Myelofibrosis

Notes

Overview

Myelofibrosis is a type of myeloproliferative diseasecharacterized by clonal myeloid expansion, followed by progressive fibrous connective tissue deposition in the bone marrow, resulting in bone marrow failure. Clonal evolution can also occur, with an increased risk of transformation to acute myeloid leukemia. In addition, disabling constitutional symptoms secondary to the high circulating levels of proinflammatory cytokines and hepatosplenomegaly frequently impair quality of life.

Definition

Myeloproliferative disorder: are clonal stem disorders characterised by leukocytosis, thromboytosis, erythrocytosis, splenomegaly, and bone marrow hypercelluarity. Includes myelofibrosis, essential thrombocytopaenia and polycythaemia
Primary Myelofibrosis: one of the chronic myeloproliferative disorders, where there is replacement of bone marrow with collagenous connective tissue and progressive fibrosis
Secondary Myelofibrosis: Myelofibrosis caused secondary to another disease such as essential thrombocytopnaeia or polycythaemia rubra vera
Essential Thrombocytopaenia: one of the chronic myeloproliferative disorders, in which too many platelets are produced in the bone marrow
Polycythaemia rubra vera: one of the chronic myeloproliferative disorders, which are collectively characterized by clonal proliferation of myeloid cells with variable morphologic maturity and hematopoietic efficiency.

Remember

Three main types of myeloproliferative disorders are PRV, ET and PMF.

Hypersplenism triad: splenomegaly, pancytopenia and normocellular bone marrow.

Haemtopoesis

Spleen Anatomy and Physiology

Aetiology and Risk Factors

Aetiology

Exact mechanism of disease is unknown but factors include:

Chromosomal abnormality (ie. retinoblastoma gene mutation)
JAK2 mutation (50%) → causes proliferation and survival of cells
JAK/STAT mutation → causes proliferation and survival of cells
MPL mutation → thrombopoietin receptor protein mutation → proliferation and survival of megakaryotes
Thrombopoietin receptor gene mutation
Overexpression of thrombopoietin
Abnormal cytokine release (Growth factors) by cells in bone marrow, mainly megkaryotes → proliferation of fibroblasts → ↑collagen and fibrosis

Risk Factors

Radiation Exposure
Age >65yo

Clinical Manifestation

General

Fatigue (60%)
Splenomegaly (50%)
Hepatomegaly
Pruritis

Symptoms of splenomegaly (50% of cases)

Early satiety
Abdominal discomfort
LUQ pain
Dragging sensation in abdomen
Should tip pain (irritation of the diaphragm)

Symptoms of hypermetabolic state

Low grade fever
Night sweats
Weight loss
Fatigue
Bone pain

Sites and signs and symptoms of extramedullary haematopoesis

Pleura – pleural effusion
Lungs – pneumoniae and pulmonary hypertension
Heart – pericardial effusion
Peritoneum – ascites
Genitourinary tract – obstruction, dysuria

Investigations

Full Blood Count – anaemia
Full Blood Smear – nucleated red blood cells, tear drop red blood cells (dacrocytes)
EUC – ↑uric acid
LFT – ↑alkaline phosphatase, ↑lactate dehydrogenase

Imaging Investigations – CT or MRI
Bone Biopsy
Bone Aspiration – dry aspiration

Other tests

RF, ANA, Anti-CCP
↑CD43

Diagnosis The 2008 WHO criteria include a combination of the following findings:

Presence of megakaryocyte proliferation and atypia, usually accompanied by reticulin and/or collagen
WHO criteria for polycythemia vera (PV), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), or other myeloid neoplasm not met
Demonstration of a clonal marker (eg, JAK2 or MPL)
Leukoerythroblastosis
Palpable splenomegaly
Anemia
Increased serum lactate dehydrogenase level

Differential Diagnosis

MAJOR CAUSES OF SPLENOMEGALY
Aetiology	Conditions
Congestion	Cirrhosis, Heart Failure, Thrombosis of portal/hepatic/splenic vein
Malignancy	Lymphoma, Leukaemia, Myeloproliferative disorders, Primary or secondary tumour
Infection	Viral (hepatitis, infectious mononucleosis, cytomegalovirus), bacterial (Salmonella, TB), parasitic (malaria, toxoplasmosis, schistosomiasis), infective endocarditis
Inflammation	Sarcoids, SLE, Rheumatoid arthritis (Felty syndrome)
Infiltrative, nonmalignant	Gacuher’s disease, Niemann-pick disease, Amyloid, Langerhan cell histiocytosis
Haematologic (hypersplenic) states	Haemolytic anaemias, Sick cell disease (children)

More information on the differential diagnosis of Splenomegaly.

Remember

No direct relation between splenic size and hypersplenism, however hypersplenism is more common among those who have gross splenomegaly.

Pathology

Extensive fibrosis – Collagen and/or reticulin
Megarkaryote proliferation and hyperplasia
Immature granulocytosis

Pathophysiology

Side note

Hypersplenism is a triad of splenomegaly, pancytopenia and normocellular bone marrow. Splenomegaly increases the spleen’s mechanical filtering and destruction of RBCs and often of WBCs and platelets. Compensatory bone marrow hyperplasia occurs in those cell lines that are reduced in the circulation.

Treatment

Overview

The initial management of patients with PMF is largely dictated by the risk of disease progression and estimated overall survival as calculated by prognostic scores

Asymptomatic (30% of patients)

Folic acid supplement
Pyridoxine supplement
Peginterferon alfa
Follow up every 6 months with specialist

Symptomatic

Bone marrow transplant – if suitable

Side note

Bone marrow transplant offers the only currative potential for patients with PMF, however only a selected few will be able to have this.

The JAK2 inhibitor (Ruxolitinib) – not only if JAK2 postitive but can help reduce spleen size.
- Thialidomide + prednisalone if Ruxolitinib is ineffective
Hydroxyurea – reduce spleen size, control thrombocytosis and leukocytosis, and/or constituional symptoms
Red cell transfusion – for anaemia
Danazol +/- erythropoetin – for anaemia
Allopurinol – for hyperuricaemia
local irradiation – for the management of symptomatic extramedullary haematopoiesis
Splenectomy – if other treatment does not work and symptoms can not be controlled

Side note

Interferon therapy can be limited by its induction of leukopenia or thrombocytopenia, but it can decrease splenomegaly. This is particularly useful in pregnancy where chemotherapy and thalidomide are contraindicated.

Pharmacology

Ruxolitinib is a JAK2 inhibitor used to treat myeloproliferative disorders. JAK2 (and other kinases) are responsible for the mediation of cytokine and growth factor signalling which in turn effect immune function and hematopoiesis. Side effects anemia, equilibrium disturbance, labyrinthitis, meniere’s disease, dizziness, headache, vertigo, neutropenia, thrombocytopenia, orthostatic dizziness, weight gain and flatulence. No contraindications.

Pharmacology

Danazol is a synthetic steroid (androgen) with antigonadotropic and anti-estrogenic activities that acts as an anterior pituitary suppressant by inhibiting the pituitary output of gonadotropins. Danazol is usually used to treat endometriosis and fibrocystic breast disease (in patients unresponsive to simple measures). Also used for the prophylactic treatment of all types of hereditary angioedema in males and females. Danazol has been shown to stimulate erythropoiesis in patients with refractory anemia, leading to increased Hb level, reticulocytosis, and decreased need for blood transfusions. Side effects of androgen therapy include fluid retention, increased libido, hirsutism, abnormal liver function tests, and hepatic tumors.

Management post Splenectomy

Prophylaxis for Post-splenectomy infection:
- Vaccinate 2-3 weeks before elective splenectomy: Pneumococcal vaccine, Hemophilus influenza type B (Hib) vaccine, Meningococcal group C vaccine, Influenza vaccine
- Lifelong Antibiotic prophylaxis should be offered in all cases where a patient has an absent or dysfunctional spleen, especially in the first two years after splenectomy, for all children aged up to 16, and when there is underlying impaired immune function: Long-term penicillin 500mg 12 hourly (erythromycin if allergic to penicillin)
- Revaccination of pneumococcal vaccine: in every 5 years and influenza vaccine anually
- Antimalarial chemoprophylaxis: if needed (travel to endemic area)
- General Measures: carrying a “No Spleen” card which details vaccinations, antibiotic therapy and what action should be taken in case of a flu-like illness, advice to seek urgent medical attention at early signs of infection in the future, irrespective of prophylaxis, aspirin prophylaxis against thrombosis is dependent upon the platelet level and should be controlled by a specialist haematologist
Post splenectomy hematological features:
- Thrombocytosis: persists in 30% cases
- WBC count: usually normal but there may be mild lymphocytosis and monocytosis
- Red cell morphology: Howell-Jolly bodies (Nuclear remnants), Pappenheimer bodies (contain sideroblastic granules), Heinz bodies (Denatured hemoglobin), Target cells, Nucleated erythrocyte (occasionally)

Complications and Prognosis

Complications

Extramedullary involvement
Anaemia
Haemorrhage
Infections
Complications of splenomegaly
Postral hypertension
Leukaemia (20%)
Hyperuricaemia → gout and renal stone formation

Prognosis

Primary myelofibrosis has a median lifespain of ~5.5 years. Death is usually a consequence of bone marrow failure (haemorrhage, anaemia, or infection), transformation to acute leukaemia, portal HTN, heart failure, cachexia, or myeloid metaplasia with organ failure.