LEUKEMIAS Dr Nazzal Bsoul Hematologist Al Bashir Hospital

LEUKEMIAS Dr. Nazzal Bsoul Hematologist Al Bashir Hospital

Terminology Leukos: White Aimia: Blood Leukemia----Leukaemia ? Hematology-----Haematology ? Leukemoid reaction:

Definition Leukemia: is a cancer of the blood or bone marrow characterized by abnormal proliferation of blood cells, usually WBCs(Leukocytes). Acute leukemia: rapid increase of immature blood cells. Chronic leukemia: excessive build up of relatively mature, but still abnormal blood cells.

Leukemoid Reaction A leukemoid reaction describes a high WBC count with neutrophilia, usually in response to infection. The WBC count may be as high as 50, 000 /micro. L and can easily mimic CML or AML.

Features Suggesting Leukemoid Reaction Toxic granulation. High LAP score. Presence of an obvious cause for the neutrophilia.

Signs and Symptoms Most of the signs and symptoms are due to: 1 -Anemia. 2 -Leukopenia. 3 -Thrombocytopenia. Bicytopenia, Pancytopenia. All symptoms associated with leukemia can be attributed to other diseases, consequently, leukemia is always diagnosed by laboratory investigations.

Causes Leukemia, like other malignancies, results from somatic mutations in the DNA. Certain mutations produce leukemia by activating oncogenes or deactivating tumor suppressor genes. These mutations may occur spontaneously or as a result of exposure to radiation or carcinogenic substances, and likely to be influenced by genetic factors.

Causes-cont’d Ionizing radiation Viruses: Human T-lymphotropic virus (HTLV-1) Chemicals: Benzene, chemotherapy. Smoking: slight increase in leukemia incidence. Genetic predisposition toward developing leukemia: Down syn. , Fanconi anemia

Acute Myeloid Leukemia

Definition Acute myeloid leukemia (AML): acute myelogenous leukemia, acute nonlymphocytic leukemia. AML consists of a group of relatively welldefined hematopoietic neoplasms involving precursor cells commited to the myeloid line(WBCs, RBCs, PLTs)

Chracteristics AML is characterized by a clonal proliferation of myeloid precursors with a reduced capacity to differentiate into mature cellular elements. As a result, there is an accumulation of leukemic blasts or other immature forms in the BM, peripheral blood, and other tissues with a variable reduction in the production of normal RBCs, platelets, and mature granulocytes.

Epidemiology AML is the most common acute leukemia in adults (80%). In USA 3 -5 cases per 100 000 population. In contrast AML accounts for less than 10% of acute leukemia cases in children less than 10 years of age. The M/F ratio is approximately 5: 3.

Epidemiology-cont’d AML has been associated with the following: 1 -Environmental factors: chemicals, radiation, tobacco, and chemotherapy. 2 -Genetic abnormalities: Down syndrome, Fanconi anemia. 3 -Other benign hematological disorders: Paroxysmal nocturnal hemoglobinuria 4 -Malignant hematological disorders: MDS, MPN

Classification Multiple classification systems. FAB classification: French-American-British Classification. FAB Classification relies on morphologic, cytochemical, and immunophenotyping criteria to define 8 major subtypes (M 0 -M 7)

Clinical Presentation Patients with AML present usually with symptoms related to pancytopenia: 1 -Anemia. 2 -Leukopenia with neutropenia. 3 -Thrombocytopenia.

Pathological Features CBC and differential. Blood film (smear). Bone marrow examination: BM aspirate and trephine biopsy. 1 -Morphology. 2 -Immunephenotyping. 3 -Cytogenetics and molecular biology.

WBC Count in AML WBC count in AML can be high, normal, or low. Median WBC count in AML is 15 000/u. L. 20% of patients have > 100 000/u. L 25 -40% of patients have <5000/u. L 95% of patients have blast cells on blood film.

Treatment AML is usually treated with: 1 -Chemotherapeutic agents. 2 -Bone marrow transplantation (BMT), hematopoietic stem cell transplantation (HSCT). 3 -Supportive treatment: blood transfusion, PLT transfusion, Granulocyte colony stimulating factor (G-CSF), i. v fluids, antibiotics.

Prognosis The response to treatment and overall survival of patients with AML are heterogenous. Prognostic factors are related to patient and tumor characteristics: 1 -Age 2 -Performance status 3 - Karyotype

Adverse Clinical Predictors Advanced age. Poor performance status. History of exposure to cytostatic agents or radiotherapy. (Therapy-related AML). History of MDS or other hematological diseases

Chronic Myeloid Leukemia (CML)

Terminology Chronic myeloid leukemia (CML). Chronic myelocytic leukemia. Chronic myelogenous leukemia. Chronic granulocytic leukemia (CGL).

Definition CML is a myeloproliferative neoplasm characterized by the dysregulated production and uncontrolled proliferation of mature and maturing granulocytes with fairly normal differentiation. CML is associated with the fusion of genes: BCR(on chromosome 22)and ABL 1(on chromosome 9), resulting in the BCR/ABL 1 fusion gene.

This abnormal fusion gene (protein) typically results from a reciprocal translocation between chromosome 9 and 22, t(9; 22). (Philadelphia chromosome)

Epidemiology CML accounts for 15 -20 % of leukemias in adults. Annual incidence of 1 -2 cases per 100, 000 Median age at presentation is 60 years. Exposure to ionizing radiation is the only known risk factor. The prevalence of CML is steadily increasing due to ? .

Clinical manifestation CML has a triphasic or biphasic course: 1 -Chronic phase: 85% of pts. at dg. 2 -Accelerated phase: WBC count is more difficult to control. 3 -Blast crisis: a condition resembling acute leukemia (AML, ALL).

Clinical findings at dg. vary among reported series and also depend upon the stage of the disease at dg. 20 -50% of patients are asymptomatic. 50 -80% of patients are symptomatic: Systemic symptoms(fatique, w. loss, excessive sweating, bleeding due to PLT dysfunction).

Clinical findings-cont’d Abdominal symptomatology: Lt. UQ pain, early satiety, nausea, vomiting. Tenderness over the lower sternum. Other frequent findings include: Splenomegaly: 48 -76% of cases. Anemia: 45 -62% of cases. Leukocytosis: WBC count above 100, 000/micro. L. Thrombocytosis: 15 -34% of cases.

Peripheral blood Leukocytosis: median WBC count 100, 000 /micro. L(range 12 -1000/micro. L). Anemia: 45 -60%. Normochromic, normocyt. Thrombocytosis: above 600, 000(15 -30%) Blood film: all stages of maturation. LAP score: Low (Leukemoid reaction high or N) Absolute basophilia, eosinophilia, monocytosis.

Bone marrow aspirate and biopsy: 1 -Granulocytic hyperplasia. 2 - Increase in reticulin fibrosis and vascularity.

Genetics Genetic testing for: t(9; 22)(q 32; q 11, 2) Philadelphia chromosome. BCR/ABL 1 fusion gene Fusion m. RNA gene product Conventional cytogenetic analysis (karyotyping) Florescence in situ hybridization (FISH) Reverse transcription PCR (RT-PCR).

Diagnosis CML is suspected in a patient with some of the findings mentioned above(syst. complaints, early satiety, hepatosplenomegaly, leukocytosis…. ) Morphologic features in the blood and BM. Confirmed by genetic studies.

Differential diagnosis Leukemoid reaction. Juvenile myelomonocytic leukemia(JMML) Chronic myelomonocytic leukemia(CMML) Atypical CML. Chronic eosinophilic leukemia. Chronic neutrophilic leukemia. Other myeloproliferative neoplasms. Other Ph chromosome-posit. Malignancies.

Prognosis The stage of disease at dg. is the strongest single predictor of outcome in patients with CML. Scoring systems: Sokal prognostic score: 4 clinical variables: 1 -Spleen size 2 -Percent blasts. 3 -Age 4 -PLT count above 700, 000/micro. L.

Treatment of CML Available treatment options: 1 -Allogeneic hematopoietic stem cell transplantation (HSCT, BMT): curative treatment option. 2 -Disease control without cure using tyrosine kinase inhibitors (TKIs). 3 -Palliative therapy with cytotoxic agents 4 -Investigational therapies: Farensyl transferase inhibitors, dicitabine.

Choice of therapy Factors influencing the choice of therapy: 1 -Phase of the disease. 2 -Availability of a donor for HSCT. 3 -Patient age. 4 -Presence of co-morbidities. 5 -Response to treatment with TKIs.

Tyrosine Kinase Inhibitors (TKIs) TKIs target the active tyrosine kinase implicated in the pathogenesis of CML. 1 -First-generation oral TKIs: Imatinib (Glivec, Cemivil). 2 -Second-generation TKIs: Nilotinib (Tasigna), Dasatinib. Although TKIs do not cure CML, these agents are able to achieve long-term control of the disease.

THANK YOU