Hematologic

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

Hierarchy of Hematopoietic Differentiation

Scadden DT, Longo DL. Hematopietic stem cells. In: Harrisons Hematology and

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

oAccording to cell maturation:

o Acute leukemia
o Chronic leukemia

Hence, there are four broad classification of leukemia:

o Acute myelogenous leukemia (AML)
o Acute lymphocytic leukemia (ALL)
o Chronic myelogenous leukemia (CML)
o Chronic lymphocytic leukemia (CLL)

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

WHO Classification System

Wetzler M, Marcucci G, Bloomfield CD. Acute and chronic myeloid leukemia. In: Harrisons Hematology and Oncology. 2nd ed.
2013

Molecular Prognostic Markers in

AML

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

Clinical Manifestation (Physical

Findings)
One or more of the following might be found:
o Pale.
o Fever.
o Evidence of infection.
o Splenomegaly, hepatomegaly, lymphadenopathy.
o Sternal tenderness.
o Hemorrhage.
o Infiltration of the gingivae, skin, soft tissues, or the meninges with leukemic blasts at
diagnosis is characteristic of the monocytic subtypes and those with 11q23 chromosomal
abnormalities.
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.

Diagnostic and Pretreatment

Workup
History and P.E.

Complete workup.

Laboratory and
Radiologic

Intervention for
specific patients

CBC with manual

Dental evaluation
differential cell
(for those with poor
count.
dentition)
Bone marrow
Lumbar puncture
aspirate and biopsy
(for those with
(morphology,
symptoms of CNS
cytogenetics, flow
involvement)
cytometry,
Screening spine MRI
molecular studies).
(for patients with
HLA typing for
back pain, lower
potential allogeneic
extremity
HSCT.
weakness,
paresthesias)
Blood chemistry
tests.
Clotting studies.
Viral serologies.
Echocardiogram
Wetzler M, Marcucci G, Bloomfield CD. Acute and chronic myeloid leukemia. In: Harrisons Hematology and Oncology. 2nd ed.
Chest X-ray.
2013

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 Chromosome findings at diagnosis are currently the most important independent

prognostic factor:

o t(15;17) have a very good prognosis

(approximately 85% cured),
o t(8;21) and inv(16) a good prognosis
(approximately 55% cured),
o Those with no cytogenetic
abnormality have a moderately
favorable outcome (approximately
40% cured).
o Patients with a complex karyotype,
t(6;9), inv(3), or -7 have a very poor
prognosis.
o Treatment related:

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 Induction for Age

<60y

Treatment Post Induction for

Age <60y

Treatment Post Induction for

Age <60y

Treatment Post Remission for

Age <60y

Treatment Induction for Age

60y

Treatment Post Induction for

Age 60y

Treatment Post Remission for

Age 60y

Treatment APL

Treatment APL, High Risk

Treatment APL,
Low/Intermediate Risk

Treatment APL, Post-Consolidation

Therapy

Treatment CNS Leukemia

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.

o The use of growth factors is still controversial.

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.

Chronic Myeloid Leukaemia (C92.1): 2009-2011

Average Number of New Cases Per Year and Age-Specific

Incidence Rates per 100,000 Population, UK

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.

o Lymphadenopathy and myeloid sarcomas are unusual poor prognosis signs

Wetzler M, Marcucci G, Bloomfield CD. Acute and chronic myeloid leukemia. In: Harrisons Hematology and Oncology. 2nd ed.
2013

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

Hematologic Findings (Bone

Marrow)
o Cellularity is increased,
o Increased myeloid-to-erythroid ratio.
o The blast percentage is generally
normal or slightly elevated.
o Basophilia, eosinophilia, monocytosis
may be present.
o Collagen fibrosis is unusual at
presentation, yet significant degrees
of reticulin stainmeasured fibrosis
are noted in about half of the
patients.

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 Percentage of circulating blasts,

o Percentage of circulating blasts,

o Spleen size,

o Spleen size,

o Platelet count,

o Platelet count,

o Age,

o age,

o Cytogenetic clonal evolution.

o Percentage of eosinophils and basophils

The clinical outcome is variable.

Before imatinib mesylate, death was expected in 10% of patients within 2 years
and in about 20% yearly thereafter.
The median survival time was 4 years.

Treatment (Chronic Phase)

Treatment (Advanced Phase)

Treatment

Treatment

(Supportive Care for Leukocytosis and

Thrombocytosis)
SYMPTOMATIC LEUKOCYTOSIS

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

Proportion of Cases (US, 2010)

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

L1 small uniform blasts (e.g., typical childhood acute lymphoblastic leukemia)

L2 larger and more variable size cells.
L3 uniform cells with basophilic and sometimes vacuolated cytoplasm (e.g., typical Burkitts lymphoma cells).

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.

Treatment - Supportive Care

o Steroid.
o Transfusions.
o GCSF.
o Laxatives.
o Hyperleukocytosis apheresis.

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.

Chronic Lymphocytic Leukaemia (C91.1): 2009-2011

Average Number of New Cases Per Year and Age-Specific
Incidence Rates per 100,000 Population, UK

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

o Recurrent infection due to acquired hypogammaglobulinaemia.

o Autoimmune phenomena:
o Direct Coombs Test positive in 1020% cases, warm antibody AIHA in <50% these cases.
o Autoimmune thrombocytopenia in 12%.

Diagnosis
AS LEUKEMIA (CLL)

AS LYMPHOMA (SLL)

o Monoclonal B Lymphocytes 5.0 x 109/L in peripheral blood.

o Monoclonal B Lymphocytes >5.0 x 109/L in peripheral blood.
o Clonality of B cells should be confirmed by flow cytometry.

o Lymphadenopathy and/or splenomegaly.

o Should be confirmed by histopathology evaluation of lymph node
biopsy.

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.

o Allogeneic SCT has been successful in small numbers of younger,

symptomatic patients with high risk CLL and HLA-matched siblings.

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