What Are Myeloproliferative Neoplasms?

The article will introduce the definition, pathology, classification, complications, and treatments of myeloproliferative neoplasm (MPN), helping everyone have a clearer understanding of what they are.

Introduction

Definition and overview of myeloproliferative neoplasms

Myeloid neoplasms are divided into acute myeloid leukaemia and chronic myeloid neoplasms according to the percentage of peripheral blood or bone marrow (BM) blasts. In simpler terms, this means these diseases are classified according to whether it is bone marrow or blood cells that are dividing uncontrollably. Myeloproliferative Neoplasms (MPN), a kind of chronic myeloid neoplasm, also called Philadelphia chromosome-negative myeloproliferative neoplasms, are rare clonal neoplastic disorders of the myeloid haematopoietic stem cells (HSC).¹ A disease characterised by clonal myeloid hyperplasia of stem cell origin with mutations in the genes JAK2, CALR, and MPL. Other disease features include leukocytosis (increase in white blood cell count), splenomegaly (an enlarged spleen), thrombosis (increased risk of clots), haemorrhage, microcirculatory symptoms, pruritus (itching), and transformation into more aggressive forms of the condition (known scientifically as leukemic or fibrotic transformation risk). 

According to the WHO classification, there are seven subtypes of MPN: chronic myeloid leukaemia (CML), chronic neutrophil leukaemia (CNL), polycythaemia vera (PV), primary myelofibrosis (PMF), and essential thrombocythemia Eosinophilic thrombocythemia (ET), Chronic Eosinophilic Leukaemia-Not Specified (CEL) and MPN, Not Classifiable (MPN-u). Among them, the three subtypes PV, PMF, and ET are associated with mutations in the genes encoding Janus kinase2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (TpoR/MPL).² 

Incidence and prevalence.

CML is common in older people, ranging from 65 to 74 years old. The median age of diagnosis is 65 years old, about 67.6% of patients have a 5-year survival rate, and the median age of death is about 77 years old. The median age of PV is 60 years old. More individuals assigned to males at birth (AMAB) are affected than individuals assigned to females at birth (AFAB), with a ratio of approximately 1.8:1. The estimated incidence of PV ranges from 0.4 to 2.8 per 100,000 per year. The median age of ET is 60 years, it is more common in people AFAB, with a ratio of 1:2. The estimated incidence of ET is 1 to 2.5/100,000/year, which increases with age. The median age at PMF diagnosis was 67 years. The incidence rate is 0.8 - 2.1/100,000/year. Other MPNs, such as CNL, CEL, and unclassified MPNs, are rare.³

Shared features of MPNs

JAK2 V617F mutation

Explanation of the JAK2 mutation

Specific genetic mutations in the programming of bone marrow and blood cells can lead to the development of these conditions. MPN somatic mutations are divided into "driver" mutations, JAK2, CALR, and MPL, and "other" mutations, ASXL1, SRSF2, U2AF1, etc. It is now widely accepted that driver mutations are critical to actually triggering MPNs, while 'other' mutations may contribute to disease progression and leukemic transformation. Among them, JAK2 mutations are found in about 70% of MPNs. Janus kinase genes are a class of protein kinases that phosphorylate signal transducer and activator of transcription (STAT) in the JAK-STAT pathway. Activation of this pathway leads to the pathogenesis of MPN, a somatic mutation involving the substitution of valine to phenylalanine at codon 617 within the pseudokinase domain (JAK2 V617F).⁴

Its role in MPNs

The JAK/STAT signalling cascade is activated in many metabolic functions, immune cell function and control of haematopoiesis. Including the activation of erythropoietin receptor (EpoR), thrombopoietin receptor (TpoR/MPL) and granulocyte colony-stimulating factor receptor (G-CSFR) to activate the pathway to drive cell proliferation, promote red blood cells, platelets and granulocytes generation. In addition, it is also closely related to functions such as metabolism, cell cycle control, apoptosis, DNA damage response and direct or indirect transcriptional control.¹

Diagnostic significance

Currently, for many myeloid neoplasms, morphological examination is still the main diagnostic method. MPN, on the other hand, had no morphological abnormalities. The vast majority of MPNs have JAK gene mutations. Therefore, detecting mutations based on JAK targets is the main detection method for MPN detection.

Bone marrow and blood findings

Examination of bone marrow and peripheral blood

Examination of bone marrow and peripheral blood is a crucial diagnostic step in evaluating and diagnosing myeloproliferative neoplasms (MPNs), a group of disorders characterised by the abnormal proliferation of blood cells in the bone marrow. Morphological assessment is used to determine the disease stage. Bone marrow (BM) aspiration is essential.⁵

Morphological features

In many MPNs, the bone marrow shows increased cellularity, meaning there are higher-than-normal cells. Some MPNs, such as essential thrombocythemia (ET) and primary myelofibrosis (PMF), are characterised by increased numbers of megakaryocytes (large bone marrow cells) and their precursors. It may also lead to intramedullary fibrosis in primary myelofibrosis (PMF).

Differences between MPNs and other conditions

The homeostasis of the bone marrow microenvironment associated with myeloproliferative neoplasms is disrupted at multiple levels, which jointly promote the proliferation, survival, and migration of mutant MPN-HSCs (haematopoietic stem cells). Elevated expression levels of JAK2 promote abnormal proliferation and survival of mutant HSCs while inhibiting the function of normal HSCs. JAK2 mutations also have enhanced osteoclast genesis, creating a rich osteoclast environment that favours the proliferation and survival of the MPN-associated mutant cell population.⁵

Classification of myeloproliferative neoplasms

Essential thrombocythemia (ET)

Definition and characteristics

ET is a haematological disorder characterised by the overproduction of certain blood cells, resulting in excess of platelets.

Pathophysiology and genetic mutations

There are three main risk factors for thrombosis: the history of thrombosis, JAK2/MPL mutation, and advanced age. Gene-associated mutations are mainly mutations or DNA variants of JAK2, CALR, or MPL. However, about 53% of ET patients are due to other genetic mutations, the most common being TET2, ASXL1, DNMT3A and SF3B1.⁶

Clinical presentation and symptoms

The main symptom is increasing platelets. In addition to clonal thrombocytosis, mild splenomegaly, leukocytosis, microvascular symptoms, thrombotic and hemorrhagic complications, increased incidence of early miscarriage, increased risk of leukemic transformation or fibrosis progression in varying proportions of ET patients.⁶

Diagnostic criteria

The World Health Organization (WHO) diagnostic requirements for ET are platelet count ≥ 450 × 10(9)/L, the presence of one of the three driver mutations of JAK/CALR/MPL or the absence of driver mutations, and the exclusion of other causes of thrombocytosis (reactivity and clonality), and assessment of bone marrow morphology.⁶

Treatment options and management

The treatment of ET is mainly Risk-adapted therapy. In this study, patients with ET were divided into 4 risk groups according to the 3 major risk factors for thrombosis. "Very low-risk", "low-risk", and "intermediate-risk" diseases are mainly treated with aspirin. The difference is the number of times the medicine is taken daily. Among them, "intermediate risk" can be considered cytoreductive therapy, but it is unnecessary. For the "high-risk" population of elderly patients with a history of thrombosis or JAK2/MPL mutations, in addition to repeated aspirin therapy, systemic anticoagulation is also required. There are also some treatment options for hydroxyurea intolerant or refractory patients, such as pegylated interferon-α (IFN-α) and busulfan.⁶

Polycythemia vera (PV)

Definition and characteristics

PV is a chronic haematological disorder involving the uncontrolled proliferation of myeloid blood cells within the bone marrow (also known as myeloproliferative), primarily affecting the erythroblast lineage. Usually presents as incidentally found elevated haemoglobin and haematocrit levels or after evaluation for thrombotic or bleeding events.⁷ Compared with other diseases, PV has more frequent thrombosis and a higher incidence of progression to myelofibrosis (MF).²

Pathophysiology and genetic mutations

95% of PV patients are due to JAK2 V617F (exon 14 of JAK2) gene mutation. The remaining 5% of PV patients are almost all caused by mutations in exon 12 of the JAK2 gene, mainly due to activation of the EpoR signalling pathway leading to polycythaemia.¹

Clinical presentation and symptoms

Pre-polycythaemia and overt polycythaemia manifested as normochromic erythrocytes, polycythaemia with elevated haemoglobin, leukocytosis, and thrombocytosis. In the post-polycythaemia stage of myelofibrosis, peripheral blood is characterised by leukocytosis, teardrop RBCs, and erythroid dysplasia.³

Diagnostic criteria

Untreated patients can only survive for 6 to 18 months, while adequate treatment can extend life expectancy to more than 10 years.⁷ The first step in diagnosing PV is JAK2 mutation screening. In order to improve the accuracy of diagnosis, it is generally recommended to measure the serum erythropoietin (EPO) level at the same time. It is estimated that the EPO level of more than 85% of PV patients is lower than normal. 

In addition, there is a bone marrow examination, which can be used to discover the symptoms of supraventricular tachycardia associated with JAK2 mutations. However, this symptom does not meet the WHO criteria for PV or other MPNs. The WHO classification system defines this presentation as MPN-U, which also includes occult PV cases.⁸

Treatment options and management

The primary treatment for PV is planned phlebotomy and daily low-dose aspirin therapy. For aspirin therapy, twice-daily dosing was more potent and effective in antiplatelet activity than once-daily dosing. Therefore, it should be taken in smaller, more frequent doses.⁸

For patients with low PV risk, phlebotomy may cause serious side effects, so treatment with cytoreductive drugs, such as peg-IFN (peginterferon alfa-2b). For high-risk PV patients, cytoreductive therapy is indicated in addition to phlebotomy and aspirin therapy.⁸ Hydroxyurea (HU) medicine shows good safety and efficacy in treating high-risk diseases. However, it should be noted that for patients under the age of 40, it is recommended to use hydroxyurea with caution because long-term use can cause leukaemia.⁷ Three drugs are currently considered for Hydroxyurea intolerant or resistant patients: pegylated IFN-α, ruxolitinib, and busulfan. The first choice is pegylated interferon.⁸

Primary myelofibrosis (PMF)

Definition and characteristics

PMF is a rare bone marrow disorder that disrupts the body's normal production of blood cells. Approximately 15% of patients with ET or PV develop a PMF-like phenotype over time, termed post-ET or post-PV MF. It is further subdivided into "pre-fibrotic" and "overt-fibrotic" PMF.⁴

Pathophysiology and genetic mutations

Myelofibrosis in PMF is often associated with JAK2, CALR, or MPL mutations. In addition, it is currently believed that abnormal cytokines produced by clonal cells and the host immune response led to PMF-related bone marrow stromal changes, ineffective erythropoiesis, cachexia, and systemic symptoms.⁴

Clinical presentation and symptoms

Clinical manifestations of PMF include severe anaemia, marked hepatosplenomegaly, systemic symptoms (e.g., fatigue, night sweats, fever), cachexia, bone pain, splenic infarction, pruritus, thrombosis, and haemorrhage. Ineffective erythropoiesis and hepatosplenic extramedullary haematopoiesis are the main causes of anaemia and organomegaly.⁴

Diagnostic criteria

The clinical manifestations and mutational features of profibrotic PMF are similar to those of ET, and careful morphological examination is required to differentiate the two. The megakaryocytes in ET were distributed in loose clusters, large in size and mature-like, while the megakaryocytes in PMF were distributed in tight clusters, abnormally mature, hyperchromatic nuclei, and irregularly folded. The distinction between ET and profibrotic PMF has prognostic significance.

Treatment options and management

The only current treatment that can prolong survival or potentially cure MF is allogeneic hematopoietic stem cell transplantation (AHSCT). However, this treatment method has certain risks, so it is best to listen to the doctor's careful consideration.

On the other hand, current pharmacological treatments for PMF are mostly palliative and have not been shown to be beneficial in modifying the natural history of the disease or prolonging survival. For example, JAK2 inhibitor therapy has not been shown to reverse myelofibrosis or induce complete or partial remission. Its value is limited to relieving symptoms and reducing spleen size, and it has some side effects.⁴

Complications and prognosis

Potential complications

Thrombosis and embolism

Arterial or venous thrombosis is the leading cause of morbidity and mortality in PV and ET. In addition, thrombus formation at atypical sites is also very likely. Compared with patients without MPN, the incidence of thrombosis was significantly increased in MPN patients, especially in the months after diagnosis.⁹

Bleeding disorders

Bleeding is also a problem in MPN patients, especially those with ET and PMF, with gastrointestinal and mucocutaneous sites being the most common sites. Analysis shows that thrombocytosis is one of the most important risk factors for bleeding.⁹

Transformation to acute leukaemia

Some MPN diseases, including chronic myeloid leukaemia (CML), polycythaemia vera (PV) and primary myelofibrosis (PMF), can turn into the acute stage or turn into leukaemia.¹⁰

Prognosis and Survival Rates

With the advent of tyrosine kinase inhibitors, the prognosis of CML has improved significantly. Different mutated genes have different prognoses. Patients with CALR exon 9 mutations had a better survival benefit than those with JAK2 or MPL mutations. Patients with ET have a good prognosis and a normal life expectancy. Older age (greater than 70 years), leukocytosis, and thrombosis are prognostic factors for poorer survival in PV patients.³

Ongoing research and emerging therapies

Current research initiatives and clinical trials

Since JAK gene mutations are present in almost all cases of MPN, JAK inhibitors are being investigated. For example, fedratinib, momelotinib, and pacritinib have undergone phase 3 clinical trials so far. In addition, fedratinib was recently approved for ruxolitinib-intolerant or resistant patients.

Many new drugs that inhibit other pathways are also currently under investigation. These inhibitors include PI3/AKT inhibitors (e.g., buparlisib), LSD1 (H3K4-specific histone demethylase) inhibitors (bomedemstat), BET inhibitors (e.g., CPI-0610), telomerase inhibitors agents (such as imelastat), Aurora kinase inhibitors (such as alisertib), BCL-2/BCL-X inhibitors.¹

Promising treatment avenues

In addition to inhibiting related pathways, there are also some other ways. PTG-300 (Rusfertide) is a hepcidin mimetic (controls hematocrit) whose mechanism of action involves limiting iron utilisation (i.e., negative iron regulation) to promote erythropoiesis. Haematocrit can be maintained by subcutaneous injection of a certain dose.⁸

Summary

Myeloproliferative neoplasm (MPN) is a chronic myeloid neoplasm. Its main feature is clonal myeloid hyperplasia of stem cell origin. Another hallmark is mutations in JAK2, CALR, and MPL. The vast majority of MPN diseases are caused by mutations in these three genes. MPN disease can be divided into many subtypes, among which ET, PV, and PME are three common subtypes. ET is mainly thrombocytosis. PV usually manifests as elevated haemoglobin and hematocrit levels, predisposing to thrombosis. PMF is a bone marrow disorder that disrupts the body's normal production of blood cells. MPN has several complications, such as blood clots, bleeding, and acute leukaemia. These complications increase the mortality rate of the disease.

In addition to morphological detection and bone marrow aspiration, the diagnostic method can be JAK gene detection for gene mutation. The treatment approach for MPN aims to limit the risk of thrombosis with antiplatelet agents, anticoagulants, therapeutic phlebectomy, and tumour debulking therapy, including hydroxyurea and interferon alfa; JAK inhibitors, including ruxolitinib An additional targeted therapy is offered. Hematopoietic stem cell transplantation is the only chance for a complete cure but is rarely indicated due to the associated significant toxicity and risk of death. Aspirin is a commonly used therapeutic drug, and it is very effective in suppressing the disease when taken in small amounts and many times. Several new drugs are in development, some of which are already in clinical trials. Some patients can improve the cure rate by participating in clinical trials.