Myeloproliferative Neoplasm


Myeloproliferative neoplasm are a group of disorders characterized by bone marrow proliferation with increase in the number of blood cells. The proliferation my be limited to one cell line or may involve more than on cell line. They are distinct from acute leukaemia but carry the risk into evolving into leukaemia as a terminal event. This article discusses general aspects of myeloproliferative neoplasm. The disease entities will be discussed elsewhere.

Progressive myelofibrosis was the first myelroliferative neoplasm to be described. It was described by Gustav Heuck in 1879. This was followed by chronic myeloid leukaemia (CML) by John Hughes Bennett in 1845, polycythaemia vera (PV) described by Louis Henri Vaquez in 1892 and essential thrombocytosis (ET) described by Emil Epstein in 1934. The term myeloproferative disease was coined by Dameshek in 1951 to describe seven conditions that he thought were manifestations of “proliferation of bone marrow to a hitherto undiscovered stimulus” (Blood 1951; 6:372-75). The seven conditions were chronic granulocytic leukaemia (now chronic myeloid leukaemia), polychthaemia vera, agnigeic myeloid metaplasia (now primary myelofibrosis), thrombocytosis (essential thrombocytosis), megakaryocytic leukaemia and erythroleukaemia (including DeGuglielmo’s syndrome). As the malignant nature of these disease was not apparent till recently they were referred to as myeloproliferative disorder. The recognistion of the neoplastic in nature of the diseases has resulted in the change in the name from myelproliferative disorder to myeloprlferative neoplasm.

The WHO 2016 classification of myeloproliferative neoplasm includes the following disease

  1. Chronic myeloid leukaemia (CML)
  2. Chronic neutrophilic leukaemia (CNL)
  3. Polycythaemia vera (PV)
  4. Progressive myelofibrosis (PMF)
  5. Essential thrombocytosis (ET)
  6. Chronic myeloproliferative neoplasm unclassified
  7. Chronic eosinophilia leukaemia NOS
Myeloproliferative disease

Pathogenesis of myeloproliferative diseases

Pathogenesis of Myeloproliferative Neoplasm

The bone marrow proliferates in response to an initiating event (see figure above). This event remains to be discovered. Bone marrow proliferation results in increased blood counts. Increase in erythrocytes results in polycythaemia and features of hyperviscosity. Increased leukocyte counts result in leukostasis. The leucocytes counts that can cause leukostasis are only seen in CML. Thrombocytosis increases the risk of thrombosis. With time a MPN disease progresses. Progression either results in blast transformation or myelofibrosis as the terminal event. CML is more likely to progress to blast crisis and non-CML MPNs to myelofibrosis. Splenomegaly is an early feature of CML. Spleen in enlarged because of infiltration of the spleen by neoplastic haemopoietic cells despite there being no myelofibrosis. In non-CML splenomegaly occurs late and is a result of extra-medullary haematopoiesis due to myelofibrosis.

Clinical Aspects og Myeloproliferative Neoplasm

The myeloproliferative disease have the following common features

  1. Clonal proliferation of bone marrow: The Philadelphia chromosome associated with CML was the first chromosomal abnormality associated with a malignancy. The Philadelphia chromosome is a t(9;22) translocation that results in the formation of the BCR-ABL1 fusion gene. It proved the clonal nature of CML. Mutations proving the clonality of non-CML myeloproliferative neoplasm have been discovered. These include the JAK2, MPL and CALR mutations found in PV, PMF and ET. CNL is characterised by mutations in CSF3R. These mutations are the “undiscovered stimulus” Dameshek wrote about.
  2. Increased Blood Counts: Myeloprolifarative neoplasm have increase leucocytes, erythrocytes and thrombocytes alone or in combinations.
  3. Splenomegaly: Splenomagaly is a future of all myeloproliferative neoplasm. It is most pronounced in CML and PMF. The underlying mechanisms of splenomegaly in the conditions are different. Patients with CML have infiltration. Some develop myelofibrosis. Massive splenomegaly in myeloproliferative neoplasm than CML indicated bone marrow fibrosis.
  4. Overlapping clinical features: The clinical features of myeloproliferative neoplasm overlap. Polycythaemia is only seen in PV. Leucocytosis is a feature of all conditions other than ET. The type of leucocytosis can distinguish entities. Exteme leucocytosis with premature myeloid forms points to CML. But all patients with CML do not have extreme leucocytosis. Neutrophilic leucocytosis is a feature of CNL. Thrombocytosis is a featured shared by myeloproliferative neoplasm. As discussed below myelofibrosis develops in all myeloproliferative diseases. All myeloproliferative neoplasia are at risk of transforming into acute leukaemia. Despite the use of BCR-ABL1 tyrosine kinase inhibitors the risk is of acute leukaemia transformation is highest for CML.
  5. Development of bone marrow fibrosis: As myeloproliferative neoplasia progress bone marrow fibrosis increases. Myelofibrosis develops fastest in progressive myelofibosis. CML often does not develop clinically evident fibrosis but transforms to acute leukaemia as a terminal event. Development of fibrosis results in pancytopenia. Once fibrosis sets in it is not possible to tell the nature of the pre-fibrotic myeloproliferative neoplasm.
  6. Transforamation to acute leukaemia: All myeloproliferative neoplasia have a risk of evolving to acute leukaemia. This is known as blast crisis. The risk is greatest in CML.
  7. A tendency for thrombosis: Myeloproliferative neoplasm increase the risk of thrombosis. The risk is highest in ET and PV.

Treatment of Myerloproliferative Neoplasm

The goals of therapy of myeloproliferative neoplasia are

  1. Prevention and treatment of complications of increased cell counts
  2. Prevention of progression of MPN
  3. Erradicating the malignant clone

Prevention and treatment of complications of increased cell counts

Acute complication of myeloproliferative neoplasia include Leukostasis hyperviscosity and thrombosis. Polycythaemia is addressed by phlebotomy. Leukostasis is treated by measures to reduce counts (see Hyperleukoytosis and leukocytosis). Thrombocytosis of ET is treated low dose aspirin with or without hydroxyurea. The exact combination depends on the diagnosis and the risk stratification. Low dose aspirin is administered to patients with PV and PMF as they are at risk of thrombosis.

Prevention of progression of MPN

The only MPN where progression can be retarded is CML. The use of BCR-ABL1 tyrosine kinase inhibitors (BCR-ABL1 TKI) like imatinib, nilotinib or dasatinib prevent progression. The longest results are available for imatinib. Eithty five percent of the patients are alive at 10 years compared to a median survival of 45.4 with busulifan and58.2 months with hydroxyurea (Blood. 1993 Jul 15;82(2):398-407).

Eradicating the malignant clone

Supression of the BCR-ABL1 positive clone does not result in eradication of the malignant clone. More than half the patients in deep remission have a relapse of CML in one year off stopping BCR-ABL1 TKI therapy. Allogenic stem cell transplant offers the only possibility of cure in CML. The safety and efficacy of BCR-ABL1 TKIs has reduced the role of allogenic stem cell transplant in CML. It is now used in patients who are poorly controlled with upfront BCR-ABL1 TKI therapy. Allogenic stem cell transplant may be used in selected patients with PV, ET and PMF but does not form a front line therapy.

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Calreticulin and Myeloproliferative Neoplasm


Myeloproliferative neoplasm (polycythaemia vera [PV], essential thrombocytosis [ET], progressive myelofibrosis [PMF]) are a group of diseases that are characterised by increased proliferation of blood cells, splenomegaly, myelofibrosis, thrombosis and risk of malignant transformation.  The year 2005 was a landmark year for myeloproliferative diseases. Four groups of scientists identified the presence of JAK2V617F mutations in PV. This mutation is present in about 98% patients with PV. Mutations of exon 12 of the JAK2 gene can be found in 1-2% of the PV. These patients do not show the JAK2V617F mutation. The discovery of these mutations gave a genetic definition PV making diagnosis objective.

PV is diagnosed by the presence primary erythrocytosis in the precession of a JAK2 mutation referred to above. Chronic myeloid leukaemia is diagnosed by demonstrating the BCR-ABL1 translocation. JAK2V617F is also present in 50-60% of ET and PMF. Mutation of the gene MPL is found in 1-2%  patients of ET and 5-10% of the patients with PMF. The presence of these mutation helps make diagnosis. However, The diagnosis of PMF and ET in a large proportion of patients requires exclusion of a reactive disorder and other myeloproliferative diseases because these patients (38-49% of ET and 30-45% of PMF) have no genetic marker.

Two publications have shown that a large proportion of the patients with ET and PMF who do not have JAK have mutation calreticulin (CALR) (N Engl J Med. 2013;369(25):2391-2405,  N Engl J Med. 2013;369(25):2379-2390). In addition to ET and PMF CALR mutations are found in the MDS/MPN overlap disorder and refractory anemia with ring sideroblasts with thrombocytosis (RARS-T). They are rare or absent in other myeloid or lymphoid neoplasms or solid tumors.

Calreticulin (CALR) is a major calcium binding protein. The gene for calreticulin is located on 19p13.2. About a quarter of ET and MF have mutation in the CALR gene. All CALR mutations are localised to exon 9 and generate a 1bp frameshift. As a result of this most or almost all the C terminal negative amino acids and calcium binding sites are lost.  There is a complete loss of the KDEL endoplasmic reticulum binding sequence. These mutations have been identified in the haemopoietic stem cell and progenitor compartments. CALR mutations and JAK2 mutations are mutually exclusive.

CALR mutated myeloproliferative disease have a distinct clinical profile. These patients have a lower haemoglobin, lower leukocyte count, higher platelet count and a lower risk of thrombosis. Patients of PMF carrying a CALR mutation have a longer survival than those carrying JAK2 or MPL mutations. Patients with ET carrying the CALR mutations have a longer survival than those carrying the JALK2 mutation. There is no difference between the survival of ET patients carrying CALR mutations and MPL mutations.

Mutated CALR appears to stimulate STAT pathway. It appears to physically bind with the thrombopoietin receptor to stimulate STAT. The erythropoietin receptor is not needed for this action (Blood. 2015;10.1182/blood-2015-11-681932Blood. 2015;126:LBA-4).

 

 

 

Clinical Manifestations of Polycythaemia


Figure 1. Plethora of the face Figure 2. Plathoric mucosa Figure 3. Palmar erythrma

This 50 year old male presented with an incidentally diagnosed haemoglobin of 21.2g/dL. He had no symptoms. Despite a dark complexion the malar plethora its evident. Mucosal plethora and palmar erythrma is evident.