms such as night sweats and weight loss. Fiber grade of 1 of a three-graded score in the bone marrow biopsy was reported in 26.2% of cases. 27.0% of patients presented withleftshiftingwith a few peripheral blasts. JAK2 positivity was found in 57.1%, CALR in 32.7 and MPL in 3.3% of cases. Only 5.9% were triple negative. 5-, 10- and 20-year survival rates were 87.6%, 67.0% and 28.8% respectively (38.2% of patients followed to death). Cumulative rate of progression into overt fibrosis was 34.2% after 10 and 58.8% after 20 years (Fig. 2). Discussion: Our data highlight important features of prePMF. Firstly, compared to ET, it has a later onset. More importantly, thrombocytosis is not a feature limited to ET, but is also frequently seen in prePMF and is therefore not suitable to accurately characterize MPN at time of diagnosis. However, leukocytosis and elevated LDH levels are features uncommon for ET as is fiber grade > 0 that is almost never seen in the WHO-defined ET, but relatively common in prePMF. Splenomegaly and presence of a few blasts are generally signs of beginningextramedullaryhematopoiesis are therefore more commonly associated with early stages primary myelofibrosis. Lastly, overall survival and fibrosis-free survival is substantially impaired in prePMF in comparison to data previously published for ET and similar to polycythemiavera. In conclusion, prePMF is a distinct entity, that while sharing some features of ET, most notably thrombocytosis, shows several striking features that should be regarded when investigating newly diagnosed MPN patients. Figure Figure. Figure Figure. Disclosures Gisslinger: Baxalta: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AOP Orphan: Consultancy, Honoraria.

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Beyond JAK-STAT: novel therapeutic targets in Ph-negative MPN

Hematology ◽

10.1182/hematology.2019000048 ◽

2019 ◽

Vol 2019 (1) ◽

pp. 407-414 ◽

Cited By ~ 1

Author(s):

Aaron T. Gerds

Keyword(s):

Myeloproliferative Neoplasms ◽

Philadelphia Chromosome ◽

Primary Myelofibrosis ◽

Disease Modification ◽

Constitutive Activation ◽

Emerging Therapies ◽

Formation And Evolution ◽

Improvement In Survival ◽

Stat Pathway

Abstract The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) share a common pathobiology of constitutive activation of the JAK and STAT pathway, despite having the 3 distinct phenotypes of essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Targeting the JAK-STAT pathway has led to remarkable clinical benefit, including reduction in splenomegaly, amelioration of cytokine-driven symptoms, improvement in quality of life, and even some improvement in survival. However, targeting this pathway has not resulted in consistent disease modification by current metrics, including a reduction in mutant allele burden or reversal of fibrosis. Moreover, targeting JAK-STAT can lead to limiting treatment-emergent side effects, such as anemia and thrombocytopenia. Continued discovery points to a complex system of pathogenesis beyond JAK-STAT driving the formation and evolution of MPNs. This article reviews the successes and limitations of JAK-STAT inhibition, surveys the strategies behind emerging therapies, and discusses the challenges that are present in moving beyond JAK-STAT.

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Emerging treatments for classical myeloproliferative neoplasms

Blood ◽

10.1182/blood-2016-10-695965 ◽

2017 ◽

Vol 129 (6) ◽

pp. 693-703 ◽

Cited By ~ 54

Author(s):

Alessandro M. Vannucchi ◽

Claire N. Harrison

Keyword(s):

Clinical Trials ◽

Myeloproliferative Neoplasms ◽

Phase 1 ◽

Cardiovascular Complications ◽

Jak2 Inhibitor ◽

Molecular Abnormalities ◽

Emerging Treatments ◽

Novel Target ◽

Current Guidelines

Abstract There has been a major revolution in the management of patients with myeloproliferative neoplasms (MPN), and in particular those with myelofibrosis and extensive splenomegaly and symptomatic burden, after the introduction of the JAK1 and JAK2 inhibitor ruxolitinib. The drug also has been approved as second-line therapy for polycythemia vera (PV). However, the therapeutic armamentarium for MPN is still largely inadequate for coping with patients’ major unmet needs, which include normalization of life span (myelofibrosis and some patients with PV), reduction of cardiovascular complications (mainly PV and essential thrombocythemia), prevention of hematological progression, and improved quality of life (all MPN). In fact, none of the available drugs has shown clear evidence of disease-modifying activity, even if some patients treated with interferon and ruxolitinib showed reduction of mutated allele burden, and ruxolitinib might extend survival of patients with higher-risk myelofibrosis. Raised awareness of the molecular abnormalities and cellular pathways involved in the pathogenesis of MPN is facilitating the development of clinical trials with novel target drugs, either alone or in combination with ruxolitinib. Although for most of these molecules a convincing preclinical rationale was provided, the results of early phase 1 and 2 clinical trials have been quite disappointing to date, and toxicities sometimes have been limiting. In this review, we critically illustrate the current landscape of novel therapies that are under evaluation for patients with MPN on the basis of current guidelines, patient risk stratification criteria, and previous experience, looking ahead to the chance of a cure for these disorders.

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Is There a Role for Direct Oral Anticoagulants in the Primary and Secondary Prevention of Myeloproliferative Neoplasm Associated Thrombosis?

Hemato ◽

10.3390/hemato2040053 ◽

2021 ◽

Vol 2 (4) ◽

pp. 769-780

Author(s):

Uzma Faruqi ◽

Karen A. Breen

Keyword(s):

Myeloproliferative Neoplasms ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Philadelphia Chromosome ◽

Myeloproliferative Neoplasm ◽

Haematopoietic Stem Cell ◽

Polycythaemia Vera ◽

Unusual Site ◽

Thrombotic Risk ◽

Randomised Control Trials

Philadelphia chromosome negative myeloproliferative neoplasms (MPN) are clonal haematopoietic stem cell disorders. Of the MPNs, polycythaemia vera (PV) and essential thrombocythaemia (ET) confer a high thrombotic risk which may be the presenting feature of the disease. Thrombotic complications consist of both arterial and venous events and the presence of the JAK2 V617F mutation is associated with higher risk. Patients presenting with an unprovoked thrombus, particularly at an unusual site, e.g., splanchnic circulation, should be screened for the presence of this mutation. Historically, warfarin has been the only option for oral anticoagulation; however, there is now increasing evidence and practise to use direct oral anticoagulants (DOACs) in cancer. The seminal randomised control trials have demonstrated non-inferiority compared to low molecular weight heparin (LMWH) with a preferable bleeding profile. DOACs are now the first line treatment for atrial fibrillation and venous thromboembolic disease, as recommended by NICE, and therefore there is increasing familiarity with these agents. Furthermore, there are now targeted antidotes available. This paper reviews evidence for efficacy and safety of DOACs in MPN. Whilst no randomised control trials have been performed, several retrospective studies and reviews of registry data have reproducibly demonstrated that, alongside cytoreduction, DOACs represent an effective modality of anticoagulation for treatment of venous thromboembolism in MPN. Furthermore, dosing regimens provide the option for longer term secondary prophylaxis. Use of DOACs in arterial thrombosis is an area for future development and there is already some evidence for utility in peripheral vascular disease.

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Comorbidities Such As Thromboembolic Events Significantly Worsen Patient-Reported Quality of Life (QoL) and Symptoms in Myeloproliferative Neoplasms (MPN) - Data from the Bioregistry of the German Study Group for MPN (GSG-MPN)

Blood ◽

10.1182/blood-2018-99-112377 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4292-4292

Author(s):

Susanne Isfort ◽

Frank Stegelmann ◽

Martine Klausmann ◽

Holger Schulz ◽

Wiebke Hollburg ◽

...

Keyword(s):

Quality Of Life ◽

Research Funding ◽

Myeloproliferative Neoplasms ◽

Symptom Burden ◽

Study Group ◽

Thromboembolic Events ◽

German Study ◽

Night Sweats ◽

Support Research

Abstract Introduction: Ph-negative myeloproliferative neoplasms (MPN) represent a heterogeneous group of hematological malignancies which differ in various aspects such as clinical manifestation, underlying genetic aberrations, cytomorphological features and life expectancy. However, across all subtypes, patients (pts) with MPN often suffer from severe symptoms, resulting in an impairment of the quality of life (QoL). Methods: The German Study Group for MPN (GSG-MPN) Bioregistry is a non-interventional prospective study including pts of at least 18 years with diagnosis of Ph-negative MPN according to WHO criteria (2008) having provided written informed consent. The Bioregistry study also includes assessment of QoL at baseline and on an annual basis, with all pts completing the standardized MPN-SAF-TSS questionnaire (German version) and an additional item indicating pts' subjective overall QoL on an 11-point Likert scale. Total scores range from 0 to 90 and were calculated if at least 6 items were answered (Emanuel RM et al., J Clin Oncol. 2012; 30 (33): 4098-103.)). Clinical variables, as documented in the registry, included comorbidities, reported symptoms as assessed by the physician, bleeding, and thromboembolic events (TEE). For statistical analysis, standard descriptive methods, Spearman correlation coefficient, Wilcoxon test/Kruskal-Wallis test for significance testing, and Kendall´s tau-b statistics were used. Results: 1,403 pts who had completed at least six items of the QoL assessment at baseline were included in this analysis. Median age at diagnosis was 58 years (interquartile range [IQR] 22), 98% were Caucasian, 50% were female. 494 pts were diagnosed with essential thrombocythemia (ET, 35%), 444 pts with polycythemia vera (PV, 32%), 302 pts with primary myelofibrosis (PMF, 22%), 83 pts with MPN-unclassifiable (MPNu, 6%), 43 pts with post-ET-myelofibrosis (pET-MF, 3%) and 37 pts with post-PV-myelofibrosis (pPV-MF, 3%). The most common complaint reported via the MPN-SAF-TSS was fatigue, occurring in more than 80% of the pts in all entities except MPNu (77%). More than 50 % of pts in each entity reported to suffer from early satiety, night sweats, concentration problems, or overall impairment of QoL. Table 1 summarizes all 9 symptoms and overall QoL from the questionnaire categorized by entity. Interestingly, the pts suffering from PET-MF reported the highest symptom burden, while PPV-MF pts showed the lowest overall symptom burden (median total QoL score of 23 vs. 16; p=0.01). The strongest correlations among the different symptoms were seen for fatigue and overall QoL (Spearman´s rho 0.57, p<0.001) as well as concentration problems and overall QoL (Spearman´s rho 0.33, p<0.001). Furthermore, the impact of variables such as age, comorbidities and TEE on QoL was assessed. Abdominal discomfort increased with age (rho = -0.14, p<0.001). A history of TEE before baseline assessment correlated significantly with fatigue scores (Spearman rho= 0.07, p<0.01) and with concentration problems (rho=0.07, p<0.01). With an increasing number of TEE, scores for both of these items worsened over time (p< 0.01, respectively). Moreover, MPN-total score (MPN-TSS) was higher in pts with more comorbidities (Median: 18 (IQR:23), and 25 (27) for pts with <3 versus ≥3 comorbidities, respectively, p= 0.017). Next, we compared data on 5 of the pts symptoms (reported in the questionnaire) to their assessment by the treating physician (only 5 items were available both in the questionnaire and in our registry database) in order to understand whether the "physician´s opinion" is congruent with the patient´s reported outcome in the questionnaire. While there were clear associations between the two data sources, there were also significant discrepancies, e.g., the physician did not indicate fatigue in about 20% of pts with self-assessed fatigue score of >=6 points. The most concordant symptom was night sweats (further details in table 2). Conclusions: Most MPN pts suffer from a significant symptom burden which impairs their QoL. TEE influence fatigue and concentration problems. The perception of symptoms (particularly with respect to fatigue) differs between pts and treating physician which suggests that questionnaires should be used on a routine basis in order to faithfully reflect patient´s degree of suffering from MPN and/or treatment. Disclosures Isfort: Amgen: Other: i.e. travel support; Mundipharma: Other: i.e. travel support; Roche: Other: i.e. travel support; Incyte/Ariad: Consultancy; Pfizer: Consultancy, Honoraria, Other: i.e. travel support; BMS: Honoraria; Novartis: Consultancy, Honoraria, Other: i.e. travel support; Alexion: Other: i.e. travel support; Hexal: Other: i.e. travel support. Stegelmann:Novartis: Consultancy, Honoraria. Al-Ali:Gilead: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Alexion: Honoraria; Novartis: Consultancy, Honoraria, Other: Travel support, Research Funding; Celgene: Honoraria, Other: Travel support, Research Funding. Goethert:BMS: Consultancy, Honoraria, Other: i.e. travel support; Incyte: Consultancy, Honoraria, Other: i.e. travel support; Pfizer: Consultancy, Honoraria; Novartis: Honoraria; Proteros Biostructures: Honoraria; AOP Orphan: Other: i.e. travel support. Haenel:Novartis: Honoraria; Takeda: Honoraria; Roche: Honoraria; Amgen: Honoraria. Platzbecker:Celgene: Research Funding. Griesshammer:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Brümmendorf:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Takeda: Consultancy.

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