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Malignancies
SMF HEMATOLOGI- ONKOLOGI MEDIK ILMU PENYAKIT
DAL AM
R UM AH S AK IT P U S AT KAN K E R N ASION AL D H ARM AIS
Leukemia
Cancer that starts in blood-forming tissue, such as the
bone marrow, and causes large numbers of abnormal
blood cells to be produced and enter the bloodstream.
http://www.cancer.gov/cancertopics/types/leukem
Types of Leukemia
o According to cell type:
o Myelogenous leukemia
o Lymphocytic leukemia
http://www.hematology.org/Patients/Cancers/Leukemia.as
Acute Myelogenous
Leukemia (AML)
A g ro u p o f c l o n a l h e m a t o p o i e t i c s t e m c e l l d i s o r d e r s i n w h i c h b o t h a b l o c k
i n d i ff e re n t i a t i o n a n d u n c h e c ke d p ro l i f e r a t i o n re s u l t i n t h e a c c u m u l a t i o n
o f m y e l o b l a s t s a t t h e ex p e n s e o f n o rm a l h e m a t o p o i e t i c p re c u r s o r .
http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hematology-oncology/acutemyelogenous-leukemia
Epidemiology
o The incidence is 3.5 per 100,000
people per year.
o The age-adjusted incidence is higher in
men than in women (4.3 vs 2.9).
o Incidence increases with age.
o The median age at diagnosis is 67 years.
The acute myeloid leukemia incidence rates by sex
and age for the US male and female in 2007.
http://
www.medinfographics.com/cancer-statistics/leukemia/acute-myeloid-leukemia-cancer-statistics/acute-myeloid-leukemia-incidenc
e-by-sex-and-age
Wetzler M, Marcucci G, Bloomfield CD. Acute and chronic myeloid leukemia. In: Harrisons Hematology and Oncology. 2nd ed.
2013
Risk Factors
o Heredity
o Radiation
o Chemical and other occupational exposures
o Drugs
Wetzler M, Marcucci G, Bloomfield CD. Acute and chronic myeloid leukemia. In: Harrisons Hematology and
Oncology. 2nd ed. 2013
FAB
Classification
ttp://www.elsevierimages.com/image/28067.htm
Wetzler M, Marcucci G, Bloomfield CD. Acute and chronic myeloid leukemia. In: Harrisons Hematology and Oncology. 2nd ed.
2013
Wetzler M, Marcucci G, Bloomfield CD. Acute and chronic myeloid leukemia. In: Harrisons Hematology and Oncology. 2nd ed.
2013
Clinical Manifestation
(Symptoms)
o Nonspecific symptoms that are the consequence of anemia, leukocytosis,
leukopenia or leukocyte dysfunction, or thrombocytopenia, such as:
o Fatigue or weakness
o Anorexia and weight loss.
o Fever with or without an identifiable infection.
o Abnormal hemostasis (bleeding, easy bruising).
o Bone pain, lymphadenopathy, nonspecific cough, headache, or diaphoresis.
o Nearly half have had symptoms for 3 months before the leukemia was
diagnosed.
Wetzler M, Marcucci G, Bloomfield CD. Acute and chronic myeloid leukemia. In: Harrisons Hematology and Oncology. 2nd ed.
2013
Hematologic Findings
o Anemia :
o Usually normocytic normochromic.
o Decreased erythropoiesis reduced reticulocyte count
o RBC survival is decreased by accelerated destruction.
o Active blood loss also contributes to the anemia.
o Trombositopenia:
o Platelet counts <100,000/L are found at diagnosis in 75% of patients, and about 25% have counts
<25,000/L.
o Both morphologic and functional platelet abnormalities can be observed, such as:
o Large and bizarre shapes with abnormal granulation.
o Inability of platelets to aggregate or adhere.
Wetzler M, Marcucci G, Bloomfield CD. Acute and chronic myeloid leukemia. In: Harrisons Hematology and Oncology. 2nd ed.
2013
Hematologic Findings
o Leukocyte:
o Median presenting leukocyte count is about 15,000/L.
About 25 - 40% of patients have counts <5000/L, and
20% have counts >100,000/L.
o <5% have no detectable leukemic cells in the blood.
o The cytoplasm often contains primary (nonspecific)
granules, and the nucleus shows fine, lacy chromatin
with one or more nucleoli characteristic of immature
cells.
o Abnormal rod-shaped granules called Auer rods are
not uniformly present, but when they are, myeloid
lineage is virtually certain.
o Poor neutrophil function may be noted.
Wetzler M, Marcucci G, Bloomfield CD. Acute and chronic myeloid leukemia. In: Harrisons Hematology and Oncology. 2nd ed.
2013
Diagnosis
AML is diagnosed if one of the following three feature is present in bone
marrow (FAB Criteria):
1. At least 30%* of the total nucleated cells are blast cells, or
2. Erythroblasts 50% of total nucleated cells and at least 30% of nonerythroid cells are blast cells (lymphocytes, plasma cells and macrophages
also being excluded from the differential count of non-erythroid cells), or
3. The characteristic morphological features of acute promyelocytic
leukaemia (APL) are present.
Note:
* The WHO criterion applies cut-off at least 20% blast cells found either in
bone marrow or peripheral blood.
Complete workup.
Laboratory and
Radiologic
Intervention for
specific patients
Prognostic Factors
oClinical:
o Age at diagnosis
o Performance status
o A prolonged symptomatic interval with
cytopenias or a history of an antecedent
hematologic disorder preceding diagnosis.
o AML developing after treatment with
cytotoxic agents
o A high presenting leukocyte count
oMolecular:
o NPM1 mutations (without concurrent
presence of FLT3-ITD) and CEBPA
mutations favorable outcome
o FLT3-ITD predicts a poor outcome
o Achievement of CR.
Treatment
Risk Stratification
Response Criteria
Note:
o The initial goal is to quickly induce CR. When it is obtained, further therapy must be used to prolong survival and achieve cure.
o Patients failing to achieve CR treatment failures.
o Bone marrow biopsy should be performed if spicules are absent from the aspirate sample.
o If there is a question of residual leukemia BM aspiration/biopsy should be repeated ini one week.
Cheson BD, et al. Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response
Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003
Relaps Definition
o Reappearance of leukemic blasts in the peripheral blood, or
o The finding >5% blast in the bone marrow, not attributable to another
cause, or
o Extramedulary relapse.
Treatment APL
Treatment APL,
Low/Intermediate Risk
Treatment-Supportive Care
o Adequate and prompt blood bank support is critical to therapy of AML:
o Leukocyte-depleted products should be used and irradiated blood products for patients receiving
immunosuppresive therapy.
o RBC transfusions should be administered to keep the hemoglobin level >8 g/dL, aim higher in:
o active bleeding
o DIC
o congestive heart failure.
o Platelet transfusions should be given to maintain a platelet count 10,000/L, aim for higher levels in:
o febrile patients
o during episodes of active bleeding or DIC.
o Infection management:
o Antibacterial and antifungal prophylaxis is likely to be beneficial.
o Early initiation of empirical adequate broad-spectrum antibacterial and antifungal antibiotics has
significantly reduced the number of patients dying of infectious complications.
Treatment-Supportive Care
o Saline or steroid eye drops should be administered to both eyes 4 times
daily for all patients undergoing high-dose cytarabine (HiDAC) therapy until
24 hours post completion of cytarabine.
o Tumor lysis syndrome prophylaxis:
o Hydration.
o Urine alkalinization (may be contraindicated with increased phosphate)
o Allopurinol or rasburicase.
Chronic
Myelogenous
Leukemia (CML)
A CLONAL EXPANSION OF A HEMATOPOIETIC STEM CELL
POSSESSING A RECIPROCAL TRANSLOCATION BETWEEN
CHROMOSOMES 9 AND 22.
Epidemiology
o The incidence is 1.5 per 100,000
people per year.
o The age adjusted incidence is higher
in men than in women (1.9 vs 1.1).
o The incidence of CML increases
slowly with age until the middle
forties, when it starts to rise rapidly.
http://www.cancerresearchuk.org/cancer-info/cancerstats/types/leukaemiacml/incidence
Risk Factors
o No clear correlation with exposure to cytotoxic drugs, viral etiology,
radiation. controversial.
o Cigarette smoking accelerated the progression to blast crisis lowers
survival in CML.
Clinical Manifestation
o The clinical onset of the chronic phase is generally insidious.
o Asymptomatic Health-screening tests diagnosed.
o Fatigue, malaise, and weight loss.
o Splenic enlargement early satiety and left upper quadrant pain or mass.
o Related to granulocyte or platelet dysfunction infections, thrombosis, bleeding.
o Due to leukostatic manifestations or thrombosis:
o vasoocclusive disease,
o cerebrovascular accidents,
o myocardial infarction,
o venous thrombosis,
o priapism,
o visual disturbances,
o pulmonary insufficiency.
Hematologic Findings
(Peripheral)
oElevated WBC counts, with increases in both
immature and mature granulocytes.
oUsually <10% blasts and promyelocytes, with the
majority of cells being myelocytes,
metamyelocytes, and band forms.
oPlatelet counts are almost always elevated at
diagnosis.
oA mild degree of normocytic normochromic
anemia might present.
oLeukocyte alkaline phosphatase is low.
oPhagocytic functions are usually normal.
oHistamine production secondary to basophilia is
increased in later stages pruritus, diarrhea, and
flushing.
http://upload.wikimedia.org/wikipedia/commons/f/fc/Chronic_Myeloid_Leukemia_smear_2009
-04-09.JPG
Wetzler M, Marcucci G, Bloomfield CD. Acute and chronic myeloid leukemia. In: Harrisons Hematology and Oncology.
2nd ed.
2013
http://www.midb.jp/blood_db/DBimage/0701/86e8619d.jp
Wetzler M, Marcucci G, Bloomfield CD. Acute and chronic myeloid leukemia. In: Harrisons Hematology and Oncology. 2nd ed.
2013
Chromosomal Findings
o The cytogenetic hallmark is the t(9;22)(q34;q11.2).
o Originally recognized by the presence of a shortened chromosome 22 (22q-)
Philadelphia chromosome.
o Some patients may have complex translocations (variant translocations)
involving three, four, or five chromosomes.
o All patients should have evidence of the translocation molecularly or by
cytogenetics or FISH to make a diagnosis of CML.
Phases of Disease
o Chronic phase
o Acceleration phase
o Blast Crisis
Prognostic Factors
SOKAL INDEX
HASFORD SYSTEM
o Spleen size,
o Spleen size,
o Platelet count,
o Platelet count,
o Age,
o age,
Treatment
Treatment
SYMPTOMATIC THROMBOCYTOSIS
o Hydroxiurea
o Apheresis
o Hydroxiurea
o Imatinib
o Antiaggregants
o Dasatinib
o Anagrelide
o Nilotinib
o Apheresis
o Clinical trial
Lymphoid Cells
Malignancies
Introductions
o Arise from cells of the immune system at different stages of differentiation,
resulting in a wide range of morphologic, immunologic, and clinical findings.
o Range from the most indolent to the most aggressive human malignancies.
o Some almost always present as leukemia, some almost always present as
lymphomas, while some others can present as either two.
o Leukemia primary involvement of bone marrow and blood.
o Lymphoma solid tumors of the immune system.
WHO Classification
Acute
Lymphoblastic
Leukemia (ALL)
MALIGNANT TUMOR OF HEMOPOIETIC PRECURSOR CELLS
OF THE LYMPHOID LINEAGE PROBABLY ARISING FROM THE
MARROW IN MOST CASES.
Incidence
o Commonest malignancy in childhood
o Majority of cases in the 210 age
group (median 3.5 years).
o Five times more frequent in
childhood than AML.
o Rare leukaemia in adults, 0.7 to
1.8/100,000 annually.
o In adults, there is a peak at 1524
years and a further peak in old age
(>80 years).
Etiology
o Unknown.
o Predisposing factors
o Ionizing radiation
o Congenital predisposition in Downs (20-fold in childhood), Blooms, Klinefelters
and Fanconis syndromes.
o Chemicals,
o Pollution,
o Viruses,
o Urban/rural population movements,
o Fathers radiation exposure,
o Radon levels
o Proximity to power lines have all been postulated.
Classification
Clinical Manifestation
o Anaemia weakness, lethargy, breathlessness, lightheadedness and palpitations.
o Infection particularly chest, mouth, perianal, skin (Staphylococcus, Pseudomonas,
HSV, Candida) fever, malaise, sweats.
o Haemorrhage purpura, menorrhagia and epistaxis, bleeding gums, rectal, retina.
o Leucostasis hypoxia, retinal haemorrhage, confusion, diffuse pulmonary shadowing.
o Mediastinal involvement SVC obstruction.
o CNS involvement cranial nerve palsies especially of facial VII nerve, sensory
disturbances and meningism.
o Widespread lymphadenopathy, mild to moderate splenomegaly, hepatomegaly, and
orchidomegaly.
Hematologic Findings
o Total WBC usually high with blast
cells on film but may be low
(previously known as aleukaemic
leukaemia).
o Hb, neutrophils and platelets often
low and clotting may be deranged.
o Bone marrow heavily infiltrated with
blasts (20%).
Diagnostic Workup
o CBC and blood film.
o Bone marrow aspirate biopsy.
o Bone marrow cytogenetics.
o Immunophenotyping of blood or marrow blasts.
o CXR and CT scan needed if ALL has B-cell or T-cell phenotype for abdominal
or mediastinal lymphadenopathy respectively.
o 2 Lumbar puncture mandatory to detect occult CNS involvement (may be
postponed until treatment reduces high peripheral blast count to prevent
seeding). (Notefundoscopy, CT head scan and platelet transfusion usually
required)
Treatment
Consists of four contiguous phases:
1. Remission induction.
2. CNS prophylaxis generally combines cranial irradiation and intrathecal
chemotherapy.
3. Consolidation therapy.
4. Maintenance therapy OR allogenic/autologous stem cell transplantation.
Prognostic Factors
o Older age.
o High leucocyte count.
o Immunophenotype pro-B-ALL and pro-T-ALL have poorer outcomes;
o Cytogenetics Ph+ very poor prognosis: <10% LFS after chemotherapy;
o Long time to CR (>45 weeks)
o High minimal residual disease (MRD) level after induction (>103);
persistent/increasing MRD during consolidation.
Prognosis
o Childhood High cure rate.
o Adult Leukaemia-free survival (LFS) <30% at 5 years (patients > 50 years
1020%).
Chronic
Lymphocytic
Leukemia (CLL)
P R O G R E S S I V E A C C U M U L AT I O N O F M AT U R E - A P P E A R I N G , F U N C T I O N A L LY I N C O M P E T E N T ,
L O N G - L I V E D B LY M P H O C Y T E S I N P E R I P H E R A L B L O O D , B O N E M A R R O W , LY M P H N O D E S ,
SPLEEN, LIVER AND SOMETIMES OTHER ORGANS.
Incidence
o 2.5/100,000 per annum.
o Predominantly disease of elderly (in over
70s, >20/100,000).
o Median age at diagnosis 65 years.
o Male: Female ratio 2:1.
o Commonest leukemia in Western adults
(2530% of all leukaemias).
o Presentation can be as either leukemia or
lymphoma (small lymphocytic lymphoma).
o When presenting as a lymphoma, it
accounts for 7% of non-Hodgkins
lymphomas.
http://www.cancerresearchuk.org/cancer-info/cancerstats/types/leukaemiacll/incidence/
Drew Provan, et al. Oxford handbook of clinical haematology.
2nd
edition. 2004
Etiology
o Unknown.
o No causal relationship with radiation, chemicals or viruses.
o Small proportion are familial.
o 90% have high levels of BCL-2 defects in intracellular apoptotic pathways
lymphocyte accumulation.
Clinical Manifestation
o Often asymptomatic; if symptomatic weight loss, night sweats, general malaise.
o Lymphocytosis (>5.0 x 109/L) on routine CBC.
o More advanced disease:
o Lymphadenopathy: painless, often symmetrical
o Splenomegaly
o Hepatomegaly
o BM failure (due to infiltration) anemia, neutropenia and thrombocytopenia
Diagnosis
AS LEUKEMIA (CLL)
AS LYMPHOMA (SLL)
As Leukemia
As Lymphoma
Clinical Staging
Treatment
o Asymptomatic patients observation.
o Chemotherapy reserved for patients with symptomatic or progressive disease:
o Anemia (Hb <10g/dL) or thrombocytopenia (<100 x 10 9/L),
o Constitutional symptoms >10% weight loss in 6 months, fatigue, fever, night
sweats,
o Progressive lymphocytosis >300 x 109/L; doubling time <12 months,
o Symptomatic lymphadenopathy/ hepatosplenomegaly,
o Autoimmune disease refractory to steroids,
o Repeated infections hypogammaglobulinaemia.
Prognosis
o CLL remains an incurable disease with current therapy apart from a few
allografted patients
o Infection is major cause of morbidity and mortality in symptomatic patients.
o Advanced stage patients eventually develop refractory disease and bone
marrow failure.
o Terminally some refractory patients show prolymphocytic transformation.
o A minority (<10%) develop high grade NHL (Richters syndrome) abrupt
onset; chemoresistant; median survival 4 months.
o Second malignancy (skin, colon) occurs in up to 20%.
Thank You