LEUKEMIA Medrockets.com

OVER VIEW The stem cells are committed to produce specific types of blood cells. Lymphoid stem cells produce either T or B lymphocytes. Myeloid stem cells differentiate into three broad cell types: RBCs, WBCs, and platelets. Medrockets.com

Function of the bone marrow The bone marrow is found in the inside of bones. The marrow in the large bones of adults produces blood cells. Approximately 4% of our total bodyweight consists of bone marrow.  There are two types of bone marrow: 1. Red marrow, made up mainly of myeloid tissue. 2. Yellow marrow, made up mostly of fat cells.

Red marrow can be found in the flat bones, such as the breast bone, skull, vertebrae, shoulder blades, hip bone and ribs. Red marrow can also be found at the ends of long bones, such as the humerus and femur. 

White blood cells (lymphocytes), red blood cells and platelets are produced in the red marrow. Red blood cells carry oxygen, white blood cells fight diseases. Platelets are essential for blood clotting. Yellow marrow can be found in the inside of the middle section of long bones. 

White blood cells, which help to body fight infection. Red blood cells, which carry oxygen to all parts of the body. Platelets, which help in blood clot. If a person loses a lot of blood the body can convert yellow marrow to red marrow in order to raise blood cell production. 

DEFINITION Leukamia is a group of malignant disorder, affecting the blood and blood –forming tissue of the bone marrow lymph system and spleen. The word Leukemia comes from the Greek leukos which means "white" and aima which means "blood". Medrockets.com

ETIOLOGY Congenital anomaly Heredity Infections: Human T cell leukaemia-lymphoma virus I (HTLV-I) Environmental factors – Ionising radiation – Chemical carcinogens – Certain drugs. Association with diseases of immunity: Immunodeficiency diseases like AIDS and iatrogenic immunosuppression induced by chemotherapy or radiation, Congenital anomaly Medrockets.com

The lack of control causes – PATHOPHYSIOLOGY The lack of control causes – nomal bone marrow to be replaced by immature and undifferentiated leukocytes or blat cells . – abnormal immature leukocytes then circulates in the blood and infiltrate the blood forming organs ( liver , spleen, lymph nodes) and other sites throughout the body.

LASSIFICATION OF LEUKAMIA • French-American-British (FAB) CLASSIFICATION – Based on morphology and cytochemistry,# – It divides AML into 8 subtypes (M0 to M7) • WHO CLASSIFICATION (2002) – differs from revised FAB classification – limited reliance on cytochemistry for making the diagnosis of subtype of AML – Based on clinical, cytogenetic and molecular abnormalitie

WHO CLASSIFICATION (2002) • AML with recurrent cytogenetic abnormalities • AML with multilineage dysplasia • AML and MDS (Myelodysplastic Syndrome), therapy-related • AML, not otherwise categorised Medrockets.com

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Classification of Lukemia

Acute lymphatic leukaemia (ALL) Usually occurs before 14 years of age peak incidence is between 2-9 years of age, older adult Pathophysiology It arising from a single lymphoid stem cell, with impaired maturation and accumulation of the malignant cells in the bone marrow.

Clinical features of ALL Anemia Bleeding Lymphaedopathy Infection Fever Pallor Anorexia Fatigue Weakness Bone, joint and abdominal pain Increase intracranial press. Medrockets.com

ALL Diagnosis Low RBCs count, Hb, Hct, low platelet count , low normal or high WBC count. Blood smear show immature lymph blasts. Treatment Chemotherapeutic agent, it involve three phases Induction: Using vincristine and prednisone. Consolidation: Using modified course of intensive therapy to eradicate any remaining. Maintenance

Treatment Cont. Prophylactic treatment of the CNS , intrathecal administration and /or craniospinal radiation with eradicate leukemic cells. Eat diet that contains high in protein, fibres and fluids. Avoid infection (hand washing, avoid crowds),injury Take measure to decrease nausea and to promote appetite, smoking and spicy and hot foods. Maintain oral hygiene. Medrockets.com

Acute Myelogenous Leukamia (AML) It occurs at any age but occurs most often at adolescence and after age of 55 Characterized by the development of immature myeloblasts in the bone marrow. Clinical manifestations of AML are divided into 2 groups due to – Bone marrow failure – Organ infiltration Medrockets.com

Clinical Features: Bone marrow failure Anaemia producing pallor, lethargy, dyspnoea. • Bleeding manifestations due to thrombocytopenia causing spontaneous bruises, petechiae, bleeding from gums and other bleeding tendencies. • Infections are quite common and include those of mouth, throat, skin, respiratory, perianal and other sites. • Fever : no obvious source of infection can be found and may occur in the absence of infection Medrockets.com

Clinical Features: Organ infiltration • due to replacement of the marrow and other tissues by leukaemic cells. • Pain and tenderness of bones (e.g. sternal tenderness) - bone infarcts or subperiosteal infiltrates by leukaemic cells. • Lymphadenopathy and enlargement of the tonsils may occur • Splenomegaly of moderate grade may occur – Splenic infarction, subcapsular haemorrhages, and rarely, splenic rupture may occur. • Hepatomegaly Medrockets.com

Laboratory Findings The diagnosis of AML is made by a combination of routine blood picture and bone marrow examination, coupled with cytochemical stains and other special laboratory investigations. • BLOOD PICTURE. – Anaemia. – Thrombocytopenia: moderately to severely reduced (below 50,000/μl) but occasionally it may be normal. – White blood cells: ranges from subnormal-to-markedly elevated values • 25% of patients – reduced to 1,000-4,000 /μl. • More often, however, there is progressive rise in white cell count which may exceed 100,000/μl in more advanced disease. • Majority of leucocytes in the peripheral blood are blasts and there is often neutropenia due to marrow infiltration by leukaemic cells.

BONE MARROW EXAMINATION • Cellularity: Typically, the marrow is hypercellular but sometimes a ‘blood tap’ or ‘dry tap’ occurs. • Leukaemic cells – generally tightly packed with leukaemic blast cells – Romanowsky stains: cytochemical stains may be employed to know the type of leukaemia. Erythropoiesis. • Erythropoietic cells are reduced. • Megakaryocytes. They are usually reduced or absent. • Cytogenetics: shows karyotypic abnormalities in 75% of cases which may have a relationship to prognosis. • Immunophenotyping. AML cells express CD13 and CD33 antigens. M7 shows CD41 and CD42 positivity. Medrockets.com

Treatment and Complications • ANAEMIA AND HAEMORRHAGE. – Anaemia and haemorrhage are managed by fresh blood transfusions and platelet concentrates. – Patients with severe thrombocytopenia (platelet count below 20,000/μl) require regular platelet transfusions • haemorrhage is an important cause of death in these cases • CYTOTOXIC DRUG THERAPY – Aim: firstly induce remission, secondly to continue therapy to reduce the hidden leukaemic cell population by repeated courses of therapy. – The most effective treatment of AML is a combination of 3 drugs: cytosine arabinoside, anthracyclines (daunorubicin, adriamycin) and 6-thioguanine. – Another addition is amsacrine (m-AMSA) administered with cytosine arabinoside, with or without 6-thioguanine. • BONE MARROW TRANSPLANTATION – Bone marrow (or stem cell) transplantation from suitable allogenic or autologous donor – The basic principle of marrow transplantation is to reconstitute the patient’s haematopoietic system after total body irradiation and intensive chemotherapy – kill the remaining leukemic cell – Bone marrow transplantation has resulted in cure in about half the cases.

• Remission rate with AML is lower (50-70%) than in ALL, Prognosis • Remission rate with AML is lower (50-70%) than in ALL, • Often takes longer to achieve remission, and disease- free intervals are shorter. • AML is most malignant of all leukaemia • Survival with treatment is 12-18 months. Medrockets.com

Chronic lymphocytic Leukaemia (CLL) The incidence of CLl increases with age and is rare under the age of 35.It is common in men. It is characterized by proliferation of small, abnormal , mature B lymphocytes, often leading to decreased synthesis of immunoglobulin and depressed antibody response. The number of mature lymphocytes in peripheral blood smear and bone marrow are greatly increased Medrockets.com

CLL Clinical Manifestation Usually there is no symptoms. Chronic fatigue , weakness , anorexia, splenomegaly , lymphadenopathy, hepatomegaly. Signs and Symptoms Pruritic vesicular skin lesions . Anaemia Thrombocytopenia. The WBC count is elevated to a level between 20,000 to 100,000. Increase blood viscosity and clotting episode. Medrockets.com

Management Treatment is only when there are symptoms, particular anaemia , thrombocytopenia , enlarged lymph nodes and spleen appear. Chemotherapy agents such as chlorambucil , and the glucocorticoids. Medrockets.com

Chronic Myelogenous Leukaemia(CML) Excessive development of mature neoplastic granulocytes in the bone marrow – Move into the peripheral blood in massive numbers – Ultimately infiltrate the liver and spleen Occurs between 25-60 years of age. Peak 45 year It is caused by benzene exposure and high doses of radiation. It is associated with Philadelphia chromosome Philadelphia chromosome is the chromosome abnormality that causes chronic myeloid leukemia Medrockets.com

Clinical Manifestation There is usually no symptoms. The classic symptoms, include: Fatigue, weakness, fever. Weight loss, joint & bone pain. Massive splenomegaly The accelerated phase of disease(blostic phase) is characterized by increasing number of granulocytes in the peripheral blood. There is a corresponding anaemia and thrombocytopenia. Medrockets.com

Laboratory Findings • The diagnosis of CML is generally possible on blood picture alone. However, bone marrow, cytochemical stains and other investigations are also useful • BLOOD PICTURE – Anaemia. Anaemia is usually of moderate degree and is normocytic normochromic in type. – White blood cells. Characteristically, there is marked leucocytosis (approximately 200,000/μl or more at the time of presentation). The natural history of CML consists of 3 phases—chronic, accelerated, and blastic. • Chronic phase: begins as a myeloproliferative disorder and consists of excessive proliferation of myeloid cells of intermediate grade (i.e. myelocytes and metamyelocytes) and mature segmented neutrophils. • Accelerated phase: increasing degree of anaemia, blast count in blood or marrow between 10-20%, marrow basophils 20% or more, and platelet count falling below 1,00,000/μl. • Blastic phase or blast crisis: blood or marrow blasts >20%. Myeloid blast crisis in CML is more common and resembles AML. – Auer rods are not seen in myeloblasts of CML in blast crisis. – Platelets. Platelet count may be normal but is raised in about half the cases.

• OTHER INVESTIGATIONS BONE MARROW EXAMINATION • Cellularity: hypercellularity with total or partial replacement of fat spaces by proliferating myeloid cells. • Myeloid cells: predominate in the bone marrow with increased myeloid-erythroid ratio. The differential counts of myeloid cells in the marrow show similar findings as seen in the peripheral blood with predominance of myelocytes. • Erythropoiesis: normoblastic but there is reduction in erythropoietic cells. • Megakaryocytes: are conspicuous but lare usually smaller in size than normal. • Cytogenetics: the characteristic chromosomal abnormality called Philadelphia (Ph) chromosome (90-95%) • CYTOCHEMISTRY • The only significant finding on cytochemical stains is reduced scores of neutrophil alkaline phosphatase (NAP) • These helps to distinguish CML from myeloid leukaemoid reaction in which case NAP scores are elevated • OTHER INVESTIGATIONS • Elevated serum vitamin B 12 and vitamin B12 binding capacity. • Elevated serum uric acid (hyperuricaemia).

Treatment Knowledge of molecular mechanism of CML has brought about major changes in its therapy. • The approach of modern therapy in CML is targetted at removal of all malignant clones of cells bearing BCR/ABL fusion protein, • So that patient reverts back to prolonged non-clonal haematopoiesis. • This is achievable by the following approaches – Imatinib oral therapy – Allogenic bone marrow (stem cell) transplantation. – Interferon-α. – Chemotherapy – Others: splenic irradiation, splenectomy and leucopheresis. • The most common cause of death (in 80% cases) in CML is disease acceleration and blastic transformation The commonly drugs are hydroxyurea and busulfan The only potential curative therapy of CML is the bone marrow transplant. Medrockets.com

Treatment of Leukamia depends The type of leukemia (acute or chronic) Age Whether leukemia cells were found in cerebrospinal fluid Medrockets.com

watchful waiting, chemotherapy, targeted therapy, MANAGEMENT watchful waiting, chemotherapy, targeted therapy, radiation therapy, and stem cell transplant. Medrockets.com

chemotherapy People with acute leukemia need to be treated right away. The goal of treatment is to destroy signs of leukemia in the body and make symptoms go away. This is called a remission. After people go into remission, more therapy may be given to prevent a relapse. Medrockets.com

The 3 phases of treatment protocols are Induction phase; the usual criteria for complete remission are 5% of the bone marrow cells and normal peripheral blood counts. Once remission completes the consolidation phase begins. Consolidation phase; modified course of intensive chemotherapy are given to eradicate any remaining disease. Usually a higher dose of one or more chemotherapeutic agents are administered. Maintenance phase; small dose of different combination of chemotherapeutic agents are given every 3 to 4 weeks. This phase may continue for a year or longer and is structured to allow the client to live as normal life as possible

Targeted therapy This affects only tumor cells and spare normal cells. hence decreasing the associated toxicities. Gemtuzumab ozofamicin (mylotarg) is an anti D33nmonoclonal antibody linked to calicheamicin, which is potent cytotoxic agent. STEM CELL TRANSPLANT Goal; Totally eliminate leukemic cells from the body using combinations of chemotherapy with or without total body irradiation Eradicates patient’s hematopoietic stem cells Replaced with those of an HLA-matched (Human Leukocyte Antigen) Medrockets.com

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