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.
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].
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]:
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].
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].
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].
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].
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].
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].
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.
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].
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.