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Leukemias
Copyright, 1996 © Dale Carnegie & Associates, Inc.
The development of Leukemiauncontrolled and accelerated production of haematopoietic stem
cell, progenitors, or mature blood cells which results in incomplete or defective cell maturation
Acute Lymphocytic Leukemia (ALL)
Acute Mylogenous Leukemia (AML)
Chronic Lymphocytic Leukemia (CLL)
Chronic Mylogenous Leukemia (CML)
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Demographics of Leukemia Patients
ALL11%
CLL26%
AML31%
CML15%
others17%
CLL=Chronic Lymphocytic
ALL=Acute Lymphocytic
CML=Chronic Mylogenous
AML=Acute Mylogenous
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Stem cells and growth factors in haematopoietic cell development.
page 1003
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Hematopoietic stem cells give rise to two major progenitor cell lineages, myeloid and lymphoid
progenitors
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ALLALL MM MM CLLCLL LymphomasLymphomas
Hematopoieticstem cell
Neutrophils
Eosinophils
Basophils
Monocytes
Platelets
Red cells
Myeloidprogenitor
Myeloproliferative disordersMyeloproliferative disordersAMLAML
Lymphoidprogenitor T-lymphocytes
Plasma
cells
B-lymphocytes
nanaïïveve
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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.
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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.
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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)).
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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),
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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
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Pictures Of Blood
Normal human blood
White Cell Red Cell
Platelet
Blood with leukemia
BlastsRed Cell
Platelet
White Cell
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Development of Leukemia in the Bloodstream
Stage 1- Normal Stage 2- Symptoms Stage 3- Diagnosis
Stage 4- Worsening
Stage 5a- Anemia
Stage 5b- Infection
Legend
White Cell
Red Cell Platelet Blast Germ Sources from Leukemia, by D. Newton and D. Siegel
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DEFINITIONAcute 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.
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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
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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).
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Acute leukemia diagnostic algorithm.
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Lymphoblast/myeloblast
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Acute lymphoblastic leukemia ALL-L1
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Acute lymphoblastic leukemia ALL-L1
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Acute lymphocytic leukemia ALL-L2
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Acute lymphocytic leukemia ALL-L3
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Acute lymphocytic leukemia ALL-L3
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Acute myeloid leukemia AML-M0
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Acute myeloid leukemia AML-M1
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Acute myeloid leukemia AML-M2
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Acute myeloid leukemia AML-M2 + peroxidase
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Acute myeloid leukemia AML-M3
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Acute myeloid leukemia AML-M3 hypogranular
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Acute myeloid leukemia AML-M4
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Acute myeloid leukemia AML-M5
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Acute myeloid leukemia AML-M6
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Acute myeloid leukemia AML-M7
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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.
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Cont:
Special consideration:CNS:
-neuroprophylaxis:
- meningeal infiltration:
Testis:or chidectomy/radiotherapy if testis involvement.
by intrathecal chemotherapy, high dose by intrathecal chemotherapy, high dose systemic MTX or Aracytine. OR systemic MTX or Aracytine. OR
cerebrospinal irradiationcerebrospinal irradiation
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Prognosis in ALL parametersparameters GoodGood poorpoorWBC lowlow High(>50x10 High(>50x10 9 9 /l)/l)
Gender GirlsGirls BoysBoys
Immunophenotype C-ALLC-ALL B-ALLB-ALL
Age ChildChild Adult or infant.Adult or infant.
Cytogenetic Normal,hyperdiploid,Normal,hyperdiploid, Ph+,11q23rearrangements.Ph+,11q23rearrangements.
Time to clear blast from blood
< 1week< 1week >1week>1week
Time to remission <4weeks<4weeks >4weeks>4weeks
Cns disease at presentation
AbsentAbsent PresentPresent
Minimal residual disease.
Negative at 1-3 monthsNegative at 1-3 months Still positive at 3-6 months.Still positive at 3-6 months.
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Prognosis in AML parametersparameters FavorableFavorable unfavorableunfavorable
CytogenticsCytogentics T(15;17).T(15;17).
T(8;21).T(8;21).
Inv(16).Inv(16).
Deletion of Deletion of chromosome5or7.chromosome5or7.
11q2311q23
T(6;9)T(6;9)
Abn(3q)complex Abn(3q)complex rearrangmentsrearrangments
BM response to BM response to remission inductionremission induction
<5% blasts after first <5% blasts after first coursecourse
>20% blasts after first >20% blasts after first course.course.
ageage <60yrs<60yrs >60yrs>60yrs
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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
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CLINICAL Localized or generalized lymphadenopathy
Splenomegaly (30-40% of cases)Hepatomegaly (20% of cases)
PetechiaePallor
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lymphadenopathy
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Chronic lymphocytic leukemia
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Hairy-cell leukemia
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Smudge Cells
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Smudge Cells
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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 Bcell-specific differentiation antigens (CD19, CD20, and CD24) and be CD5(+)
3) A bone marrow aspirates showing greater than 30% lymphocytes
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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
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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
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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
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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
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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.
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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
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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
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HEPATOSPLENOMEGALY
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chronic phase accelerated phase
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accelerated phase blast crisis
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blast crisis
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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
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Treatment Algorithm