A RARE HAEMATOLOGICAL DISEASE WITH BAD OUT COME

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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