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Post-Polycythemia Vera Myelofibrosis

Post-PV MF

Post-polycythemia vera myelofibrosis is a condition in which polycythemia vera, a disorder of excessive red cell production, triggers malignant transformation of hematopoietic stem cells and causes bone marrow scarring. The diagnosis is made based on laboratory findings and identification of JAK2 V617F mutation, a mutation confirmed in > 95% of cases. Palliative measures, transplantation, surgery and in the last several years, JAK inhibitors are used in therapy.

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Presentation

The clinical presentation may be either insidious or abrupt. Most common symptoms are night sweats, unexplained fever of > 37.5°C and weight loss of more than 10% in the last 6 months [9]. Clinical findings may reveal splenomegaly, which invariably occurs as a result of extramedullary hematopoiesis [8]. GI irritation, portal hypertension and profuse weakness that leads to decreased physical activity are also encountered and are substantial causes of morbidity [8].

Splenomegaly
  • Our present case suggests the potential risk of TLS development after ruxolitinib treatment, particularly in patients with massive splenomegaly. KEYWORDS: myelofibrosis; ruxolitinib; splenomegaly; tumor lysis syndrome[ncbi.nlm.nih.gov]
  • Presence of diabetes or another neoplasia was associated with higher ROS levels (p 0.05), splenomegaly, hepatomegaly, and peripheral blasts with lower HoloTC levels (p 0.005).[ncbi.nlm.nih.gov]
  • Clinical findings may reveal splenomegaly, which invariably occurs as a result of extramedullary hematopoiesis.[symptoma.com]
  • The risk factors for post-PV MF transformation included WBC count 13 x 10 9 /L, platelet count 550 10 9 /L and splenomegaly at diagnosis of PV.[ash.confex.com]
Palpable Spleen
  • spleen size ( P 0.002) in post-PV MF.[nature.com]
  • In a dose-escalation trial, treatment with pomalidomide resulted in   50 % reduction in palpable spleen size in 11 % (2/19) of patients [ 22 ]. The most recent study evaluated low-dose (0.5 mg/day) pomalidomide in 58 patients with MF.[jhoonline.biomedcentral.com]
Anemia
  • Myelofibrosis patients with ASXL1 lesions were more likely to have received anemia-directed therapy compared to those without lesions [15/26 (58%) versus 11/39 (23%); P 0.02].[ncbi.nlm.nih.gov]
  • Consequently, the severity of anemia implies worse outcomes, as does splenomegaly and findings of 10% blasts in peripheral blood or bone marrow.[symptoma.com]
  • Anemia (Hg 65 years at diagnosis of post-PV MF were identified as significant risk factors for poor survival of patients with post-PV MF.[ash.confex.com]
  • Clinically, patients present with symptoms related to thrombocytosis/leukocytosis, anemia and/or progressive splenomegaly.[springermedizin.de]
Fatigue
  • Seventy-one percent of all patients reported fatigue at least once during the intervention period (maximum grade 2) and 50% reported diarrhea (maximum grade 2). Table 2. All reported adverse events (AEs) listed in regard to prevalence.[haematologica.org]
  • Symptoms include heart attack, stroke, deep venous thrombosis, Headaches, lack of concentration and fatigue. The disease may be controlled by chemotherapy, transfusions, transplant and medications.[prnewswire.com]
  • As a result of profound proliferation of cells from the bone marrow, inflammatory cytokines concentrations are released causing constitutional symptoms such as fatigue, weakness, weight loss, night sweats and low-grade fever.[symptoma.com]
  • As a result of what’s happening in your body, you might notice symptoms including: Headaches Blurred vision Dizziness Tiredness and fatigue Sweating and night sweats Skin itchiness (also called pruritus) Erythromelalgia – an intense, burning pain and[canadianmpnnetwork.ca]
  • Some of the most common treatment side effects include: nausea dizziness pain or tingling in the hands and feet fatigue shortness of breath fever temporary hair loss Side effects usually go away after your treatment is completed.[healthline.com]
Weight Loss
  • loss and other constitutional symptoms.[symptoma.com]
  • With regard to symptoms, 43% reported fatigue and 29% reported weight loss during the six months prior to inclusion. Patients’ characteristics and laboratory data at baseline are listed in Table 1 . Table 1. Demographic data for included patients.[haematologica.org]
  • Other symptoms may include: Fatigue A general feeling of discomfort Difficulty breathing Weight loss Fever and night sweats Anemia Abnormal bleeding Patients with myelofibrosis have an increased risk of bleeding.[stanfordhealthcare.org]
  • Constitutional symptoms, such as night sweats, pruritus, weight loss and fever may be treated with Jakafi.[mpnresearchfoundation.org]
  • Other symptoms were night sweats (49%), bone pain (43%), fever (13%) weight loss (10%) and spleen pain (4%). What causes PV? The cause of PV is unknown.[canadianmpnnetwork.ca]
Fever
  • The main manifestations of the disease are constitutional complaints such as weakness, malaise, low-grade fever and weight loss, while splenomegaly, as a result of secondary hematopoiesis, is the main clinical finding.[symptoma.com]
  • Other symptoms may include: Fatigue A general feeling of discomfort Difficulty breathing Weight loss Fever and night sweats Anemia Abnormal bleeding Patients with myelofibrosis have an increased risk of bleeding.[stanfordhealthcare.org]
  • Constitutional symptoms, such as night sweats, pruritus, weight loss and fever may be treated with Jakafi.[mpnresearchfoundation.org]
  • Some of the most common treatment side effects include: nausea dizziness pain or tingling in the hands and feet fatigue shortness of breath fever temporary hair loss Side effects usually go away after your treatment is completed.[healthline.com]
  • MF patients can also suffer from debilitating constitutional symptoms, such as drenching night sweats, fatigue, severe itching (pruritus), abdominal pain, fever and bone pain.[geron.com]
Weakness
  • GI irritation, portal hypertension and profuse weakness that leads to decreased physical activity are also encountered and are substantial causes of morbidity. Patient history is the single most important part of the workup.[symptoma.com]
  • This causes symptoms such as anaemia, fatigue, weakness, and an enlarged spleen. The Jump clinical trial is an expanded access Phase 3b study of Jakavi for the treatment of MF. So far 2,233 MF patients have been involved with Jump.[patientworthy.com]
  • Side effects include fever, weakness, nausea, and vomiting which limits the useful of this medication. Busulfan for PV For patients that have failed hydroxyurea and/or interferon alpha, busulfan, a chemotherapeutic medication, may be used.[verywell.com]
  • Common symptoms include headaches, blurred vision, fatigue, weakness, dizziness, itchy skin and night sweats. Enlargement of the spleen (splenomegaly) is also common and occurs in around 75 per cent of cases.[leukaemia.org.au]
Dyspnea
  • Grade 3 AEs included anemia (n 3), neutrophil decrease (n 2), amylase increase (n 2), lipase increase (n 2), diarrhea (n 2), colitis (n 1), dyspnea (n 1), pneumonia (n 1), and other infections (n 2). The case of sepsis was the only grade 4 AE.[hematologytimes.com]
  • The four most frequent non-hematologic adverse reactions reported at a higher frequency in the Jakavi group than in the BAT group were diarrhea (14.5%), muscle spasm (11.8%), dizziness (11.8%) and dyspnea (10.0%) respectively.[newswire.ca]
  • Occasionally, increased red cell volume and viscosity cause weakness, headache, light-headedness, visual disturbances, fatigue, and dyspnea. Pruritus often occurs, particularly after a hot bath. The face may be red and the retinal veins engorged.[mpncanada.com]
Abdominal Pain
  • MF patients can also suffer from debilitating constitutional symptoms, such as drenching night sweats, fatigue, severe itching (pruritus), abdominal pain, fever and bone pain.[geron.com]
  • Enlargement of the spleen (splenomegaly) and liver (hepatomegaly) may cause severe abdominal pain.[mpninfo.org]
  • Splenectomy/Splenic Irradiation: If the main symptom is abdominal pain and discomfort due to a very large spleen, or if the need for blood and platelet transfusions is very high, or if there is no response to medical treatment, it may be beneficial to[mpnvoice.org.uk]
  • The most commonly reported side effects include headaches, fast or forceful heart beat (palpitations), diarrhoea, weakness, fluid retention, nausea, dizziness, abdominal pain and shortness of breath.[leukaemia.org.au]
Hepatomegaly
  • Presence of diabetes or another neoplasia was associated with higher ROS levels (p 0.05), splenomegaly, hepatomegaly, and peripheral blasts with lower HoloTC levels (p 0.005).[ncbi.nlm.nih.gov]
  • If hepatomegaly occurs, patients might also have variceal bleeding related to portal hypertension or ascites. B. History Part 2: Prevalence: The peak incidence of primary myelofibrosis (PMF) is between 50-70 years of age.[clinicaladvisor.com]
  • Hepatomegaly. Pallor. Petechiae and ecchymosis. Neutropenia may cause opportunistic infection - eg, oral thrush. Lymphadenopathy. Signs of portal hypertension. Gout.[patient.info]
  • Enlargement of the spleen (splenomegaly) and liver (hepatomegaly) may cause severe abdominal pain.[mpninfo.org]
  • In some cases the liver may also be enlarged.This is called hepatomegaly. Some people experience gout, which usually presents as a painful inflammation of the big toe or foot.[leukaemia.org.au]
Night Sweats
  • Most common symptoms are night sweats, unexplained fever of 37.5 C and weight loss of more than 10% in the last 6 months. Clinical findings may reveal splenomegaly, which invariably occurs as a result of extramedullary hematopoiesis.[symptoma.com]
  • Other symptoms may include: Fatigue A general feeling of discomfort Difficulty breathing Weight loss Fever and night sweats Anemia Abnormal bleeding Patients with myelofibrosis have an increased risk of bleeding.[stanfordhealthcare.org]
  • […] fatigue, fever, night sweats and weight loss.[mpnresearchfoundation.org]
  • Other symptoms were night sweats (49%), bone pain (43%), fever (13%) weight loss (10%) and spleen pain (4%). What causes PV? The cause of PV is unknown.[canadianmpnnetwork.ca]
  • MF patients can also suffer from debilitating constitutional symptoms, such as drenching night sweats, fatigue, severe itching (pruritus), abdominal pain, fever and bone pain.[geron.com]
Female Sterility
  • Highly effective contraception methods include: Total abstinence or Male partner or female sterilization or Combination of any two of the following (a b or a c, or b c): a. Use of oral, injected or implanted hormonal methods of contraception, b.[clinicaltrials.gov]
Amenorrhea
  • Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral[clinicaltrials.gov]

Workup

Patient history is the single most important part of the workup. A prior diagnosis of PV should definitely raise suspicion of post-PV myelofibrosis in the setting of constitutional symptoms. Erythrocytosis may develop in numerous physiological and pathological conditions (e.g. hypoxic states, various malignancies, use of erythropoietin, renal disease, etc). For this very reason, specific diagnostic criteria have been proposed [2] [3]:

  • Major criteria - Levels of hemoglobin > 18.5 g/dL in men and > 16.5 g/dL in women, indications of increased red cell volume (markedly increased hematocrit, elevated red cell mass greater than 25% above mean normal predicted value), or presence of V617F or other similar JAK mutations.
  • Minor criteria - EPO levels below normal values, endogenous production of erythroid colonies in vitro (in the absence of EPO), or hypercellularity and prominent proliferation of erythroid, granulocytic and megakaryocytic lineages shown on bone marrow biopsy (known as panmyelosis) [10].

To confirm PV, either two major and one minor or one major and two minor criteria are necessary and a 97% success rate is predicted with this criteria [3]. In addition to PV, moderate-to-severe fibrosis of the bone marrow (2–3 on 0–3 scale or grade 3–4 on 0–4 scale) is a diagnostic hallmark of post-PV MF, while clinical findings such as splenomegaly and constitutional symptoms further support these findings [9].

Treatment

Until recently, palliative care through splenectomy, radiotherapy and use of various drugs (hydroxyurea, Thalidomide alkylating agents) have neither relieved symptoms nor prevented complications. [8]. Allogeneic hematopoietic stem cell transplant has shown to be the only potentially curative mode of therapy for patients with any form of myelofibrosis, but numerous challenges are faced when opting for this procedure - presence of one or more comorbidities due to advanced age of patients, optimal timing and a very limited number of suitable donors [11]. Recent introduction of JAK inhibitors in clinical practice has dramatically reduced the severity of symptoms, as a 45% reduction rate in post-PV MF was achieved through the use of ruxolitinib, a JAK2 and JAK1 inhibitor [11]. Drugs such as tasocitinib, lestaurtinib, pacritinib and several others have shown to significantly reduce the activity of various growth factors and pro-inflammatory cytokines and are undergoing phased clinical trials. [11]. Namely, ruxolitinib and other JAK2 inhibitors are potent inducers of anemia and thrombocytopenia that may be life-threatening for patients who present with lower RBC and platelet counts, which is why careful evaluation must be conducted prior to their administration [11]. Unfortunately, studies have so far concluded that the use of JAK2 inhibitors does not prolong survival rates of patients in a significant manner, but further research is necessary to determine their optimal utilization [11].

Prognosis

Several reports have been published stating that less than 10% of patients progress to MF from PV [15], whereas a 15-year risk of PV progression to post-PV MF is around 6%, with an incidence rate of 5.1 per 1000 person years [6]. Other authors, however, suggest that the incidence rate of post-PV MF is up to 14% [15]. Although marked differences exist in patient outcomes, ranging from 1-10+ years [16], progressive hemoglobin and platelet reduction eventually develops in most cases and carries a poor prognosis, as median survival rates of 5.7-8 years are determined [6] [7]. Consequently, the severity of anemia implies worse outcomes, as does splenomegaly and findings of ≥ 10% blasts in peripheral blood or bone marrow [7] [16].

Etiology

PV belongs to the group of "BCR-ABL1-negative" myeloproliferative diseases (MPNs), together with essential thrombocythemia and primary myelofibrosis, which turned the attention to other etiologic mechanisms [11]. In the past decade, two key mutations of the JAK2 molecule on chromosome 9 have been identified - substitution of valine to phenylalanine at amino acid position 617 (V617F) and exon 12 mutations (seen only in about 2-3% of PV cases) [2] [4]. Although the vast majority of patients are heterozygous for JAK2V617F, homozygous mutations through a phenomenon of uniparental disomy have also been discovered in some individuals [11]. Although JAK2 mutations are a constitutive finding in post-PV MF, it is hypothesized that they are not the only factors involved in the pathogenesis and some other genetic events are presumably involved as well [11] [12].

Epidemiology

Large-scale European studies have established a prevalence of PV between 0.4-2.8 per 100,000 individuals per year, suggesting that it is rarely encountered in clinical practice [13]. Myelofibrosis (regardless of the underlying cause) has shown an even lower rate of occurrence: 0.1-1 per 100,000 individuals per year [13]. United States, on the other hand, has much higher prevalence rates of PV : 44-57 per 100,000 individuals. Unlike studies conducted in Europe, the rates of post-PV MF have been identified in the United States [5]. Namely, between 0.3-0.7 per 100,000 individuals develop this myeloproliferative disorder [5]. Most patients are either older adults or belong to the elderly population [6], supported by the fact that less than 20% of patients are < 50 years old [14]. Gender predilection is currently not determined. PV patients who are older than 60 years and have a history of previous thrombosis, as well as thrombocytosis are considered to be at greatest risk for development of myelofibrosis [3] [7], whereas a WBC count of > 15 × 109/L at the diagnosis of PV is a significant predictor of evolution of post-PV MF [6].

Sex distribution
Age distribution

Pathophysiology

Under physiological circumstances, the JAK-STAT signaling pathway is crucial for he development of various cell lineages and functions of the immune system. More specifically, JAK2 is an essential component of EPO, granulocyte-macrophage colony stimulating factor (GM-CSF), thrombopoietin, growth hormone and interleukins 3 and 5 signaling [11], whereas signal transducers and activators of transcription (STAT) are the next step of the signaling cascade, resulting in expression of genes that trigger proliferation, migration differentiation and angiogenesis of numerous lineages [11]. Additionally, numerous pro-inflammatory cytokines, such as IL-12, IL-1, IL-6 (in addition to IL-3 and 5), have shown to be influenced by the JAK/STAT pathway, which could explain why myelofibrosis patients in general are in a hypercatabolic state and thus trigger chronic weight loss and other constitutional symptoms [11]. The pathogenesis of post-PV MF starts with enhanced gene expression as a result of hypersensitivity of JAK2 to cytokine signaling [4] [11], inducing aberrant production of erythrocytes, megakaryocytes and granulocytes [6] Upregulated gene expression occurs due to phosphorylation of proteins and a gain-of-function mutation that creates a profoundly more active JAK/STAT signaling pathway, hematopoietic proliferation [11].

Prevention

Since myelofibrosis is considered to be a progression of PV, screening for JAK2 mutations may be of significant benefit in determining the possibility of post-PV MF [3]. Although much has been discovered in terms of pathogenesis, prevention of post-PV MF is currently not possible.

Summary

Myelofibrosis is considered to be a severe and life-threatening clonal hematopoietic stem cell malignancy that arises from primary hematologic diseases and secondary causes - essential thrombocytosis and polycythemia vera (PV), a disease primarily encountered in older patients (> 50 years) that is characterized by abnormal production of erythrocytes, platelets and granulocytes in the absence of an apparent physiologic stimulus [1] [2]. Until recently, the exact reason why PV can progress to myelofibrosis (now known as post-polycythemia vera myelofibrosis, or post-PV MF) was unknown, but studies have determined that mutations of janus kinase 2 (JAK2), a cytoplasmic signaling molecule, were identified in more than 95% of patients [3]. The V617F JAK mutation leads to hypersensitivity of bone marrow cells to erythropoietin (EPO) and several proliferative cytokines [4], leading to aberrant production of primarily erythrocytes, but also megakarocytes and granulocytes. Over time, constant stimulation of hematopoietic differentiation damages the bone marrow and causes extensive fibrosis, the hallmark of post-PV MF. Although it is considered to be a rare disease, with estimated prevalence rates of 0.3-0.7 per 100,000 individuals in the United States [5], early recognition is of vital importance in prolonging the life of the patient since survival rates range between 5-8 years from the time of diagnosis [6] [7]. The main manifestations of the disease are constitutional complaints such as weakness, malaise, low-grade fever and weight loss, while splenomegaly, as a result of secondary hematopoiesis [8], is the main clinical finding [9]. To make the diagnosis of post-PV MF, it is imperative to obtain a detailed patient history and confirm PV, followed by laboratory studies and bone marrow biopsy that will show panmyelosis [10]. Splenectomy, use of various immunomodulating drugs and palliative care have been used in these patients as main forms of therapy until the introduction of JAK inhibitors, which significantly reduce the burden of clinical symptoms [11]. Survival rates remain unchanged in these agents, however, and the only potentially curative procedure is allogeneic hematopoietic stem cell transplantation, but numerous risks (older age, co-morbidities, suitability of donors) impair its more frequent use [11]. Because myelofibrosis occurring on the grounds of PV may be fatal within several years, screening of at-risk patients for JAK2 mutations is advisable, so that early recognition of the disease may be possible [3].

Patient Information

Post-polycythemia vera myelofibrosis (post-PV MF) is a term that describes the evolution of polycythemia vera (a disorder of abnormal production of red and white blood cells, as well as platelets) into a malignant disease in which genetic mutations lead to profound stimulation of further cell production, ultimately causing scarring of the bone marrow. Until recently, the exact reason why this pathological event occurred was unknown. Now mutations of signaling molecules (JAK2) that stimulate cytokines and growth factors that promote cell production from the bone marrow have been identified in more than 95% of patients. This condition is most frequently diagnosed in older adults (> 60 years) and approximately 0.3-0.7 per 100,000 individuals develop post-PV MF in the United States. As a result of profound proliferation of cells from the bone marrow, inflammatory cytokines concentrations are released causing constitutional symptoms such as fatigue, weakness, weight loss, night sweats and low-grade fever. Additionally, an enlarged spleen is almost always observed, as it is over- worked destroying the abnormally elevated platelets and red blood cells. To make the diagnosis, it is imperative to obtain a detailed patient history and find out whether polycythemia vera was diagnosed in the past few decades based on the criteria defined for the disease. Treatment principles were initially directed toward palliative care, including removal of spleen, radiation and use of drugs that reduce inflammation and suppress the activity of the immune system, but because JAK2 mutations are discovered in more than 95% of patients, the group of JAK inhibitor drugs is becoming the mainstay of therapy. Despite the fact that stem cell transplantation may provide curative effects, elderly patients with multiple comorbidities may not be suitable for this procedure. The prognosis is currently not good, as median survival rates are between 5-8 years after diagnosis. Although the 10 and 15-year risk of PV progressing to myelofibrosis ranges between 5-14%, respectively, screening of all patients suffering from polycythemia vera for JAK mutations may be of significant benefit in long-term monitoring.

References

Article

  1. Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 18e. New York, NY: McGraw-Hill; 2012.
  2. Means RT. JAK2 V617F and the evolving paradigm of polycythemia vera. Korean J Hematol. 2010;45(2):90-94.
  3. Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA, et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood 2007;110:1092-1097.
  4. James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):1144-1148.
  5. Mehta J, Wang H, Iqbal SU, et al. Epidemiology of myeloproliferative neoplasms in the United States. Leuk Lymphoma 2014;55:595-600.
  6. Passamonti F, Rumi E, Caramella M, et al. A dynamic prognostic model to predict survival in post-polycythemia vera myelofibrosis. Blood 2008;111:3383–3387.
  7. Bai J, Ai L, Zhang L, et al. Incidence and risk factors for myelofibrotic transformation among 272 Chinese patients with JAK2-mutated polycythemia vera. Am J Hematol. September 2015; Sep 8.
  8. Randhawa J, Ostojic A, Vrhovac R, Atallah E, Verstovsek S. Splenomegaly in myelofibrosis—new options for therapy and the therapeutic potential of Janus kinase 2 inhibitors. J Hematol Oncol. 2012;5:43.
  9. Barosi G, Mesa RA, Thiele J, Cervantes F, Campbell PJ, Verstovsek S,et al. Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the international working group for myelofibrosis research and treatment. Leukemia. 2008;22:437–438.
  10. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. 2011;29(6):761-770.
  11. Sonbol MB, Firwana B, Zarzour A, et al. Comprehensive review of JAK inhibitors in myeloproliferative neoplasms. Ther Adv Hematol. 2013;4(1):15-35.
  12. Nussenzveig RH, Swierczek SI, Jelinek J, et al. Polycythemia vera is not initiated by JAK2V617F mutation. Exp Hematol. 2007;35:32–38.
  13. Moulard O, Mehta J, Fryzek J, et al. Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union. Eur J Haematol 2014;92:289-297.
  14. Beauverd Y, Alimam S, McLornan DP, Radia DH, Harrison CN. Disease characteristics and outcomes in younger adults with primary and secondary myelofibrosis. Br J Haematol. 2016; Jun 13.
  15. Cerquozzi S, Tefferi A. Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: a literature review of incidence and risk factors. Blood Cancer J. 2015;5:e366.
  16. Tam CS, Kantarjian H, Cortes J, et al. Dynamic model for predicting death within 12 months in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. J Clin Oncol. 2009;27(33):5587–5593.

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Last updated: 2018-06-21 17:30