Myeloproliferative neoplasm

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Myeloproliferative neoplasm
Other namesMyeloproliferative diseases (MPDs)
Myelogram of person with a myeloproliferative disorder.png
Myelogram of someone with a myeloproliferative disorder.
Specialty Hematology and oncology

Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers in which excess red blood cells, white blood cells or platelets are produced in the bone marrow. Myelo refers to the bone marrow, proliferative describes the rapid growth of blood cells and neoplasm describes that growth as abnormal and uncontrolled.

Contents

The overproduction of blood cells is often associated with a somatic mutation, for example in the JAK2, CALR, TET2, and MPL gene markers.

In rare cases, some MPNs such as primary myelofibrosis may accelerate and turn into acute myeloid leukemia. [1]

Classification

MPNs are classified as blood cancers by most institutions and organizations. [2] In MPNs, the neoplasm (abnormal growth) starts out as benign and can later become malignant.

As of 2016, the World Health Organization lists the following subcategories of MPNs: [3]

Causes

MPNs arise when precursor cells (blast cells) of the myeloid lineages in the bone marrow develop somatic mutations which cause them to grow abnormally. There is a similar category of disease for the lymphoid lineage, the lymphoproliferative disorders acute lymphoblastic leukemia, lymphomas, chronic lymphocytic leukemia and multiple myeloma. [4] Genetics is believed to play a central role in the development of MPNs, specially in developing thromboembolic and bleeding complications. [5]

Diagnosis

People with MPNs might not have symptoms when their disease is first detected via blood tests. [6] 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 [7] or direct sequencing of the patient's DNA. [8] According to WHO diagnostic criteria published in 2016, myeloproliferative neoplasms are diagnosed as follows: [9]

Chronic myeloid leukemia

Chronic myeloid leukemia (CML) has a presence of the hallmark Philadelphia Chromosome (BCR-ABL1) mutation.

Chronic neutrophilic leukemia

Chronic neutrophilic leukemia (CNL) is characterized by a mutation in the CSF3R gene and an exclusion of other causes of neutrophilia.

Essential thrombocythemia

Essential thrombocythemia (ET) is diagnosed with a platelet count greater than 450 × 109/L and is associated with the JAK2 V617F mutation in up to 55% of cases [10] and with an MPL (thrombopoietin receptor) mutation in up to 5% of cases. [11] There should be no increase in reticulin fibers and the patient should not meet the criteria for other MPNs, in particular Pre-PMF.

Polycythemia vera

Polycythemia vera (PV) is associated most often with the JAK2 V617F mutation greater than 95% of cases, whereas the remainder has a JAK2 exon 12 mutations. High hemoglobin or hematocrit counts are required, as is a bone marrow examination showing "prominent erythroid, granulocytic and megakaryocytic proliferation with pleomorphic, mature megakaryocytes."

Prefibrotic/early primary myelofibrosis

Prefibrotic primary myelofibrosis (Pre-PMF) is typically associated with JAK2, CALR, or MPL mutations and shows reticulin fibrosis no greater than grade 1. Anemia, splenomegaly, LDH above the upper limits and leukocytosis are minor criteria. [12]

Overtly fibrotic myelofibrosis

Like pre-PMF, overt primary myelofibrosis is associated with JAK2, CALR, or MPL mutations. However, a bone marrow biopsy will show reticulin and/or collagen fibrosis with a grade 2 or 3. Anemia, splenomegaly, LDH above the upper limits and leukocytosis are minor criteria.

MPN-U

Patients with otherwise unexplained thrombosis and with neoplasms that cannot be classified in one of the other categories.

Treatment

No curative drug treatment exists for MPNs. [13] Hematopoietic stem cell transplantation can be a curative treatment for a small group of patients, however MPN treatment is typically focused on symptom control and myelosuppressive drugs to help control the production of blood cells.[ citation needed ]

The goal of treatment for ET and PV is prevention of thrombohemorrhagic complications. The goal of treatment for MF is 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. [14]

Recently, a JAK2 inhibitor, namely ruxolitinib, has been approved for use in primary myelofibrosis. [15] Trials of these inhibitors are in progress for the treatment of the other myeloproliferative neoplasms.

Incidence

Although considered rare diseases, incidence rates of MPNs are increasing, in some cases tripling. It is hypothesized that the increase may be related to improved diagnostic abilities from the identification of the JAK2 and other gene markers, as well as continued refinement of the WHO guidelines. [16]

There is wide variation in reported MPN incidence and prevalence worldwide, with a publication bias suspected for essential thrombocythemia and primary myelofibrosis. [17]

History

The concept of myeloproliferative disease was first proposed in 1951 by the hematologist William Dameshek. [18] The discovery of the association of MPNs with the JAK2 gene marker in 2005 and the CALR marker in 2013 improved the ability to classify MPNs. [19]

MPNs were classified as blood cancers by the World Health Organization in 2008. [20] Previously, they were known as myeloproliferative diseases (MPD).

In 2016, Mastocytosis was no longer classified as an MPN. [21]

Related Research Articles

<span class="mw-page-title-main">Eosinophilia</span> Excess number of eosinophil cells in the blood

Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 5×108/L (500/μL). Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 × 109/L (i.e. 1,500/μL). The hypereosinophilic syndrome is a sustained elevation in this count above 1.5 × 109/L (i.e. 1,500/μL) that is also associated with evidence of eosinophil-based tissue injury.

<span class="mw-page-title-main">Polycythemia vera</span> Overproduction of red blood cells by the bone marrow

In oncology, polycythemia vera (PV) is an uncommon myeloproliferative neoplasm in which the bone marrow makes too many red blood cells. The majority of cases are caused by mutations in the JAK2 gene, most commonly resulting in a single amino acid change in its protein product from valine to phenylalanine at position 617.

<span class="mw-page-title-main">Polycythemia</span> Laboratory diagnosis of high hemoglobin content in blood

Polycythemia is a laboratory finding in which the hematocrit and/or hemoglobin concentration are increased in the blood. Polycythemia is sometimes called erythrocytosis, and there is significant overlap in the two findings, but the terms are not the same: polycythemia describes any increase in hematocrit and/or hemoglobin, while erythrocytosis describes an increase specifically in the number of red blood cells in the blood.

<span class="mw-page-title-main">Philadelphia chromosome</span> Genetic abnormality in leukemia cancer cells

The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells. This chromosome is defective and unusually short because of reciprocal translocation, t(9;22)(q34;q11), of genetic material between chromosome 9 and chromosome 22, and contains a fusion gene called BCR-ABL1. This gene is the ABL1 gene of chromosome 9 juxtaposed onto the breakpoint cluster region BCR gene of chromosome 22, coding for a hybrid protein: a tyrosine kinase signaling protein that is "always on", causing the cell to divide uncontrollably by interrupting the stability of the genome and impairing various signaling pathways governing the cell cycle.

<span class="mw-page-title-main">Chronic myelogenous leukemia</span> Medical condition

Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which a proliferation of mature granulocytes and their precursors is found; characteristic increase in basophils is clinically relevant. It is a type of myeloproliferative neoplasm associated with a characteristic chromosomal translocation called the Philadelphia chromosome.

<span class="mw-page-title-main">Tumors of the hematopoietic and lymphoid tissues</span> Tumors that affect the blood, bone marrow, lymph, and lymphatic system

Tumors of the hematopoietic and lymphoid tissues or tumours of the haematopoietic and lymphoid tissues are tumors that affect the blood, bone marrow, lymph, and lymphatic system. Because these tissues are all intimately connected through both the circulatory system and the immune system, a disease affecting one will often affect the others as well, making aplasia, myeloproliferation and lymphoproliferation closely related and often overlapping problems. While uncommon in solid tumors, chromosomal translocations are a common cause of these diseases. This commonly leads to a different approach in diagnosis and treatment of hematological malignancies. Hematological malignancies are malignant neoplasms ("cancer"), and they are generally treated by specialists in hematology and/or oncology. In some centers "hematology/oncology" is a single subspecialty of internal medicine while in others they are considered separate divisions. Not all hematological disorders are malignant ("cancerous"); these other blood conditions may also be managed by a hematologist.

<span class="mw-page-title-main">Essential thrombocythemia</span> Overproduction of platelets in the bone marrow

In hematology, essential thrombocythemia (ET) is a rare chronic blood cancer characterised by the overproduction of platelets (thrombocytes) by megakaryocytes in the bone marrow. It may, albeit rarely, develop into acute myeloid leukemia or myelofibrosis. It is one of the blood cancers wherein the bone marrow produces too many white or red blood cells, or platelets.

Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is activation and growth of mutated cells in the bone marrow. This is most often associated with a somatic mutation in the JAK2, CALR, or MPL genes. In PMF, the bony aspects of bone marrow are remodeled in a process called osteosclerosis; in addition, fibroblast secrete collagen and reticulin proteins that are collectively referred to as (fibrosis). These two pathological processes compromise the normal function of bone marrow resulting in decreased production of blood cells such as erythrocytes, granulocytes and megakaryocytes, the latter cells responsible for the production of platelets.

<span class="mw-page-title-main">Anagrelide</span> Chemical compound

Anagrelide is a drug used for the treatment of essential thrombocytosis, or overproduction of blood platelets. It also has been used in the treatment of chronic myeloid leukemia.

<span class="mw-page-title-main">Chronic myelomonocytic leukemia</span> Medical condition

Chronic myelomonocytic leukemia (CMML) is a type of leukemia, which are cancers of the blood-forming cells of the bone marrow. In adults, blood cells are formed in the bone marrow, by a process that is known as haematopoiesis. In CMML, there are increased numbers of monocytes and immature blood cells (blasts) in the peripheral blood and bone marrow, as well as abnormal looking cells (dysplasia) in at least one type of blood cell.

Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm that features a persistent neutrophilia in peripheral blood, myeloid hyperplasia in bone marrow, hepatosplenomegaly, and the absence of the Philadelphia chromosome or a BCR/ABL fusion gene.

<span class="mw-page-title-main">Thrombopoietin receptor</span> Protein-coding gene in the species Homo sapiens

The thrombopoietin receptor also known as the myeloproliferative leukemia protein or CD110 is a protein that in humans is encoded by the MPL oncogene.

<span class="mw-page-title-main">Basophilia</span> Medical condition

Basophilia is the condition of having greater than 200 basophils/μL in the venous blood. Basophils are the least numerous of the myelogenous cells, and it is rare for their numbers to be abnormally high without changes to other blood components. Rather, basophilia is most often coupled with other white blood cell conditions such as eosinophilia, high levels of eosinophils in the blood. Basophils are easily identifiable by a blue coloration of the granules within each cell, marking them as granulocytes, in addition to segmented nuclei.

<span class="mw-page-title-main">Acute megakaryoblastic leukemia</span> Blood marrow cancer originating in megakaryoblast cells

Acute megakaryoblastic leukemia (AMKL) is life-threatening leukemia in which malignant megakaryoblasts proliferate abnormally and injure various tissues. Megakaryoblasts are the most immature precursor cells in a platelet-forming lineage; they mature to promegakaryocytes and, ultimately, megakaryocytes which cells shed membrane-enclosed particles, i.e. platelets, into the circulation. Platelets are critical for the normal clotting of blood. While malignant megakaryoblasts usually are the predominant proliferating and tissue-damaging cells, their similarly malignant descendants, promegakaryocytes and megakaryocytes, are variable contributors to the malignancy.

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<span class="mw-page-title-main">Fedratinib</span> Chemical compound

Fedratinib, sold under the brand name Inrebic, is an anti-cancer medication used to treat myeloproliferative diseases including myelofibrosis. It is used in the form of fedratinib hydrochloride capsules that are taken by mouth. It is a semi-selective inhibitor of Janus kinase 2 (JAK-2). It was approved by the FDA on 16 August 2019.

<span class="mw-page-title-main">Gandotinib</span> Chemical compound

Gandotinib (LY-2784544) is an experimental drug developed by Eli Lilly for treatment of cancer. It is a small molecule JAK2 inhibitor, with additional minor inhibition of STAT3.

Robert Kralovics is a Slovak born geneticist, working in the area of blood neoplasms.

Clonal hypereosinophilia, also termed primary hypereosinophilia or clonal eosinophilia, is a grouping of hematological disorders all of which are characterized by the development and growth of a pre-malignant or malignant population of eosinophils, a type of white blood cell that occupies the bone marrow, blood, and other tissues. This population consists of a clone of eosinophils, i.e. a group of genetically identical eosinophils derived from a sufficiently mutated ancestor cell.

Prefibrotic primary myelofibrosis (Pre-PMF) is a rare blood cancer, classified by the World Health Organization as a distinct type of myeloproliferative neoplasm in 2016. The disease is progressive to overt primary myelofibrosis, though the rate of progression is variable and not all patients progress. Symptoms and presentation can mimic essential thrombocythemia, with the main differentiator for pre-PMF being the presence of fibrosis in the bone marrow.

References

  1. ↑ "Preventing Myelofibrosis from Progressing to Acute Myeloid Leukemia". Cure Today. Retrieved 2023-02-18.
  2. ↑ "Are Myeloproliferative Neoplasms (MPNs) Cancer?". #MPNresearchFoundation. Archived from the original on 2020-07-11. Retrieved 2020-07-10.
  3. ↑ Arber, Daniel A.; Orazi, Attilio; Hasserjian, Robert; Thiele, Jürgen; Borowitz, Michael J.; Le Beau, Michelle M.; Bloomfield, Clara D.; Cazzola, Mario; Vardiman, James W. (2016-05-19). "The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia". Blood. 127 (20): 2391–2405. doi: 10.1182/blood-2016-03-643544 . ISSN   0006-4971. PMID   27069254.
  4. ↑ Thapa B, Fazal S, Parsi M, Rogers H (2021). "Myeloproliferative Neoplasms". National Library of Medicine. StatPearls Publishing. PMID   30285359 . Retrieved 8 July 2021.
  5. ↑ Chia, Yuh Cai (2021). "Molecular Genetics of Thrombotic Myeloproliferative Neoplasms: Implications in Precision Oncology". Genes & Diseases. doi: 10.1016/j.gendis.2021.01.002 – via Science Direct.
  6. ↑ "Symptoms, Diagnosis, & Risk Factors | Seattle Cancer Care Alliance". www.seattlecca.org. Retrieved 2020-07-10.
  7. ↑ Levene, Malcolm I.; Lewis, S. M.; Bain, Barbara J.; Imelda Bates (2001). Dacie & Lewis Practical Haematology. London: W B Saunders. p. 586. ISBN   0-443-06377-X.
  8. ↑ Magor GW, Tallack MR, Klose NM, Taylor D, Korbie D, Mollee P, Trau M, Perkins AC (September 2016). "Rapid Molecular Profiling of Myeloproliferative Neoplasms Using Targeted Exon Resequencing of 86 Genes Involved in JAK-STAT Signaling and Epigenetic Regulation". The Journal of Molecular Diagnostics. 18 (5): 707–718. doi: 10.1016/j.jmoldx.2016.05.006 . PMID   27449473.
  9. ↑ Barbui, Tiziano; Thiele, Jürgen; Gisslinger, Heinz; Kvasnicka, Hans Michael; Vannucchi, Alessandro M.; Guglielmelli, Paola; Orazi, Attilio; Tefferi, Ayalew (2018-02-09). "The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion". Blood Cancer Journal. 8 (2): 15. doi:10.1038/s41408-018-0054-y. ISSN   2044-5385. PMC   5807384 . PMID   29426921.
  10. ↑ Campbell PJ, Scott LM, Buck G, Wheatley K, East CL, Marsden JT, et al. (December 2005). "Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study". Lancet. 366 (9501): 1945–53. doi:10.1016/S0140-6736(05)67785-9. PMID   16325696. S2CID   36419846.
  11. ↑ Beer PA, Campbell PJ, Scott LM, Bench AJ, Erber WN, Bareford D, et al. (July 2008). "MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort". Blood. 112 (1): 141–9. doi: 10.1182/blood-2008-01-131664 . PMID   18451306.
  12. ↑ Mesa, Reuben. "What is Prefibrotic Primary Myelofibrosis?". Patient Power. HealthCentral LLC. Retrieved 23 June 2023.
  13. ↑ "Summary". www.meduniwien.ac.at. Archived from the original on 2022-05-23. Retrieved 2020-07-09.
  14. ↑ Tefferi, Ayalew; Vainchenker, William (2011-01-10). "Myeloproliferative Neoplasms: Molecular Pathophysiology, Essential Clinical Understanding, and Treatment Strategies". Journal of Clinical Oncology. 29 (5): 573–582. doi:10.1200/JCO.2010.29.8711. ISSN   0732-183X. PMID   21220604.
  15. ↑ Tibes R, Bogenberger JM, Benson KL, Mesa RA (October 2012). "Current outlook on molecular pathogenesis and treatment of myeloproliferative neoplasms". Molecular Diagnosis & Therapy. 16 (5): 269–83. doi:10.1007/s40291-012-0006-3. PMID   23023734. S2CID   16010648.
  16. ↑ Roaldsnes, Christina; Holst, René; Frederiksen, Henrik; Ghanima, Waleed (2017). "Myeloproliferative neoplasms: trends in incidence, prevalence and survival in Norway". European Journal of Haematology. 98 (1): 85–93. doi:10.1111/ejh.12788. ISSN   1600-0609. PMID   27500783. S2CID   19156436.
  17. ↑ Titmarsh, Glen J.; Duncombe, Andrew S.; McMullin, Mary Frances; O'Rorke, Michael; Mesa, Ruben; De Vocht, Frank; Horan, Sarah; Fritschi, Lin; Clarke, Mike; Anderson, Lesley A. (June 2014). "How common are myeloproliferative neoplasms? A systematic review and meta-analysis". American Journal of Hematology. 89 (6): 581–587. doi: 10.1002/ajh.23690 . ISSN   1096-8652. PMID   24971434.
  18. ↑ Dameshek W (April 1951). "Some speculations on the myeloproliferative syndromes". Blood. 6 (4): 372–5. doi: 10.1182/blood.V6.4.372.372 . PMID   14820991.
  19. ↑ "Understanding MPNs- Overview | MPNRF". #MPNresearchFoundation. Retrieved 2020-07-10.
  20. ↑ "Myeloproliferative Neoplasms". Cancer Support Community.
  21. ↑ Barbui T, Thiele J, Gisslinger H, Kvasnicka HM, Vannucchi AM, Guglielmelli P, et al. (February 2018). "The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion". Blood Cancer Journal. 8 (2): 15. doi:10.1038/s41408-018-0054-y. PMC   5807384 . PMID   29426921.
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