IDIOPATHIC MYELOFIBROSIS Treatment and Management.pptx

Introduction
Idiopathic Myelofibrosis (IMF), also known as primary myelofibrosis (PMF), is a rare type of chronic leukemia that affects the bone marrow, leading to its scarring (fibrosis). This condition is part of a group of diseases called myeloproliferative neoplasms (MPNs), which are characterized by the abnormal proliferation of blood cells produced in the bone marrow. IMF results in severe anemia, weakness, fatigue, and an enlarged spleen (splenomegaly), significantly impacting the quality of life and survival of affected individuals.

Pathophysiology
IMF involves the abnormal clonal proliferation of hematopoietic stem cells. The exact cause remains unknown, but the condition is often associated with genetic mutations such as Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL). These mutations lead to dysregulated signaling pathways that promote the excessive production of blood cells and the release of cytokines, contributing to bone marrow fibrosis.

Clinical Presentation
Patients with IMF typically present with symptoms related to anemia, splenomegaly, and systemic symptoms like fatigue, night sweats, and weight loss. The anemia is usually normochromic and normocytic, and the spleen enlargement can cause discomfort and early satiety. In advanced stages, extramedullary hematopoiesis can occur, leading to hepatomegaly and other complications.

Diagnosis
Diagnosis of IMF requires a combination of clinical, laboratory, and pathological evaluations:

Blood Tests: Complete blood count (CBC) often shows anemia, leukocytosis, or thrombocytosis. Peripheral blood smear may reveal teardrop-shaped red cells (dacrocytes).
Bone Marrow Biopsy: The definitive diagnosis is made by a bone marrow biopsy showing fibrosis, atypical megakaryocytes, and the absence of a significant increase in blasts.
Genetic Testing: Identification of JAK2, CALR, or MPL mutations supports the diagnosis and helps differentiate IMF from other MPNs.
Differential Diagnosis
Differentiating IMF from other causes of bone marrow fibrosis and other MPNs, such as polycythemia vera (PV) and essential thrombocythemia (ET), is crucial. This differentiation is achieved through clinical assessment, bone marrow biopsy, and genetic testing.

Prognosis
The prognosis for IMF varies significantly among patients. The median survival ranges from 5 to 7 years, but some patients may live longer. Prognostic factors include age, hemoglobin levels, white blood cell count, platelet count, and the presence of specific genetic mutations. The International Prognostic Scoring System (IPSS) and its updated versions (DIPSS and DIPSS-plus) are commonly used to stratify patients into different risk categories.

Management
There is no cure for IMF, but various treatment options are available to manage symptoms and improve quality of life:

Supportive Care: Blood transfusions for anemia and medications to alleviate symptoms like pain and spleen discomfort.
Pharmacother

1. IDIOPATHIC MYELOFIBROSIS Shajahan Arfan

2. Idiopathic myelofibrosis (IM) is also called primary myelofibrosis or chronic idiopathic myelofibrosis A progressive, chronic disease in which the bone marrow is replaced by fibrous tissue and blood is made in organs such as the liver and the spleen, instead of in the bone marrow. Epidemiology : peak incidence between age 60–70 years

3. Idiopathic myelofibrosis is a chronic disorder, which means that it develops slowly over time. Eventually it causes fibrous, or scar, tissue to form in the bone marrow. The scarring means the bone marrow can’t work normally. It makes fewer red blood cells and usually too many white blood cells. Platelets may be increased or decreased. Fibrous tumours may also develop outside of the bone marrow

4. ETIOLOGY

5. Doctors don’t know what causes idiopathic myelofibrosis, but about half of the people with this disease have a change, or mutation, in the JAK2 (Janus kinase 2) gene. What causes this gene mutation is not known. PATHOGENES IS the stem cell change → marrow hematopoietic disturbance →increase of dysmorphic megakaryocytes in marrow → release of cytokines (PDGF, ECGF, TGF- β) → stimulate proliferation of fibroblast → fibrous tissue accumulation

6. CLINICAL MANIFESTATIONS Idiopathic myelofibrosis may not cause any signs or symptoms in its early stages. Symptoms develop as more scar tissue forms in the bone marrow and it can’t work normally. 25% of patients are asymptomatic at the time of diagnosis • Weakness, fatigue, weight loss • Splenomegaly: left upper quadrant abdominal pain (The weight of the spleen can exceed 1000 g) • Hyperproliferative phase (early phase): Thrombocytosis (→ thromboembolic events) Leukocytosis • Pancytopenic phase (late phase): Erythrocytopenia → anemia Thrombocytopenia → petechial bleeding Leukopenia → increased susceptibility to infections

7. fatigue weakness paleness shortness of breath bruising weight loss fever frequent infections night sweats feeling full after eating a small amount discomfort or a feeling of fullness in the abdomen (if the liver and spleen are enlarged) bone pain

8. DIAGNOSIS complete blood count (CBC) to measure the number and quality of white blood cells, red blood cells and platelets blood chemistry tests to show how well certain organs are working reverse transcriptase polymerase chain reaction (RT-PCR) to see if cells in a sample of blood and bone marrow have the JAK2 mutation bone marrow aspiration and biopsy to confirm whether or not you have idiopathic myelofibrosis

9. DIAGNOSIS Laboratory studies: ↑ leukocyte alkaline phosphatase, LDH, and uric acid • Peripheral blood smear: dacrocytes (teardrop cells) • Bone marrow aspiration: punctio sicca (Dry aspiration, severely reduced cell count, and extensive bone marrow fibrosis; alternative procedure: biopsy ) *In myelofibrosis, RBCs shed tears (teardrop cells), because they have been forced out of the fibrosed bone marrow (extramedullary hematopoiesis)

10. BONE MARROW IN MYELOFIBROSIS

11. TREATMENT Hyperproliferative phase - Prevent thromboembolisms: antiplatelet drug (aspirin 100 mg) - Control cell count: hydroxyurea, interferon alpha, cladribine Pancytopenic phase - JAK2 inhibitor: R uxolitinib ( Ruxolitinib is administered to manage severe consitutional symptoms and/or splenomegaly in patients who cannot undergo allogenic stem cell transplantation) - Periodic transfusions (The majority of patients require regular transfusions to manage anemia as the disease progresses) - Low-dose thalidomide plus glucocorticoids (Low-dose thalidomide plus glucocorticoids can be administered to manage anemia and improve leukocyte and platelet count)

12. DRUG THERAPY Drugs may be used alone to improve blood cell counts or lessen symptoms. These drugs include: ruxolitinib ( Jakavi ) hydroxyurea ( Hydrea ) interferon alfa (Intron A, Wellferon ) danazol ( Danocrine ) prednisone anagrelide ( Agrylin ) lenalidomide (Revlimid)

13. SUPPORTIVE THERAPY You may be offered iron and folate supplements if you have anemia. If the anemia is severe, you may need to have blood transfusions. Bisphosphonates are drugs that stop the body from breaking down bone. They also help strengthen bones. You may be given the bisphosphonate zoledronic acid ( Zometa ) if you have idiopathic myelofibrosis.

14. RADIATION THERAPY Radiation therapy uses high-energy rays or particles to destroy cancer cells. During external beam radiation, a machine directs radiation through the skin to the tumour and some of the tissue around it. Some people with idiopathic myelofibrosis will have external beam radiation therapy. It can be used to treat an enlarged spleen, bone pain or tumours that develop outside of the bone marrow.

15. Surgery Surgery to remove the spleen (called splenectomy) may be done if an enlarged spleen is causing pain. It can also be done to help return blood cell counts to normal. Stem cell transplant A stem cell transplant may be a treatment option for some younger people who have advanced idiopathic myelofibrosis.

16. Follow-up Follow-up after treatment is an important part of cancer care. Follow-up for idiopathic myelofibrosis is often shared among the cancer specialists (oncologists) or blood specialists (hematologists) and your family doctor. Your healthcare team will work with you to decide on follow-up care to meet your needs. Don’t wait until your next scheduled appointment to report any new symptoms and symptoms that don’t go away.

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