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MYELOFIBROSIS BY DR .MAGDI AWAD SASI 2014

MYELOFIBROSIS

Primary myelofibrosis (PMF) is a chronic, usually idiopathic disorder characterized by

bone marrow fibrosis, splenomegaly, and anemia with nucleated and teardrop-shaped

RBCs. Diagnosis requires bone marrow examination and exclusion of other conditions

that can cause myelofibrosis (secondary myelofibrosis). Treatment is often supportive,

but JAK2 inhibitors such as ruxolitinib may decrease symptoms, and stem cell

transplantation may reverse fibrosis.

Essential for diagnosis:

Tear drop poikilocytosis on peripheral smear

Leukoerythroblastic blood picture ,giant abnormal platelets

Hypercellular bone marrow with reticulin or collagen fibrosis

Definition :

Myelofibrosis is a disorder of the bone marrow, in which the marrow is replaced by scar (fibrous) tissue.

It is a myeloproliferative characterized by :

1. Fibrosis of the bone marrow

2. Splenomegally

3. Leukoerythroblastic peripheral blood film with tear drop poikilocytosis

Myelofibrosis (MF) is a chronic blood cancer in which excessive scar tissue forms in the bone

marrow and impairs its ability to produce normal blood cells. MF is thought to be caused by

abnormal blood stem cells in the bone marrow. The abnormal stem cells produce more mature

cells that grow quickly and take over the bone marrow, causing both fibrosis (scar tissue

formation) and chronic inflammation. As a result, the bone marrow becomes less able to create

normal blood cells and blood cell production may move to the spleen, causing enlargement, or to

other areas of the body. Classified as a myeloproliferative neoplasm (MPN), MF can arise on its

own (primary myelofibrosis, PMF), or as a progression of polycythemia vera (post-PV-MF) or

essential thrombocythemia (post-ET-MF). The manifestations of PMF, post-PV-MF and post-ET-MF

are virtually identical and treatment is generally the same for all three.

Pathophysiology :

Myelofibrosis is excessive bone marrow fibrosis and loss of hematopoietic cells, with subsequent

marked increase in extramedullary hematopoiesis (primarily in the liver and spleen, which enlarge

significantly). The cause is mysenchymal for fetal hematopoiesis reactivated.

Myelofibrosis may be primary or secondary to a number of hematologic, malignant, and

nonmalignant conditions .

PMF is more common than secondary myelofibrosis and results from neoplastic transformation of

a multipotent bone marrow stem cell. Bone marrow fibrosis occurs in response to increased secretion

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MYELOFIBROSIS BY DR .MAGDI AWAD SASI 2014

of platelets derived growth factor . These PMF progeny cells stimulate bone marrow fibroblasts

(which are not part of the neoplastic transformation) to secrete excessive collagen.

In primary myelofibrosis, chemicals released by high numbers of platelets and abnormal

megakaryocytes (platelet forming cells) over-stimulate the fibroblasts. This results in the

overgrowth of thick coarse fibres in the bone marrow, which gradually replace normal bone

marrow tissue. Over time this destroys the normal bone marrow environment, preventing the

production of adequate numbers of red cells, white cells and platelets. This results in anaemia,

thrombocytopenia ,leukopenia and the production of blood cells in areas outside the bone marrow

for example in the spleen and liver, which become enlarged as a result.

The peak incidence of PMF is between 50 and 70 yr.

In PMF, large numbers of nucleated RBCs (normoblasts) and granulocytes are released into the

circulation (leukoerythroblastosis). Serum LDH level is often elevated. Bone marrow failure

eventually occurs, with consequent anemia and thrombocytopenia. Rapidly progressive,

chemotherapy-incurable acute leukemia develops in about 10% of patients.

Malignant or acute myelofibrosis, an unusual variant, has a more rapidly progressive downhill

course; this variant is best classified as megakaryocytic leukemia.

Long-term exposure to high levels of benzene or very high doses of ionising radiation may

increase the risk of primary myelofibrosis in a small number of cases. Around one third

of people with myelofibrosis have been previously diagnosed with polycythaemia (post-

polycythaemic myelofibrosis) or essential thrombocythaemia (post-ET myelofibrosis).

Age and incidence: --

It is insidious in onset

The peak incidence of PMF is between 50 and 70 yr.

Primary myelofibrosis is a rare chronic disorder diagnosed in an estimated 1 per 100,000

population. It can occur at any age but is usually diagnosed later in life, between the ages of 60

and 70 years. The cause of primary myelofibrosis remains largely unknown. It can be classified as

either JAK2 mutation positive (having the JAK2 mutation) or negative (not having the JAK2

mutation).

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MYELOFIBROSIS BY DR .MAGDI AWAD SASI 2014

Conditions Associated With Myelofibrosis

Condition Examples

Malignancies Cancer with bone marrow metastases

Hodgkin lymphoma

Leukemias (particularly chronic myelogenous and hairy

cell)

Multiple myeloma

Non-Hodgkin lymphoma

Polycythemia vera (15 to 30% of patients in the spent

phase)

Essential thrombocythemia

Infections Osteomyelitis

TB

Primary pulmonary

hypertension

–

Toxins Benzene

Thorium dioxide

X- or γ-radiation

Autoimmune disorders(rarely) SLE

Systemic sclerosis

Clinical features :

Age -- 50years and over

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MYELOFIBROSIS BY DR .MAGDI AWAD SASI 2014

Around 20 per cent of people have no symptoms of primary myelofibrosis when they are

first diagnosed and the disorder is picked up incidentally as a result of a routine

blood test. For others, symptoms develop gradually over time.

For others, symptoms develop gradually over time. PANCYTOPENIA + ORGANOMEGALLY + CONSTITUIONAL SYMPTOMS

Tiredness, weakness, or shortness of breath with mild exertion. These symptoms usually

result from anemia (low red blood cell count) or chronic inflammation.

Fullness, discomfort or pain in the left upper area of the abdomen and early satiety, as a

result of an enlarged spleen pressing on the stomach and other organs(1/3 of patients)

Abdominal discomfort can also result from an enlarged liver (hepatomegaly), which

occurs in around two-thirds of cases.

Feeling pain or fullness below the ribs on the left side.

Feeling full sooner than normal when eating.

Fever, caused by inflammation or infection

Night sweats, caused by inflammation

Weight loss or malnutrition, caused by inflammation and an enlarged spleen pressing on

the stomach and bowels

Bone pain Itching (pruritus), caused by a chronic state of inflammation Easy bleeding or bruising, as a result of low platelet counts or otherwise compromised

blood coagulation Susceptibility to infection, as a result of low white blood cell count or diminished

production of antibodies Joint pain, caused by gout. Gout may develop as a result of excessive uric acid

production. Portal hypertension caused by a progressively enlarging spleen. Portal hypertension can

lead to varices (dilated veins) within the stomach and esophagus, which may rupture and

bleed. Liver function may be compromised as well.

Abnormal growth of blood forming cells outside of the bone marrow (called

extramedullary hematopoiesis, or EMH) can occur in different parts of the body, including

lymph nodes, lungs, and spinal cord, causing symptoms in these areas. EMH occurs when

blood-forming cells leave the bone marrow and settle in other organs.

Uncommonly, the patient may present with bleeding and abdominal pain.

Cutaneous myelofibrosis is a rare skin condition characterized by dermal and

subcutaneous nodules

Physically:

Splenomegally is present and sometimes massive (( cardinal feature )).

The spleen continues to enlarge which leads to early satiety painful episodes of splenic

infarction may occur .

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MYELOFIBROSIS BY DR .MAGDI AWAD SASI 2014

Hepatomegally is present in 50% of cases.

Later----progressive bone marrow failure takes place as the marrow become fibrotic.

A. Anemia-----sever where the RBC transfusion necessary

B. Thrombocytopenia ----bleeding

Later in course of disease ;the patient become cachetic and may experience sever bone

pain especially lower legs .

Hematopoiesis in liver ----portal hypertension ,ascitis ,oesophageal varices -----liver

failure.

How is Myelofibrosis diagnosed?

Primary myelofibrosis is diagnosed using a combination of a physical examination showing the

presence of an enlarged spleen, blood tests and a bone marrow examination. Primary

myelofibrosis is only diagnosed when other causes of marrow fibrosis (including leukaemia,

lymphoma, other types of cancer that have spread to the bone marrow) have been ruled out.

LABORATORY FINDING:

A doctor reviews many factors before making a diagnosis. Every case of MF is different, so a

medical history, a physical examination and laboratory tests are needed.

Even if people living with myelofibrosis do not have symptoms, they may have signs.

PMF should be suspected in patients with splenomegaly, splenic infarction, anemia, or

unexplained elevations in LDH. If the disorder is suspected, CBC should be done and peripheral

blood morphology and bone marrow should be examined, including cytogenetic testing. If

myelofibrosis is detected on bone marrow examination (eg, by increased fibroblasts and collagen

as detected by reticulin staining, osteosclerosis), other disorders associated with myelofibrosis

should be excluded by appropriate clinical and laboratory evaluation.

Tests that may be done include:

CBC (complete blood count) with blood smear

Bone marrow examination

Genetic testing

Anemia is typically present and usually increases over time. Blood cell morphology is variable.

RBCs are poikilocytic. Reticulocytosis and polychromatophilia may be present; teardrop-shaped

RBCs (dacryocytes) are characteristic morphologic features. Nucleated RBCs and neutrophil

precursors are typically present in peripheral blood. WBC counts are usually increased but are

highly variable; a low WBC count tends to indicate a poor prognosis. Neutrophils are usually

immature, and myeloblasts may be present, even in the absence of acute leukemia. Platelet

counts initially may be high, normal, or decreased; however, thrombocytopenia tends to

supervene as the disorder progresses.

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MYELOFIBROSIS BY DR .MAGDI AWAD SASI 2014

Higher than normal numbers of white cells and platelets may be found in the early stages of this

disorder, but low white cell and platelet counts are common in more advanced disease.

RBC----- patients are almost invariably anemic

at presentation.

WBC---- is variable decreased, normal

,increased may be increased to 50000/ml

PLATELET----variable

Peripheral blood film----characteristic

Significant poikilocytosis ((variation in cell

shape)) with tear drop forms

Leukoerythroblastic (immature myeloid

with erythroid forms)

Nucleated RBCS are present

Myeloid series is less striking shifted

with immature forms (promyelocytes

with myeloblastosis)

Platelet morphology may be bizarre

;gaint degranulated platelet forms

(megakaryocyte fragments)

The triad of TEAR DROP POIKILOCTOSIS,

LEUKOERYTHROBLASTIC, GAINT ABNORMAL PLATELETS is almost diagnostic of

myelofibrosis.

If diagnosis is difficult, CD34+ cell count on peripheral blood can be done. Levels are much higher

in patients with PMF.

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MYELOFIBROSIS BY DR .MAGDI AWAD SASI 2014

Bone marrow--- cant be aspirated (dry tap), biopsy is preferred.

Though early in the

course of disease,

it is hypercellular

with marked

increase in

megakaryocyte.

At this stage,

fibrosis is detected

by silver stain

demonstrating

increased reticulin

fibers .

(Normal fine

reticulin pattern

lost and replaced

by coarse

bands).

Because

demonstration of

bone marrow

fibrosis is

required and

fibrosis may not be uniformly distributed, biopsy should be repeated at a different

site if the first biopsy is nondiagnostic. About 50% of patients have

a JAK2 mutation. Some have a mutation of the calreticulin gene. Later ,biopsy shows:

1.Sever fibrosis

2.Replacement of hemopoietic precursor by collagen

DIFFERENTIAL DIAGNOSIS:

1. Leukoerythroblastic blood film----

Sever infection

Sever inflammation

D/D----Tear drop poikilocytosis +Giant platelet

2. BONE MARROW FIBROSIS :

Can be caused by:

A. Metastatic carcinoma

B. Hodgkins disease

C. Hairy cell leukemia

D. Tuberculosis

E. Polycythemia rubra vera

F. Exposure to benzene

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MYELOFIBROSIS BY DR .MAGDI AWAD SASI 2014

Other myeloproliferative :

PRV-------------------------------------------increase HCT

ESSENTIAL THROMBOCYTOPENIA

CML---------------------------------------Increase WBC, Decrease LAP, Philadelphia chromosome.

Certain factors affect prognosis and treatment options for primary myelofibrosis.

Prognosis (chance of recovery) depends on the following:

1. The age of the patient.

2. The number of abnormal red blood cells and white blood cells.

3. The number of blasts in the blood.

4. Whether there are certain changes in the chromosomes.

5. Whether the patient has symptoms such as fever, night sweats, or weight loss.

TREATMENT:

In the past, the treatment of myelofibrosis has depended on the symptoms and degree of

the low blood counts.

In young people, bone marrow or stem cell transplants appear to improve the outlook, and

may cure the disease. A long-term (5 year) remission is possible for some patients with

bone marrow transplantation. Such treatment should be considered for younger patients

and some others.

No specific treatment

Because myelofibrosis generally progresses slowly, people who have it may live for 10

years or longer, but outcomes are determined by how well the bone marrow functions.

Occasionally, the disorder worsens rapidly. Treatment aims to delay the progression of

the disorder and to relieve complications.

The one known curative treatment is allogeneic stem cell transplantation, but this

approach involves significant risks. Other treatment options are largely supportive, and do

not alter the course of the disorder (with the possible exception of ruxolitinib). These

options may include regular folic acid, allopurinol or blood transfusions. Dexamethasone,

α interferon and hydroxyurea (also known as hydroxycarbamide) may play a role.

Anemic patients ------RBC transfusion

Androgens ------Oxymethalone or Testosterone

This reduce transfusion requirement 1/3 of patients and poorly tolerated by

women.

Lenalidomide and thalidomide may be used in its treatment, though peripheral

neuropathy is a common troublesome side-effect.

Recombinant erythropoietin (epoetin alfa)--- helpful in small number of patient to

stimulate the bone marrow for red blood cells synthesis.

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MYELOFIBROSIS BY DR .MAGDI AWAD SASI 2014

Splenectomy (( routinely not performed )) except in :

1. Sever thrombocytopenia

2. High RBC transfusion requirement

3. Recurrent painful episodes with huge spleen.

4. Massive splenomegally

Interferon

Survival ----- 5 years----------

End stage myelofibrosis characterized by--------

Generalized debility

Liver failure

Bleeding from thrombocytopenia

In November 2011, the FDA approved ruxolitinib (Jakafi) as a treatment for

myelofibrosis. Ruxolitinib is a twice daily drug which serves as an inhibitor of JAK 1 and 2.

The New England Journal of Medicine (NEJM) published results from two Phase III studies of

Jakafi™ (ruxolitinib), a JAK1 and JAK2 inhibitor recently approved by the Food and Drug

treatment with Jakafi was associated with improved overall survival compared to placebo.

Janus-associated kinase (JAK) inhibitors—This drug class inhibits enzymes called “JAK1” and

“JAK2,” which are involved in the production of blood cells.

Ruxolitinib (JakafiTM), given by mouth, is the first JAK inhibitor and currently the only drug

approved by the FDA to treat symptoms and signs of MF, including an enlarged spleen, night

sweats, itching and bone or muscle pain. It is indicated for treatment of patients with intermediate-

or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis

and post essential thrombocythemia myelofibrosis. The most common side effects affecting the

blood cells are thrombocytopenia and anemia. Other common side effects include bruising,

dizziness and headache. Patients should be aware that after discontinuation of Jakafi,

myelofibrosis signs and symptoms are expected to return. There have been isolated cases of

patients discontinuing Jakafi during acute intervening illnesses after which the patient’s clinical

course continued to worsen. It has not been established whether discontinuation of therapy

contributed to the clinical course of these patients. When discontinuing Jakafi therapy for reasons

other than thrombocytopenia, gradual tapering of the dose of Jakafi may be considered

Possible Complications

Acute myelogenous leukemia Blood clots Liver failure