Myeloproliferative neoplasm

Myeloproliferative Neoplasm

The myeloproliferative neoplasms (MPNs), previously myeloproliferative diseases (MPDs), are a group of diseases of the bone marrow in which excess cells are produced. They are related to and may evolve into, myelodysplastic syndrome and acute myeloid leukemia, although the myeloproliferative diseases, on the whole, have a much better prognosis than these conditions. The concept of myeloproliferative disease was first proposed in 1951 by the hematologist William Dameshek. In the most recent World Health Organization classification of hematologic malignancies, this group of diseases was renamed from “myeloproliferative diseases” to “myeloproliferative neoplasms”. This reflects the underlying clonal genetic changes that are a salient feature of this group of disease.
Chronic myeloproliferative disorders are a group of slow-growing blood cancers in which the bone marrow makes too many abnormal red blood cells, white blood cells, or platelets, which accumulate in the blood. The type of myeloproliferative disorder is based on whether too many red blood cells, white blood cells, or platelets are being made. Sometimes the body will make too many of more than one type of blood cell, but usually, one type of blood cell is affected more than the others.

There are 6 types of chronic myeloproliferative disorders: chronic myelogenous leukemia (CML), polycythemia vera, primary myelofibrosis (also called chronic idiopathic myelofibrosis), essential thrombocythemia, chronic neutrophilic leukemia, and chronic eosinophilic leukemia. Chronic myeloproliferative disorders sometimes become acute leukemia, in which too many abnormal white blood cells are made.
The increased numbers of blood cells may not cause any symptoms, but a number of medical problems or symptoms may occur. The risk of thrombosis is increased in some types of MPN.

Causes

All MPNs arise from precursors of the myeloid lineages in the bone marrow. The lymphoid lineage may produce similar diseases, lymphoproliferative disorders (acute lymphoblastic leukemia, lymphomas, chronic lymphocytic leukemia, and multiple myeloma).

Most Philadelphia chromosome negative cases have an activating JAK2 or MPL mutation. Mutations in CALR have been found in the majority of JAK2 and MPL-negative essential thrombocythemia and myelofibrosis. In 2005, the discovery of the JAK2V617F mutation provided the first evidence that a fraction of persons with these disorders has common molecular pathogenesis. Patients with JAK2V617F-negative polycythemia vera are instead positive for another class of activating JAK2 mutations – the JAK2 exon 12 mutations.

A subset may additionally have mutations in the genes LNK, CBL, TET2, ASXL1, IDH, IKZF1 or EZH2; the pathogenetic contribution of these mutations is being studied.

Symptoms

Signs that you have one of these disorders include:

Anemia (you don’t have enough red blood cells to carry oxygen)
Shortness of breath
Pale skin
Weakness and fatigue
Lack of appetite
Bleeding in excess (even when you get a minor cut)
Sinus infections
Skin infections
Urinary tract infections (UTIs)
Headaches
Fatigue
Bruising easily
Night Sweats
Fevers
Petechiae (tiny red spots under your skin)

Diagnosis

In the early stages of MPD, many people don’t have any symptoms. This makes it a challenge to diagnose. Any signs that do show up are often thought to be other, more common health problems.

You may need to see a doctor who specializes in MPD to be diagnosed. Blood tests will be ordered to get more details about your health. To confirm the diagnosis, a bone marrow biopsy is often done.

To do this, a hollow needle will be put into your hipbone or breastbone. Then a sample of blood, bone marrow or bone will be removed and sent to a lab. There, it can be checked under a microscope to look for cancer cells.

Treatment

The resources below provide information about treatment options for this condition. If you have questions about which treatment is right for you, talk to your healthcare professional.

Management Guidelines
The NORD Physician Guide for Chronic myeloproliferative disorders was developed as a free service of the National Organization for Rare Disorders (NORD) and it’s medical advisors. The guides provide a resource for clinicians about specific rare disorders to facilitate diagnosis and treatment of their patients with this condition.

FDA-Approved Treatments
The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for the treatment of this condition. Learn more orphan products.
Imatinib mesylate (Brand name: Gleevec®) – Manufactured by Novartis Pharmaceuticals Corp.
FDA-approved indication: Treatment of adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with PDGFR (platelet-derived growth factor receptor)
National Library of Medicine Drug Information Portal
There is presently no known cure for rumination. Proton pump inhibitors and other medications have been used to little or no effect.[14] Treatment is different for infants and the mentally handicapped than for adults and adolescents of normal intelligence. Among infants and the mentally handicapped, behavioral and mild aversion training has been shown to cause improvement in most cases.[15] Aversion training involves associating ruminating behavior with negative results and rewarding good behavior and eating. Placing a sour or bitter taste on the tongue when the individual begins the movements or breathing patterns typical of his or her ruminating behavior is the generally accepted method for aversion training, although some older studies advocate the use of pinching.[citation needed] In patients of normal intelligence, rumination is not an intentional behavior and is habitually reversed using diaphragmatic breathing to counter the urge to regurgitate. Alongside reassurance, explanation and habit reversal, patients are shown how to breathe using their diaphragms prior to and during the normal rumination period. A similar breathing pattern can be used to prevent normal vomiting. Breathing in this method works by physically preventing the abdominal contractions required to expel stomach contents.

Supportive therapy and diaphragmatic breathing have shown to cause improvement in 56% of cases, and total cessation of symptoms in an additional 30% in one study of 54 adolescent patients who were followed up 10 months after initial treatments. Patients who successfully use the technique often notice an immediate change in health for the better. Individuals who have had bulimia or who intentionally induced vomiting in the past have a reduced chance for improvement due to the reinforced behavior. The technique is not used with infants or young children due to the complex timing and concentration required for it to be successful. Most infants grow out of the disorder within a year or with aversive training.
Diagnosis
Depending on the nature of the myeloproliferative neoplasm, diagnostic tests may include red cell mass determination (for polycythemia), bone marrow aspirate and trephine biopsy, arterial oxygen saturation and carboxyhaemoglobin level, neutrophil alkaline phosphatase level, vitamin B12 (or B12 binding capacity), serum urate[12] or direct sequencing of the patient’s DNA.

According to the WHO Classification of Hematopoietic and Lymphoid Neoplasms 2008, myeloproliferative neoplasms are divided into categories by diagnostic characteristics as follows:

Chronic myeloid leukemia
Chronic myeloid leukemia (CML) with the defining translocation t(9;22); Philadelphia chromosome

Essential thrombocythemia
Essential thrombocythemia (ET) is associated with the JAK2 V617F mutation in up to 55% of cases and with an MPL (thrombopoietin receptor) mutation in up to 5% of cases:

Cellular phase – increased large megakaryocytes with fibrosis and little increase in other bone marrow elements
Fibrotic phase – collagenous fibrosis with lack of marrow elements
These disorders are still being revised according to more specific genetic mutations and how often patients end in a fibrotic marrow event.

Polycythemia Vera
Polycythemia vera (PV) is associated most often with the JAK2 V617F mutation in greater than 95% of cases, whereas the remainder has a JAK2 exon 12 mutations:

Cellular phase – increased megakaryocytes which cluster, reticulin fibrosis, later trichrome fibrosis, and increased myeloid and erythroid precursors
Fibrotic phase – collagenous fibrosis with lack of marrow elements
Primary myelofibrosis
Primary myelofibrosis (PMF) is associated with the JAK2V617F mutation in up to 50% of cases, the JAK2 exon 12 mutations in 1-2% of cases, and the MPL (thrombopoietin receptor) mutation in up to 5% of cases:

Prefibrotic/cellular phase – increased, small and atypical megakaryocytes which cluster, reticulin fibrosis, later trichrome (collagenous) fibrosis, and increased myeloid precursors
Fibrotic phase – collagenous fibrosis with lack of marrow elements
Treatment
While investigational drug therapies exist, no curative drug treatment exists for any of the MPDs. The goal of treatment for ET and PV is the prevention of thrombohemorrhagic complications. The goal of treatment for MF is the amelioration of anemia, splenomegaly, and other symptoms. Low-dose aspirin is effective in PV and ET. Tyrosine kinase inhibitors like imatinib have improved the prognosis of CML patients to near-normal life expectancy.

Recently, a JAK2 inhibitor, namely ruxolitinib, has been approved for use in primary myelofibrosis. Trials of these inhibitors are in progress for the treatment of the other myeloproliferative neoplasms.