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Leukemia Copyright, 1996 © Dale Carnegie & Associates, Inc. Leukemia Leukaemias are malignant disorders of the haematopoietic stem cell compartment, characteristically associated with increased numbers of white cells in the bone marrow and/or peripheral blood. The course of leukaemia may vary from a few days or weeks to many years, depending on the type. 4 main types of leukemia Acute or chronic Myeloid or Lymphocytic Demographics of Leukemia Patients CLL=Chronic Lymphocytic ALL 11% others 17% ALL=Acute Lymphocytic CML=Chronic Mylogenous AML=Acute Mylogenous CML 15% CLL 26% AML 31% Stem cells and growth factors in haematopoietic cell development. page 1003 Hematopoietic stem cells give rise to two major progenitor cell lineages, myeloid and lymphoid progenitors Leukemia Development The development of Leukemia uncontrolled and accelerated production of haematopoietic stem cell, progenitors, or mature blood cells which results in incomplete or defective cell maturation ALL CLL Lymphomas MM naïve B-lymphocytes Lymphoid progenitor AML Hematopoietic stem cell Myeloid progenitor Plasma cells T-lymphocytes Myeloproliferative disorders Neutrophils Eosinophils Basophils Monocytes Platelets Red cells Main Types Acute Lymphocytic Leukemia (ALL) Acute Mylogenous Leukemia (AML) Chronic Lymphocytic Leukemia (CLL) Chronic Mylogenous Leukemia (CML) Acute leukemia is characterized by a rapid increase in the numbers of immature blood cells. Crowding due to such cells makes the bone marrow unable to produce healthy blood cells. Immediate treatment is required in acute leukemia due to the rapid progression and accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs of the body. Acute forms of leukemia are the most common forms of leukemia in children. Chronic leukemia is characterized by the excessive build up of relatively mature, but still abnormal, white blood cells. Typically taking months or years to progress, the cells are produced at a much higher rate than normal cells, resulting in many abnormal white blood cells in the blood. Whereas acute leukemia must be treated immediately, chronic forms are sometimes monitored for some time before treatment to ensure maximum effectiveness of therapy. Chronic leukemia mostly occurs in older people, but can theoretically occur in any age group. Pathophysiology Malignant transformation usually occurs at the pluripotent stem cell level, although it sometimes involves a committed stem cell with more limited capacity for differentiation. Abnormal proliferation, clonal expansion, and diminished apoptosis (programmed cell death) lead to replacement of normal blood elements with malignant cells. Main Signs and symptoms 1. Hyperplasia or hyperproliferation of affected cell - uncontrolled proliferation of malignant cells and their spreading (in bone marrow, peripheral blood and organ infiltration (spleen (nausea or feeling of fullness due to an enlarged liver and spleen), lymph nodes, skin, gastrointestinal tract, central nervous system (neurological symptoms (headaches)). Main Signs and symptom 2. Malignant cells replace normal bone marrow elements leading to a) anemia (clinical manifestation - dyspnea and pallor), b) thrombocytopenia (people with leukemia may easily become bruised, bleed excessively, or develop pinprick bleeds (petechiae), c) neutropenia (clinical manifestation - frequent infection, ranging from infected tonsils, sores in the mouth, or diarrhea to life-threatening pneumonia or opportunistic infections), Main Signs and symptom 3. Nonspecific symptoms of intoxication (feeling sick, such as having fevers, chills, night sweats and other flu-like symptoms, or feeling fatigued), 4. Metabolic and Electrolyte Abnormalities Pictures Of Blood Platelet Red Cell White Cell Platelet White Cell Blasts Red Cell Normal human blood Blood with leukemia Development of Leukemia in the Bloodstream Stage 1- Normal Stage 2- Symptoms Stage 3- Diagnosis Legend White Cell Red Cell Platelet Blast Germ Stage 5a- Anemia Stage 4- Worsening Sources from Leukemia, by D. Newton and D. Siegel Stage 5b- Infection ACUTE LEUKEMIA DEFINITION Acute leukemias are clonal malignant hematopoietic disorders resulting from genetic alterations in normal hematopoietic stem cells. These alterations disrupt normal differentiation and/or cause excessive proliferation of abnormal immature “leukemic” cells or “blasts.” As the disease progresses, leukemic cells accumulate in the bone marrow, blood, and organs, displacing normal progenitor cells and suppressing normal hematopoiesis. Clinical presentation Common symptoms of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are a reflection of bone marrow failure and include fatigue, bruising or bleeding, fever, and infection. Pancytopenia: WBCinfection. Hb anemia. platelets bleeding. Organ infiltration: Lymphadenopathy. Splenomegally. Hepatomegally. CNS: 5-10% of patient with ALL Investigations: CBC: 60% of pts have an elevated WBC. Most are anemic Most are thrombocytopenic 90% have blast in the periphral blood film. electrolytes: Hypo/hyper kalemia Hypomagnesimia hyperphosphatemia Hypermetabolism: LDH. uric acid. DIC: Most common with promyelocytic leukemia, small% monocytic leukemia & ALL Bone marrow biopsy and aspirate: 30%or more of all nucleated cells are blast. Radiology: CXR: mediastinal mass(T-cell ALL) Osteopenia or lytic lesion 50% of patients with ALL.(itractable pain). Acute leukemia diagnostic algorithm. French-American-British (FAB) Classification of Acute Myelogenous Leukemia M0 AML with no Romanowsky or cytochemical evidence of differentiation M1 Myeloblastic leukemia with little maturation M2 Myeloblastic leukemia with maturation M3 Acute promyelocytic leukemia (APL) M3h APL, hypergranular variant M3v APL, microgranular variant M4 Acute myelomonocytic leukemia (AMML) M4eo AMML with dysplastic marrow eosinophils M5 Acute monoblastic leukemia (AMoL) M5a AMoL, poorly differentiated M5b AMoL, differentiated M6 “Erythroleukemia” M6a AML with erythroid dysplasia M6b Erythroleukemia M7 Acute megakaryoblastic leukemia (AMkL) Lymphoblast/myeloblast Acute lymphoblastic leukemia ALL-L1 Acute lymphoblastic leukemia ALL-L1 Acute lymphocytic leukemia ALLL2 Acute lymphocytic leukemia ALLL3 Acute lymphocytic leukemia ALLL3 Acute myeloid leukemia AML-M0 Acute myeloid leukemia AML-M1 Acute myeloid leukemia AML-M2 Acute myeloid leukemia AML-M2 + peroxidase Acute myeloid leukemia AML-M3 Acute myeloid leukemia AML-M3 hypogranular Acute myeloid leukemia AML-M4 Acute myeloid leukemia AML-M5 Acute myeloid leukemia AML-M6 Acute myeloid leukemia AML-M7 Management: A-Supportive measure: -isolation in positive laminer flux room -insertion of central line -family and patient support by permanent social worker -AlKaline diuresis to prevent tumor lysis syndrome -oropharynx/GIT decontamination to prevent fungal infection -IV antibiotics for infection -Blood transfusion if anemia and thrombocytopenia. Cont: Special consideration: CNS: -neuroprophylaxis: by intrathecal chemotherapy, high dose systemic MTX or Aracytine. OR cerebrospinal irradiation - meningeal infiltration: Testis: or chidectomy/radiotherapy if testis involvement. Prognosis in ALL parameters Good poor WBC low High(>50x10 9 /l) Gender Girls Boys Immunophenotype C-ALL B-ALL Age Child Adult or infant. Cytogenetic Normal,hyperdiploid, Ph+,11q23rearrangements. Time to clear blast from blood < 1week >1week Time to remission <4weeks >4weeks Cns disease at presentation Absent Present Minimal residual disease. Negative at 1-3 months Still positive at 3-6 months. Prognosis in AML parameters Cytogentics BM response to remission induction age Favorable unfavorable T(15;17). T(8;21). Inv(16). Deletion of chromosome5or7. 11q23 T(6;9) Abn(3q)complex rearrangments <5% blasts after first course >20% blasts after first course. <60yrs >60yrs Chronic lymphocytic leukemia (1) Is characterised by the accumulation of nonproliferating mature-appearing lymphocytes in the blood, marrow, lymph nodes, and spleen In most cases, the cells are monoclonal B lymphocytes that are CD5+ T cell CLL can occur rarely CLINICAL Localized or generalized lymphadenopathy Splenomegaly (30-40% of cases) Hepatomegaly (20% of cases) Petechiae Pallor lymphadenopathy Chronic lymphocytic leukemia Hairy-cell leukemia Smudge Cells Smudge Cells The diagnostic criteria for CLL 1) A peripheral blood lymphocyte count of greater than 5 G/L, with less than 55% of the cells being atypical 2) The cell should have the presence of Bcellspecific differentiation antigens (CD19, CD20, and CD24) and be CD5(+) 3) A bone marrow aspirates showing greater than 30% lymphocytes Investigations Pretreatment studies of patients with CLL should include examination of: complete blood count peripheral blood smear reticulocyte count Coomb’s test renal and liver function tests serum protein electrophoresis immunoglobulin levels plasma 2 microglobulin level If available immunophenotyping should be carried out to confirm the diagnosis Bone marrow biopsy and cytogenetic analysis is not routinely performed in CLL Staging (1) Rai Classification for CLL 0 - lymphocytosis (>5 G/L) I - lymphocytosis + lymphadenopathy II - lymphocytosis + splenomegaly +/-lymphadenopathy III - lymphocytosis + anemia (Hb <11g%) +/lymphadenopathy or splenomegaly IV - lymphocytosis + thrombocytophenia (Plt <100G/L) +/- anemia +/-lymphadenopathy +/- splenomegaly Staging (2) Binet Classification for CLL A. < 3 involved areas, Hb > 10g%, Plt > 100G/L B. > 3 involved areas, Hb > 10g%, Plt > 100G/L C. - any number of involved areas, Hb < 10g%, Plt < 100G/L Prognosis Rai classification stage 0 I II III IV median survival (years) >10 > 8 6 2 < 2 Binet classification stage A B C median survival (years) > 10 7 2 Treatment Treatment is reserved for patients with low- or intermediate risk disease who are symptomatic or have progressive disease (increasing organomegaly or lymphocyte doubling time of less than 12 months) and patients with high -risk disease Alkylating agents (chlorambucil, cyclophosphamide) Nucleoside analogs (cladribine, fludarabine) Biological response modifiers Monoclonal antibodies Bone marrow transplantation And systemic complications requiring therapy antibiotics immunoglobulin steroids blood products Chronic Myeloid Leukemia Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate. Consequently, the peripheral blood cell profile shows an increased number of granulocytes and their immature precursors, including occasional blast cells. Chronic myeloid leukemia Leukemia Chronic Myelogenous Leukemia Cancer of the granulocytes or monocytes, compared to leukocytes in lymphocytic leukemia Comprises about 14% of all adult leukemias Males slightly higher than females One of the first cancers to have a specific genetic link to a chromosomal mutation identified for the disease Philadelphia Chromosome Pathophysiology Disorder of the stem cells in bone marrow General infection fighting cells are the most harmed > granulocytes and monocytes (aka, neutrophils) These immature cells take over the body’s mature neutrophils and hinder the body’s ability to fight infection properly CML is caused by a genetic mutation with chromosomes 9 and 22 in the body Abl on chromosome 9 is translocated to chromosome 22 and fuses with Bcr This ABL-BCR protein is an unregulated tyrosine kinase and thus, is the source of the reproduction of immature granulocytes Other functions include: upstream changes of DNA repair mechanisms, suppression of the body’s programmed cell death proteins, and changes in cytoskeletal structures HEPATOSPLENOMEGALY The disease has 3 clinical phases, and it follows a typical course of an initial chronic phase, in which the disease process is easily controlled; followed by a transitional and unstable course (accelerated phase); and, finally, a more aggressive course (blast crisis), which usually is fatal. Accelerated phase , which may last for several months. The survival of patients diagnosed in this phase is 1-1.5 years. This phase is characterized by poor control of the blood counts with myelosuppressive medication and the appearance of peripheral blast cells ( 15%), promyelocytes ( 30%), basophils ( 20%), and platelet counts less than 100,000 cells/ L unrelated to therapy. The doses of the medications need to be increased; splenomegaly may not be controllable by medications, and anemia can worsen. Bone pain and fever, as well as an increase in bone marrow fibrosis, are harbingers of the last phase. Acute phase, or blast crisis, o is similar to acute leukemia, and survival is 3-6 months at this stage. Bone marrow and peripheral blood blasts of 30% or more are characteristic. Skin or tissue infiltration also defines blast crisis. Cytogenetic evidence of another Ph-positive clone (double) or clonal evolution (other cytogenetic abnormalities such as trisomy 8, 9, 19, or 21, isochromosome 17, or deletion of Y chromosome) usually is present. blast crisis Treatment Options: Pharmacotherapy Newer drugs are prolonging chronic phase and increasing the number of patients who enter into remission They are easier on the body versus SCT Old Standard: hydroxyurea (no possible cytogenic response) or interferon alpha + cytarabine New Standard: tyrosine kinase inhibitors Imatinib, dasatanib, nilotonib Stem Cell Transplant Using bone marrow from a donor to “resupply” the patient Can be the only “curative” measure, although many drawbacks Must be good candidates for surgery Must have a relatively short time from diagnosis to transplant Matching donor Possible relapse of CML Rejection (GVHD) A small number of patients show some resistance to Imatanib The BRC-ABL transcript has the ability to mutate and thus make imatinib ineffective Imatinib binds to the closed conformation and BRC-ABL can mutate to the open conformation and thus makes imatanib ineffective Two 2nd generation TKIs have proven to be more potent and are in trials to determine effectiveness against resistance to imatanib Treatment Algorithm