scholarly journals Aktualitások a primer myelofibrosis ellátásában

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.

scholarly journals THE JAK2V617F POINT MUTATION INCREASES THE OSTEOCLAST FORMING ABILITY OF MONOCYTES IN PATIENTS WITH CHRONIC MYELOPROLIFERATIVE NEOPLASMS AND MAKES THEIR OSTEOCLASTS MORE SUSCEPTIBLE TO JAK2 INHIBITION

2018 ◽  
Vol 10 ◽  
pp. e2018058
Author(s):  
Emmanouil Spanoudakis ◽  
Menelaos Papoutselis ◽  
Ioanna Bazntiara ◽  
Eleftheria Lamprianidou ◽  
Xrisa Kordella ◽  
...  
Keyword(s):  
Point Mutation ◽  
Genomic Dna ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Cellular Level ◽  
Hemopoietic Stem Cell ◽  
Jak2 Inhibitor ◽  
Chronic Myeloproliferative Neoplasms ◽  
Cell Niche ◽  
Jak2 Inhibition

JAK2V617F is a gain of function point mutation that occurs in Myeloproliferative Neoplasm (MPN) patients and deranges their hemopoiesis at cellular level. We speculate that hyperfunctioning JAK2 can modify osteoclast (OCL) homeostasis in MPN patients. We studied 18 newly diagnosed MPN patients and four age-matched normal donors (ND). Osteoclast forming assays started from selected monocytes also and under titrated concentrations of the JAK2 Inhibitor AG-490 (Tyrphostin). Genomic DNA was extracted from the formed osteoclasts, and the JAK2V617F/JAK2WT genomic DNA ratio was calculated. OCLs formed from monocytes derived from heterozygous (Het) for the JAK2V617F mutation MPN patients, were three times more compared to those from JAK2 wild type (WT) MPN patients (p=0,05) and from ND as well (p=0,03). The ratio of JAK2V617F/JAK2WT genomic DNA was increased in OCLs compared to the input monocyte cells showing a survival advantage of the mutated clone. In comparison to ND and JAK2 WT MPN patients, OCLs from patients JAK2V617F (Het) were more susceptible to JAK2 inhibition. These alterations in osteoclast homeostasis, attributed to mutated JAK2, can deregulate the hemopoietic stem cell niche in MPN patients.

scholarly journals What are the current treatment approaches for patients with polycythemia vera and essential thrombocythemia?

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 480-488 ◽  
Author(s):  
Alessandro M. Vannucchi ◽  
Paola Guglielmelli
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
State Of The Art ◽  
Myeloproliferative Neoplasms ◽  
Symptom Burden ◽  
Current Treatment ◽  
Interferon Α ◽  
Jak2 Inhibitor ◽  
Chronic Myeloproliferative Neoplasms

Abstract Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms that are characterized by thrombohemorrhagic complications, symptom burden, and impaired survival mainly due to thrombosis, progression to myelofibrosis, and transformation to acute leukemia. In this manuscript, we will review the most recent changes in diagnostic criteria, the improvements in risk stratification, and the “state of the art” in the daily management of these disorders. The role of conventional therapies and novel agents, interferon α and the JAK2 inhibitor ruxolitinib, is critically discussed based on the results of a few basic randomized clinical studies. Several unmet needs remain, above all, the lack of a curative approach that might overcome the still burdensome morbidity and mortality of these hematologic neoplasms, as well as the toxicities associated with therapeutic agents.

scholarly journals Combination approach to diagnosis and treatment of an elderly patient with chronic Ph-negative myeloproliferative neoplasm and concomitant surgical pathology. Clinical observation

MD-Onco ◽  
2021 ◽  
Vol 1 (1) ◽  
pp. 61-65
Author(s):  
Yu. E. Ryabukhina ◽  
P. A. Zeynalova ◽  
O. I. Timofeeva ◽  
F. M. Abbasbeyli ◽  
T. V. Ponomarev ◽  
...  
Keyword(s):  
Elderly Patient ◽  
Essential Thrombocythemia ◽  
Early Stage ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Left Femur ◽  
Hematopoietic Stem ◽  
Chronic Myeloproliferative Neoplasms

Chronic myeloproliferative neoplasms (CMPN), Ph-negative, are of clonal nature, develop on the level of hematopoietic stem cell and are characterized by proliferation of one or more hematopoietic pathways. Currently, the group of Ph-negative CMPN includes essential thrombocythemia, primary myelofibrosis, polycythemia vera, myeloproliferative neoplasm unclassifiable.Identification of mutations in the Jak2 (V617F), CALR, and MPL genes extended understanding of biological features of Ph-negative CMPN and improved differential diagnosis of myeloid neoplasms. Nonetheless, clinical practice still encounters difficulties in clear separation between such disorders as primary myelofibrosis, early-stage and transformation of essential thrombocythemia into myelofibrosis with high thrombocytosis. Thrombocytosis is one of the main risk factors for thromboembolic complications, especially in elderly people.A clinical case of an elderly patient with fracture of the left femur developed in the context of Ph-negative CMPN (myelofibrosis) with high level of thrombocytosis is presented which in combination with enforced long-term immobilization and presence of additional risk created danger of thrombosis and hemorrhage during surgery and in the postoperative period.

scholarly journals CHRONIC MYELOPROLIFERATIVE NEOPLASMS: A COLLABORATIVE APPROACH

2010 ◽  
Vol 2 (2) ◽  
pp. e2010017
Author(s):  
Lisa Pieri ◽  
Paola Guglielmelli ◽  
Alessandro Maria Vannucchi
Keyword(s):  
Acute Leukemia ◽  
Clinical Course ◽  
Myeloproliferative Neoplasms ◽  
Clinical Manifestations ◽  
Primary Myelofibrosis ◽  
The Other ◽  
Collaborative Approach ◽  
Chronic Myeloproliferative Neoplasms ◽  
Key Issues ◽  
Oriented Approach

The classic chronic myeloproliferative neoplasms (MPN) include different entities that pose significant challenges for their optimal diagnosis, treatment and overall management. Polycythemia Vera and Essential Thrombocythemia are the most common among chronic myeloproliferative neoplasms (MPNs); major causes of morbidity and mortality are represented by arterial and venous thrombosis, as well as evolution to myelofibrosis or transformation to acute leukemia. However, survival is only minimally affected. Therapy aims at reducing the rate of thrombosis without increasing the risk of hematologic transformation which could be caused by exposure to cytotoxic drugs. On the other hand, survival is significantly reduced in primary myelofibrosis, and the clinical manifestations may be disabling. In the absence of therapies with the potential of curing the disease, a careful risk-oriented approach is employed for stratifying patients to the most appropriate, currently available, therapeutic options. In this brief review, we will discuss some of the key issues that can arise along the clinical course of MPNs and require an integrated, strictly patient-oriented, approach.

Novel, Potent and Selective JAK2 Inhibitors.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3777-3777
Author(s):  
Thomas Radimerski ◽  
Fabienne Baffert ◽  
Catherine H. Regnier ◽  
Alain De Pover ◽  
Carole Pissot ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Mechanistic Model ◽  
Leukemic Cell ◽  
Primary Myelofibrosis ◽  
Myeloproliferative Disorders ◽  
Amino Acid Position ◽  
Chronic Myeloproliferative Neoplasms ◽  
Promising Target ◽  
Potent Inhibition

Abstract Abstract 3777 Poster Board III-713 The recent discovery of an acquired activating point mutation in JAK2, substituting valine at amino acid position 617 for phenylalanine, has greatly improved our understanding of the molecular mechanism underlying chronic myeloproliferative neoplasms. Strikingly, the JAK2V617F mutation is found in nearly all patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia and from primary myelofibrosis. Thus, JAK2 represents a promising target for the treatment of myeloproliferative disorders and considerable efforts are ongoing to discover and develop inhibitors of the kinase. Here, we report potent inhibition of JAK2V617F and JAK2 wild type enzymes by novel small molecule inhibitors, which act in an ATP-competitive manner. The profile of a lead compound from this class will be presented that displays more than twenty-fold selectivity towards JAK2 within the JAK family, as well as excellent selectivity in broader kinase profiling. The compound blunts constitutive STAT5 phosphorylation in JAK2V617F-bearing cells, with concomitant suppression of cell proliferation and induction of apoptosis. In vivo, the inhibitor exhibited good oral bioavailability and is efficacious in suppressing leukemic cell spreading and splenomegaly in a Ba/F3 JAK2V617F cell-driven mouse mechanistic model as well as polycythemia and extramedullary erythropoiesis in mouse and rat models. Disclosures: Radimerski: Novartis: Employment, Equity Ownership. Baffert:Novartis: Employment. Regnier:Novartis: Employment. De Pover:Novartis: Employment. Pissot:Novartis: Employment. Gerspacher:Novartis: Employment. Brueggen:Novartis: Employment. Tavares:Novartis: Employment. Blasco:Novartis: Employment. Ledieu:Novartis: Employment. Nolan:Novartis: Employment. Ruetz:Novartis: Employment. Chene:Novartis: Employment. Erdmann:Novartis: Employment. Drueckes:Novartis: Employment. Furet:Novartis: Employment. Lang:Novartis: Employment. Trappe:Novartis: Employment. Vangrevelinghe:Novartis: Employment. Wartmann:Novartis: Employment. Hofmann:Novartis: Employment.

scholarly journals Bone marrow megakaryocytic activation predicts fibrotic evolution of Philadelphia-negative myeloproliferative neoplasms.

Haematologica ◽  
2020 ◽  
pp. 0-0
Author(s):  
Mattia Schino ◽  
Vincenzo Fiorentino ◽  
Elena Rossi ◽  
Silvia Betti ◽  
Monica Di Cecca ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myeloproliferative Neoplasms ◽  
Rapid Evolution ◽  
Progression Free Survival ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Serum Levels ◽  
Chronic Myeloproliferative Neoplasms ◽  
Calr Mutations ◽  
Wbc Count

Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) have been traditionally considered as indistinctly slowly progressing conditions; recent evidence proves that a subset of cases have a rapid evolution, so that MPNs’ prognosis needs to be personalized. We identified a new morphological parameter, defined as Megakaryocytic Activation (M-ACT) based on the coexistence of megakaryocytic emperipolesis, megakaryocytes (MK) clusters formation and evidence of arrangement of collagen fibers around the perimeter of MK. We retrospectively analyzed the bone marrow biopsy of two MPNs cohorts of patients with polycythemia (PV) (n=64) and non-PV patients [including essential thrombocythemia (ET), and early/prefibrotic primary myelofibrosis (PMF)] (n=222). M-ACT showed a significant correlation with splenomegaly, white blood cell (WBC) count, and LDH serum levels in both groups, with JAK2 V617F allele burden in PV patients, and with CALR mutations, and platelet count in non-PV patients. Progression-free survival, defined as PV-to-secondary MF progression and non-PV-to-overt PMF, was worse in both PV and early/prefibrotic PMF patients with M-ACT in comparison to those without M-ACT (P<.0001). Interestingly, M-ACT was not found in the subgroup of ET patients. In conclusion, M-ACT can be helpful in the differential diagnosis of MPNs and can represent a new morphologic parameter with a predictive value for progression of MPNs.

JAK2 Inhibitor Therapy in Chronic Myeloproliferative Neoplasms Ph(-): Hematologic, Clinical and Molecular Responses

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5059-5059
Author(s):  
Ana Esther Kerguelen Fuentes ◽  
Dolores Hernández-Maraver ◽  
Miguel Angel ◽  
Canales Albendea ◽  
Ana Rodriguez de la Rua
Keyword(s):  
Clinical Response ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Molecular Response ◽  
Spleen Size ◽  
Molecular Responses ◽  
Allele Burden ◽  
Jak2 Inhibitor ◽  
Chronic Myeloproliferative Neoplasms ◽  
Jak2 Inhibitors

Abstract Abstract 5059 JAK2 inhibitors are known to improve symptoms, to control myeloproliferation and to reduce splenomegaly in patients diagnosed with chronic myeloproliferative neoplasms (MPNs)Ph(-). However their ability to decrease the allele burden and achieve molecular responses is controversial. Objective: To evaluate hematologic, clinical and molecular responses according to the criteria of the European LeukemiaNet and European Myelofibrosis Network in 13 patients treated with JAK2 inhibitors. Material and Methods: We performed a prospective study in the Haematology Service of the Hospital La Pazbetween 1987 and 2012 in 13 patients diagnosed with NMP Ph (-) and treated with of JAK2 inhibitors: 5 secondary mylofibrosis (SFM)to homozygous polycythemia vera JAK (+), 4 SFM to essential thrombocythemias JAK (-), 2 primary myelofibrosis (one JAK (-) and one heterozygous JAK (+)) and 2 homozygous PV JAK (+) resistant to hydrea. The RT-PCR was performed at 6 or 12 months after the first determination of the allelic burden. Median follow-up was 3 months (1 – 15). A) Hematologic Response (HR): 3/5 SFM to PV(1)/TE JAK(-)(2) reached HR at 3 months of initiation of JAK2 inhibitor to 20mg/day. Molecular and clinical response were not evaluated. B) Clinical Response: Three patients had a reduction in the spleen size. Only one patient in the SFM group had a reduction in the spleen size (18 cm before the drug was commenced to 13. 7 cm) and the allele burden decrease from 55% to 23% after 5 months of therapy with JAK2 inhibitor at 25mg/12h (increase of 5mg/12h after 15 days of initiation of medication). 2/3 MFS to TE JAK(-) had a reduction from 15, 3 cm before the drug was commenced to 9 cm after 3 months of therapy with JAK2 inhibitor at 20 mg/12h. 3/3 MFP JAK(-) had a 6cm reduction in spleen size. Twenty cm splenomegaly was documented before starting JAK2 inhibitor to 15 mg/day. C) Molecular Response: 2/5 SFM to PV decreased the previous allele burden value. One patient decreased by 25% the previous allele burden value (99. 28%) at 6 months of JAK2 inhibitor. Second patient decreased by 13% the previous allele burden value (55%) at 6 months of starting JAK2 inhibitor to 25 mg/day. In 1/2 PV, the previous allele burden value (93. 17%) decreased by 11. 4% at 6 months of starting JAK2 inhibitor at 100mg/24h. D) Lack of response and disease progression: One patient with SMF secondary to JAK 2 (-) ET had dose reductions from 20 mg twice a day secondary to grade IV thrombocytopenia and renal toxicity. Patient finally developed acute leukemia. Conclusions: Our study confirms that JAK2 inhibitors reduce splenomegaly in MPNs JAK(-)and JAK(+). Prospective studies with an adequate sample size are necessary to demonstrate whether splenomegaly and symptom reductions achieved with inhibition of JAK2 could be associated to decrease the allele burden and achieve molecular responses in MPNs JAK(+). Disclosures: No relevant conflicts of interest to declare.

scholarly journals Acute Myeloid Leukemia Evolving from JAK 2-Positive Primary Myelofibrosis and Concomitant CD5-Negative Mantle Cell Lymphoma: A Case Report and Review of the Literature

2012 ◽  
Vol 2012 ◽  
pp. 1-6
Author(s):  
Diana O. Treaba ◽  
Salwa Khedr ◽  
Shamlal Mangray ◽  
Cynthia Jackson ◽  
Jorge J. Castillo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cell Lymphoma ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Chronic Myeloproliferative Neoplasms ◽  
Mantle Cell ◽  
Lymphoid Aggregates ◽  
Acute Myeloid

Primary myelofibrosis (formerly known as chronic idiopathic myelofibrosis), has the lowest incidence amongst the chronic myeloproliferative neoplasms and is characterized by a rather short median survival and a risk of progression to acute myeloid leukemia (AML) noted in a small subset of the cases, usually as a terminal event. As observed with other chronic myeloproliferative neoplasms, the bone marrow biopsy may harbor small lymphoid aggregates, often assumed reactive in nature. In our paper, we present a 70-year-old Caucasian male who was diagnosed with primary myelofibrosis, and after 8 years of followup and therapy developed an AML. The small lymphoid aggregates noted in his bone marrow were neoplastic in nature and represented bone marrow involvement by a CD5-negative mantle cell lymphoma (MCL) that presented without any associated lymphadenopathy. We reviewed the English medical literature to identify a single case report of simultaneous association of AML and a MCL in the bone marrow. The unusual association presented here suggests an increase in observer awareness to apparently benign lymphoid aggregates in chronic myeloproliferative neoplasms.

scholarly journals Újdonságok, aktualitások a polycythaemia vera diagnosztikájában és kezelésében

2016 ◽  
Vol 157 (44) ◽  
pp. 1743-1751
Author(s):  
Imelda Marton ◽  
Zsófia Simon ◽  
Zita Borbényi
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Polycythaemia Vera ◽  
Inadequate Response ◽  
Jak2 Inhibitor ◽  
Associated Symptoms ◽  
Night Sweats ◽  
Concentration Loss

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.

scholarly journals JAK inhibitors for myeloproliferative neoplasms: clarifying facts from myths

Blood ◽  
2012 ◽  
Vol 119 (12) ◽  
pp. 2721-2730 ◽  
Author(s):  
Ayalew Tefferi
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Best Supportive Care ◽  
Jak Inhibitors ◽  
Treatment Benefit ◽  
Jak2 Inhibitor ◽  
Select Group ◽  
Salutary Effect ◽  
Modifying Effect ◽  
Long Term Impact ◽  
Special Circumstances

Abstract On November 16, 2011, the Food and Drug Administration approved ruxolitinib (a JAK1 and JAK2 inhibitor) for use in the treatment of high and intermediate risk myelofibrosis. This is welcome news for those patients in whom such therapy is indicated and treatment benefit outweighs attendant risk. The question is who are these patients, what should they expect in terms of both short-term effects and long-term impact, and why would they choose ruxolitinib over other JAK inhibitors that are freely available for use in a research setting. Ruxolitinib and most other JAK inhibitors exert a salutary effect on constitutional symptoms and splenomegaly but have yet to produce histopathologic or cytogenetic remissions, reverse bone marrow fibrosis, or improve survival over best supportive care. Furthermore, the palliative value of JAK inhibitors is diminished by notable side effects, including anemia, thrombocytopenia, gastrointestinal disturbances, metabolic abnormalities, peripheral neuropathy, and hyperacute relapse of symptoms during treatment discontinuation. Therefore, risk-benefit balance favors use of currently available JAK inhibitors in only a select group of patients with myelofibrosis, and their potential value in polycythemia vera, outside of special circumstances (eg, intractable pruritus), is undermined by the absence of evidence for a disease-modifying effect and presence of arguably superior alternatives.

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