Management Of Myeloproliferative Neoplasms Research Articles

New approaches to standard of care in early-phase myeloproliferative neoplasms: can interferon-α alter the natural history of the disease?

The classical BCR::ABL-negative myeloproliferative neoplasms (MPN) include Polycythemia Vera (PV), Essential Thrombocytemia (ET), and Primary Myelofibrosis (PMF). They are acquired clonal disorders of the hematopoietic stem cells (HSC) leading to hyperplasia of one or several myeloid lineages. MPN are caused by three main recurrent mutations, JAK2V617F and mutations in the calreticulin (CALR) and the thrombopoietin receptor (MPL) genes. Here, we review the general diagnosis, the complications, and the management of MPN. Second, we explain the physiopathology of the natural disease development and its regulation, which contributes to MPN heterogeneity. Thirdly, we describe the new paradigm of the MPN development highlighting the early origin of driver mutations decades before the onset of symptoms and the consequence on early detection of MPN cases in the general population for early diagnosis and better medical management. Finally, we present the interferon alpha (IFNα) therapy as a potential early disease-modifying drug after reporting its good hematological and molecular efficacies in ET, PV and early MF in clinical trials as well as its mechanism of action in pre-clinical studies. As a result, we may expect that, in the future, MPN patients will be diagnosed very early during the course of disease and that new selective therapies under development, such as IFNα, JAK2V617F inhibitors and CALRmut monoclonal antibodies, would be able to intercept the mutated clones.

Challenging Scenarios in the Management of Myeloproliferative Neoplasms

Challenging Scenarios in the Management of Myeloproliferative Neoplasms

Increased CXCL10 (IP-10) is associated with advanced myeloproliferative neoplasms and its loss dampens erythrocytosis in mouse models

Key studies in pre-leukemic disorders have linked increases in pro-inflammatory cytokines with accelerated phases of the disease, but the precise role of the cellular microenvironment in disease initiation and evolution remains poorly understood. In myeloproliferative neoplasms (MPNs), higher levels of specific cytokines have been previously correlated with increased disease severity (tumor necrosis factor-alpha [TNF-α], interferon gamma-induced protein-10 [IP-10 or CXCL10]) and decreased survival (interleukin 8 [IL-8]). Whereas TNF-α and IL-8 have been studied by numerous groups, there is a relative paucity of studies on IP-10 (CXCL10). Here we explore the relationship of IP-10 levels with detailed genomic and clinical data and undertake a complementary cytokine screen alongside functional assays in a wide range of MPN mouse models. Similar to patients, levels of IP-10 were increased in mice with more severe disease phenotypes (e.g., JAK2V617F/V617F TET2-/- double-mutant mice) compared with those with less severe phenotypes (e.g., CALRdel52 or JAK2+/V617F mice) and wild-type (WT) littermate controls. Although exposure to IP-10 did not directly alter proliferation or survival in single hematopoietic stem cells (HSCs) in vitro, IP-10-/- mice transplanted with disease-initiating HSCs developed an MPN phenotype more slowly, suggesting that the effect of IP-10 loss was noncell-autonomous. To explore the broader effects of IP-10 loss, we crossed IP-10-/- mice into a series of MPN mouse models and showed that its loss reduces the erythrocytosis observed in mice with the most severe phenotype. Together, these data point to a potential role for blocking IP-10 activity in the management of MPNs.

Management of classical Philadelphia chromosome-negative myeloproliferative neoplasms in Asia: consensus of the Asian Myeloid Working Group.

Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized clinically by the proliferation of one or more hematopoietic lineage(s). The classical Philadelphia-chromosome (Ph)-negative MPNs include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The Asian Myeloid Working Group (AMWG) comprises representatives from fifteen Asian centers experienced in the management of MPN. This consensus from the AMWG aims to review the current evidence in the risk stratification and treatment of Ph-negative MPN, to identify management gaps for future improvement, and to offer pragmatic approaches for treatment commensurate with different levels of resources, drug availabilities and reimbursement policies in its constituent regions. The management of MPN should be patient-specific and based on accurate diagnostic and prognostic tools. In patients with PV, ET and early/prefibrotic PMF, symptoms and risk stratification will guide the need for early cytoreduction. In younger patients requiring cytoreduction and in those experiencing resistance or intolerance to hydroxyurea, recombinant interferon-α preparations (pegylated interferon-α 2A or ropeginterferon-α 2b) should be considered. In myelofibrosis, continuous risk assessment and symptom burden assessment are essential in guiding treatment selection. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in MF should always be based on accurate risk stratification for disease-risk and post-HSCT outcome. Management of classical Ph-negative MPN entails accurate diagnosis, cytogenetic and molecular evaluation, risk stratification, and treatment strategies that are outcome-oriented (curative, disease modification, improvement of quality-of-life).

Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia.

Progression to aggressive secondary acute myeloid leukaemia (sAML) poses a significant challenge in the management of myeloproliferative neoplasms (MPNs). Since the physiopathology of MPN is closely linked to the activation of interferon (IFN) signalling and that AML initiation and aggressiveness is driven by leukaemia stem cells (LSCs), we investigated these pathways in MPN to sAML progression. We found that high IFN signalling correlated with low LSC signalling in MPN and AML samples, while MPN progression and AML transformation were characterized by decreased IFN signalling and increased LSC signature. A high LSC to IFN expression ratio in MPN patients was associated with adverse clinical prognosis and higher colony forming potential. Moreover, treatment with hypomethylating agents (HMAs) activates the IFN signalling pathway in MPN cells by inducing a viral mimicry response. This response is characterized by double-stranded RNA (dsRNA) formation and MDA5/RIG-I activation. The HMA-induced IFN response leads to a reduction in LSC signature, resulting in decreased stemness. These findings reveal the frequent evasion of viral mimicry during MPN-to-sAML progression, establish the LSC-to-IFN expression ratio as a progression biomarker, and suggests that HMAs treatment can lead to haematological response in murine models by re-activating dsRNA-associated IFN signalling.

Revisiting Circulating Extracellular Matrix Fragments as Disease Markers in Myelofibrosis and Related Neoplasms.

Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPNs) arise due to acquired somatic driver mutations in stem cells and develop over 10-30 years from the earliest cancer stages (essential thrombocythemia, polycythemia vera) towards the advanced myelofibrosis stage with bone marrow failure. The JAK2V617F mutation is the most prevalent driver mutation. Chronic inflammation is considered to be a major pathogenetic player, both as a trigger of MPN development and as a driver of disease progression. Chronic inflammation in MPNs is characterized by persistent connective tissue remodeling, which leads to organ dysfunction and ultimately, organ failure, due to excessive accumulation of extracellular matrix (ECM). Considering that MPNs are acquired clonal stem cell diseases developing in an inflammatory microenvironment in which the hematopoietic cell populations are progressively replaced by stromal proliferation-"a wound that never heals"-we herein aim to provide a comprehensive review of previous promising research in the field of circulating ECM fragments in the diagnosis, treatment and monitoring of MPNs. We address the rationales and highlight new perspectives for the use of circulating ECM protein fragments as biologically plausible, noninvasive disease markers in the management of MPNs.

Primary Arterial Hypertension and Drug-Induced Hypertension in Philadelphia-Negative Classical Myeloproliferative Neoplasms: A Systematic Review

The impact of primary arterial hypertension (HTN) in myeloproliferative neoplasms (MPNs) remains unclear, with scant literature available, mostly focusing on cardiovascular risk factors as a singular entity or on organ-specific HTN. Furthermore, available studies reporting findings on drug-induced HTN in MPNs report varying and contradictory findings. In consideration of the above, this study set out to systematically review the available literature and shed light on the occurrence of HTN in MPNs, its association with thrombosis, as well as the drugs used in MPN management that could increase blood pressure. The literature search yielded 598 potentially relevant records of which 315 remained after the duplicates (n = 283) were removed. After we screened the titles and the abstracts of these publications, we removed irrelevant papers (n = 228) and evaluated the full texts of 87 papers. Furthermore, 13 records did not meet the inclusion criteria and were excluded from the systematic review. Finally, a total of 74 manuscripts were entered into the qualitative synthesis and included in the present systematic review. Our systematic review highlights that HTN is the most common comorbidity encountered in MPNs, with an impact on both the occurrence of thrombosis and survival. Moreover, drug-induced HTN remains a challenge in the management of MPNs. Further research should investigate the characteristics of patients with MPNs and HTN, as well as clarify the contribution of HTN to the development of thrombotic complications, survival and management in MPNs. In addition, the relationship between clonal hematopoiesis of indeterminate potential, HTN, cardiovascular disease and MPNs requires examination in upcoming assessments.

Management of Myeloproliferative Neoplasms in the Molecular Era: From Research to Practice

The 1960 discovery of the Philadelphia chromosome in chronic myeloid leukemia (CML) marked the beginning of the modern genomic era of oncology. In the following years, the molecular underpinnings of CML were unraveled, culminating in the development of the first molecularly targeted therapy: imatinib. Imatinib revolutionized CML management, inducing deep molecular responses for most patients and aligning survival curves with those of age-matched control participants. Five additional tyrosine kinase inhibitors are now approved for CML: dasatinib, nilotinib, bosutinib, ponatinib, and asciminib (approved October 2021). The 2005 discovery of JAK2 mutations in myelofibrosis (MF) sparked enthusiasm that molecularly targeted therapies could have a similar impact in that disease. Three JAK inhibitors are now available for MF: ruxolitinib, fedratinib, and pacritinib (approved February 2022). JAK inhibitors are helpful for improving symptoms and splenomegaly but still only scratch the surface of MF pathophysiology. Clinical research testing novel agents, next-generation JAK inhibitors, and combinations of JAK inhibitors plus novel agents is moving at a tremendous pace in the hope that outcomes for patients with MF may mirror those with CML one day. This review provides an update on the status of clinical care and research for MF and addresses ongoing issues related to CML management.

Management of Myeloproliferative Neoplasms (MPNs)

To provide up to date guidance, practice recommendations and highlight barriers to medication adherence in the long-term management of chronic myeloproliferative neoplasms (MPNs). Current drug therapy for MPN is not curative and has not been shown to prolong survival. The main indication for treatment is the prevention of thrombosis and medication adherence remains a challenge in this group of patients. Identifying potentially modifiable barriers to medication adherence including primary nonadherence and non-persistent adherence enables timely interventions to be put in place and improve overall medication adherence. A systematic review of peer-reviewed literature and expert opinions was performed using electronic databases (PubMed, EMBASE, MEDLINE, and Web of Science) that were searched for articles reporting MPN and medication adherence. Discussions A case vignette is discussed throughout the article and expert opinion with international peer reviewed guidelines that are authored to support clinical decision making at the point of care were utilised. The evidence base was combined with more practical/clinical (data based) insight from real world clinical practice. Adoption of a broad range of digital health care activities and services in the health care system (telehealth applications) by the advanced practice providers (Non-Medical Prescribers-NMPs) in MPN clinics included medication prescribing and management, oral drug compliance and adherence evaluations, interventions, chronic care management, counselling and patient education on treatments. Current drug therapy for MPN is neither curative nor has it been shown to prolong survival, and medication adherence remains a challenge in this group of patients. The longevity of the patients' disease course may contribute to the high risk of non-adherence in this patient cohort. Poor adherence to long-term therapies severely compromises the effectiveness of treatment. Adherence interventions should be tailored to the needs of the patient in order to achieve maximum impact. Interventions aimed at improving adherence provide the best experience and outcome for the patient and their families and can have a profound impact on the quality of life and mitigation of disease consequences.

Analysis of genetic variants in myeloproliferative neoplasms using a 22-gene next-generation sequencing panel

BackgroundThe Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs), namely essential thrombocythaemia (ET), polycythaemia vera (PV) and primary myelofibrosis (PMF), are a group of chronic clonal haematopoietic disorders that have the propensity to advance into bone marrow failure or acute myeloid leukaemia; often resulting in fatality. Although driver mutations have been identified in these MPNs, subtype-specific markers of the disease have yet to be discovered. Next-generation sequencing (NGS) technology can potentially improve the clinical management of MPNs by allowing for the simultaneous screening of many disease-associated genes.MethodsThe performance of a custom, in-house designed 22-gene NGS panel was technically validated using reference standards across two independent replicate runs. The panel was subsequently used to screen a total of 10 clinical MPN samples (ET n = 3, PV n = 3, PMF n = 4). The resulting NGS data was then analysed via a bioinformatics pipeline.ResultsThe custom NGS panel had a detection limit of 1% variant allele frequency (VAF). A total of 20 unique variants with VAFs above 5% (4 of which were putatively novel variants with potential biological significance) and one pathogenic variant with a VAF of between 1 and 5% were identified across all of the clinical MPN samples. All single nucleotide variants with VAFs ≥ 15% were confirmed via Sanger sequencing.ConclusionsThe high fidelity of the NGS analysis and the identification of known and novel variants in this study cohort support its potential clinical utility in the management of MPNs. However, further optimisation is needed to avoid false negatives in regions with low sequencing coverage, especially for the detection of driver mutations in MPL.

Management of Myeloproliferative Neoplasms during Pregnancy: A Systematic Review

▪Introduction:Myeloproliferative neoplasms (MPN) include essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). Pregnancy in the presence of MPN increases the risk of thrombosis, hemorrhagic events, pre-eclampsia, progression to myelofibrosis (MF) or acute myeloid leukemia (AML) leading to poor fetal outcome.Methods:We conducted a literature search on PubMed, Embase, Web of Science, and Clinicaltrials.gov using MeSH terms and key words for MPN, PV, and ET from date of inception to January 2021. We excluded studies reporting less than 10 patients and those not in English language.Results:ET studies:How et al. (121 pregnancy (P)/52 women (W)) reported Aspirin (ASA) was protective and was used in 51.2% P (n=62/107) with OR (odd's ratio) of 0.304 (p=0.048; 90% CI 0.102-0.795). Similar benefit of ASA was also reported by Gangat e t al.(2009) (63P/36W ; P loss 21% in 24 patients receiving ASA vs 75% in 12 patients not receiving ASA), Niittyvuopio et al. (40P/16W; live births (LB) in all 13 P treated with ASA or ASA with prior cytoreduction therapy vs 67% complications and 56% loss of P in patients not treated with ASA), Randi et al. (1999) (16P/13W; 7/13 LB occurred on ASA, and only one P was lost on ASA), Bangerter et al.( 17P/9W; 100% P treated with ASA resulted in LB vs 45% LB in P without any treatment, p=0.04), and Pagliaro et al. (15P/9W; ASA monotherapy (n=3/15P) or ASA+ subcutaneous heparin (n=7/15P) resulted in nine LB). Cincotta e t al. (30P/12W) reported 79% LB with ASA or IFN-α vs 38% LB without any treatment (p=0.06). Among the treatment cohort, 5/7 patients on ASA had a LB, and all 4/4 patients on IFN-α had a LB.However, Beressi et al. (31P/18W) reported 4/8 untreated and 10/19 ASA treated P were lost with no statistically significant benefit. Palandri et al. reported 24P/13W treated with IFN-α (n=1), IFN-α + ASA (n=2) and ASA alone (n=9). The LB rate was not influenced significantly with treatment at conception (treated vs. untreated: 8/12 vs. 7/12, P=0.99). Melillo e t al. (122P/92W) reported no benefit with ASA. IFN-α had positive outcomes with 95% LB than patients not receiving IFN-α with 71.6% LB (OR 0.10 (95%CI: 0.013-0.846, p=0.034)). JAK2 mutation was associated with poorer outcomes (OR 6.19; 95%CI: 1.17-32.61; p=0.038). Wright et al. (43P/20W) reported no statistically significant difference between no treatment (n=16/43), ASA alone (n=24/43), ASA+cytoreduction (n=2/43), and low molecular weight heparin (LMWH) (n=1/43) groups.Passamonti et al.( 96P/58W ) reported statistically significant worse outcomes in JAK2 negative patients, no statistically significant benefit in JAK2 positive patients (p=0.05) with ASA and higher complications with conception while on cytoreduction therapy (n=6/13 abortion, n=3/13 pre-eclampsia).ET + Other MPN studies:Gangat et al. (2020) reported (152W ET and 36W PV) that in 95P/55W with ET, 60% pregnancy loss occurred without ASA vs 27% with ASA (p=0.02). All 4/36W with PV who were treated with one or more of ASA, enoxaparin, and hydroxyurea delivered LB, and 50% developed venous thromboembolism. Sokolowska et al. reported 104P/60W with MPN (47 ET, 3 PV, and 10 PMF) treated with various combinations of cytoreduction therapy (IFN-α in 48P, apheresis in 1P and anticoagulation (LMWH+ASA in 10, LMWH alone in 19 and ASA alone in 24P) during the pregnancy with 72.1% LB. Lapoirie et al. stratified 27P/14W (ET 19P/9W, PV 8P/5W) with MPN into high risk (67%) and standard risk and found significant P loss in all high-risk P that did not receive ASA (n=2). Maternal complications occurred in 3 high-risk P that received ASA. 77% of P treated with ASA, LMWH, or both resulted in a LB. Alimam et al. (58W; ET 47, PV 5, PMF 5, MPN-unclassified 1) reported better than predicted outcomes in 88% of women receiving ASA during P, 38% receiving ASA + prophylactic LMWH and 3% receiving ASA + therapeutic LMWH resulting in 58 LB with a P loss rate of 1.7/100 (95% CI; 0.04-9.24).PV studies:Irene et al. (24P/15W) reported a 40% incidence of P loss without antithrombotic therapy vs 10.5 % P loss receiving ASA, LMWH, or both. Willie e t al. divided 32P/14W with PV into two groups (treatment group: 18 P, treated with ASA during P and LMWH for six weeks postpartum; non-treatment group: 14 P) with 72% vs 14% LB respectively.Conclusion:Use of ASA, LMWH and cytoreductive therapy is the existing practice for pregnancies with MPN. However, proper evidence via a RCT is an unmet need. [Display omitted] DisclosuresAnwer: Janssen pharmaceutical: Honoraria, Research Funding; BMS / Celgene: Honoraria, Research Funding; Allogene Therapeutics: Research Funding; GlaxoSmithKline: Research Funding.

MPN-369: Potential Applications of Liquid Biopsy in BCR-ABL1-Negative Myeloproliferative Neoplasms: A Systematic Review

Introduction In recent years, the use of liquid biopsy in solid and blood cancers has become an interesting option in the field of cancer diagnostics and cancer management. However, the potential applications of liquid biopsy have not been assessed in BCR-ABL1-negative myeloproliferative neoplasms (MPNs). Objective To investigate the potential applications of liquid biopsy in MPNs. Methods We performed a systematic search of Web of Science, PubMed/MEDLINE, and The Cochrane Library. Publications were retrieved from the inception of these databases until May 7, 2021. We only analyzed articles published in English, French, Italian, and Romanian. Only original articles or research letters exploring the potential applications of liquid biopsy in MPNs were included in the final analysis. Reviews, case reports, conference abstracts, and books were excluded. Results A systematic search was performed of Web of Science, PubMed/MEDLINE, and The Cochrane Library. In total, 198 potentially relevant papers were detected. Following the removal of duplicates (n=85), 113 records were screened. After the exclusion of irrelevant manuscripts, based on the screening of their titles and abstracts (n=81), we examined the full texts of 33 manuscripts. Finally, after we applied the exclusion and inclusion criteria, 27 original articles were included in this review. Overall, the 27 studies assessed included 1,336 patients diagnosed with classical MPNs and were conducted predominantly in Europe (n=22; n=10 for Italy, n=4 for France), followed by Asia (n=4), and Australia (n=1). Most studies were observational (cross-sectional: n=25) in design and included all subtypes of classical MPNs (n=8), whereas others analyzed ET in particular (n=7), PV in particular (n=3), or PV+ET (n=3). The analyzed studies investigated the levels of cell-free DNA (n=1), extracellular vesicles (n=7), microparticles (n=14), or circulating endothelial cells (n=5) in MPNs. Flow-cytometry was by far the most commonly employed method of detection (n=23). Conclusions Based on the findings of this systematic review, we may hypothesize that in the near future, liquid biopsy might emerge as an important tool for the diagnosis and management of MPNs.

Impact of Mutational Profile on the Management of Myeloproliferative Neoplasms: A Short Review of the Emerging Data.

Philadelphia-chromosome negative myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by an increased risk of thrombosis and progression to acute myeloid leukemia. MPN are associated with driver mutations in JAK2, CALR and MPL which are crucial for the diagnosis and lead to a constitutive activation of the JAK-STAT signaling, independent of cytokine regulation. Moreover, most patients have concomitant mutations in genes involved in DNA methylation, chromatin modification, messenger RNA splicing, transcription regulation and signal transduction. These additional mutations may arise before, in the context of clonal hematopoiesis of indeterminate potential (CHIP), or after the acquisition of the driver mutation. The clinical phenotype of MPN results from complex interactions between mutations and host factors. The increased application of next-generation sequencing (NGS) techniques to a large series of patients with MPN has expanded the knowledge of mutational landscape and contributed to define the clinical significance of mutations. This molecular information is being increasingly used to refine diagnosis, risk stratification, monitoring of residual disease and response to treatment. ASXL1, SRSF2, EZH2, IDH1/IDH2 and U2AF1 mutations are associated with a more advanced disease and reduced overall survival in primary myelofibrosis (PMF), whereas spliceosome mutations in Polycythemia vera (PV) and essential thrombocythemia (ET) adversely affect both overall (SF3B1, SRSF2 in ET and SRSF2 in PV) and myelofibrosis-free (U2AF1, SF3B1 in ET) survival. This review discusses current knowledge of the molecular landscape of MPN, and how the availability of those molecular information may impact patient management.

The Next Generation of JAK Inhibitors: an Update on Fedratinib, Momelotonib, and Pacritinib.

Ruxolitinib is the first FDA-approved JAK inhibitor for the treatment of myeloproliferative neoplasms and is an effective means of controlling symptom burden and improving splenomegaly. However, a majority of patients will develop disease progression with long-term use. Fedratinib, momelotinib, and pacritinib are three newer-generation JAK inhibitors being prospectively evaluated and we will discuss their roles in the treatment of myeloproliferative neoplasms. Fedratinib has a role in both JAK-inhibitor naive intermediate-/high-risk myelofibrosis patients and in patients that have previously received ruxolitinib. It has recently received FDA approval for these indications as well. Momelotinib does not appear to have an advantage over ruxolitinib with regards to improving splenomegaly in intermediate-/high-risk JAK-inhibitor naive myelofibrosis. However, increased rates of transfusion independence have been noted with momelotinib. Pacritinib has been studied in myelofibrosis patients with significant baseline anemia and thrombocytopenia; these trials support the use of pacritinib in myelofibrosis patients with significant thrombocytopenia. While ruxolitinib is effective in reducing the symptom burden and splenomegaly of patients with myeloproliferative neoplasms, a majority of patients will ultimately progress on therapy. Newer-generation JAK inhibitors including fedratinib, momelotinib, and pacritinib are being prospectively evaluated to determine their appropriate roles in the management of myeloproliferative neoplasms. In addition, both combination therapies with JAK inhibitors and novel investigational therapies are being actively explored.

PB2223 INTERFERON THERAPY FOR PREGNANT PATIENTS WITH MYELOPROLIFERATIVE NEOPLASMS IN JAPAN

Background:Philadelphia chromosome (Ph)‐negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis, are clonal hematopoietic disorders characterized by the overproduction of terminally differentiated hematopoietic cells. Although PV and ET have a favorable prognosis, the incidence of thromboembolic and hemorrhagic complications is high. Thus, the goal of the current treatment strategy for patients with PV and ET is to prevent these events. MPNs mainly occur in the elderly, but can also occur in younger patients, including childbearing‐aged women. For ET in particular, there is a second peak in female patients in their thirties. In addition, the risk of miscarriage and other complications in pregnant MPN patients is higher than that in the general population; therefore, the management of MPNs during pregnancy is often discussed. The European LeukemiaNet and British Committee for Standards in Haematology have suggested interferon (IFN) therapy for MPN patients during high‐risk pregnancy. However, there are currently no guidelines in Japan.Aims:To evaluate the efficacy and safety of IFN therapy for pregnant patients with MPNs in Japan.Methods:We retrospectively analyzed eight patients with MPNs who were treated using IFN‐alpha during pregnancy at our institute. This study was approved by the ethics review board of Juntendo University Hospital.Results:One patient with PV and seven patients with ET were included. Among the ET patients, three patients harbored the JAK2 V617F mutation, whereas three patients harbored the CALR type 1 or 2 mutation. The other patient was defined as having triple‐negative ET. All ET patients had JAK2 V617F mutation, history of miscarriage, or history of platelet counts higher than 1,500 x 109/L, which is why we considered their pregnancies to be high‐risk. The dose of IFN‐alpha was from 9 million units to 21 million units per week, and the median value was 9 million units per week. Two patients started IFN before pregnancy to prepare for pregnancy, whereas six patients were treated after confirming pregnancy. All patients received low‐dose aspirin and low‐molecular‐weight heparin or heparin in the perinatal stage. The most frequent adverse event of IFN was fever, but it occurred only for the first few days. All patients continued IFN therapy until delivery. The median platelet count of the seven ET patients was 1,129 x 109/L before IFN therapy, which decreased to 336 x 109/L at the time of delivery. The hematocrit level of the patient with PV decreased from 47.0% to 40.9%, and the JAK2 V617F allele burden decreased from 87.2% to 75.4%. Two babies were born at a low birth weight, however, all of the babies’ Apgar scores were in the normal range. Neither hemorrhagic nor thromboembolic complications were reported. Significant placental infarcts were found in only one patient.Summary/Conclusion:This study represents the largest single center examination of IFN treatment for MPN patients during pregnancy in Japan, and suggests the safety and efficacy of IFN therapy for pregnant patients with MPNs. Although evidence for treatment is limited and the use of IFN for Ph‐negative MPNs is not approved in Japan, we suggest considering IFN therapy for pregnant patients with MPNs.

Results from the Myeloproliferative Neoplasm Patient Care Survey: Patient Care Opportunities and Challenges

▪Background:The myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) can be characterized by heterogeneous symptoms, disease features, and prognosis. Timely monitoring of blood counts and if needed, referral for discussion of stem cell transplant (SCT), are critical to optimizing survival and quality of life. In connection with the MPN SCT Transplantation Timing Taskforce's (MS3T's) work in developing the DIPPS-based Stem Cell Spectrum Timing Tool, the survey was deployed to explore factors contributing to delayed entry to SCT. National Comprehensive Cancer Network (NCCN) guidelines for MPNs strongly recommend referral to specialized centers with expertise in the management of MPNs (Mesa et. al. 2017). To date, efforts to assess the timing and quality of MPN patient care from the patient's perspective have been minimal.Methods:Patients were recruited from MPN-related Facebook pages, subscribers of MPNforum Magazine and E-mail support groups including the MPN-NET, MPDchat, and the MPN Research Foundation. Hematologists, MPN patients, and advocates constructed the 11-item survey questions and content. The survey was available for patient response between July 4-11th2018. Patients were queried on MPN type, time of diagnosis, and details regarding knowledge of their MPN disease features and care.Data:Demographics.Overall 2382 MPN patients responded to the online survey. Of these, 901 (38%) patients had ET, 865 (36%) had PV, 561 (24%) had MF, 41 (2%) had MPN-unclassifiable or MPN/MDS overlap and 15 (1%) did not respond. Among MF patients, 56% reported having primary MF, 42% secondary MF, 1% prefibrotic MF, and 1% reported having already undergone SCT (1% did not specify type of MF or transplant). The majority of patients were diagnosed with their MPN by a hematology/oncology (77.8%) or family practice (15 %) physician.MPN Care provider and monitoring: Out of all respondents, 35% reported being cared for by an MPN specialist, 36% were not cared for by an MPN specialist and 27% were unsure if their provider was an MPN specialist. Overall less than half (42%) of patients reported having sought a second opinion from an MPN specialist. The majority (87%) of participants knew their mutational status relating to the highly publicized and widely tested JAK2 V617F mutation (73.8%) and CALR (10.2%). However, a statistically insignificant number of patients had any idea of other driving and secondary mutations including MPL, EZH2, SRSF2, IDH1/2 or ASLX-1. Blood counts were reviewed by a hematologist for the majority of patients (93% responded “yes”, 4% responded “sometimes”, 3% responded “no”).SCT Referral: Among ET and PV, <1% of patients reported being referred to SCT. For MF, 34% of participants reported having been referred for SCT discussion (30% for primary MF and 28% for secondary MF).Conclusions: MPN patients often report receiving care outside of the care of an MPN specialist. Additionally, despite the poor outcomes and higher likelihood of progression to AML, less than a third of patients with secondary MF report being referred for SCT discussion. Independent validation of patient responses, particularly in regards to MPN specialized care and timing of transplant discussion should be investigated further. However, these patient responses suggest many patients may be receiving less than optimal MPN care. These results demonstrate the importance of community hematology/oncology physician and patient education regarding optimal MPN care. DisclosuresMesa:UT Health San Antonio - Mays Cancer Center: Employment; Celgene: Research Funding; Novartis: Consultancy; Incyte Corporation: Research Funding; Pfizer: Research Funding; CTI Biopharma: Research Funding; Genentech: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding. Palmer:Novartis: Research Funding. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Speakers Bureau. Verstovsek:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Scherber:Gilead: Honoraria.

Clinical Utility of Next-generation Sequencing in the Management of Myeloproliferative Neoplasms: A Single-Center Experience.

Although next-generation sequencing (NGS) has helped characterize the complex genomic landscape of myeloid malignancies, its clinical utility remains undefined. This has resulted in variable funding for NGS testing, limiting its accessibility. At our center, targeted sequencing (TAR-SEQ) using a 54-gene NGS myeloid panel is offered to all new patients referred for myeloid malignancies, as part of a prospective observational study. Here, we evaluated the diagnostic, prognostic, and potential therapeutic utility of clinical grade TAR-SEQ in the routine workflow of 179 patients with myeloproliferative neoplasms (MPN). Of 13 patients with triple negative (TN) MPN, who lacked driver mutations in JAK2, CALR, and MPL, TAR-SEQ confirmed clonal hematopoiesis in 8 patients. In patients with intermediate-risk myelofibrosis (MF), TAR-SEQ helped optimize clinical decisions in hematopoietic cell transplant (HCT)-eligible patients through identifying a high molecular risk (HMR) mutation profile. The presence of an HMR profile favored HCT in 9 patients with intermediate-1 risk MF. Absence of an HMR profile resulted in a delayed HCT strategy in 10 patients with intermediate-2 risk MF, 7 of which were stable at the last follow-up. Finally, TAR-SEQ identified patients with various targetable mutations in IDH1/2 (4%), spliceosome genes (28%), and EZH2 (7%). Some of these patients can be potential candidates for future targeted therapy trials. In conclusion, we have demonstrated that TAR-SEQ improves the characterization of TN MPN, can be integrated in clinical practice as an additional tool to refine decision making in HCT, and has the potential to identify candidates for future targeted therapy trials.

Thromboembolism prophylaxis in patients with Philadelphia-negative myeloproliferative neoplasms-Clinical practice among Nordic specialists.

Patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) have higher risks of developing thromboembolisms compared to the general population. International guidelines on the management of MPNs therefore include recommendations concerning thromboembolism prophylaxis. In clinical practice, strict adherence to guidelines may be challenging and dependent on factors such as physician experience, outpatient clinic setting, and access to therapy; however, no data exist on physician adherence or patient compliance to thromboembolism prophylaxis in MPNs. The Nordic Myeloproliferative Neoplasm Study Group (NMPN) performed a survey among Nordic hematology specialists with the aim of documenting the implementation of international recommendations in a region of Northern Europe with similar healthcare systems. The study showed that Nordic specialists managed their patients in accordance with international guidelines concerning medical intervention, but to a lesser degree regarding the management of additional cardiovascular risk factors. The survey also drew attention to the common clinical dilemma of combining antiaggregatory agents with vitamin K antagonists (VKA), or novel oral anticoagulants (NOAC), as well as phlebotomy limits in female polycythemia vera patients. The results of this study highlight the importance of considering all risk factors for thrombosis and an optimal collaboration with the primary healthcare sector.

Myeloproliferative neoplasms: updates on molecular pathophysiology, diagnosis and treatment strategies.

Myeloproliferative neoplasms (MPNs) are chronic hematopoietic stem cell disorders, including polycythemia vera, essential thrombocytosis, and primary myelofibrosis. The JAK2V617F mutation was identified in 2005, followed by the discovery of the JAK2 exon12, MPNW515 mutation, and CALR mutation. About 90% of patients with BCR/ABL negative MPNs have been shown to have one of these driver mutations. In addition, mutations in epigenetic regulators and RNA splicing genes were found to co-exist with driver mutations and to play critical roles in the disease progression of MPNs. Currently, evaluations of these gene mutations are essential for the diagnosis of MPNs, and are also necessary for estimating the clinical course and the risk of disease progression. Guidelines for the management of MPNs were based on the results of large clinical trials. Furthermore, recent advancements in understanding the pathogenesis of MPNs are anticipated to promote the development of MPN-targeted therapies such as JAK2 inhibitors. Clinical trials for patients with PMF and PV have confirmed the efficacies of JAK2 inhibitors.

Individualizing Care for Patients With Myeloproliferative Neoplasms: Integrating Genetics, Evolving Therapies, and Patient-Specific Disease Burden.

Individualized medicine is important for patients with myeloproliferative neoplasms (MPNs), including essential thrombocythemia, polycythemia vera, and myelofibrosis, which are heterogeneous in terms of genetic mutation profile, prognosis, disease burden, and symptoms. Status of MPN driver mutations in JAK2, CALR, and MPL (or lack of one of these mutations) and other myeloid mutations (ASXL1, SRSF2, CBL, and IDH1/2, among others) affects diagnosis and prognosis. Management begins with estimating the prognosis, disease burden including MPN symptoms, and prevention of vascular events. Allogeneic stem cell transplantation is the definitive therapy in a subset of patients with myelofibrosis, the majority of whom receive JAK inhibition with ruxolitinib to relieve splenomegaly and symptoms and to prolong survival. Ruxolitinib is now a second-line therapy in polycythemia vera, with pegylated interferon being evaluated as a potential front-line therapy compared with hydroxyurea. The therapeutic landscape is evolving to include new JAK inhibitors, which may affect cytopenias (pacritinib and momelotinib), combination therapies including ruxolitinib, and novel targets such as pentraxin and telomerase. Assessing the therapeutic efficacy (including symptom impact) and toxicity of these new approaches is necessary to determine longitudinal management of MPNs in clinical practice and is a key component of "individualizing" care for patients with MPNs.